High-Dose Nitroglycerin for Sympathetic Crashing Acute Pulmonary Edema

Abstract

Background

Sympathetic crashing acute pulmonary edema (SCAPE), formerly known as flash pulmonary edema, is an extreme complication of heart failure. In SCAPE, left ventricular dysfunction results in a surge of adrenergic activity and increased left atrial pressure. This causes distension of the pulmonary capillaries, interstitial edema, and flooding of the alveolar spaces, ultimately resulting in hypoxia. Identifying SCAPE can be challenging due to a lack of universally accepted diagnostic criteria; however, patients often present with a sudden onset of severe dyspnea, life-threatening pulmonary congestion, and high systolic blood pressure. Clinical guidelines recommend the use of noninvasive positive pressure ventilation and intravenous (IV) nitroglycerin in patients with acute heart failure syndrome and dyspnea. Timely initiation of these therapies is essential to prevent the need for intubation and invasive mechanical ventilation. Due to limited available data, there is wide variability in the administration and dosing of high-dose nitroglycerin (HDN) for patients with SCAPE.

Purpose

The purpose of this literature review is to assess the impact of different dosing and administration regimens of HDN for the treatment of patients with SCAPE. Treatment impacts, such as intubation and intensive care unit admission rates, symptom improvement, length of stay, and associated adverse effects, will be evaluated.

Methods

A literature review of articles published from 2000 to 2025 was conducted using MEDLINE (PubMed) and Science Direct databases. Search terms included nitroglycerin [Title], high-dose nitroglycerin [Title], low-dose nitroglycerin [Title], acute pulmonary edema, SCAPE, sympathetic acute crashing pulmonary edema, acute hypertensive heart failure, acute decompensated heart failure, and acute heart failure syndrome. Studies were eligible for inclusion if they were full-text observation studies or randomized controlled trials published in English. They must have analyzed in-hospital IV HDN, defined as greater than 100 mcg/min continuous infusion or greater than 500 mcg bolus dosing for patients with acute decompensated heart failure, SCAPE, or hypertensive crisis with acute pulmonary edema.

Conclusions

Despite limited supporting evidence, significant benefits were consistently observed in patients with SCAPE who received HDN vs low-dose nitroglycerin. Key findings across multiple studies indicated that HDN increased symptom resolution and decreased the incidence of intubation, hospital and emergency department lengths of stay, admission rates, and major adverse cardiac events at 30 days. Cumulative evidence suggests that an initial bolus dose of 600 to 1000 mcg, used alone or alongside a continuous HDN infusion (starting potentially at 100 mcg/min), is a reasonable and promising empiric treatment strategy, as there does not seem to be a notable risk of hypotension or adverse events associated with HDN bolus dosing.

Introduction

Heart failure (HF) is a common, complex condition that occurs when the heart is unable to provide an adequate supply of oxygen-rich blood to the body due to impaired ventricular filling or ejection. If not managed appropriately, HF can lead to serious, acute complications. Acute heart failure syndromes (AHFS) refers to a broad clinical spectrum of syndromes characterized by the rapid onset or worsening of HF symptoms.¹ AHFS can range in severity from mild pulmonary edema to cardiogenic shock, and it often requires emergency attention.¹ On the extreme end of the AHFS spectrum is sympathetic crashing acute pulmonary edema (SCAPE). SCAPE historically was referred to as flash pulmonary edema because of its rapid symptom onset (minutes to hours). However, this terminology was clinically nonspecific and failed to distinguish it from other AHFS subtypes.¹ The nomenclature has since evolved to SCAPE, highlighting the intense sympathetic activation and acute hemodynamic collapse associated with its pathophysiology. SCAPE results from elevated cardiac filling pressures and pulmonary fluid accumulation, and it progresses in 3 main stages: (1) increased left atrial pressure that causes distension of the pulmonary capillaries, (2) interstitial edema, and (3) flooding of the alveolar spaces, which causes hypoxia.^1,2

Diagnosing SCAPE is complicated due to similarities in its clinical presentation with other AHFS subtypes, in addition to a lack of universally accepted diagnostic criteria. However, patients typically present as tachycardic, diaphoretic, and restless.¹ Table 1 highlights clinical features and presentations that may be used to aid in the diagnosis of SCAPE.^1,3,4 Rapid recognition and stabilization of SCAPE is crucial to prevent morbidity and mortality.

