“Go or No-Go” for Nitro? – Reevaluating Nitrates in the Right-Ventricular STEMI

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Seth Kelly
Emergency medicine and EMS/prehospital physician. Interested in all things resuscitation and med ed, whether in the ED, on the street, in the air, or on a mountain.

The Pre-brief

For decades, students in medicine and paramedicine training programs have been taught mnemonics like “MONA” and “MONA-BASH” to remember the key elements of treatment in acute myocardial infarction. With time, research has challenged our assumptions regarding improvements in outcomes with some of these therapies; in some cases, these are now viewed as possibly leading to no improvement in outcomes or even patient harm. One therapy, the use of nitrates such as nitroglycerin (NTG), continues to be used in the management of acute ischemic chest pain due to ST-elevation myocardial infarction (STEMI). 

Generations of medical students and paramedic students have been educated on the use of NTG to alleviate chest pain as well as the contraindications to its use. The 2013 ACC/AHA STEMI Guidelines, in particular, highlight the following as contraindications to the use of NTG for ongoing chest pain in STEMI (1):

 

  1. Marked hypotension (generally systolic <90mmHg or >30mmHg drop from baseline)
  2. Marked bradycardia
  3. Use of a 5’ phosphodiesterase inhibitor within the previous 24 to 48 hours
  4. Right-ventricular infarction

We will briefly look at some of the assumptions and data regarding this last contraindication and whether the dogma we have been taught stands up against the evidence.

Mechanism of Action

Nitroglycerin has been used to treat ischemic chest pain due to acute coronary syndrome since the 1950s. It is available in sublingual, intravenous, and transdermal formulations. Although the overall mechanism is complex, NTG serves as a pro-drug which is converted to nitric oxide, a potent vasodilator, which ultimately leads to venodilation (dose-dependent, lower dosages) and arteriodilation (dose-dependent at higher dosages). NTG is thought to decrease ischemic chest pain through coronary artery vasodilation and decreasing preload, heart strain, and afterload. All of these serve to reduce oxygen demand and increase supply of oxygen and other nutrients. (2) However, it should be noted that the utility of NTG is for symptom management. As noted in the ACC/AHA STEMI Guidelines, “although nitroglycerin can ameliorate symptoms and signs of myocardial ischemia by reducing [left ventricular] preload and increasing coronary blood flow, it generally does not attenuate the myocardial injury associated with epicardial coronary artery occlusion unless vasospasm plays a significant role.” (1)

Right-Ventricular Electrocardiography and Physiology

It is believed that as many as 40-55% of STEMI involve the inferior wall and up to 33% of these can also have significant involvement of the right ventricle. (3) Therefore, it is critical that RV ischemia be considered when evaluating a STEMI patient, including the acquisition of a right-sided EKG (leads V3R-V6R) which confirms the diagnosis if ST elevation is present. (4) Standard 12-lead EKG findings suggestive of RV infarction also include:

  • ST elevation in V1
  • ST elevation in V1 and ST depression in V2 (highly specific for RV infarction)
  • Isoelectric ST segment in V1 with marked ST depression in V2
  • ST elevation in III > II

Patients who suffer an infarction of the right ventricle can exhibit significantly depressed contractility of the right ventricle and are therefore considered to be very preload dependent. The primary concern for the use of nitrates in this population is the potential for causing profound hypotension when preload is reduced and, therefore, the focus has been on fluid loading in this population.

Research

Much of the research surrounding the use of nitroglycerin in myocardial infarction occurred in the 1980s and 1990s, including the ISIS-4 and GISSI-3 studies, which were examined in a 2009 Cochrane Review that showed only modest mortality benefit for nitrates when used within 24 hours at day 2 (RR 0.81, 95% CI [0.74,0.89], p<0.0001). No further benefit was observed with nitrate therapy beyond this point. (5) Yusuf, et al. also commented on mortality benefit for nitroglycerin (and nitroprusside) in a 1988 Lancet review. (6)

Kinch and Ryan (1994): In a review of the literature, the authors point out that animal studies of induced right ventricular infarction resulted in acute RV dilatation, an increase in right-sided filling pressures, and a decrease in RV systolic and end-diastolic pressure. This subsequent loss in atrial pressure and reduced RV contractility was theorized to be the primary cause of reduced cardiac output and aortic pressure in patients with RVMI. Because of NTG venodilation at doses typically used by emergency healthcare personnel (0.4 mg sublingually or up to 40 mg/min IV), it was suggested that a reduction in this preload would cause further decreased cardiac output and worsening cardiogenic shock, coronary perfusion, and increased cardiac oxygen demand. (7)

