Article, Cardiology

Role of high-dose intravenous nitrates in hypertensive acute heart failure

a b s t r a c t

Background: Patients with hypertensive acute heart failure (H-AHF) can decompensate rapidly and require immediate medical attention; the use of high-dose nitroglycerin is a topic of growing interest in this patient population.

Objective of the review: The purpose of this review is to provide an Evidence-based approach for the uti- lization of high-dose nitrates in the emergent management of H-AHF.

Discussion: Two randomized controlled trials, three prospective studies, two retrospective cohorts, two case series, and one case report were evaluated. Level of robust evidence and heterogeneity limit the abil- ity to draw strong conclusions regarding the use of high-dose nitrates. Despite these limitations, high- dose nitrates appeared to have an overall beneficial effect across all studies reviewed, including lower rates of mechanical ventilation, improvement in blood pressure, shorter LOS, and lower rates of ICU admission. Adverse effects were mild and infrequently reported.

Conclusions: High-dose nitrates are likely safe and may be effective, as demonstrated in the studies reviewed. High-dose NTG may be appropriate in H-AHF patients presenting with severe respiratory dis- tress and SBP >=160 mmHg or MAP >=120 mmHg. Future well-designed randomized controlled trials are needed to elucidate optimal dosing strategies and confirm safety and efficacy of high-dose nitrates.

(C) 2019

Introduction

Acute heart failure comprises a wide spectrum of clinical conditions with heterogeneous pathophysiologies and precipitat- ing factors. Hypertensive AHF (H-AHF), also known as sympathetic crashing acute pulmonary edema (SCAPE) and flash pulmonary edema, is a distinct subgroup of AHF characterized by a rapid onset of pulmonary congestion and severe dyspnea in the setting of sys- tolic hypertension (i.e. >140 mmHg) [1,2]. Nearly three-quarters of AHF patients have a history of hypertension and 50% have an initial systolic blood pressure (SBP) >140 mmHg, suggesting that H-AHF is a common phenotype of heart failure syndromes [3].

noninvasive positive pressure ventilation and intra-

venous (IV) vasodilators are cornerstone therapies for the manage- ment of H-AHF [4-6]. These targeted modalities reduce both preload and afterload, improve hemodynamics, and reduce dysp-

nea [2]. Intravenous nitroglycerin (NTG) is the agent of choice for vasodilation, and doses range from 5-200 lg/min, historically [4]. However, high-dose nitroglycerin (HDN), defined as doses

>250 lg/min, may be beneficial in the treatment of H-AHF and

there has been increased interest expressed in free open access medical education resources in recent years. Current guidelines do not make a clear endorsement for HDN and it is not considered standard of care [5,6].

* Corresponding author.

E-mail address: [email protected] (K. Wang).

The purpose of this review is to provide an evidence-based approach to the use of HDN in the emergent management of H-AHF.

Methods

A literature search pertaining to ”((nitroglycerin[Title]. OR nitrates[Title]. OR isosorbide[Title].) AND (pulmonary edema [Title]. OR pulmonary oedema[Title]. OR heart failure[Title].)) AND (high-dose[All Fields]. OR (high[All Fields]. AND dose[All Fields].) OR bolus[All Fields]. OR boluses[All Fields]. OR bolus- dose[All Fields].) AND (”humans”[MeSH Terms]. AND English [lang].)” was conducted using PubMed, and conference abstracts were also included through author consensus.

Discussion

Pathophysiology of H-AHF

Chronic hypertension perpetuates maladaptive changes in the myocardium and vasculature, leading to a dysfunctional response to changes in pressure, volume, and sympathetic tone. Addition- ally, poorly controlled hypertension leads to increased barorecep- tor tolerance and a blunted baroreceptor response, causing disinhibited sympathetic outflow and further vascular and ventric- ular dysfunction. Nearly 25% of blood volume resides in splanchnic veins at rest, and sympathetic stimulation results in marked

https://doi.org/10.1016/j.ajem.2019.06.046

0735-6757/(C) 2019

K. Wang, K. Samai / American Journal of Emergency Medicine 38 (2020) 132-137 133

vasoconstriction and abrupt redistribution of blood into the sys- temic circulation. The dysfunctional myocardium responds to the Rapid increase in preload with further elevations in ventricular wall tension and cardiac filling pressures; simultaneous increases in afterload caused by vasoconstriction further exacerbate cardiac dysfunction. The compromised system causes redistribution of blood to the pulmonary circulation with subsequent pulmonary congestion. The abrupt and Rapid progression of respiratory decompensation requires emergent management [1,7].