Evidence-based options for the initial treatment of SCAPE include noninvasive positive pressure ventilation (NPPV), vasodilators, loop diuretics, and morphine. Vasodilators such as nitroglycerin (NTG) have become an important intervention to consider for patients with SCAPE. Mechanistically, NTG is metabolized to nitric oxide (NO), which activates cyclic guanosine monophosphate and leads to smooth muscle relaxation and vasodilation. Importantly, NTG significantly reduces preload at low doses and both preload and afterload at high doses.^1,3 Although guidelines recommend an initial low intravenous (IV) dose with gradual up-titration for cardiogenic pulmonary edema, it takes time to reach an effective dose, and patients with SCAPE have limited time for intervention to improve outcomes.¹ Furthermore, higher doses of NTG are required to reduce the elevated arterial tone caused by the underlying pathophysiology of SCAPE and known sympathetic upsurge.1 The effects of high-dose nitroglycerin (HDN), such as arterial vasodilation and afterload reduction, also improve cardiac filling pressures and provide symptom relief. Although there is existing evidence supporting the use of HDN for the treatment of SCAPE, this article aims to assess the risks and benefits of different dosing and administration strategies.

Guideline Recommendations

The American College of Emergency Physicians recommends the simultaneous use of NPPV and IV NTG in patients with AHFS and dyspnea; it is recognized as the mainstay of SCAPE therapy.5 Timely initiation of NPPV and IV NTG can prevent the need for intubation and invasive mechanical ventilation.¹

There are 2 commonly used forms of NPPV (bilevel positive airway pressure [BiPAP] and continuous positive airway pressure), and there is no evidence suggesting differences in the efficacy or safety of either form for the treatment of cardiogenic pulmonary edema.^1,6 In terms of the left ventricular dysfunction seen in SCAPE, NPPV reduces preload, afterload, and myocardial oxygen demand, which improves cardiac output and re-expands the flooded alveoli.^6,7 Given its clear benefits, NPPV is used as an adjunct to acute pharmacologic therapy, such as vasodilators, in patients who present with respiratory distress.⁶

Clinical guidelines and policies provide little direction regarding the optimal dosing regimen of vasodilators for AHFS. The initial IV dose of NTG for cardiogenic pulmonary edema is 10 to 20 mcg/min, with gradual up-titration to reduce preload.^1,8 Administration of IV HDN (> 100 mcg/min) is required to achieve arterial dilation and reduce afterload.¹ Patients who do not achieve hemodynamic improvement with a dose of approximately 200 mcg/min of IV NTG are generally considered nonresponders.⁸

There is wide variability in the dosing of HDN in clinical practice, with boluses ranging from 5 to 400 mcg over 1 to 2 minutes, and infusion rates ranging from 5 to 200 mcg/min.⁹ Different administration methods have also been reported. One administration method is an initial bolus dose (500-1000 mcg over 2 min) followed by a high-dose infusion (50-250 mcg/min) with rapid up-titration to symptom improvement and eventual rate reduction/discontinuation as deemed appropriate. In addition to intermittent bolus HDN, continuous infusion NTG has also been considered as an administration method for acute pulmonary edema. Of relevance, sublingual and topical formulations of NTG have shown benefits in AHFS; more specifically, sublingual NTG (0.8 mg) has been shown to decrease systemic vascular resistance and increase cardiac index, whereas topical NTG (2.5- to 5-cm ointment) has been shown to improve pulmonary capillary wedge pressure.⁶

