Open-label, parallel, pragmatic randomized controlled trial

N= 54 

To compare the efficacy of high-dose and low-dose nitroglycerin (GTN) in patients with sympathetic crashing acute pulmonary edema (SCAPE)

High-dose GTN (n= 26)

Low-dose GTN (n= 26)

Patients aged >18 years with acute onset shortness of breath, symptoms <6 hours, systolic blood pressure (SBP) ≥160 mmHg, diastolic blood pressure (DBP) ≥100 mmHg or mean arterial pressure (MAP) ≥120 mmHg, respiratory rate (RR) ≥30/min, SpO2 <90% with bilateral crepitation on chest auscultation

Acute myocardial infarction, hypersensitivity to GTN, use of sildenafil within 24 hours or tadalafil within 48 hours, moderate to severe aortic stenosis, hypertrophic cardiomyopathy, requiring immediate intubation on emergency department (ED) arrival

Participants were randomly assigned to high-dose GTN (600-1,000 mcg bolus followed by 100 mcg/min infusion) or low-dose GTN (no bolus, 20–40 mcg/min infusion). Both groups received bi-level positive airway pressure (BIPAP) support. Monitoring included point-of-care ultrasonography (POCUS) for inferior vena cava (IVC) collapsibility and ejection fraction.

November 11, 2021 to November 30, 2022

Follow-up: up to 30 days

Primary: Symptom resolution at 6 hours and 12 hours

Secondary: Intubation rates, admission rates, length of hospital stay, short-term adverse effects of GTN, MACE at 30 days

Low-dose GTN (n= 26)

Age, years (IQR)

Male

Comorbidities

Hypertension

CKD

Diabetes

CAD

DCM

Postrenal transplant

24 (92.3%)

18 (69.2%)

5 (19.2%)

2 (7.7%)

2 (7.7%)

1 (3.8%)

26 (100%)

19 (73.1%)

8 (30.8%)

4 (15.4%)

0

0

Vitals at presentation (IQR)

RR, breath/min

SpO2

Pulse rate, bpm

SBP, mmHg

DBP, mmHg

38 (35-40)

80 (76-85)

125 (120-140)

210 (196-230)

126 (120-140)

36 (34-40)

85 (78-87)

120 (110-136)

200 (188-210)

126 (110-134)

Ejection fraction, % (IQR)

Furosemide received, mg (IQR)

Abbreviations: CAD= coronary artery disease; CKD= chronic kidney disease; DCM= dilated cardiomyopathy

p-value

Resolution by 6 hours

Resolution by 12 hours

Intubation required

ED disposition

Admission

Discharged

3 (11.5%)

23 (88.5%)

15 (57.7%)

11 (42.3%)

Length of ED stay, hours

Length of hospital stay, hours

MACE at 30 days

Abbreviations: CI= confidence interval; MACE= major adverse cardiac events

Headache (3 in high-dose group, 11 in low-dose group); no incidence of hypotension

High-dose GTN (>100 mcg/min) significantly improves outcomes in SCAPE without significant adverse effects, leading to earlier symptom resolution and shorter hospital stays compared to low-dose GTN.

Although the study had a randomized controlled design with clear outcome measures, the small sample size and open-label design may have introduced potential bias in results due to unblinded assessment. Additionally, there was a high proportion of patients with CKD, which may limit generalizability.

High-dose nitroglycerin infusion description of safety and efficacy in sympathetic crashing acute pulmonary edema: The HI-DOSE SCAPE study

Retrospective chart review

N= 67

To describe the characteristics and outcomes of patients who received an high-dose nitroglycerin (HDN) infusion (≥100 mcg/min) for the management of sympathetic crashing acute pulmonary edema (SCAPE) in the Emergency Department (ED) of a large urban academic medical center

Study cohort (N= 67)

Aged 21-89 years, initial systolic blood pressure (SBP) ≥160 mmHg, HDN infusion (rate ≥100 mcg/min within the first hour of infusion), and respiratory distress noted by ED physician

None disclosed

Patients received HDN infusion (≥100 mcg/min) in the ED. Data collected included baseline characteristics, interventions for SCAPE, and outcomes. Interventions included non-invasive positive pressure ventilation (NIPPV), sublingual or intravenous bolus nitroglycerin prior to HDN infusion, initial and maximum HDN rates within the first hour, loop diuretics, and ACE-Is or ARBs. Loop diuretic doses were converted into oral furosemide equivalents.