Pharmacology of nitrates and role in H-AHF

Organic nitrates are prodrugs which mediate smooth Muscle relaxation via nitric oxide release. Nitric oxide stimulates activa- tion of guanylyl cyclase within the smooth muscle cells and causes an increase in cyclic guanosine monophosphate [8]. The resulting dephosphorylation of myosin light-chain phosphate and subse- quent reduction of calcium concentration in the cytosol causes smooth muscle relaxation [8].

Nitroglycerin, also known as glyceryl trinitrate, is the most commonly utilized nitrate vasodilator in the United States [4]. Con-

tinuous intravenous (CIV) NTG is commonly initiated at a rate of 10 lg/min with a range of 5-200 lg/min [9]. Lower doses (<250 lg/min) primarily dilate veins resulting in decreased preload, while higher doses (>250 lg/min) also lead to arteriole

dilation and reduction in afterload [10]. High-dose NTG, adminis- tered as IV bolus or CIV, may be particularly advantageous for the treatment of AHF patients with profound hypertension, due to a more pronounced response to NTG in patients with excessive vascular resistance [10,11]. Isosorbide dinitrate (ISDN) is another nitrate available as an IV formulation internationally, excluding the United States [12]. Intravenous ISDN is dosed initially at 1- 2 mg/h; however higher doses of 10-50 mg/h may be necessary in patients with heart failure [12]. Limited evidence suggests that IV NTG is approximately eight times more potent than IV ISDN [13,14]. However, there is no widely established dosing conversion between these two agents.

Review of the literature

Nashed et al. published results from 24 cases of acute cardio- genic pulmonary edema (ACPE) treated with IV NTG boluses after failure of at least two doses of sublingual NTG in the emergency department (ED) [15]. The IV NTG bolus dose was based upon pre-

senting SBP and ranged from 50-400 lg/min over 1-2 min. Subse-

quent bolus doses were doubled at the physician’s discretion if SBP remained above 180 mmHg. The protocol was terminated if SBP decreased to below 95 mmHg, if intubation was required, or if other complications arose. Significant clinical improvement was determined by the treating physician’s judgment of patient com- fort, decreased dyspnea, decreased respiratory rate, and pulmonary examination; results are presented in Table 1. The authors con- cluded that judicious use of IV NTG boluses in the ED appeared to be safe and efficacious in treating patients with ACPE who have an inadequate response to sublingual NTG.

Nashed et al. performed a prospective trial comparing CIV NTG (conventional group, n = 12) to CIV NTG plus IV NTG boluses (HDN group, n = 9) in 21 ED patients with ACPE and SBP >150 mmHg

[16]. Intravenous NTG bolus doses were reported as up to 800 lg

over 2 min and were repeated every 5 min for a 30-min treatment period; the dosing range of CIV NTG was not reported. Baseline characteristics, including doses of other medications, initial clinical severity score (CSS), and initial arterial blood gas were similar between groups. Notably, patients were slightly older in the HDN group (87 vs. 75 years, p = 0.005). No significant differences with respect to results were found between groups (Table 1); however, there was greater improvement found in the HDN group when only patients with acidemia (pH <7.4) were analyzed (n = 9, conven- tional group; n = 6, HDN group).

Cotter et al. conducted a randomized controlled trial (RCT) of high-dose IV isosorbide dinitrate (HDISDN) (HDISDN group,

n = 52) versus high-dose furosemide plus low-dose ISDN (conven- tional group, n = 52) in patients with severe pulmonary edema pre- senting to mobile emergency units in Israel [17]. Prior to randomization, all patients received furosemide 40 mg IV and mor- phine 3 mg IV. Patients in the HDISDN group received ISDN 3 mg boluses every 5 min while patients in the conventional group received an 80 mg bolus of furosemide every 15 min and ISDN

1 mg/h (16 lg/min) increased by 1 mg/h every 10 min. The mean

dose of ISDN was 11.4 mg +- 6.8 mg in the HDISDN group and

1.4 mg +- 0.6 mg in the conventional group, while mean dose of fur- osemide was 56 mg +- 28 mg and 200 mg +- 65 mg, respectively. Mean percentage decrease in mean arterial pressure (MAP) was 19% +- 9% in the HDISDN group and 15% +- 5% in the conventional group. Results for primary outcome measures are presented in Table 1. Authors concluded HDISDN was more effective than furo- semide in controlling severe pulmonary edema.