HDN is best used for a patient profile displaying volume overload and normal to elevated blood pressure, as hypotension can occur.¹ If hypotension does occur, the infusion should be stopped, and a small crystalloid bolus may be administered before restarting the infusion.¹ Tachyphylaxis can also occur in patients receiving continuous-infusion NTG for longer than 24 hours.8 Other potential adverse effects associated with NTG include reflex tachycardia and paradoxical bradycardia.⁸ NTG should be avoided in patients with severe aortic stenosis, right ventricular infarction, hypertrophic obstructive cardiomyopathy, or recent use of PDE5 inhibitors.¹⁰ Because NTG is hepatically metabolized and liver dysfunction may prolong its clearance, liver function monitoring should be performed with extended use.¹¹ Anemia-related laboratory tests should also be assessed with prolonged therapy, as NTG can convert hemoglobin to methemoglobin.¹¹

Although data in this patient population are limited, sodium nitroprusside may be an effective alternative to NTG because it decreases preload, afterload, and arterial blood pressure (BP).⁸ At standard doses, it produces rapid venous and arterial vasodilation.⁸ However, its use requires invasive monitoring of BP and central hemodynamics, along with gradual tapering to avoid rebound vasoconstriction.⁸ Sodium nitroprusside is metabolized into NO and cyanide, with initial clearance through nonenzymatic pathways.⁸ Cyanide is then converted by the liver into thiocyanate, which is excreted by the kidneys. A significant concern with this therapy is the potential for cyanide and thiocyanate toxicity, particularly in patients with hepatic or renal dysfunction.⁸ The risk is also elevated in patients receiving doses greater than 3 mcg/kg/min for more than 72 hours.⁸

Patients may develop resistance or an attenuated response to NTG with increased doses.12 In such cases, nicardipine or other dihydropyridine calcium channel blockers may be considered, as they have demonstrated safety and efficacy in the management of hypertensive emergencies and AHFS.12 Loop diuretics and morphine have also been considered as additional regimens to vasodilator therapy, but their role for this indication is controversial, with limited supporting evidence. Overall, there are considerable inconsistencies in the clinical approaches for SCAPE management due to the absence of definitive treatment guidelines.

Although the recognized benefits and risks of NPPV, vasodilators, loop diuretics, and morphine for SCAPE have been summarized above, the potential applications of HDN for this indication are poorly understood. The purpose of this literature review is to evaluate available literature on the use of HDN in SCAPE and examine how different dosing and administration strategies influence clinical outcomes in these patients.

Methods

A literature review of articles published from 2000 to 2025 was conducted using MEDLINE (PubMed) and Science Direct. The following keywords and search terms were utilized to identify relevant articles: nitroglycerin [Title], high-dose nitroglycerin [Title], low-dose nitroglycerin [Title], acute pulmonary edema, SCAPE, sympathetic acute crashing pulmonary edema, acute hypertensive heart failure, acute decompensated heart failure, acute heart failure, and acute heart failure syndrome.

Studies were eligible for inclusion if they were full-text observation studies or randomized controlled trials published in English that analyzed in-hospital high-dose IV nitroglycerin (> 100 mcg/min continuous infusion or > 500 mcg bolus dosing) for acute decompensated heart failure, SCAPE, or hypertensive crisis with acute pulmonary edema. Studies were excluded if NTG was compared with another treatment group that did not consist of NTG. Case studies and case series were also excluded from this literature review.

Literature Review

Study 1: Kelly et al, 2023

Despite the frequent use of NTG in the emergency department (ED) for the management of SCAPE, there are no universally accepted dosing guidelines for this indication. To address this gap, investigators in a retrospective, single-center study, whose findings were published in 2023 examined the time required to achieve a 25% reduction in BP among patients receiving either low-dose nitroglycerin (LDN; < 100 mcg/min) or HDN (≥ 100 mcg/min). Patients were eligible for inclusion if they were 18 years or older, presented with acute pulmonary edema, had a systolic BP (SBP) of 180 mm Hg or higher or diastolic blood pressure (DBP) of 120 mm Hg or higher, and were started on a continuous NTG infusion. Exclusion criteria included inadequate vital sign documentation or the presence of clinical conditions necessitating defined BP targets (eg, aortic dissection, preeclampsia/eclampsia, or intracranial hemorrhage).¹³

