Background: Sympathetic Crashing Acute Pulmonary Edema (SCAPE) results from an increased systemic vascular resistance and activation of the Renin-Angiotensin-Aldosterone System (RAAS), which causes increased sodium/water reabsorption and worsening cardiac function. Additionally, sympathetic activation shifts fluid from splanchnic beds into the systemic circulation. The fluid build-up in the lungs causes hypoxia, dyspnea, and further sympathetic surge. Venodailtion from nitroglycerin (NTG) reduces bilateral ventricular pressures, SVR, and blood pressure. NTG is often used at low doses (5-40mcg) to treat SCAPE in conjunction with BPAP. Higher doses of NTG allow for veno and vasodilation, decreasing both preload and afterload. 

Previously, small trials demonstrated rapid resolution of symptoms, improved clinical outcomes, and decreased hospitalization and ICU admissions in patients with SCAPE Stemple 2020, Mathew 2021, Houseman 2023). The investigators of this study deliver the first randomized clinical trial comparing high-dose NTG to low-dose NTG in patients with SCAPE.

Paper: Siddiqua N, Mathew R, Sahu AK, et al. High-dose versus low-dose intravenous NTGe for sympathetic crashing acute pulmonary edema: a randomised controlled trial. Emerg Med J. 2024;41(2):96-102. Published 2024 Jan 22. PMID 38050078.

Clinical Question: In patients with sympathetic crashing acute pulmonary edema, does infusion of a bolus and high-dose nitroglycerin, compared to low-dose nitroglycerin, improve patient outcomes at 6 and 12 hours?

What they Did: 

• Open-label, parallel, pragmatic, randomized controlled trial
• Conducted in the ED of a tertiary care hospital in India
• Patients enrolled from November 11, 2021, to November 30, 2022
• Patients with SCAPE (defined below) were randomly assigned 1:1 to receive either low-dose or high-dose NTG
• The trial was registered in the Clinical Trial Registry of India (CTRI/2021/11/037902).

Population:

Inclusion: Patients with ALL of the following were diagnosed with SCAPE and eligible for inclusion:

• Age >18
• Onset of symptoms <6  hours to arrival 
• SBP ≥160mm Hg
• Diastolic BP ≥100mm Hg 
• MAP ≥120mm Hg
• RR ≥30/min
• SPO2 <90%
• Bilateral crepitation on chest auscultation 

Exclusion:

• Acute Myocardial Infarction 
• Hypersensitivity to NTG 
• Use of sildenafil within 24 hours 
• Use of tadalafil within 48 hours 
• Moderate to severe aortic stenosis 
• Hypertrophic cardiomyopathy 
• Patients requiring immediate intubation 

Intervention:

• High dose NTG: 
  • 600–1000 mcg bolus
  • starting infusion of 100 mcg/min

Comparator:

• Low dose NTG: 
  • No bolus
  • infusion of 20–40 mcg/min
  • Maximum infusion rate for low dose was 250 mcg/min

Outcomes:

Primary:

• Resolution of symptoms at 6 hours and 12 hours
• Determined by 2 or more of the following: 
  • RR < by 25% or RR<24min
  • BP ≤160 systolic and BP ≤100 diastolic or MAP <120
  • O2% ≥90% on room air or O2%  ≥95% on supplemental oxygen
  • One-step improvement on a Likert scale

Secondary: 

• Need for invasive mechanical ventilation
• ED Disposition
• Length of ED stay 
• Length of hospital stay 
• Major adverse cardiac event: (MACE) (AMI, stroke, cardiovascular death and heart failure)

Safety Outcomes:

• Complications associated with high-dose NTG 

Results:

• 169 patients screened for eligibility 
  • 117 patients excluded for various reasons
• 52 patients enrolled
  • 26 patients in high-dose NTG group 
  • 26 patients in low-dose NTG group

Strengths:

• The investigators asked a clinically relevant research question with patient-oriented outcomes.
• Using an RCT design increases the generalizability of the findings and helps limit potential biases.
• Block randomization was used to ensure a balanced allocation of participants, reducing selection bias.
• The pragmatic nature of the study enhances its external validity by reflecting real-world clinical practice.
• The study groups were well-balanced based on demographics, ensuring comparability between the high-dose and low-dose NTG groups.
• Researchers performed an intention-to-treat analysis, which includes all randomized patients and maintains the benefits of randomization.
• BPAP was standardized across both intervention and comparator groups, ensuring consistency in patient NIPPV management.

Limitations:

• The study was conducted at a single center in one country, limiting the findings’ external validity and generalizability to other populations.
• The authors do not specify whether patients were enrolled consecutively. Non-consecutive enrollment could introduce selection bias if certain patients were preferentially included or excluded.
• Opaque envelopes for randomization can easily be manipulated, also potentially introducing selection bias.
• The study was an open-label randomized trial, so investigators and participants knew the treatment allocations. This could introduce bias if the cohorts were treated differently.
• Studies with small sample sizes can overestimate the results and reduce the reliability of the findings.
• The median age in the study was 42 for the high-dose group and 47 for the low-dose group, with an age range of 30-55. This excludes a large demographic of older patients who might respond differently to the treatment.
• The study did not include many patients with reduced EF, limiting the applicability of the results to this patient population.
• There was no standardized protocol for titrating the NTG infusion. In an open-label trial, this lack of standardization could lead providers to more aggressively titrate the high-dose group than the low-dose group, potentially biasing the results in favor of high-dose NTG.
• The low-dose group’s maximum infusion rate was 250 mcg/min. However, the study did not clearly report a maximum infusion rate for the high-dose group, leading to difficulties comparing the two groups.
• While the number of patients with CKD was balanced between the groups, the authors did not discuss how many patients were on hemodialysis or whether they received hemodialysis as part of their treatment.
• There is no data on other interventions (e.g., antihypertensives) that could have been used for treatment. Clinicians could have more aggressively treated one cohort with other treatments administered alongside NTG, introducing conintervention bias.

