Critical Care, Critical Care Alert

Critical Care Alert: High-Dose Nitroglycerin Bolus for Sympathetic Crashing Acute Pulmonary Edema

Critical Care Alert

A 53-year-old male is brought in by EMS for dyspnea. It woke him from sleep, and he is having trouble speaking, per EMS. He is only able to utter a few words at a time, but he says he ran out of his blood pressure medications a week ago. Vital signs show a temperature of 97.8°F, HR 104, BP 224/168, and oxygen saturation of 87% on a non-rebreather placed by EMS. Point-of-care ultrasound shows diffuse B-lines bilaterally. You tell the nurse you'd like to give the patient a nitroglycerin bolus and infusion. They reply, "Sure, how much should I give?"

ARTICLE
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 Jun 29:S0736-4679(21)00467-4.

OBJECTIVE
To study the feasibility and safety of high-dose NTG combined with NIV in SCAPE. 

BACKGROUND

Sympathetic crashing acute pulmonary edema (SCAPE) is a syndrome at the extreme end of the hypertensive acute decompensated heart failure (ADHF) spectrum. Acute decompensated heart failure is a frequent cause of Emergency Department visits, traditionally characterized by increased afterload and increased cardiac filling pressures which cause fluid shifts resulting in pulmonary and systemic vascular congestion.1 

SCAPE is a clinical diagnosis, characterized by respiratory distress, hypoxia, pulmonary rales or B-lines, and hypertension.2 In acute decompensated heart failure, as cardiac and pulmonary capillary pressures rise, distention of the pulmonary capillaries leads to interstitial edema and alveolar fluid accumulation.3 While ADHF may have a slowly progressive onset, SCAPE has an onset of minutes to hours. Rapid increases in sympathetic tone and catecholamine surges increase the heart rate and decrease overall cardiac filling time. Additionally, the increased tone predisposes to further increases in capillary permeability.4 All these factors, as well as activation of the renin-angiotensin-aldosterone system (RAAS), increased endothelin activity, and decreased nitric oxide production, lead to the clinical syndrome of SCAPE.5

Classically, SCAPE treatment has relied on intravenous nitroglycerin (IV NTG) and positive pressure ventilation. Specifically, nitrates are used for preload reduction, and at higher doses begin to have afterload reducing properties as well. Traditional data recommends starting at 10-20 ug/min. However, more recent evidence and anecdotal treatments are pointing toward improved outcomes when using higher doses of IV NTG. For example, Levy et al. used 2 mg boluses of NTG in patients presenting to the ED with hypertension and acutely decompensated heart failure (compared to a group started at 30ug/min with up-titration) and found that the higher dose group had decreased rates of intubation and ICU admission.6 There have been other small studies that also demonstrate the relative safety of higher than traditional doses of NTG.7

Hypothesis
High-dose nitroglycerin is safe and provides symptom resolution in patients with SCAPE.

Design

  • Prospective observational study in a single, tertiary care ED
  • Inclusion criteria: patients 18 and older who presented with hypertensive acute heart failure (AHF) and defined to have SCAPE by the following criteria:
  • Acute onset dyspnea < 6 hrs
  • Tachypnea (RR ≥ 20 breaths/min)
  • BP ≥ 160/100
  • SpO2 ≤ 90%, or ≤ 95% on supplemental oxygen
  • Bilateral crepitations
  • Diaphoresis, agitation, or tachycardia
  • Exclusion criteria: patients intubated immediately, patients on whom CPR was performed, nitroglycerin allergy, aortic stenosis, HOCM, sildenafil use within 24 hrs, tadalafil use within 48 hrs, patients with ACS
  • Patients received a bolus of NTG ranging from 600-1000 based on their initial systolic BP immediately followed by initiation of a high-dose infusion (defined as 100 µg/min). The infusion was up-titrated by 20 µg/min every 10 min until the blood pressure was decreasing. The infusion was down-titrated by the same amount every 10 min in patients with clinical improvement.
  • All patients were simultaneously started on BPAP at 12/6. Increased by 2 cm H2O
  • Symptom resolution was defined as any two of the following: a decrease in respiratory rate (RR) by 25% of the initial reading, RR ≤24 breaths/min with patient maintaining saturation on pulse oximetry (SpO 2 ≥ 90% on room air or ≥ 95% on supplemental oxygen), subjective improvement in dyspnea and use of accessory muscles, systolic blood pressure of < 160, and disappearance of coarse crepitations in all lung fields (or disappearance of B-profile on lung ultrasound)
  • Adverse effects reported included excessive decrease in BP (reduction in SBP or MAP of 30% or more), hypotension requiring a fluid bolus, bradycardia, new-onset chest pain, new neurological deficits