Of 292 patients screened, 41 met all the inclusion criteria. Most exclusions (118/251) were due to insufficient vital sign documentation. Of the included patients, 27 (65.9%) received LDN, and 14 (34.1%) received HDN. A greater proportion of patients in the HDN group (57.1%) achieved the target BP reduction within 60 minutes, compared with only 22.2% in the LDN group, suggesting that HDN may be more effective in rapidly reducing BP. Notably, the rates of intubation and intensive care unit (ICU) admission were similar between groups, and no cases of hypotension were reported in either cohort.¹³

Although the study was well-structured, several limitations affect its generalizability. Most notably, it was a small, retrospective, single-center analysis. Baseline demographics were imbalanced: For unexplained reasons, no male patients received HDN, although men comprised 48.1% of the LDN group. Additionally, the prevalence of diabetes was higher in the LDN group (62.9% vs 21.4%). The large number of exclusions due to inadequate vital sign documentation may introduce the potential for a confounding bias. Another notable limitation is that the study evaluated only continuous NTG infusions without considering initial bolus dosing. Although the findings suggest HDN may be more effective than LDN for rapid blood pressure control, further research is warranted to explore the potential impact of bolus dosing on outcomes.¹³

Study 2: Houseman et al, 2023 (HI-DOSE SCAPE)

The HI-DOSE SCAPE study was a single-center, retrospective cohort study conducted at a tertiary care academic medical center that analyzed patients who presented with SCAPE and received HDN (rate ≥ 100 mcg/min) within the first hour of infusion. Patients were included if they were aged 21 to 89 years with an SBP of 160 mm Hg or higher and respiratory distress, as noted by the ED attending physician. Outcome data included initial and lowest SBP while receiving the HDN infusion, disposition level of care, length of stay (LOS), and the incidence of unfavorable outcomes. Unfavorable outcomes were defined as the incidence of hypotension (SBP < 90 mm Hg), intubation, or acute kidney injury (AKI).¹⁴

Of the 67 patients included, 32 (47.8%) received either supplemental sublingual NTG (n = 20; 62.5%) or IV NTG bolus dosing (n = 12; 37.5%). Of the 12 receiving IV NTG bolus dosing, 10 (83.3%) received dose of 100 mcg to 200 mcg, and only 2 (16.7%) received a dose of 1000 mcg.

The median initial infusion rate of NTG was 100 mcg/ min (IQR, 100-200), with 34 patients (50.7%) receiving a dose of 200 mcg/min or greater within the first hour. The median percentage decrease from initial SBP to nadir for patients on HDN was 32% (IQR, 23%-44%), which was consistent with patients who received only HDN and patients who received HDN with additional pharmaceutical therapies (loop diuretics with or without angiotensin- converting enzyme inhibitor/angiotensin receptor blocker therapy).¹⁴

Unfavorable outcomes occurred in 21 patients (31.3%); 14 (20.9%) required intubation, 9 (13.4%) developed AKI, and 3 (4%) developed hypotension. Only 9 patients (13.4%) were discharged directly from the ED. Of the patients who were not discharged, 20 (29.9%) were admitted to the floor, 13 (19.4%) were admitted to intermediate care, and 25 (37.3%) required ICU-level care. There was a statistically significant increase in unfavorable outcomes in patients who received an IV NTG dose of 200 mcg/min or more within the first hour (P = .02). Additionally, patients who required intubation had a median initial arterial oxygen saturation (SaO2) of 92% (range, 76%-97%) compared with a median initial SaO₂ of 98% (range, 96%-100%) in patients who did not require intubation. The incidence of AKI and hypotension was consistent with previously reported trials, but the rates of intubation in this trial were higher (21% vs 8.9%-16%).^14-16

In contrast to the 2023 study by Kelly et al, the HI-DOSE SCAPE trial incorporated the use of NTG bolus dosing. Although the average bolus dose was relatively modest (292 mcg), the study offered valuable insight into an alternative method of NTG administration. Both the 2023 study and the HI-DOSE SCAPE trial defined HDN as an infusion rate of 100 mcg/min or greater. However, in the HI-DOSE SCAPE trial, patients who received an IV NTG dose of 200 mcg/ min or greater within the first hour experienced a statistically significant increase in adverse outcomes. This finding may indicate that these patients were more critically ill at baseline, or it could suggest a potential upper limit for HDN infusion rates during the initial hour of treatment.^13,14

