Low-dose versus high-dose intravenous nitroglycerin in the treatment of sympathetic crashing acute pulmonary edema: A systematic review and meta-analysis focusing on efficacy, safety, and outcomes

doi:10.21203/rs.3.rs-4943799/v1

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Research Article

Low-dose versus high-dose intravenous nitroglycerin in the treatment of sympathetic crashing acute pulmonary edema: A systematic review and meta-analysis focusing on efficacy, safety, and outcomes

https://doi.org/10.21203/rs.3.rs-4943799/v1

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Backgound

Sympathetic crashing acute pulmonary edema (SCAPE) is a menacing medical emergency that manifests as a severe conundrum of acute heart failure (AHF), characterized by an increase in systemic vascular resistance, which results in rapid redistribution of fluid to the pulmonary circulation. While the use of high-dose nitroglycerin (NTG) is gaining traction amid this patient subset, evidence on its efficacy and safety remains scarce and therefore lack of accuracy. Our aim was to compare the efficacy and safety between high- and low-dose NTG in patients with SCAPE.

Methods

A systematic literature search was conducted using PubMed, Europe PMC, and ScienceDirect for trials comparing the outcomes of high-dose NTG in SCAPE patients to low-dose NTG. Pre-defined efficacy (symptoms resolution rate within 6 hours, mechanical ventilation rates, length of hospital stay, major adverse cardiovascular events (MACE)) and safety outcomes were summarized throughout the studies.

Results

A total of 4 studies involving 185 participants were included. Compared to low-dose NTG, high-dose subset appeared to result in shortened hospital length of stay and faster symptoms alleviation within 6 hours of admission. The primary combined endpoint of mechanical ventilation was notably reduced in high-dose as compared to low-dose group. There was no statistically significant difference in MACE risk between high- and low-dose subgroups. No adverse event (hypotension) was observed in both groups.

Conclusion

Current evidence suggests that high-dose NTG (≥100 mcg/min) delivers a modest but superior improvement in several clinical parameters and is a viable alternative to low-dose NTG in the management of SCAPE patients.

sympathetic crashing acute pulmonary edema

acute heart failure

nitroglycerin

high-dose nitroglycerin

Acute heart failure (AHF) has been identified as a frequent yet highly perilous cardiovascular condition, incorporating one of the major causes of hospital admission among adults globally, with over 1 million hospitalizations each year. AHF encompasses a diverse range of clinical maladies, with a distinct pathophysiology and risk factors [1]. It is an exceedingly lethal condition, exhibiting a mortality rate of more than 20% unless treated promptly [2, 3]. Almost two-thirds of patients who experience AHF share a hypertensive crisis profile, which is typically characterized by increased systemic vascular resistance and worsening systolic and diastolic cardiac performance, prior to and during admission [4, 5].

Sympathetic crashing acute pulmonary edema (SCAPE), also known as hypertensive acute heart failure, or flash pulmonary edema is a severe form of AHF, a “chalk and cheese” condition due to an increase in systemic vascular resistance (afterload), leading to a rapid redistribution of fluid back to pulmonary circulation caused by a sympathetic surge. This condition often progresses frantically to acute respiratory distress syndrome, demanding intubation, mechanical ventilation, and intensive care unit (ICU) admission, leaving physicians just a brief window to stitch in time for intervention [6, 7]. Thus, the management of this population will be an uphill battle due to the dramatic presentation shown by the patients.

Early administration of intravenous vasoactive agents (e.g., nitroglycerin (NTG)) is anticipated to have major impacts on patient's disease progression since such medications will provide preload reduction thus, alleviating clinical symptoms [8–10]. However, the European Society of Cardiology, in their 2021 updated policy on acute and chronic heart failure, lowered the class of recommendation for intravenous vasodilators in AHF patients with increased blood pressure (BP) from IIa to IIb [11]. These current recommendations are based on a single randomized trial [12] and numerous small observational studies [13, 14], though the vast majority adopt standard dosages of nitrates, which may be insufficient in heightened sympathetic nervous system activity circumstances such as SCAPE.

