Episode 14: High-Dose Nitroglycerin for Sympathetic Crashing Pulmonary Edema (SCAPE) with Rachel Wein, PharmD, BCPS

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Introduction

1. Acute heart failure (AHF) is a common underlying cause for dyspnea in patients presenting to EDs around the globe.^1-2  SCAPE is a subset of hypertensive heart failure which develops rapidly due to an abrupt increase in catecholamine release, subsequently leading to increased pulmonary capillary permeability and flooding of alveolar space.^3-5  Patients with SCAPE present with an abrupt onset of shortness of breath which progresses over minutes-to-hours into life-threatening pulmonary edema. This is unlike other subsets of AHF, which  traditionally progress over days.^3-5 Patients often present with extremely severe respiratory distress, restlessness, diaphoresis, and hypoxia on arrival to the ED. Patients may also be tachycardic with marked hypertension, suggesting elevated sympathetic activity in vivo.^3-7 Nitroglycerin reduces preload and, at higher doses (> 50 mcg/min), also reduces afterload. Thus, it is imperative to initiate nitroglycerin at high, effective doses in a timely manner to treat the underlying pathophysiology.⁴ Multiple studies have validated the use of high dose nitroglycerin with improvement in patient-centered outcomes which include reduction in patients requiring intubation, intensive care unit (ICU) admission, hospital length of stay, and decreased myocardial infarction.^8-13

Pathophysiology

Agrawal et al

“Underlying pathophysiologic mechanisms are similar for AHFS and SCAPE. However, there are notable differences between the two.SCAPE develops over minutes-to-hours into a life-threatening condition.”

“Sympathetic system is an important factor in cardiovascular physiology. Left ventricular dysfunction predisposes to an abrupt increase in sympathetic tone and release of catecholamines that can precipitate flash pulmonary edema.   Increased catecholamines cause increased heart rate and decreased diastolic time. It causes activation of the renin-angiotensin-aldosterone system (RAAS), which further worsens diastolic stiffening and increased diastolic pressures causing pulmonary fluid overload.   Increased sympathetic tone adversely affects the pulmonary circulation by increasing permeability and/or provoking stress failure of the pulmonary capillaries. Other factors contributing to flash pulmonary edema include decreased nitric oxide and increased endothelin activity.”

Pharmacology

Pharmacology
Mechanism of Action	Nitroglycerin, an organic nitrate, is a vasodilating agent that relieves tension on vascular smooth muscle and dilates peripheral veins and arteries.  Increases guanosine 3’5′ monophosphate (cyclic GMP) in smooth muscle and other tissues by stimulating guanylate cyclase through the formation of free radical nitric oxide. This activity results in dephosphorylation of the light chain of myosin, which improves the contractile state in smooth muscle results in vasodilation
Dose	Chest pain: 5-400 mcg/min (starting at 5)Pulmonary edema/afterload: 50-400mcg/min Titrate to symptom improvement and tolerated blood pressure
Administration	IV infusion: 50-400 mcg/min until symptom resolution IV bolus: 400-2000 mcg in syringe over 2-5 min Sublingual: 2-4 tablets (equivalent to 160-320 of IV nitroglycerin) Ointment: slow onset 30-60 min
PK/PD	Onset: IV 1-5 min; Sublingual 1-3 min Peak: IV/sublingual 3-15 min                           Duration: IV 5-10 min, sublingual 10-60 min Elimination: 22% renal
Adverse Effects	Headache, Hypotension, Syncope, Rebound hypertension, Tolerance with prolonged use  ~24 hours
Drug Interactions and warnings	PDE inhibitors, Aortic stenosis, preload dependent cardiomyopathy, hypertrophic obstructive cardiomyopathy, hypotension at any time
Compatibility	Incompatible with levofloxacin, Bactrim, daptomycin, and phenytoin

Pearls for Nitroglycerin for SCAPE

Pearls for Nitroglycerin for SCAPE
Indications to Initiate	SCAPE with SBP ≥ 160 mmHg or MAP ≥ 110 mmHg
Inclusion criteria	Adults ≥ 18 years old   Respiratory distress on NIV defined by ONE of the following (a–d): a. Tachypnea (RR > 30 breaths/min) b. Significant dyspnea (use of accessory muscles or air hunger) c. Significant hypoxia (SpO2 ≤ 90% on room air or ≤ 95% on supplemental oxygen) d. Presentation with pulmonary rales or B-lines over superior anterior lung fields on POCUS   Consecutive readings of SBP ≥ 160 mmHg or MAP ≥ 120 mmHg
Contraindications	Without a diagnosis of AHF and pulmonary edema SBP < 160 mmHg Significant drug interaction with nitroglycerin (i.e., PDE3 inhibitors, riociguat) Preload dependent patients (inferior myocardial infarction)
Monitoring and Documentation	Every 5 minutes or until symptom resolution as determined by the provider. Blood pressure, heart rate, RR, SpO2, symptoms of respiratory distress

Criteria for Symptomatic Resolution (must meet two of the following)

Criteria for Symptomatic Resolution (must meet two of the following)