Moreover, due to the retrospective design of the study, it remains unclear whether the increased need for intubation was a consequence of HDN inefficacy or a reflection of a sicker patient population compared with those in previously published studies.¹⁴

Study 3: Siddiqua et al, 2024

A single-center, open-label, randomized controlled trial was published in 2024 that analyzed the safety and efficacy of HDN compared with LDN for the treatment of patients with SCAPE, given that some providers may be hesitant to give HDN for SCAPE due to concerns of adverse effects. Patients were included if they were 18 years or older, had clinical suspicion of SCAPE, and demonstrated the following vital signs: SBP 160 mm Hg or higher and DBP 100 mm Hg or higher; or mean arterial pressure (MAP) of 120 mm Hg or greater, respiratory rate (RR) 30/min or higher, and peripheral O2 saturation (SpO2) less than 90%. Patients were excluded if they had an acute myocardial infarction, moderate to severe aortic stenosis, hypertrophic cardiomyopathy, recent use of sildenafil or tadalafil, or if they required immediate endotracheal intubation upon arrival to the ED.¹⁷

Patients were randomly assigned 1:1 to receive HDN or LDN. The HDN group was given an initial 600 to 1000 mcg bolus dose, followed by a continuous HDN infusion at a rate of 100 mcg/min. The LDN group was not given a bolus dose and was started on a continuous LDN infusion at a rate of 20 to 40 mcg/min. Primary outcomes were resolution of symptoms after 6 and 12 hours based on improvements in SBP/ DBP/MAP, RR, and SpO2. Secondary outcomes included LOS, the need for invasive mechanical ventilation, ED disposition, and major adverse cardiovascular events (MACE).¹⁷

A total of 26 patients were included in each treatment group and had similar baseline characteristics. At 6 hours, symptom resolution occurred in 17 patients (65.4%) in the HDN group compared with 3 patients (11.5%) in the LDN group (P < .001). Similarly, at 12 hours, symptom resolution occurred in 23 patients (88.5%) in the HDN group compared with only 5 (19.2%) in the LDN group (P < .001). Although not statistically significant, the relative risk difference of intubation between treatment groups was –15.4 (–32.2 to 1.4), favoring the use of HDN (P = .08). More patients in the LDN group required hospital admission (P = .002), an extended hospital LOS (P < .001), or an extended ED LOS (P < .001).¹⁷

Furthermore, the incidence of MACE at 30 days was lower in the HDN group than in the LDN group (P = .02).¹⁷ Although research regarding the use of HDN for SCAPE is limited, existing literature data demonstrates a clear benefit of using HDN compared with LDN in terms of improving symptoms and decreasing the risk of intubation, admission rates, hospital and ED LOS, and MACE incidence at 30 days.^13-17

Study 4: Mathew et al, 2021

A prospective observational pilot study published in 2021 combined the use of an HDN bolus dose followed by an HDN continuous infusion for the treatment of SCAPE. Patients were included in this study if they were 18 years or older and presented with hypertensive acute HF that met the criteria for SCAPE per department protocol, as shown in the Figure.¹⁸ Patients were excluded if they required immediate intubation or cardiopulmonary resuscitation or had a contraindication to NTG. Eligible patients received an initial bolus of NTG of 600 to 1000 mcg, depending on their initial SBP, followed by HDN continuous infusion, which was started at 100 mcg/min. NTG was then titrated every 10 minutes by 20 mcg/min until SBP began to decrease. For patients with clinical improvement, the infusion was slowly reduced at a rate of 20 mcg/min every 10 minutes. The outcomes of interest were symptom resolution at 6 hours and the proportion of adverse effects.¹⁸