Despite its profound usage, the optimal dose of NTG still unveils an up-in-the-air evidence gap, as there are no universal recommendations concerning its use in the treatment of SCAPE. High-dose NTG has emerged as a therapeutic option, as recent evidence demonstrates clinical advantages, albeit data on its efficacy and safety remains scarce due to a small number of participants and therefore lack of accuracy. Higher doses of NTG (≥ 250 micrograms per minute (mcg/min)) are known to induce both venous and arteriole dilatation, which may decrease afterload, resulting in augmented clinical response [15, 16]. However, the concern of detrimental effects from administering high-dose NTG causes many physicians to continue using the conventional way of administering low-dose NTG. The aim of this meta-analysis was to summarize the most recent evidence and compare the efficacy and safety of high-dose NTG compared with low-dose NTG in patients with SCAPE.

Protocol and registration

This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) recommendations. The review protocol was registered in the PROSPERO (Prospective Register of Systematic Reviews) international registry database under registration number CRD42024527486 [17].

Literature search strategy

We examined the databases PubMed, Europe PMC, and ScienceDirect up to June 2024. The search terms were as follows: (high dose nitroglycerin) AND (low dose nitroglycerin) AND (pulmonary edema). We employed the least number of keywords possible to maximize the initial area of inquiry and ensure the greatest number of articles were recorded. When required, the reference lists of the included research and relevant review papers were scrutinized for additional references. We tailored the search keywords to the particular requirements of each database. Our search followed PRISMA principles, and the flowchart in Fig. 1 depicts the search and screening procedures.

Study selection

We included randomized controlled trials, observational studies (both prospective and retrospective) reporting particular characteristics in high-dose NTG administration, as well as studies comparing its efficacy, safety, and outcomes (symptoms relief, mechanical ventilation, length of stay, and major adverse cardiovascular events (MACE)) at the most recent available follow-up compared with low-dose NTG in this meta-analysis. The detailed inclusion criteria were as follows: (1) SCAPE patients over 18 years old, characterized by acute dyspnea with onset of symptoms < 6 hours, SBP ≥ 160 mmHg and/or diastolic BP (DBP) ≥ 100 mmHg or a mean arterial pressure (MAP) of ≥ 120 mmHg, a respiratory rate (RR) ≥ 30 times per minute (tpm), oxygen saturation (SaO2) < 90%, and clinical features of sympathetic activation (tachycardia, diaphoresis, agitation) upon arrival [7]; (2) studies reported key exposure between high-dose and low-dose NTG, defined as a value surpassing cut-off point determined within each study in a comparative manner between the aforementioned outcomes. Our investigation required studies to publish risk estimation data with 95% confidence intervals (CI) or report sufficient data to compute the effect size.

We excluded studies in which patients: (1) suffered from non-cardiogenic pulmonary edema; (2) required immediate intubation or cardiopulmonary resuscitation; (3) contraindications to NTG (allergic reactions, hypertrophic cardiomyopathy, moderate-to-severe aortic stenosis, and use of sildenafil within 24 hours or tadalafil within 48 hours); (4) known or suspected pregnancy; (5) acute coronary syndrome. Our analysis omitted studies that failed to provide sufficient of the aforementioned data. Animal studies, review papers, editorials, comments, letters to editors, case reports/series, meta-analyses, and conference abstracts were also disregarded from our meta-analysis.

Intervention versus control groups

The intervention group comprised SCAPE patients who received an intravenous NTG infusion with a starting dose of ≥ 100 mcg/min. Our research protocol allows for investigations regarding titration of the NTG infusion at the discretion of each included study. Intravenous bolus(es) of high-dose NTG prior to the commencement of NTG infusion was also permitted at the sole decision of the physicians in the included studies. The control group comprised patients with SCAPE who had a starting infusion rate of NTG < 100 mcg/min. To correct hypoxemia and alleviate fluid overload, both groups might receive oxygen therapies and/or ventilatory support (either invasive or non-invasive strategy), as well as other cornerstones of AHF medications (e.g., diuretics), as per current recommendation [11].