Sharon et al. performed a single-center, prospective, RCT in Israel comparing HDISDN to bi-level positive airway pressure (BIPAP) plus standard-dose ISDN (BIPAP group) in patients with severe pulmonary edema presenting to mobile intensive care units (ICU) [18]. The mean dose of ISDN was 3.5 mg +- 2.5 mg in the BIPAP group compared to 10.8 mg +- 5.7 mg in the HDISDN group (p = 0.0006). Results are presented in Table 1. The study was termi- nated after an interim analysis due to the significantly high rate of adverse events in the BIPAP group (Table 2). Authors concluded that BiPAP ventilation combined with conventional therapy was inferior to HDISDN in patients with severe pulmonary edema.

Levy et al. conducted a nonrandomized, open-label, single-arm study of HDN in 29 patients with severe decompensated heart fail- ure and hypertension (SBP >160 mmHg or MAP >120 mmHg) com- pared to a nonintervention group during the same time period (n = 45) at an urban, academic ED in the U.S. [10]. Data for the non- intervention group was retrospectively abstracted; patients in this group were treated for severe decompensated heart failure during the study recruitment period, but were not enrolled in the trial and did not receive HDN. Patients received CIV NTG at an initial rate of

0.3-0.5 lg/kg/min titrated by 20 lg/min every 1-3 min (maximum

rate of 400 lg/min) and a concurrent HDN 2 mg bolus repeated

every 3-5 min up to 30 min (maximum of 20 mg). The mean dose of NTG administered in the HDN group was 6.5 mg (95% CI 5.2 to

7.8 mg). In patients who received HDN, the mean initial and final CIV NTG rates respectively were 23.6 lg/min (95% CI 15.4 to 31.9 lg/min) and 50.2 lg/min (95% CI 37.9 to 62.5 lg/min), while initial infusion rate in nonintervention patients was 31.7 lg/min (95% CI 26 to 37.3 lg/min); the final CIV NTG rate for noninterven-

tion patients was not available. Results are presented in Table 1. Authors concluded that HDN was effective in hypertensive, severely decompensated heart failure patients and was associated with a lower rate of endotracheal intubation, BIPAP, and ICU admission when compared to conventional therapy.

Freund et al. performed a single-center retrospective chart review in France comparing HDISDN (n = 25) to conventional ther- apy (CIV ISDN only or no ISDN) (n = 111) in ED patients over age 75 with a final ED diagnosis code of heart failure, left heart failure, or pulmonary edema [18]. HDISDN doses were given in increments of 3 mg as IV boluses. Patients in the HDISDN group presented with higher respiratory rate, systolic and diastolic blood pressure, and lower oxygen saturation when compared with the conventional group, suggesting a higher severity of illness. In the HDISDN group, the median number of ISDN 3 mg boluses received was 1 (IQR 1- 2), and was followed by CIV ISDN in 71% of patients, with a median dose of 2 mg/h (IQR 1-3 mg/h). Isosorbide dinitrate CIV was admin- istered in 16% of patients in the conventional group, with a median dose of 2 mg/h (IQR 1.75-3 mg/h). Results are presented in Table 1. Notably, ICU admission was reported to be higher in the HDISDN group when compared with the conventional group (28 vs. 11%, p = 0.04). Authors concluded that HDISDN was not associated with higher rates of hypotension in elderly patients with AHF.

Mallick et al. conducted a prospective cohort study in Kuwait in 41 ED patients with SCAPE for whom the ED consulted the anes- thesia service for emergent intubation [20]. These patients were described as hypertensive and among the sickest cohort of

Table 1

Summary of literature.

Author, date, country

Study design

Sample size, population, setting

Intervention

Outcomes

Results

Nashed et al., 1995, USA

Case series

n = 24 ACPEa

NTG IVB over 1-2 min; dosed based on SBP; successive doses doubled if SBP remained

Clinical improvement Mean SBP decrease

20 min: 66.7%; 30 min: 83.3%

Mean SBP decrease: 27.5%

ED

>=180 mmHg

Nashed et al., 1997, USA

Prospective

n = 21

NTG CIV (n = 12) vs.

Improvement in pH

Nonsignificant improvement in all outcomes

ACPE and SBP >150 mmHg ED

NTG CIV + NTG IVB up to 800 lg over 2 min q2 min for 30 min (n = 9)

Improvement in pCO2 Improvement in CSS

Cotter et al., 1998, Israel

RCT

n = 104

Pulmonary congestionb

HDISDN 3 mg q5 min (n = 52) vs.