January 1, 2018 to December 31, 2018

Primary: Initial and lowest systolic blood pressure (SBP) while receiving HDN infusion, incidence of intubation, hypotension (SBP < 90 mmHg), acute kidney injury (AKI) within 48 h, disposition level of care, and length of stay (LOS)

Secondary: Safety of adjunct medication therapies

Study cohort (N= 67)

Male

Black

Age, years

Body mass index, kg/m2

SBP on NTG initiation, mmHg (IQR)

Initial SaO2, % (IQR)

Initial SCr, mg/dL (IQR)

No history of ESRD

ESRD

2.12 (1.33-9.56)

1.45 (0.94-1.99)

11.05 (8.80-13.03)

Comorbidities*

HF

EF ≤40%**

EF > 40%**

ESRD

CAD

Asthma/COPD

Erectile dysfunction

51%

53%

47%

36%

25%

45%

1%

Home Medications*

Sublingual nitroglycerin

Loop diuretic

ACE-I/ARB

Thiazide-like diuretic

Aldosterone antagonist

Other antihypertensive

Phosphodiesterase-5 inhibitor

12%

16%

46%

9%

13%

69%

3%

Abbreviations: ESRD= end stage renal disease; IQR= interquartile range

* Documented in ED provider note prior to admission

** Documented within 6 months prior to admission or during hospitalization

Endpoint

Admit Level of Care

Discharge from ED

Floor

Intermediate care

Intensive care unit

13%

30%

19%

37%

Length of stay, hours (IQR)

ED

Intensive care unit

Hospital

13.7 (5.4-21.8)

53.2 (30.2-82.1)

82.6 (56.7-125.8)

Intubation (21%), AKI (13%), Hypotension (4%)

This is the largest study to date describing the use of an HDN infusion strategy for the management of SCAPE. HDN infusion may be a safe alternative strategy to intermittent bolus HDN.

Although this is the largest study to date on HDN infusion for SCAPE, with a comprehensive data collection, the retrospective design and reliance on ED physician notes for baseline characteristics introduces potential for bias, and the high intubation rate may indicate more severe patient presentation.

High-Dose Nitroglycerin Bolus for Sympathetic Crashing Acute Pulmonary Edema: A Prospective Observational Pilot Study

Prospective observational pilot study

N= 25

To assess the feasibility and safety of high-dose nitroglycerin (NTG) combined with noninvasive ventilation (NIV) in sympathetic crashing acute pulmonary edema (SCAPE)

Study cohort (N= 25)

Patients aged > 18 years with hypertensive acute heart failure (AHF) presenting with acute-onset respiratory distress of < 6 h, respiratory rate > 30 breaths/min, bilateral coarse crepitations, saturation < 90% on room air or < 95% on oxygen, sympathetic surge, and blood pressure > 160/100 mmHg

Immediate intubation or cardiopulmonary resuscitation required, contraindications to NTG (allergy, aortic stenosis, hypertrophic cardiomyopathy, recent use of sildenafil or tadalafil), and acute coronary syndromes

Bolus dose of NTG (600-1,000 mcg over 2 min) followed by high-dose infusion (100 mcg/min) and up-titrated based on response. NIV with bilevel positive pressure ventilation was used. Patients were monitored closely with frequent vitals assessment and point-of-care ultrasound.