Outcomes of interests and safety concerns

The primary outcomes of this study were the necessity of mechanical ventilation, the rate of symptoms resolution within 6 hours, the length of hospital stay, and MACE risk. Mechanical ventilation is a critical intervention for sustaining life in acute or emergent settings, particularly in patients with compromised airways, impaired ventilation, or hypoxemic respiratory failure, in which the procedure employs positive pressure breaths and hinges on the airway system's compliance and resistance.[18] The criteria for symptoms resolution are conditions in which two of the following three criteria are met: (1) a decrease in RR of at least 25% from baseline or RR ≤ 24 tpm; (2) a decrease in SBP ≤ 160 mmHg, or DBP ≤ 100 mmHg, or MAP ≤ 120 mmHg; (3) improvement from hypoxia, as evidenced by subjective improvement and an increase in SaO2 of ≥ 90% (room air) or ≥ 95% (with supplemental oxygen) [16]. MACE were characterized as a combination of cardiovascular death, myocardial infarction, ischemic stroke, as well as heart failure rehospitalization).[19] In terms of safety concerns, hypotension was defined as a fall in SBP below 90 mmHg [20], therefore NTG infusion would be stopped promptly and patients would receive suitable medical attention for the aforementioned condition.

Data extraction and risk of bias assessment

The course of data abstraction was conducted by two authors independently using a form detailing baseline characteristics of the included studies, such as first author’s name, age, sex, study design, the country in which the study was conducted, vital signs at admission, comorbidities, and medications. We also provided detailed intervention versus control protocols utilized in each study.

The Newcastle-Ottawa Scale (NOS) was implemented by the authors to independently assess the possibility of bias in each study. A study with a total score of seven or above was deemed bias-free. Research with a total score of six or less was considered to be biased and thus excluded from the research. Author discussion was applied to settle quality rating disagreements [21].

Statistical analysis

In this meta-analysis, we implemented STATA 17.0 and Review Manager 5.4 to calculate the overall effect magnitude. The Mantel-Haenszel method and generic inverse variance approach were utilized for dichotomous and continuous data, respectively. For single-arm studies, we utilized meta-analysis of proportion for every event per total. Risk ratios (RR) was used to measure binary comparison, while mean difference (MD) was used to estimate continuous variable comparison as an effect unit. I-squared (I²) was used to measure the pooled estimate's heterogeneity; a value of > 50% or a P-value < 0.10 denotes statistically significant heterogeneity. If the substantial Q statistics revealed heterogeneity among the trials, a random-effects model was used for meta-analysis. Otherwise, a fixed-effect model was utilized. Furthermore, the Egger test was utilized to quantify the publication bias. All statistical analyses were two-sided, with statistical significance attained by a P-value < 0.05.

Study selection and characteristics of the included studies

Figure 1 depicts the results of the literature search. After identifying duplicates, we discovered 109 pre-screened articles, reviewed the title and abstract of the remaining articles, and omitted 78 records. The remaining 31 entries' full-text articles were obtained and investigated. Eventually, 27 studies were deemed ineligible, and the remaining 4 were chosen for qualitative and quantitative analyses. Among these investigations, there was one randomized controlled trial, three prospective and retrospective observational studies–two of which were single-arm studies.

Baseline and clinical characteristics of the included studies are presented in Table 1. The mean age of the participants was 50.6 ± 14.9 years, 58.4% of patients were male, with a total of 185 participants. Previous hypertension, diabetes mellitus, pre-existing coronary artery disease, heart failure, and chronic kidney disease were present in 96.2%, 20.3%, 11.3%, 46.7%, and 63.2% of patients, respectively. The mean of vital signs parameters was as follows: (SBP: 211 mmHg; HR: 129 bpm; RR: 39 tpm; SaO2: 88%).