Robichaud, et al. (2016): In 1,466 prehospital STEMI cases, 821 (56.0%) received NTG. Hypotension occurred post NTG in 38/466 inferior STEMIs and 30/339 non-inferior STEMIs, 8.2% vs. 8.9%, p = 0.73. A drop in systolic blood pressure ≥ 30 mmHg post NTG occurred in 23.4% of inferior STEMIs and 23.9% of non-inferior STEMIs, p = 0.87. The authors concluded that NTG administration to patients with chest pain and inferior STEMI on their computer-interpreted electrocardiogram is not associated with a higher rate of hypotension compared to patients with STEMI in other territories. (8)

Observations

While commonly used for symptom control, data surrounding mortality benefit in early studies may show a modest benefit, at best, and are not clearly convincing. However, there are benefits to symptom control in the management of these patients, such as reduction in the stimulation of the sympathetic nervous system, thereby decreasing myocardial oxygen demand with reduced chronotropy and inotropy. 

While the physiology of a right-ventricular infarct suggests that the use of nitrates could significantly affect preload and, therefore, introduce hemodynamic instability, more recent (but limited) research has suggested this may not necessarily be as prominent as once thought. The studies investigating this are limited and this is an area that certainly warrants further investigation. As Jaton (2017) points out in his review, “even if these rare adverse events such as hypotension or arrhythmia occur, NTG has a short half-life (in vivo 3 minutes) which will resolve transient hypotension and bradycardia with minimal detriment. Adverse events related to NTG such as hypotension also are commonly responsive to fluid bolus and rarely require advanced intervention with chronotropes or inotropes.” (3).

However, nitroglycerin, regardless of the area of infarct, does have the potential to further destabilize a patient who is already hypotensive or who has labile pressures. In this population it is still necessary to assess volume status (and fluid resuscitate or use vasoactive agents as indicated) and consider the use of pain medications that can alleviate symptoms without causing the same degree of hypotension, such as fentanyl.

At the end of the day, the current accepted guidance and recommendations regarding use of nitrates in right-ventricular myocardial infarction remain to avoid their use. However, the risk may not be as serious as once thought and warrants further analysis and research. 

The Debrief

 

  • Nitrates have long been used for treatment of ischemic chest pain in acute myocardial infarction but contraindicated in cases of hypotension, bradycardia, 5’ phosphodiesterase inhibitor use, and right ventricular infarction.
  • Research from the last several decades has shown modest mortality benefit, at best, but NTG does help to alleviate chest pain which does have clinical benefit.
  • More recent data is less clear as to whether the risk of profound hypotension with nitrate use in right-sided MI is as great as we think.
  • While current ACC/AHA recommendations remain to avoid use in right-ventricular MI, fluid status assessment, pressure support and/or control, and adequate analgesia all remain key elements of patient management regardless of site of infarct.

How are you approaching the use of nitrates in inferior wall myocardial infarction with right-sided involvement? Share your thoughts in the comment box below.

References:

  1. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Jan 29;127(4):e362-425. doi: 10.1161/CIR.0b013e3182742cf6. Epub 2012 Dec 17. Erratum in: Circulation. 2013 Dec 24;128(25):e481. PMID: 23247304.
  2. Chief Corner: Nitrates and Chest Pain, University of Cincinnati Internal Medicine (July 5. 2019). Accessed at: https://www.thesilverfridge.com/blog/2019/7/2/va-noon-report-nitrates-and-chest-pain
  3. Jaton E. Inferior Wall Acute Myocardial Infarction: Not as Preload Dependent as Once Thought? Air Med J. 2017 Jan-Feb;36(1):27-29. doi: 10.1016/j.amj.2016.10.008. Epub 2017 Jan 4. PMID: 28089058.
  4. Burns E and Buttner R. Right Ventricular Infarction. Life in the Fast Lane (February 8, 2021). Accessed at: https://litfl.com/right-ventricular-infarction-ecg-library/
  5. Perez MI et al. Effect of Early Treatment with Anti-Hypertensive Drugs on Short and Long-Term Mortality in Patients with an Acute Cardiovascular Event (Review). Cochrane Database Syst Rev 2009. PMID: 19821384
  6. Yusuf S et al. Effect of Intravenous Nitrates on Mortality in Acute Myocardial Infarction: An Overview of the Randomised Trials. Lancet 1988. PMID: 2896919
  7. Kinch JW, Ryan TJ. Right Ventricular Infarction. N Engl J Med. 1994 Apr 28;330(17):1211-7. doi: 10.1056/NEJM199404283301707. PMID: 8139631.
  8. Robichaud L, Ross D, Proulx MH, Légaré S, Vacon C, Xue X, Segal E. Prehospital Nitroglycerin Safety in Inferior ST Elevation Myocardial Infarction. Prehosp Emerg Care. 2016;20(1):76-81. doi: 10.3109/10903127.2015.1037480. Epub 2015 May 29. PMID: 26024432.

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