Introduction

Global awareness of the need for emergency care and the specialization of emergency medicine are both continuously expanding. In the era of 1960s and 1970s, emergency medicine became a distinct specialty as a result of the growing demand for rapid, high-quality emergency care for patients who were admitted to hospitals with acute medical issues. It has been demonstrated that emergency medicine enhances care and outcomes for patients with emergency concerns (1). Emergency medicine is a branch of medicine that focuses on diagnosing and treating unexpected injuries or diseases. Emergency medicine encompasses the initial assessment, diagnosis, treatment, multi-provider coordination of care, and discharge of patients in need of immediate medical, surgical, or mental health attention. The practice of emergency medicine is not spatially restricted; it can take place in both hospital-based and out-of-hospital emergency departments, urgent care facilities, observation medicine units, emergency medical response vehicles, disaster sites, and via telemedicine. Planning, supervision, and medical guidance for community emergency medical response, medical control, and catastrophe preparedness are all included in emergency medicine. Emergency departments and other parts of the healthcare delivery system benefit greatly from the clinical, administrative, and leadership services that emergency medicine specialists offer (2).

Diverse multidisciplinary conditions are managed in emergency medicine settings. In the chain of survival for acute diseases including myocardial infarction, stroke, and trauma, the emergency care system is vital. Depending on the age group, the most frequent reasons for emergency visits include heart failure, pneumonia, sepsis, trauma, asthma, and chronic obstructive pulmonary disease. Although its characteristics remain timely in-hospital diagnosis and treatment, emergency care has evolved over the last 20 years to include a wider range of treatments. These encompass both pre- and post-emergency department activities such as urgent care routes for lower-acuity patients and transfers of patients to higher-acuity inpatient settings or return to their usual source of care and post-emergency department activities (3). The prompt medical attention provided to the populace in situations of emergency poses a significant challenge to the healthcare system and is becoming more and more necessary. As a result of this advancement, clinical acute and emergency medicine has advanced significantly and is currently undergoing additional professionalism. Providing emergency patients with the best care possible must be the primary goal (4).

Vasodilators are valuable in the management of acute heart failure, a condition frequently encountered in emergency medicine settings, especially when increasing afterload is the underlying cause of decompensation. The time-honored strategy of afterload reduction has primarily depended on the use of intravenous nitrovasodilators, which, when appropriately dosed, may provide significant symptom alleviation for patients with acute hypertensive heart failure (5). Moreover, a hypertensive emergency is a significant clinical phenomenon that can cause damage to the cardiovascular, neurological, and renal systems, among other organs. It may lead to potentially fatal repercussions if it is not identified and addressed promptly. Vasodilators are the cornerstone of care for hypertensive crises. Vasodilators are classified into many classes according to their site and mode of action. The most often used vasodilators are peripheral dopamine agonists, calcium channel blockers, beta, alpha, and beta blockers, as well as directly acting medications that work through the vascular nitric oxide route. By lowering peripheral resistance, the diverse types of vasodilators lower blood pressure through distinct neurohormonal signaling pathways (6).

Nitrovasodilators such as nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, and sodium nitroprusside have long been regarded as first-line treatments for acute hypertensive heart failure. These drugs function by delivering an exogenous source of nitric oxide, which subsequently binds to soluble guanylate cyclase, resulting in cyclic GMP and vascular smooth muscle relaxation (5). The hemodynamic effects of vasodilators differ considerably across drugs. Some vasodilators, such as nitrates, function predominantly on the venous side of the circulatory system, redirecting circulating blood volume away from the heart and into the venous capacitance system. As a result, both ventricular preload and venous return to the heart diminish. Intravenous nitrates significantly increase nitric oxide-induced vasodilation and have an effect within 2-3 minutes. The immediate effects include venous dilation, blood volume redistribution, reduced venous return, less congestion, and symptom relief. Higher nitrate doses, in addition to sodium nitroprusside, dilate the arteries, lowering blood pressure and left ventricular afterload. Nitrates reduce afterload, myocardial oxygen consumption, and intra-ventricular pressures. Because of their modes of action, intravenous vasodilators are thought to be beneficial in patients with acute heart failure and acute pulmonary edema, where raised cardiac and systemic blood pressures are dramatically elevated in the absence of or with low systemic fluid accumulation (7).