Table 1

Baseline and clinical characteristics of the included studies (high-dose vs. low-dose).
No.	Author (year)	Country	Study design	Intervention	Control	Total participants	Age (years)	Male (%)	Vital signs at admission	Comorbidities (%)	Medications (%)	NOS
Comparative studies
1	Kelly et al. (2023) [15]	United States	Retrospective cohort	A starting infusion rate of 100 mcg/min (max. 400 mcg/min) (no bolus). The infusion rate was up-titrated by 10 mcg/min every 3–5 min until there was a decreasing trend in SBP. NIPPV: 78.6%	A starting infusion rate of 10 mcg/min (no bolus). The infusion rate was up-titrated by 10 mcg/min every 3–5 min until there was a decreasing trend in SBP. NIPPV: 70.4%	41 (14 vs. 27)	61.2 ± 20.6 vs. 64.7 ± 14.1	0 vs. 48.1	SBP (mmHg): 210 ± 21 vs. 214 ± 24	HTN: 100 vs. 100 DM: 21.4 vs. 62.9 CAD: 14.8 vs. 21.4 HF: 85.7 vs. 70.4 CKD: 57.1 vs. 40.7	Oral nitrates: 57.1 vs. 40.7 BB: 71.4 vs. 85.2 CCB: 64.3 vs. 74.1	9
2	Siddiqua et al. (2024) [16]	India	RCT	An intravenous bolus dose of 600–1000 mcg NTG over 2 min (if SBP was 160–179 mmHg, a bolus of 600 mcg was given; if SBP was 180–199 mmHg, a bolus of 800 mcg was given; if SBP was ≥ 200 mmHg, a bolus of 1000 mcg was given) followed by a continuous infusion rate of 100 mcg/min (max. 400 mcg/min). The infusion rate was up-titrated by 20 mcg/min every 10 min until there was a decreasing trend in SBP. NIPPV: 100%	A starting infusion rate of 20–40 mcg/min (max. 250 mcg/min) (no bolus). The infusion rate was up-titrated until there was a decreasing trend in SBP. NIPPV: 100%	52 (26 vs. 26)	40 ± 14.1 vs. 48 ± 10.2	53.8 vs. 53.8	SBP (mmHg): 212 ± 27 vs. 200 ± 17 HR (bpm): 128 ± 16 vs. 122 ± 20 RR (tpm): 38 ± 4 vs. 37 ± 5 SaO2 (%): 81 ± 7 vs. 83 ± 7	HTN: 92.3 vs. 100 DM: 19.2 vs. 30.8 CAD: 7.7 vs. 15.4 HF: 7.7 vs. 0 CKD: 69.2 vs. 73.1	NR	9
Single-arm studies
3	Houseman et al. (2023) [26]	United States	Retrospective cohort	An intravenous bolus dose of 200 mcg NTG followed by a continuous infusion rate of 100 mcg/min (max. 400 mcg/min). The infusion rate was up-titrated as needed to achieve symptoms relief, according to the physician’s recommendation (unspecified). NIPPV: 73%	N/A	67	59 ± 11	63	SBP (mmHg): 212 ± 31 SaO2 (%): 94 ± 6	HTN: 69 CAD: 25 HF: 51 CKD: 36	Oral nitrates: 12 Diuretic: 13 ACE-i/ARB: 46 Aldosterone antagonist: 13	9
4	Mathew et al. (2021) [27]	India	Prospective cohort	An intravenous bolus dose of 600–1000 mcg NTG over 2 min (if SBP was 160–179 mmHg, a bolus of 600 mcg was given; if SBP was 180–199 mmHg, a bolus of 800 mcg was given; if SBP was ≥ 200 mmHg, a bolus of 1000 mcg was given) followed by a continuous infusion rate of 100 mcg/min (max. 200 mcg/min). The infusion rate was up-titrated by 20 mcg/min every 10 min until there was a decreasing trend in SBP. NIPPV: 100%	N/A	25	44.2 ± 18.8	48	SBP (mmHg): 200 ± 31 HR (bpm): 129 ± 14 RR (tpm): 40 ± 4 SaO2 (%): 81 ± 9	HTN: 76 DM: 40 CAD: 12 HF: 8 CKD: 60	NR	8
ACE-i: angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blockers; BB: beta blocker; bpm: beats per minute; CAD: coronary artery disease; CCB: calcium channel blocker; CKD: chronic kidney disease; DM: diabetes mellitus; HF: heart failure; HR: heart rate; HTN: hypertension; max.: maximum; mcg/min: micrograms per minute; min: minutes; mmHg: millimeters of mercury; N/A: not available; NIPPV: non-invasive positive pressure ventilation; NOS: Newcastle-Ottawa Scale; NR: not reported; NTG: nitroglycerin; RCT: randomized controlled trial; RR: respiratory rate; SaO2: oxygen saturation; SBP: systolic blood pressure; tpm: times per minute; vs.: versus.

