High-vs. Low-Dose NTG in SCAPE Patients: A Comparative Study

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

Intro:

SCAPE results from increased systemic vascular resistance (SVR) and activation of the Renin-Angiotensin-Aldosterone System (RAAS), leading to fluid build-up in the lungs and worsening cardiac function. NTG, reduces bilateral ventricular pressures, SVR, preload and afterload, providing symptomatic relief. This study is the first randomized clinical trial comparing high-dose NTG to low-dose NTG in SCAPE patients, building on previous smaller trials that demonstrated rapid symptom resolution and improved clinical outcomes with high-dose NTG.

Clinical Question:

In patients with SCAPE, does infusion of a bolus and high-dose nitroglycerin dose improve patient outcomes at 6 and 12 hours compared to the low-dose nitroglycerin?

Results:

Investigators screened 169 patients for eligibility, with 117 patients excluded for various reasons. 52 patients were enrolled and randomly assigned into two groups: 26 in the high-dose NTG group and 26 in the low-dose NTG group. The cumulative dose of NTG was higher in high-dose patients at the 3-hour mark but higher in low-dose patients at the 12-hour mark. The median dose of diuretics was similar in both groups (40-60 mg).

Primary Outcomes: 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.

Secondary Outcomes: 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%).

Key Points:

Methodology: Several methodological flaws that introduce bias undermine the study’s results. The lack of clarity on consecutive patient enrollment could lead to selection bias, and the single-center, single-country setting limits generalizability. The relatively young age range of participants may not represent older patients, adding sampling bias. The open-label design and absence of a standardized NTG titration protocol could have influenced care, potentially favoring the high-dose group. Other concurrent treatments were also not controlled, introducing conintervention bias, and warranting cautious interpretation of the findings.

Inside the numbers: The small sample size of this study was influenced by an unusually large absolute risk difference (ARD) of 54% used in the power calculation, which increases the chance variability of the results. Despite this, high-dose NTG showed substantial benefit, with significantly more patients experiencing symptom resolution at both 6 and 12 hours compared to low-dose NTG. Additionally, the high-dose group had better secondary outcomes, including lower intubation rates, fewer admissions, shorter hospital stays, and lower 30-day major adverse cardiac events. These impressive results suggest high-dose NTG may be highly effective, but further large-scale studies are needed to confirm these findings.

Nitroglycerin Dosing: SCAPE is a critical emergency requiring immediate intervention, and many clinicians already use high-dose NTG with reported anecdotal success. Despite some concerns about administering large NTG doses, similar doses are standard practice for acute coronary syndrome. Observational studies have shown low incidences of hypotension with high-dose NTG, suggesting it is safe for SCAPE patients. NTG’s rapid action and short half-life make managing any hypotension episodes straightforward by adjusting the infusion rate. Overall, administering a NTG bolus followed by a high-dose infusion appears to carry minimal risk for 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.

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