Resolution of tachypnea defined by RR decrease by 25% of initial reading OR RR ≤ 24 breaths/min Resolution of dyspnea defined by the use of accessory muscles or air hunger Resolution of hypoxia defined by SpO2 ≥ 90% on room air or ≥ 95% on supplemental oxygen SBP < 140 mmHg or MAP reduced by >40%

Overview of Evidence
Author, year	Design/ sample size	Intervention & Comparison	Outcome
Hsieh, 2018	Case report   n=3	Nitrostat 0.6 mg/tab x 3   IV NTG bolus 1 mg every 2 min*   IV NTG infusion 40 mcg/min*   *If prior therapy failed	High dose NTG associated with Normalize respiratory status,No intubation + no ICU admission
Paone, 2018	Case report   n= 1	IV NTG infusion   400 μg/min titrated by 50 mcg/min	High doses bolus associated with: Symptomatic resolution @ 6 minutes*
Wilson, 2016	Observational cohort   N=395	IV NTG bolus 500–2000 mcg Q3–5 min                vs   IV infusion 20–35 mcg/min                  vs   IV bolus+ infusion	High doses bolus associated with: Decreased ICU admission Shorter LOS No differences in adverse outcomes (intubation)
Levy, 2007	Observational, single arm study   n=29	IV NTG Bolus 2 mg IV every 3 min	High dose bolus associated with: Reduced intubation, need for bilevel positive pressure ventilation, and ICU admission
Sharon, 2000	RCT   n= 40	IV bolus isosorbide 4 mg Q4 min                        vs   Isosorbide infusion starting @ 10 mcg/min + BiPAP	High dose bolus associated with: Decrease intubations, MI, mortality, and Improved Pao2
Cotter, 1998	RCTn= 104	IV isosorbide dinitrate 3 mg q5 min + furosemide  50 mg                     vs   IV isosorbide infusion 16 mcg/min titrate q15min + furosemide 80 mg q15 min	High dose bolus associated with: Reduction in mechanical ventilation, MIImprovement in Pa02 and RR,Less adverse effects

Related FOAM Posts

https://emcrit.org/emcrit/scape/

https://www.grepmed.com/images/3068/sympathetic-management-treatment-pulmonary-crashing-scape-edema

Acute Pulmonary Edema

Myths in Heart Failure: Part II – ED Management

https://www.emnote.org/emnotes/high-dose-ntg-boluses

https://wikem.org/wiki/Sympathetic_crashing_acute_pulmonary_edema_(SCAPE)

References

1. Nitroglycerin. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved February 5, 2020, from http://www.micromedexsolutions.com/
2. Fromm RE, Jr, Varon J, Gibbs LR. Congestive heart failure and pulmonary edema for the emergency physician. J Emerg Med. 1995;13:71–87
3. Howlett JG. Current treatment options for early management in acute decompensated heart failure. Can J Cardiol. 2008;24(Suppl B):9B–14B.
4. Kramer K, Kirkman P, Kitzman D, Little WC. Flash pulmonary edema: Association with hypertension and reoccurrence despite coronary revascularization. Am Heart J. 2000;140:451–5.
5. Gandhi SK, Powers JC, Nomeir AM, Fowle K, Kitzman DW, Rankin KM, et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med. 2001;344:17–22
6. Agrawal N, Kumar A, Aggarwal P, Jamshed N. Sympathetic crashing acute pulmonary edema. Crit Care Med. 2016;20:39–43.
7. Mebazaa A, Yilmaz MB, Levy P, Ponikowski P, Peacock WF, Laribi S, et al. Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine. Eur J Heart Fail. 2015;17:544–58.
8. Viau DM, Sala-Mercado JA, Spranger MD, O’Leary DS, Levy PD. The pathophysiology of hypertensive acute heart failure. Heart. 2015;101:1861–7.
9. McMurray JJ, Adamopoulos S, Anker `, Auricchio A, Bohm M, Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail.2012;14:803–69.
10. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, DraznerMH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2013;62:e147–239.
11. Hsieh Y et al. Treating acute hypertensive cardiogenic pulmonary edema with high-dose nitroglycerin. Turk J Emerg Med. 2018; 18(1): 34–36.
12. Wilson SS 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):126–31.
13. Levy P et al. Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis. Ann Emerg Med. 2007;50:144–52.
14. Sharon A et al. High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema. J Am Coll Cardiol. 2000;36(3):832-7.
15. Cotter G et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet. 1998;351(9100):389-93.
16. Paone S, Clarkson L, Sin B, et al. Recognition of Sympathetic Crashing Acute Pulmonary Edema (SCAPE) and use of high-dose nitroglycerin infusion. Am J Emerg Med. 2018;36(8):1526.e5-1526.e7.
17. López-Rivera F, Cintrón Martínez HR, Castillo LaTorre C, et al. Treatment of Hypertensive Cardiogenic Edema with Intravenous High-Dose Nitroglycerin in a Patient Presenting with Signs of Respiratory Failure: A Case Report and Review of the Literature. Am J Case Rep. 2019 Jan 21;20:83-90.
18. Clemency BM, Thompson JJ, Tundo GN. Prehospital high-dose sublingual nitroglycerin rarely causes hypotension. Prehosp Disaster Med. 2013 Oct;28(5):477-81.

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