Nitroglycerin, a fast-acting vasodilator, is often used in the emergency department as a first-line treatment for angina and chest pain caused by acute coronary syndrome. It can also be used to treat other conditions, such as acute heart failure, pulmonary edoema, and aortic dissection. In the body, nitroglycerin is converted to nitric oxide, a strong vasodilator, resulting in vasodilation at lower dosages and arteriodilation at higher dosages, which reduces preload and afterload, respectively. Although nitroglycerin has traditionally been delivered as a sublingual pill and/or spray, it is frequently administered intravenously in emergency departments since it allows for titration with predictable pharmacokinetics (8). In patients with decompensated congestive heart failure with acute pulmonary edema, intravenous bolus nitroglycerin can reduce the requirement for intubation, ICU admission rate, and hospital duration of stay, in line with evidence from recent emergency department findings. While sublingual nitroglycerin effectively treats decompensated congestive heart failure patients with acute pulmonary edema in the prehospital situation (9).

Sublingual, topical, or intravenous nitroglycerin infusion is indicated as a first-line blood pressure management treatment in acute hypertension, pulmonary edema and acute coronary syndrome due to its beneficial effect on lowering preload and cardiac output. It is advantageous as a second-line therapy in hypertensive situations owing to acute sympathetic crises such as cocaine, amphetamines, monoamine oxidase inhibitor toxicities, and Irukandji Syndrome. Sublingual nitroglycerin is extensively utilized due to its antianginal effects. However, its convenience, ease of administration, and early onset of action make it a suitable drug for rapid blood pressure management in emergency medicine settings until definitive therapy is initiated (10). Since various multidisciplinary conditions are encountered in emergency medicine settings, the role of nitroglycerine in each remains underdefined in the literature. Through this systematic review, we aim to elaborately analyze the existing literature to define the beneficial role of the administration of nitroglycerine across diverse cohorts of patients reporting to emergency medicine settings. The findings will provide deep insights into the efficacious role of nitroglycerine for various diseases witnessed in the emergency department, and they can additionally help guide clinical practice to achieve optimal outcomes and increase patient satisfaction

Methods

Definition of Outcomes and Inclusion Criteria

Our study aimed to assess the significance of nitroglycerine in emergency medicine settings for various multidisciplinary conditions. As a result, we included original studies that defined the role and utilization of nitroglycerine across various diseases among emergency medicine patients specifically. Within the context of this review of multidisciplinary conditions, we considered the patient population suffering from diverse diseases necessitating emergency treatment including heart failure and other cardiovascular diseases, stroke, and pulmonary edema among others. Studies including the pediatric population were excluded. Moreover, this review excluded case reports featuring small sample sizes and lacking descriptive statistics. Nonhuman or laboratory studies, non-original or incomplete investigations, abstract-only articles, protocols, theses and articles not published in English or lacking English information were also excluded based on predetermined criteria.

Search Strategy

After achieving our desired outcomes, we conducted a brief manual screening of potential studies to extract relevant keywords for crafting an optimal search query. Our search strategy encompassed terms such as (significance OR importance OR utilization OR role) AND (nitrates OR nitroglycerine OR nitro-glycerine) AND (emergency OR ‘emergency department’ OR ‘emergency medicine’) AND (management OR treatment) AND (‘diverse diseases’ OR ‘multidisciplinary conditions’ OR ‘critical diseases’). We utilized PubMed, Science Direct, Web of Science, and the Cochrane Library as our databases for the search. To ensure inclusivity of pertinent research, we limited our search to the titles and abstracts of retrieved results. Subsequently, we employed EndNote software to compile and eliminate duplicates across all databases. Additionally, we manually scrutinized the reference lists of included studies, related reviews, and relevant sections of comparable articles in PubMed to identify any potentially overlooked papers. Throughout this systematic review, we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Screening and Extraction

Articles with irrelevant titles were excluded from consideration. In the subsequent phase, both the full text and abstracts of the papers were meticulously reviewed to determine their compliance with the inclusion criteria. To streamline the process, titles and abstracts were organized, assessed, and scrutinized for any duplicate entries using reference management software (Endnote X8). To ensure the highest quality of selection, a dual screening approach was adopted, involving one screening for the evaluation of titles and abstracts, and another for the comprehensive examination of the entire texts. Once all relevant articles were identified, a structured extraction sheet was created to capture pertinent information aligned with our specific objectives. This included delineating the desired outcomes and baseline characteristics such as study design and period, age, gender, disease or condition and the geographical location of the study, among certain others.

Quality Assessment

We collected data from the encompassed studies to evaluate the potential bias they might entail. For assessing the quality of observational studies, we employed the modified Newcastle-Ottawa Scale (11), encompassing four domains: methodological quality, comparability, outcome/exposure assessment, and outcome/exposure reporting. Each study was rated on a scale from 0 to 10 according to the extent of bias, categorized as excellent, good, satisfactory, or unsatisfactory. For the assessment of the quality of a randomized trial, the Cochrane risk of bias tool was utilized (12). This tool assesses the quality of the study by assessing risk in seven domains, including random sequence generation, allocation concealment, blinding of participants and outcomes, incomplete outcome data, selective reporting, other biases, and the overall risk of bias.