Initial treatment: 6 hours

Observation: minimum of 2 hours

Primary: Feasibility and safety of high-dose NTG combined with NIV in SCAPE

Secondary: Mean bolus of NTG given, infusion/hour doses of NTG, and correlation with systolic blood pressure

Study cohort (N= 25)

44.2 ± 18.8

13 (52%)

3.2 ± 1.4

Comorbidities

Hypertensive

Diabetic

Chronic kidney disease

Coronary heart disease

Rheumatic heart disease

Dilated cardiomyopathy

Others

19 (76%)

10 (40%)

15 (60%)

3 (12%)

2 (8%)

2 (8%)

4 (16%)

At 6 Hours

24 (22-25)

99 (98-99)

90 (89-99)

140 (131-150)

84 (80-90)

80 (80-82)

No incidence of hypotension post bolus dose; two patients had transient hypotension during infusion, which responded to fluid bolus.

The SCAPE Treatment Protocol, which includes high-dose NTG and NIV, was safe and provided rapid resolution of symptoms in SCAPE patients, reducing the need for ICU care.

Limitations of this study include the small sample size and the use of a single center, which limits generalizability to a larger patient population. Additionally, although no adverse events were observed, the lack of a long-term follow-up may limit the observation of delayed or more uncommon treatment-related sequelae.

Managing Patients With Sympathetic Crashing Acute Pulmonary Edema (SCAPE) Using the SCAPE Treatment Protocol: A Case Series

Design

Case presentation 1

A 43-year-old male with a history of coronary artery disease, left ventricular dysfunction, hypertension, and diabetes presented to the emergency department with sudden onset breathing difficulty for 6 hours, which was worsened when lying down. An initial examination found elevated blood pressure and heart rate, decreased oxygen saturation, crackles in both lungs, and an echocardiogram demonstrating reduced left ventricular function; blood tests showed very high biomarker levels suggestive of acute heart failure. Thus, the diagnosis of sympathetic crashing acute pulmonary edema (SCAPE) was made. He was treated with oxygen, bilevel-positive airway pressure, and intravenous nitroglycerin, which improved his symptoms and biomarkers over an hour. Coronary angiography revealed significant coronary stenosis that was treated with percutaneous intervention, and he was discharged 4 days later on heart failure medications without further need for nitroglycerin.

Case presentation 2

A 71-year-old female with a history of dilated cardiomyopathy, diabetes, and left ventricular dysfunction presented to the emergency department with sudden onset breathing difficulty and dizziness at rest, with examination findings of elevated blood pressure and heart rate, low oxygen levels, crackles in both lungs and echocardiogram showing reduced left ventricular function, indicative of SCAPE. She was started on bilevel-positive airway pressure and intravenous nitroglycerin according to protocol, which significantly improved her symptoms and vitals over an hour. She was subsequently discharged from the cardiac care unit after four days on oral diuretics and nitroglycerin without any reoccurrence of symptoms. She remained stable on follow-up with medication adjustments as needed.

Case presentation 3

A 70-year-old female with a history of diabetes, hypertension, and coronary artery disease presented to the emergency department with acute onset of breathing difficulty and chest discomfort, found to have elevated blood pressure and heart rate, low oxygen levels, crackles in both lungs and bedside ultrasound showing massive pulmonary edema; echocardiogram also demonstrated reduced left ventricular function. She was immediately treated with bilevel-positive airway pressure and intravenous nitroglycerin according to the stroke treatment protocol, showing improvement over an hour before the nitroglycerin was discontinued. However, she had to remain in the emergency department for two days due to a lack of intensive care beds, with continued positive airway support tapered before discharge with stable vitals without requiring further nitrate therapy.

Study Author Conclusions

The SCAPE treatment protocol, using high-dose nitroglycerin and noninvasive positive pressure ventilation, can provide relief to patients within an hour, as seen in the cases presented here. It would be prudent for emergency physicians to use the STP for managing patients with SCAPE presenting to their EDs. Randomized controlled studies need to be performed to further validate the algorithm-based management strategy.