High- versus low-dose NTG and outcomes of interest

Mechanical ventilation was observed in 10% (1–18%) of the high-dose group (Fig. 2). Patients in high-dose subset also exhibited a considerably lower risk of mechanical ventilation in comparison to opposing group (RR = 0.31 (0.10–0.96); P = 0.04; I² = 0%) (Fig. 3). Moreover, our pooled results suggest that subjects within high-dose group experienced much faster symptoms alleviation (RR = 3.88 (1.95–7.71); P < 0.001; I² = 27%) (Fig. 4) and decreased in length of hospital stay (MD: -47.49 hours (-93.76, -1.21); P = 0.04; I² = 78%) (Fig. 5), respectively. However, the combined results of two comparative studies suggest that subjects within high-dose group had no significant difference in the risk of MACE compared with individuals in low-dose group (RR = 0.41 (0.06–2.68); P = 0.35; I² = 72%) (Fig. 6). The rate of adverse event (hypotension) was 0% in both groups.

Publication bias

We were unable to conduct a qualitative analysis of funnel plots to identify publication bias due to a paucity of research in our analysis. Hence, the Egger test was used to quantitatively detect publication bias, and our findings revealed that a small study effect was not identified.

The most noteworthy in this study was that patients assigned to high-dose NTG experienced a greater improvement in lowering the necessity of mechanical ventilation, a shorter duration of hospital stay, and an increased likelihood of achieving faster symptoms relief during the course of treatment. However, the odds of MACE risk reduction and safety profile were comparable in both groups. To our knowledge, this is thus far the first meta-analysis comparing high- and low-dose of NTG in terms of the efficacy, safety, and outcomes for the treatment of SCAPE, as will be captivatingly discussed in the remainder of this article.

To fully comprehend the correlation between the previously mentioned findings and the improvement of outcomes in SCAPE, it is vital to understand the pathogenesis of SCAPE since the findings of this meta-analysis are directly related to the disease's pathophysiology. SCAPE is the most devastating form of the AHF spectrum, with nearly identical underlying pathomechanisms. However, a key difference distinguishes between the two, specifically the predominance of vasoconstriction conditions caused by sympathetic nervous system hyperactivation, exacerbated by a decrease in nitric oxide (NO) production caused by concomitant endothelial dysfunction due to the underlying condition of heart failure itself. The majority of SCAPE patients have chronic left ventricular dysfunction (both systolic and diastolic function due to hypertension). In our research of immensely hypertensive patients (96.2%), transitory aggravation of diastolic dysfunction is believed to be the most prevalent mechanism for retaliating to the cause of decompensation. An increase in end-diastolic volume in the presence of poor ventricular compliance significantly raises diastolic pressure and causes a build-up of fluid in the lungs [22, 23].

Nitroglycerin has been recognized as an essential cure-all and the key solution to this particular issue. At low-moderate dosages, nitroglycerin primarily impacts preload via a venodilation mechanism; however, at high doses of > 250 mcg/min, arteriolar dilatation occurs, lowering afterload, which plays a critical role in the management of this malady [15, 16]. Nearly half of the population in this meta-analysis had pre-existing heart failure and were undergoing extended nitrate treatment, which may be uniquely resistant to this class of medications, thus explaining the need for larger than standard dosages (known as vascular tolerance) [10]. Our findings are consistent with this and add to the body of knowledge on a topic that is gaining traction, demonstrating the effectiveness and safety of high-dose NTG usage for SCAPE. An agile yet hard-hitting intervention within the initial medical contact of treatment for SCAPE has been shown to correspond with faster symptoms relief, lower incidence of mechanical ventilation, and shorter length of hospital stay (Fig. 3–5).