A total of 25 patients were enrolled in the study, with a high prevalence of chronic kidney disease (CKD; 60%) among participants. The mean NTG bolus dose administered was 872 mcg, with a maximum cumulative dose of 35 mg, notably higher than the average bolus doses (292 mcg) reported in the HI-DOSE SCAPE study.^14,18 Although no episodes of hypotension were observed following bolus administration, 2 patients experienced transient hypotension during the infusion phase. Both cases responded promptly to a small fluid bolus, and the NTG infusion was successfully reinitiated after 10 minutes. The investigators suggested that the hypotension was more likely attributable to volume depletion rather than the effects of HDN itself. This was confirmed using bedside ultrasound, which revealed a reduced inferior vena cava (IVC) diameter and increased collapsibility in both patients. This highlights the importance of immediate access to bedside ultrasound to assess IVC parameters in patients at risk of volume depletion.¹⁸

Only 1 patient required intubation due to intolerance of noninvasive ventilation. The remaining 24 were discharged home directly from the ED, with an average LOS of 15 hours. Symptom resolution was achieved in 11 patients (45.8%) within 3 hours, and the remaining 13 (54.2%) improved within 6 hours. The authors hypothesized that the high prevalence of CKD and preexisting antihypertensive therapy among participants may have contributed to refractory hypertension observed in some cases. Despite its small sample size, the study supports existing evidence that HDN bolus administration, alone or in combination with an HDN infusion, is an effective strategy for managing SCAPE. This approach may reduce ED LOS, need for intubation, and time to symptom resolution, while maintaining a low risk of hypotension.¹⁸

Study 5: Wilson et al, 2017

A retrospective, observational cohort study published in 2017 compared the safety and efficacy of HDN when administered as intermittent boluses, a continuous infusion, or a combination of both for the treatment of hypertensive acute heart failure (H-AHF). This study included patients 18 years or older who were treated with IV NTG in the ED for H-AHF. Patients were excluded if NTG was administered for other indications, such as acute coronary syndrome, blood pressure control, or hypertensive emergencies unrelated to H-AHF. The primary outcomes included the need for ICU admission and hospital LOS. Secondary outcomes included ED and ICU LOS and the incidence of adverse events. Other outcome data included rates of mechanical ventilation and use of BiPAP in the ED.¹⁶

A total of 395 patients were included in this observational study. Dosing protocols and information by patient group are summarized in Table 2.¹⁶ Baseline demographics were similar between the intermittent bolus group and the continuous infusion group. The combination group presented with significantly higher SBP (P < .001) and DBP (P = .003) than the other experimental groups, and a significantly higher RR (P < .001) than the continuous infusion group. In conjunction, the findings in the combination group may represent a more severely ill patient population compared with the other experimental groups. Additionally, fewer patients in the combination group were on critical home cardiac medications, including aspirin (P = .005), ß-blockers (P = .007), and/ or loop diuretics (P = .006). This could suggest a potentially underrepresented or undertreated population, correlating to a more severe symptom presentation.¹⁶

In an unadjusted analysis, the intermediate bolus group demonstrated a decreased rate in ICU admission (P < .0001; P < .0001) and hospital LOS (P = .006; P = .039) compared with the other experimental groups. An increase in the 30-day H-AHF readmission rate was also observed in the continuous infusion group compared with the other experimental groups (intermittent bolus group, P = .001; combination group, P = .01). There were no statistically significant differences among any of the study groups in adverse events, including hypotension, myocardial injury, or worsening of renal function. Additionally, there were no differences in ED or ICU LOS, and the use of BiPAP and in-hospital mortality rates were similar across study groups.

Although not statistically significant (P = .096), there was an increased need for mechanical ventilation in the combination group compared with the other experimental groups. It is unclear whether this correlation is due to a potentially ineffective treatment or the aforementioned difference in symptom severity in this treatment group.¹⁶

Because this retrospective study had unbalanced cohorts, an adjusted model was used to account for clinically relevant confounders. The adjusted regression models demonstrated trends similar to the unadjusted analysis. More specifically, there was still a strong association between the intermittent bolus group and a reduced ICU admission rate. The hospital LOS was shorter in the intermittent bolus group than in the continuous infusion group. In alignment with the unadjusted analysis, the use of intubation and BiPAP and the incidence of adverse events were similar across study groups.¹⁶

Table 3^13-18 provides a summary of all 5 studies reviewed in this literature review, including their designs, treatment groups, and notable results.