Taming the Tiger: Ultra high dose nitroglycerin in managing sympathetic crashing acute pulmonary edema patient

Design

Case presentation

A 60-year-old male presented to the emergency department with complaints of acute severe shortness of breath for 3 hours, along with expressions of extreme discomfort. The patient had no prior comorbidities but had a history of smoking for 30 years. Bedside ultrasonography suggested acute pulmonary edema, while electrocardiograms revealed sinus tachycardia, right arterial enlargement, and left ventricular hypertrophy. Thus, the diagnosis of SCAPE was made, and the patient received SCAPE treatment consisting of nitroglycerin 1 mg bolus IV, then 100 mcg/min infusion. The infusion was increased to 250 mcg/min as the systolic blood pressure was not decreasing. Despite this, the patient was not improving, so two further bolus doses of 1 mg, 15 minutes apart, were administered, then two more doses of 1.5 mg bolus, 15 minutes apart. The patient was eventually deemed refractory to conventional treatment, but due to the absence of alternatives, an additional 2 mg of nitroglycerin was administered, and the patient's condition finally improved.

Study Author Conclusions

A total of 9 mg bolus and 76 mg infusion of nitroglycerin were administered to the patient before improvements were seen. No adverse events were observed during the emergency stay and follow-up. This is the first report describing the safe and effective administration of an ultra-high dose bolus/highest dose ever and prolonged high dose infusion for SCAPE.

High-dose nitroglycerin infusion for the management of sympathetic crashing acute pulmonary edema (SCAPE): A case series

Design

Case presentation 1

A 68-year-old male with a history of hypertension, hyperlipidemia, coronary artery disease, and heart failure presented to the emergency department via emergency medical services (EMS) experiencing chest pain and shortness of breath after heavy lifting, found to be in respiratory distress with elevated vital signs, wheezes on lung exam, and ultrasound showing diffuse lung B-lines. He was treated with bilevel positive airway pressure and intravenous nitroglycerin starting at 400 mcg/min and up-titrated to 800 mcg/min, with significant symptom improvement as the infusion was tapered. No adverse effects like hypotension occurred, and mechanical ventilation was avoided. After a 2 hour observation period, he was admitted to the cardiology service and discharged within 24 hours, determined that running out of antihypertensive medications 3 days prior was the main precipitant of his acute decompensation.

Case presentation 2

EMS responded to a 51-year-old male experiencing sudden onset shortness of breath for 45 minutes who had hypertension, diabetes, and hyperlipidemia. He was in acute distress, requiring tripoding with tachypnea, rales, and edema. EMS administered sublingual nitroglycerin, lowering his blood pressure before CPAP and nitroglycerin paste were applied. In the emergency department (ED he had accessibility muscle use and pulmonary edema on chest x-ray. He was transitioned to bilevel positive airway pressure and started on an intravenous nitroglycerin infusion up-titrated for improvement, which was slowly tapered over four hours with monitoring and no adverse effects. Poorly controlled hypertension was deemed the cause, and his anti-hypertensive regimen was modified prior to discharge with outpatient follow-up.

Case presentation 3

A 51-year-old woman presented via EMS to the emergency department after 5 hours of sudden onset chest pain and dyspnea, in acute distress upon arrival. Initial testing found pulmonary edema on chest x-ray and acidosis on blood gas. She was treated with high-flow oxygen and started on an intravenous nitroglycerin infusion up-titrated for symptom improvement, which was resolved without needing bilevel-positive airway pressure. She had a history of heart failure with preserved ejection fraction, hypertension, diabetes, and breast cancer, receiving chemotherapy. The exacerbation was attributed to a hypertensive emergency and volume overload, complicating her lengthy hospital stay due to hypervolemia, neutropenia, and urinary tract infection.

Case presentation 4

A 69-year-old female presented via EMS with abrupt onset shortness of breath and work of breathing, found to have low oxygen saturation improving with high-flow oxygen. Examination demonstrated respiratory distress, rhonchi, and rales on lung exam, and chest x-ray showed pulmonary edema. She was placed on bilevel-positive airway pressure and started on an intravenous nitroglycerin infusion maintained at doses over 150 mcg/min for about two hours with improvement and no side effects reported. She had a history of heart failure with preserved ejection fraction, atrial fibrillation, diabetes, pulmonary embolism, and leukemia treated with medications. Her hospital course included diuresis, antibiotics for pneumonia, and cardiac testing revealing new left ventricular dysfunction before discharge with medication adjustments after six days.

