What are the benefits of sublingual nitroglycerin in EMS or Urgent Care? What are the safety risks if there is no IV access?

Comment by InpharmD Researcher

The lack of IV access can pose safety concerns, particularly in cases of nitroglycerin overexposure resulting in hypotension, as the recommended treatment involves administration of IV fluids. If IV access is unavailable, then caution is advised to ensure that patients in the EMS or urgent care receive an appropriate dose of nitroglycerin. The benefits of prehospital sublingual nitroglycerin in the EMS setting appear minimal at best, with one chart review demonstrating a clinically significant reduction in pain. Safety concerns have been relatively minor, as high-dose sublingual nitroglycerin has rarely resulted in hypotension, with transient cases primarily occurring in older adults.

Background

A 2013 retrospective cohort analysis examined the safety of a high-dose sublingual nitroglycerin protocol for patients experiencing acute decompensated heart failure (ADHF) in the prehospital setting. Conducted using data from a single large Emergency Medical Services (EMS) agency over a six-month period, the investigation reviewed 95 instances of multiple simultaneous nitroglycerin (MSN) tablets administration by EMS providers among 75 patients. Vital signs immediately before and after MSN administration were analyzed to determine changes in systolic blood pressure (SBP), with hypotension defined as SBP <100 mmHg. Doses were stratified based on regional EMS guidelines, which recommended either two tablets (0.8 mg) for SBP >160 mmHg or three tablets (1.2 mg) for SBP >200 mmHg, administered every five minutes as needed. The analysis excluded cases with incomplete vital signs documentation and assessed each administration as a separate event. Findings demonstrated a mean reduction in SBP of -14.7 ± 30.7 mmHg, with a range spanning from a decrease of 132 mmHg to an increase of 159 mmHg. Among the total administrations, hypotension occurred in three instances (3.2%), all of which involved older adults (aged >65) who received two tablets. Notably, these episodes of hypotension were transient, resolving within minutes, and all patients showed concurrent respiratory improvement. The majority of administrations (68%) involved two tablets, with a mean SBP change of -16.4 mmHg, while 31% involved three tablets, with a smaller mean change of -10.1 mmHg. This cohort analysis emphasized the safety and feasibility of this prehospital MSN protocol, highlighting its potential as an alternative to intravenous (IV) nitroglycerin, albeit with recommendations for further evaluation of long-term outcomes and adherence to dosing protocols. [1]

A dated 1994 prospective observational study evaluated the safety of prehospital sublingual nitroglycerin administration by advanced life support (ALS) providers. Over a five-month period, nitroglycerin-related changes in vital signs and cardiac rhythm were analyzed in 300 adult patients treated for presumed myocardial ischemia or congestive heart failure. Using a standardized data sheet, ALS providers recorded patient demographics, medical history, and pre- and post-nitroglycerin vital signs, with exclusions for cases involving concurrent medication administration or incomplete data collection. A convenience sample of 52 patients with similar presentations but no nitroglycerin exposure was used as a comparison group. The investigation reported that 1.33% of patients experienced adverse effects, primarily bradycardia with hypotension, occurring unpredictably and requiring interventions like IV atropine or fluid boluses. A significant, though moderate, correlation was noted between higher baseline SBP and its degree of reduction following nitroglycerin administration. Among patients without symptomatic adverse events, a single nitroglycerin dose resulted in a mean SBP drop of 14 mm Hg (95% confidence interval [CI]; 11 to 16 mmHg) without significant changes in heart rate. Four symptomatic events, including one instance of asystole and apnea, occurred across 300 treated patients, highlighting the potential severity of adverse outcomes even in otherwise stable individuals. These findings emphasize the need for heightened awareness among prehospital providers when administering nitroglycerin in the field. [2]