Another aspect worth considering is that congestion is not usually synonymous with volume overload. It should be noted that SCAPE occurs as a result of an abrupt fluid redistribution from the central circulation into the pulmonary vasculature, leading to the notion that vascular mechanisms play a vital part in the pathophysiology of the disease rather than in the context of total body volume changes or fluid overload. Hence, diuretics might serve a role, but they are not always required in the early phases of resuscitation, given that SCAPE patients are not usually volume-overloaded (often volume-depleted due to fluid redistribution from systemic to the pulmonary circulation). Poor renal perfusion due to significant vasoconstriction induced by the SCAPE state prevents diuretics from reaching the renal tubules and exerting their effects. Furthermore, over-diuresis causes further volume depletion, resulting in a vicious loop of stress-related responses and sympathetic surges [24–27]. This emphasizes the importance of bedside echocardiography in measuring patient hemodynamics, as hypovolemic individuals are more susceptible to hypotension from high-dose NTG administration. It is critical to assess the underlying pathomechanism of this acute presentation to determine whether diuretics (preload) are necessary for these patients rather than vasodilators (afterload).

Limitations

Several limitations still warrant consideration in this meta-analysis. First, we were unable to do meta-regression to determine the direct effect on our outcomes of interest due to a paucity of research and data on confounding factors. Second, a considerable number of patients in our studies had chronic renal disease, which is difficult to treat and frequently resistant to blood pressure medications. Future prospective observational studies focusing on SCAPE patients with normal kidney function are still warrant to better understand the effect of high-dose NTG in this subset of patients. Limitations also include a small number of studies, with uneven ethnic representation. Hence, results should be extrapolated with caution to patients of various ethnic backgrounds.

In summary, our meta-analysis indicates that high-dose NTG is beneficial not only for lowering the necessity for mechanical ventilation but also in improving the rate of symptoms relief and reducing the length of hospital stay in SCAPE patients, with no associated increase in adverse events when compared to low-dose NTG.

ACE-i

angiotensin-converting enzyme inhibitor

ARB

angiotensin II receptor blockers

beta blocker

bpm

beats per minute

CAD

coronary artery disease

CCB

calcium channel blocker

CKD

chronic kidney disease

diabetes mellitus

heart failure

heart rate

HTN

hypertension

max.

maximum

mcg/min

micrograms per minute

min

minutes

mmHg

millimeters of mercury

N/A

not available

NIPPV

non-invasive positive pressure ventilation

NOS

Newcastle-Ottawa Scale

not reported

NTG

nitroglycerin

RCT

randomized controlled trial

respiratory rate

SaO2

oxygen saturation

SBP

systolic blood pressure

tpm

times per minute

vs.

versus

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Funding

Not applicable.

Author Contribution

MP, WK, and RP conceived and designed the study. WK and RP performed study selection, data extraction, and interpreted the data. WK and RP performed extensive search of relevant topics. WK performed statistical analysis. HSP, MI, TID, and MRA performed review and extensive editing of the manuscript. All authors contributed significantly to the writing of the manuscript. All authors approved the final manuscript.

Acknowledgement

None.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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No competing interests reported.

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Low-dose versus high-dose intravenous nitroglycerin in the treatment of sympathetic crashing acute pulmonary edema: A systematic review and meta-analysis focusing on efficacy, safety, and outcomes

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Abstract

Figures

BACKGROUND

METHODS

Protocol and registration

Literature search strategy

Study selection

Intervention versus control groups

Outcomes of interests and safety concerns

Data extraction and risk of bias assessment

Statistical analysis

RESULTS

Study selection and characteristics of the included studies

High- versus low-dose NTG and outcomes of interest

Publication bias

DISCUSSION

Limitations

CONCLUSION

Abbreviations

Declarations

Funding

Author Contribution

Acknowledgement

Availability of data and materials

References

Additional Declarations

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