Results

Search Results

We executed the search methodologies outlined previously, resulting in the identification of a total of 225 citations, subsequently reduced to 214 following the removal of duplicates. Upon screening titles and abstracts, only 55 citations met the eligibility criteria for further consideration. Through full-text screening, this number was further refined to 6 articles aligning with our inclusion and exclusion criteria. Figure 1 provides an in-depth depiction of the search strategy and screening process.

Results of Quality Assessment

Upon evaluating the quality of the studies included, it was determined that overall, the studies exhibited good quality with minimal risk of bias, except for one study, which showed unsatisfactory quality. The detailed findings of the quality assessment are presented in Tables 1 and 2.

Table 1: Newcastle-Ottawa Scale of each included non-randomized studies.
Study	Selection	Comparability	Outcome	Total score	Quality
Greenwood JC, et al. (2022) (13)	4	0	2	6	Good
Bosson N, et al. (2019) (14)	4	2	1	7	Good
Aziz EF, et al. (2011) (15)	4	1	2	7	Good
Vuylsteke A, et al. (2011) (16)	3	0	1	4	Unsatisfactory
Steele R, et al. (2006) (17)	4	0	2	6	Good

Table 2: Cochrane risk of bias for randomized controlled study.
Studies	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Other bias	Overall
Cerbin LP, et al. (2018) (18)	Moderate	Unclear	Low	Low	Low	Low	Low	Low

Figure 1: PRISMA Flow diagram

Characteristics of the included studies

We incorporated a total of 6 studies encompassing 9452 patients, published between 2006 and 2022 (13-18). All participants in these studies were aged above 60 years of age, with 57.29% being male and 42.70% female. Notably, all the studies were observational with a single post-hoc analysis, multicentre study. Geographically, all the studies were from United States except one study which was from Europe. A comprehensive summary of the baseline characteristics of these studies can be found in Table 3. Discrepancies in sample sizes across the included papers likely stem from differences in study objectives and inclusion criteria.

Study outcome measures

The use of nitroglycerine across various multidisciplinary conditions encountered in the emergency medicine setting was assessed. The majority of the patients presented with heart failure, followed by cases of hypertension, pulmonary oedema, circulatory shock, stroke, acute coronary syndrome or myocardial infarction, and chest pain. Almost three studies reported that significant symptomatic relief was observed post nitroglycerine administration (14, 17, 18), while another two of the included studies demonstrated that improvement in symptoms were also noted (13, 15). Regarding the utilization of nitroglycerin in the emergency medicine setting, a study by Bosson et al. noted that almost 44% of the patients received nitroglycerin, while Cerbin et al. observed that intravenous nitroglycerin administration was higher for patients presenting in off-hours (18% vs. 11%) (14, 18). Moreover, a study by Steele et al. indicated that 66% of the participants responded well to nitroglycerine, whereas 34% did not (17). Primarily, two of the included studies assessed the adverse events among which one study did not find any difference between patients receiving nitroglycerine and those not receiving this vasodilator (14). However, another study by Vuylsteke et al. observed hypotension within 72 hours of initiation of treatment (16) (Table 4). Overall, the findings demonstrate the efficacious role of nitroglycerine in the management of various multidisciplinary conditions encountered in emergency medicine settings; however, the generalizability of these findings is constrained due to the limited evidence available in this regard, which highlights the need for further clinical research.

Table 3: Baseline characteristics included studies.
Studies	Publisher journal	Year of publication	Country of the patients	Study design	Study period	Total Number of participants	Treatment group/control group	Age	Gender of total participants Male %/Female%
Greenwood JC, et al. (13)	Sci Rep.	2022	USA	observational	2021	40	20/20	64 ± 9/ 67 ± 11	75%/25%
Bosson N, et al. (14)	Prehospital Emerg Care.	2019	USA	prospective	2015-2016	780	340/440	median= 63 years	61%/39%%
Cerbin LP, et al. (18)	JACC Heart Fail	2018	US	Post hoc analysis, multicenter	NR	7141	Regular Hours :3843/off-Hours:3298	median=67 years	65.78%/34.22%
Aziz EF, et al. (15)	Hospital practice (1995)	2011	USA	retrospective study	NR	430	diuretics and NTG: 46	72 ± 13	43%/57%
Vuylsteke A, et al. (16)	Crit Care	2011	European countries, multicenter	observational study	2009	791	ED/Perioperative: 180/229	median =70 years	48%/52%
Steele R, et al. (17)	Canadian Journal of Emergency Medicine	2006	USA	Prospective observational cohort	NR	270	177/93	64 years	51%/49%