Relevant Prescribing Information

Per the prescribing label, as hypotension associated with nitroglycerin overdose is the result of vasodilation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. No specific antagonist to the vasodilator effects of nitroglycerin is known. Keep the patient recumbent in a shock position and comfortably warm. Passive movement of the extremities may aid venous return. Intravenous infusion of normal saline or similar fluid may also be necessary. [3]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What are the benefits of sublingual nitroglycerin in EMS or Urgent Care? What are the safety risks?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Safety and Effectiveness of Field Nitroglycerin in Patients with Suspected ST Elevation Myocardial Infarction
Design	Retrospective chart review N= 780
Objective	To determine the association of out-of-hospital sublingual nitroglycerin (NTG) administration with changes in blood pressure, heart rate, and pain scores in patients treated by EMS for suspected ST-segment elevation myocardial infarction (STEMI)
Study Groups	Received NTG (n= 340) No Field NTG (n= 440)
Inclusion Criteria	Adult patients transported for suspected STEMI to one of three high-volume STEMI Receiving Centers (SRC)
Exclusion Criteria	Patients with initial systolic blood pressure (SBP) less than 100mmHg, primary complaint of trauma, or cardiac arrest on EMS arrival
Methods	Patients with persistent chest pain received sublingual NTG 0.4 mg, repeated twice if needed. Data collected included initial field and ED vital signs, field NTG treatment, in-hospital management, and outcomes.
Duration	From July 1, 2015 to December 31, 2016
Outcome Measures	Primary: Change in SBP Secondary: Frequency of hypotension (SBP <100mmHg), bradycardia (HR <60), drop in SBP ≥30mmHg, out-of-hospital cardiac arrest (OHCA), change in pain score
Baseline Characteristics		Received NTG (n= 340)		No Field NTG (n= 440)
	Age, median (IQR)	63 (54-75)		70 (58-82)
	Male Sex	69%		56%
	Race/Ethnicity Asian Black Hispanic Pacific Islander/Hawaiian White Other	5% 35% 12% 1% 36% 10%		8% 35% 10% 0.5% 38% 9%
	Initial Field Vital Signs, median (IQR) SBP Diastolic BP (DBP) Mean arterial pressure (MAP) Heart rate (HR)	144 (128-167) 87 (75-100) 107 (94-120) 88 (72-104)		140 (115-160) 80 (70-95) 101 (86-116) 88 (70-108)
	Initial Pain Score, median (IQR)	8 (5-9)		0 (0-0)
	Final Diagnosis STEMI NSTEMI Angina Other	46% 10% 3% 41%		9% 6% 2% 83%
Results		Received NTG (n= 340)	No Field NTG (n= 440)	Measure of Difference
	SBP	-10 (IQR -27, 2)	-3 (IQR -20, 9)	-6 mmHg (95%CI -9, -3)
	MAP	-9 (IQR -20, 3)	-4 (IQR -17, 6)	-4 mmHg (95%CI -7, -1)
	Drop in SBP ≥ 30 mmHg	5.3%	6.7%	1.4% (95%CI -2.0, 4.8)
	ED Hypotension	9.1%	12.1%	2.9% (95%CI -1.4, 7.2)
	ED Bradycardia	7.2%	9.7%	2.5% (95%CI -1.5, 6.4)
	OHCA	0.3%	0.9%	Fischer exact, p= 0.2
	For patients with an initial pain score > 0, the average change in pain score for patients treated with NTG was -2.6 (95%CI -3.0, -2.2), while patients who did not receive NTG had a change in pain score of -1.4 (95%CI -1.8, -1.0).
Adverse Events	See Results
Study Author Conclusions	Field NTG resulted in pain reduction and did not result in a clinically significant decrease in blood pressure compared with patients who did not receive NTG, nor an increased frequency of hypotension or bradycardia on ED arrival.
InpharmD Researcher Critique	Strengths include a large sample size and real-world setting. Limitations include retrospective design, potential unmeasured confounders, and limited generalizability to rural settings. The study did not collect data on additional field interventions, which may have influenced outcomes.

References:

Bosson N, Isakson B, Morgan JA, et al. Safety and Effectiveness of Field Nitroglycerin in Patients with Suspected ST Elevation Myocardial Infarction. Prehosp Emerg Care. 2019;23(5):603-611. doi:10.1080/10903127.2018.1558318

Adverse events after prehospital nitroglycerin administration in a nationwide registry analysis
Design	Retrospective cross-sectional study N= 80,760
Objective	To determine demographic and clinical factors associated with adverse events after prehospital nitroglycerin (NTG) administration
Study Groups	Adverse event (n= 5914) No adverse event (n= 74,422)
Inclusion Criteria	Adults (≥18 years) with chest pain given oral or sublingual NTG by EMS, with vital signs obtained within 10 minutes of administration
Exclusion Criteria	Encounters without demographic information, advanced airway interventions prior to NTG, systolic blood pressure (SBP) < 90 mmHg, mean arterial pressure (MAP) < 65 mmHg, heart rate (HR) < 50 or > 120 beats per minute (bpm), altered mental status (AMS) prior to NTG, interfacility transport patients
Methods	Data from 1322 EMS agencies were analyzed using descriptive statistics and logistic regression models adjusting for age, sex, race, ethnicity, IV access, and initial vital signs.
Duration	1-year period (1/2019–1/2020)
Outcome Measures	Adverse events (SBP < 90 mmHg, HR < 50 or > 120 bpm, MAP < 65 mmHg, change in mental status)
Baseline Characteristics	Characteristic	Adverse event (n= 5914)	No adverse event (n= 74,422)	Total
	Age, years, median (IQR)	63 (52–75)	61 (50–72)	61 (50–72)
	Male	3132 (53%)	38,810 (52%)	41,942 (52%)
	Race White Black Other	77% 17% 6%	70% 23% 7%	71% 22% 7%
	Intravenous access	83%	84%	84%
	Initial SBP, mmHg	146 (127–168)	156 (138–179)	156 (138–179)
	Initial HR, bpm	93 (77–107)	85 (74–97)	86 (74–98)
Results	Causal criteria type	Number of adverse events
	SBP (<90 mmHg)	1533 (2%)
	HR (<50 bpm or >120 bpm)	3967 (5%)
	MAP (<65 mmHg)	1725 (2%)
	AMS	132 (0.2%)
	Total	5984 (7%)
	Increasing age (OR = 1.02, 95%CI:1.01–1.02) and HR (OR = 1.03, 95%CI:1.02–1.03) were associated with increased odds of adverse events, while SBP (OR = 0.99, 95%CI:0.98–0.99) and IV access obtained prior to NTG (OR = 0.92, 95%CI:0.85–0.99) was inversely associated.
Adverse Events	See Results
Study Author Conclusions	Adverse events following prehospital NTG administration were rare, especially in patients with an SBP > 110 and a HR < 100, and less frequent in those with existing IV access. Demographics were not found to be clinically significant.
InpharmD Researcher Critique	Strengths include large sample size and comprehensive data collection, whereas limitations are retrospective design, potential data entry errors, lack of long-term outcomes, and generalizability issues due to regional data focus. The findings were not further differentiated between oral and sublingual NTG use.

References:

Popp LM, Lowell LM, Ashburn NP, Stopyra JP. Adverse events after prehospital nitroglycerin administration in a nationwide registry analysis. Am J Emerg Med. 2021;50:196-201. doi:10.1016/j.ajem.2021.08.006