Primary Outcome
Proportion of SCAPE patients who had resolution of symptoms at 6 hrs and proportion of patients who developed adverse events due to the use of the SCAPE treatment protocol

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

RESULTS
Demographics

  • 25 patients
  • Mean age: 44.2
  • 52% female
  • Mean symptoms duration: 3.2 hrs

NTG

  • Mean bolus dose of NTG was 872 µg
  • Mean cumulative dose of NTG was 35 mg
  • No hypotension after bolus dose
  • 2/25 patients had hypotension (after a small fluid bolus, infusion was restarted)

BPAP

  • 6/25 required escalation of BPAP setting to 16/10 cm H2O
  • 12/25 required 50 µg fentanyl to improve BPAP tolerability
  • 1/25 intubated due to BPAP intolerance

Symptomatic outcomes

  • 24/25 discharged from ED
  • 1/25 intubated and sent to ICU
  • 11 of these patients had symptoms resolution at 3 hrs
  • All patients had symptom resolution at 6 hrs
  • Average LOS for those discharged home was 15 hrs

Authors Conclusions and Limitations

  • Use of a SCAPE Treatment Protocol resulted in rapid resolution of symptoms among patients presenting in SCAPE and thus, obviating the need for ICU care in most patients.
  • The combination of high-dose NTG with NIV was well tolerated.
  • Single-center study with small sample size
  • Findings may not be generalizable to the more heterogeneous population of India or around the world.
  • Careful patient selection was implemented, which included a subset of AHF patients with extreme clinical presentations
  • Relatively short hospital period: no longer-term follow-up so no knowledge of recurrent symptoms, subsequent decompensation, and any prolonged effects of NTG.

Conclusions and Applications for the ED

  • While high dose NTG has been used in the treatment of "flash" pulmonary edema or "SCAPE," very few studies have documented its safety
  • In a small, single-center study in India, a combination of high dose NTG with both a bolus and infusion in conjunction with NIPPV appears safe and effective in the right patient population
  • Limitations of the study include:
  • Single-center, non-randomized trial
  • Very small sample size
  • No control group
  • Potentially homogenous patient population that could limit generalizability
  • Follow-up time of study to only 15 hrs limits potential long term side-effects and safety
  • Observational trials can only prove correlation, not causation

In our ED, we have been using anywhere from a 400-800 µg bolus and infusions anywhere from 100-400 µg/min. This paper adds some evidence that this practice is safe and effective in the treatment of SCAPE.


References

  1. Agrawal N, Kumar A, Aggarwal P, Jamshed N. Sympathetic crashing acute pulmonary edema. Indian J Crit Care Med. 2016;20(12):719-723.
  2. Paone S, Clarkson L, Sin B, Punnapuzha S. 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.
  3. Ware LB, Matthay MA. Clinical practice. Acute pulmonary edema. N Engl J Med. 2005;353(26):2788-2796.
  4. West JB, Mathieu-Costello O. Stress failure of pulmonary capillaries in the intensive care setting. Schweiz Med Wochenschr. 1992;122(20):751-757.
  5. Rimoldi SF, Yuzefpolskaya M, Allemann Y, Messerli F. Flash pulmonary edema. Prog Cardiovasc Dis. 2009;52:249–59.
  6. 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. 
  7. Nashed AH, Allegra JR. Intravenous nitroglycerin boluses in treating patients with cardiogenic pulmonary edema. Am J Emerg Med. 1995;13(5):612-613. 

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