Discussion:

Inside the numbers:

The sample size is very small, driven by the investigators’ pursuit of an unusually large absolute risk difference (ARD) of 54% in their power calculation. Typically, ARDs are much smaller, often less than 10%, even for effective treatments, because baseline risks for many conditions are relatively low (Ranganathan 2016). Choosing a large ARD reduces the required sample size but increases the difficulty of demonstrating statistical significance. Nonetheless, investigators found a substantial statistically significant benefit favoring high-dose NTG. However, differences in outcomes in studies with small sample sizes are particularly vulnerable to chance.

At 6 hours, 53.9% more patients with SCAPE experienced symptom resolution with high-dose NTG compared to low-dose NTG. At 12 hours, 69.3% more patients with SCAPE experienced symptom resolution with high-dose NTG compared to low-dose NTG. Based on the data, at 6 hours, if resuscitationists treat approximately 2 patients with high-dose NTG, one patient will experience symptom resolution. The NNT shrinks to approximately 1.5 at 12 hours. These findings are extraordinary for a single therapy in patients with a life-threatening critical illness. Yet, it is unlikely that future larger multicenter RCTs will reproduce results of this magnitude.

The secondary outcomes are equally provocative, though it’s essential to consider that studies are powered for the primary outcome, and secondary outcomes are hypothesis-generating only. Patients in the high-dose NTG group were intubated less often (3.8% vs. 19.2%), admitted less often (11.5% vs. 57.7%), had shorter lengths of ED stays (median 11 hours vs. 24 hours) and hospital stays (median 12 hours vs. 72 hours), and had a lower 30-day MACE (3.8% vs. 26.9%). Perhaps counterintuitively, the high-dose NTG group used much lower doses of NTG at 12 hours compared to the low-dose NTG group (median dose of 26.1 mg vs. 89.7 mg). High-dose NTG outperformed low-dose NTG in important patient-centered clinical and resource utilization variables.

High-Dose Nitroglycerin in Practice:

SCAPE is a life-threatening emergency that demands immediate intervention. There is freedom in these life-and-death situations, and resuscitationists often attempt treatments with a strong scientific rationale but little empirical evidence—like dual sequence defibrillation in ventricular tachycardia. As such, many clinicians already use high-dose NTG for patients with SCAPE and report excellent anecdotal success. 

Despite some apprehension about administering a 600–1000 mcg bolus of NTG, similar doses are already standard practice for acute coronary syndrome. We routinely administer 500 mcg of NTG via sublingual spray or tablet for up to 3 doses, totaling 1500 mcg over 15 minutes. Additionally, In an observational trial of hypertensive patients with heart failure, clinicians treated patients with large bolus doses of 2000 mcg of NTG with a low incidence of hypotension (<2%) and no difference compared to lower dose cohorts (Wilson 2016). We might argue that the highest dose used in this trial was not high enough for the sickest patients, but it was still likely higher than many would be comfortable administering.

NTG has a rapid onset of action and a short half-life of 1-4 minutes. Any episodes of hypotension can be managed by simply reducing the infusion rate or stopping it altogether. In this trial, no patients in either cohort experienced hypotension. In previous studies, hypotension with high-dose NTG was relatively low at only 2–4% (Stemple 2020, Mathew 2021, Houseman 2023). Administering a NTG bolus followed by a high-dose infusion seems to carry minimal risk for patients with SCAPE.

Author’s Conclusion: “…For patients presenting to ED with SCAPE, high-dose GTN (>100 mcg/min) may be helpful in early resolution and favourable outcomes compared with the conventional ‘low dose’ GTN.”

Our Conclusion:

In patients with SCAPE, high-dose NTG shows promise, and this trial yields impressive results. Clinical experience also favors this aggressive approach. We now have an RCT to support how many resuscitationists have been practicing for years. Nonetheless, several methodologic flaws and biases must be considered, and high-dose NTG needs further validation in large, multicenter, international RCTs. However, the benefits of high-dose NTG outweigh the risks when considering the totality of positive existing evidence and its favorable safety profile against the potential for morbidity and mortality in critically ill SCAPE patients.

Clinical Bottom Line:

Based on clinical experience and the available evidence, high-dose nitroglycerin should be a standard part of management in patients with SCAPE

References:

1. 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. PMID: 32278569
2. 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. PMID: 34215472
3. 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. PMID: 36327753
4. Siddiqua N, Mathew R, Sahu AK, et al. High-dose versus low-dose intravenous NTGe for sympathetic crashing acute pulmonary edema: a randomised controlled trial. Emerg Med J. 2024;41(2):96-102. Published 2024 Jan 22. PMID 38050078.
5. Ranganathan P, Pramesh CS, Aggarwal R. Common pitfalls in statistical analysis: Absolute risk reduction, relative risk reduction, and number needed to treat. Perspect Clin Res. 2016;7(1):51-53. PMID: 26952180
6. 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. PMID: 27825693

For More FOAMed, Check Out:

First10EM: High dose nitroglycerin is correct dose nitroglycerin

Guest Post By:

Marco Propersi, DO FAAEM
Vice-Chair, Emergency Medicine
Assistant Emergency Medicine Residency Program Director
Vassar Brothers Hospital, Poughkeepsie, New York
Twitter/X: @marco_propersi

Atinuke Anjoola Amoo, MD
PGY-2 Emergency Medicine Resident
Vassar Brothers Hospital, Poughkeepsie, New York
E-mail: atinuke.amoo@nuvancehealth.org

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter/X: @EMSwami)