Conclusion

There is limited research available regarding the use of HDN for the treatment of SCAPE. Even with limited supporting evidence, significant benefits have been observed in patients with SCAPE who received HDN vs those who received LDN.17 Such benefits include an increase in symptom resolution and a decrease in intubation and admission rates, hospital and ED LOS, and MACE incidence at 30 days.¹⁷ Most of the larger studies that analyzed HDN utilized initial starting doses of 100 mcg/min or more, or NTG doses of 100 mcg/ min or more within the first hour.^13,14,17,18 Although the 2017 study by Wilson et al did not utilize the same definition of HDN, the maximum NTG rate was higher in the combination dosing group (60 mcg/min; IQR, 30- 100) vs the continuous infusion-only group (35 mcg/min; IQR, 20-50) which may be a contributing factor to the non–statistically significant increased incidence of the need for mechanical intubation in the continuous infusion group (P = .096).16 Overall, based on available literature, an appropriate starting dose of a continuous infusion of HDN could be 100 mcg/min.^13-18

Cumulative evidence suggests a reasonable initial bolus dose of NTG is 600 to 1000 mcg, either alone or with a continuous infusion of HDN. Additional NTG bolus dosing may be done every 3 to 5 minutes, with a maximum single bolus dose of 2000 mcg.^14,16-18 Although the 2017 study by Wilson et al utilized NTG boluses as high as 2000 mcg, due to the small amount of data available regarding these high bolus doses, caution is advised when using a single bolus dose closer to 2000 mcg.¹⁶ To the authors’ knowledge, only 1 study has directly compared different dosing and administration regimens of HDN for SCAPE. This study’s results suggest potential benefits of using HDN bolus dosing for patients who initially present to the ED for suspected SCAPE to improve symptoms and decrease intubation rates and LOS. However, given the limitations of this study and the lack of comparative studies, this claim cannot be confirmed.16 Overall, there does not seem to be a notable risk of hypotension or adverse events using HDN bolus dosing, making this a potentially promising empiric treatment option for patients who present with SCAPE.^13,16,17 If patients have symptom resolution from the HDN bolus dose alone, it is possible that the continuous infusion may not need to be started.

For patients with hypotension as a suspected result of HDN, the HDN infusion should be temporarily held, and the patient’s fluid status should be examined. If the patient is deemed a candidate, small fluid boluses should be given to correct hypotension, and the HDN infusion should be restarted, potentially at a lower rate depending on patient-specific factors.^13-18

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13. Kelly GS, Branstetter LA, Moran TP, Hanzelka N, Cooper CD. Lowversus high-dose nitroglycerin infusion in the management of acute pulmonary edema. Am J Emerg Med. 2023;65:71-75. doi:10.1016/j. ajem.2022.12.022

14. Houseman BS, Martinelli AN, Oliver WD, Devabhakthuni S, Mattu A. High-dose nitroglycerin infusion description of safety and efficacy in sympathetic crashing acute pulmonary edema: the HI-DOSE SCAPE study. Am J Emerg Med. 2023;63:74-78. doi:10.1016/j. ajem.2022.10.018

15. Levy P, Compton S, Welch R, et al. Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis. Ann Emerg Med. 2007;50(2):144- 152. doi:10.1016/j.annemergmed.2007.02.022

16. Wilson SS, Kwiatkowski GM, Millis SR, Purakal JD, Mahajan AP, Levy PD. 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. doi:10.1016/j.ajem.2016.10.038

17. Siddiqua N, Mathew R, Sahu AK, et al. High-dose versus low-dose intravenous nitroglycerin for sympathetic crashing acute pulmonary edema: a randomised controlled trial. Emerg Med J. 2024;41(2):96- 102. doi:10.1136/emermed-2023-213285

18. Mathew R, Kumar A, Sahu A, Wali S, Aggarwal P. High-dose nitroglycerin bolus for sympathetic crashing acute pulmonary edema: a prospective observational pilot study. J Emerg Med. 2021;61(3):271-277. doi:10.1016/j.jemermed.2021.05.011