Study Author Conclusions

Described here is a case series of four patients who safely and effectively received high-dose nitroglycerin infusions for the management of SCAPE.

Treating acute hypertensive cardiogenic pulmonary edema with high-dose nitroglycerin

Design

Case presentation 1

A 65-year-old female with a history of heart failure and hypertension presented to the emergency department experiencing acute dyspnea and chest tightness; she was found to be anxious, diaphoretic, and have elevated vital signs, bilateral rales, non-specific EKG changes, and signs of acute pulmonary edema on imaging. While sublingual nitroglycerin tablets provided no relief, she was started on bilevel-positive airway pressure and intravenous nitroglycerin push doses followed by a low-dose infusion, which normalized her vitals and allowed discontinuation of respiratory support after a total nitroglycerin dose of 6mg over 15 minutes. She was admitted and later confirmed to have congestive heart failure, then successfully treated with diuretics and digoxin prior to discharge from the general ward several days later.

Case presentation 2

A 60-year-old male with a history of hypertension, diabetes, and end-stage renal disease on regular hemodialysis presented to the emergency department with severe shortness of breath for several hours, found to be hypoxic with rales and radiographic evidence of pulmonary edema. His dyspnea worsened on high-flow oxygen and sublingual nitroglycerin tablets, so he was placed on bilevel positive airway pressure and treated with four successive intravenous nitroglycerin boluses, which lowered his blood pressure and resolved his respiratory distress, allowing discontinuation of supportive ventilation. Hemodialysis was scheduled later that day and he was discharged after the procedure without further issue.

Case presentation 3

A 65-year-old male with a history of hypertension, diabetes, and end-stage renal disease on dialysis presented to the emergency department with progressive dyspnea and diaphoresis, found to be hypoxic and tachycardic with radiographic pulmonary edema. Despite high-flow oxygen and sublingual nitroglycerin, bilevel positive airway pressure support and three successive intravenous nitroglycerin boluses stabilized his condition and obviated the need for intubation. His vital signs normalized before the scheduled hemodialysis that day, after which he could breathe comfortably on a low-flow oxygen source and was discharged without any issues following the dialysis treatment.

Study Author Conclusions

In conclusion, our cases demonstrated that SCAPE patients usually present to the ED with extreme respiratory distress associated with diaphoresis, restlessness, and high blood pressure (usually SBP > 180 mm Hg). Emergency physicians must know how to manage SCAPE with high-dose nitrates and NIPPV because, when treated promptly, one will not only save a life but also obviate the need for endotracheal intubation and ICU admission. Future prospective, randomized, multi-center trials are warranted to confirm the SCAPE hypothesis.

Recognition of severe crashing acute pulmonary edema (SCAPE) and use of high-dose nitroglycerin infusion

Design

Case presentation

An 87-year-old man presented to the emergency department with severe shortness of breath and was found to be in respiratory distress with crackles and ultrasound findings concerning pulmonary edema. He had a history of atrial fibrillation, hypertension, and COPD and was on multiple medications. He was initiated on bilevel-positive airway pressure and a high-dose intravenous nitroglycerin protocol starting at the maximum rate based on symptom criteria. Within six minutes of the nitroglycerin infusion, he met the criteria for resolution of respiratory distress and hypoxia such that the infusion was discontinued. He remained in the emergency department for observation for three hours without further issues before being transferred to the medical ward.

Study Author Conclusions

Our patient presented with shortness of breath, hypertension, and tachycardia, with a positive finding of B-lines during bedside ultrasound. Using our SCAPE-nitro protocol, HDN was administered in a safe and effective manner. The patient’s symptoms resolved within 6 minutes of receiving HDN and required no further pharmacological management.