Furosemide IVB 80 mg q15 min and ISDN CIV

Mortality MV

Mortality: 2% vs. 6%, p = 0.61

MV: 13% vs. 40%, p = 0.004

Prehospital mobile EDs

1 mg/h, ” by 1 mg/h q10 min (n = 52)

MI

MI: 17% vs. 37%, p = 0.047

Sharon et al., 2000, Israel

RCT

n = 40

Severe pulmonary edemab

HDISDN 4 mg q4 min (n = 20) vs.

BIPAP and ISDN CIV 10 mcmol/min ” by 10

Mortality MV

Mortality: 0% vs. 10%, p = 0.49

MV: 20% vs. 80%, p = 0.0004

mcmol/min q5-10 min (n = 20)

Prehospital mobile ICUs

MI

MI: 10% vs. 55%, p = 0.006

Combined death/MV/MI

Combined: 25% vs. 85%, p = 0.0003

Recovery rate (measured

Recovery rate: HDISDN group showed quicker improvement

Levy et al., 2007, USA

Open-label

n = 29

NTG IVB 2 mg q3-5 min up to 10 doses + NTG

by RR, SpO2 and pulse) MV within 6 h

MV: 13.8% vs. 26.7%

study vs. non- intervention

Severe decompensated HFc and HTN (SBP >160 mmHg

CIV 0.3-0.5 lg/kg/min ” by 20 lg/min q1-3 min (n = 29) vs.

BIPAP

BIPAP: 6.9% vs. 20%

group

or MAP >120 mmHg)

ICU admission

ICU admission: 37.9% vs. 80%

ED

Non-HDN (n = 45)

LOS

LOS: 4.1 vs 6.2 days

Freund et al., 2011,

Retrospective

n = 136

ISDN 3 mg IVB (n = 25) vs.

Minimum SBP in ED

116 vs. 116 mmHg, p = 0.99

France

review

CHFd and age >= 75 years

ISDN CIV only or no ISDN (n = 111)

Hospital LOS

14 vs. 11 days, p-0.2

ED

In-hospital mortality

4% vs. 10%, p = 0.3

Mallick et al., 2011,

Prospective

n = 41

NIPPV + NTG IVB

Intubation

Intubation: n =0

Kuwait

cohort study

SCAPE and required intubation

Improvement in SpO2 and RR

Improvement

ED

hemodynamic stability

SBP <100 mmHg: n = 2, no intervention required

Need for diuretics

Not reported

Wilson et al., 2017, USA

Retrospective review

n = 395

NTG for AHFe

NTG IVB up to 2 mg q3-5 min (n = 124) vs. NTG CIV (n = 182) vs.

ICU admission Hospital LOS

ICU: 48.4% vs. 68.7% vs. 83%

Hospital LOS: 3.7 vs. 4.7 vs. 5 days

ED

Combination (n = 89)

Hsieh et al., 2018,

Case series

n = 3

1: 3 NTG SL then NTG IVB 1 mg q2 min (6 mg

All three patients had BP & HR normalize and were able to come off

Taiwan

total) & 40 lg/min

SCAPEf 2: 3 NTG SL then NTG IVB 1 mg q2 min (4 mg total)

ED 3: 3 NTG SL then NTG IVB 1 mg q2 min (3 mg total)

BiPAP; one was admitted to floor and discharged several days later, other two were discharged after receiving dialysis

Paone et al., 2018, USA Case report n = 1 HDN via infusion per protocol: Start at 400 lg/ Patient required 6 min of HDN patient no longer in distress and

SCAPEg ED

min & ; by 50 lg/min q5 min until symptom

resolution per criteria

required no further treatment prior to transfer to floor

134

K. Wang, K. Samai / American Journal of Emergency Medicine 38 (2020) 132-137

ACPE: acute cardiogenic pulmonary edema; AHF: acute heart failure; BIPAP: bi-level positive airway pressure; BP: blood pressure; CHF: congestive heart failure; CIV: continuous intravenous infusion; CSS: clinical severity score; CV: cardiovascular; ED: emergency department; HDN: high dose nitroglycerin; HF: heart failure; HTN: hypertension HR: heart rate; ICU: intensive care unit; ISDN: isosorbide dinitrate; IVB: Intravenous bolus; MAP: mean arterial pressure; MI: myocardial infarction; MSN: multiple sublingual nitroglycerin; MV: mechanical ventilation; NIPPV: non-invasive positive pressure ventilation; NTG: nitroglycerin; PaO2: partial pressure of oxygen; PCO2: partial pressure of carbon dioxide; RCT: randomized controlled trial; RR: respiratory rate; SBP: systolic blood pressure; SCAPE: sympathetic crashing acute pulmonary edema; SL: sublingual; SpO2: oxygen saturation; SVT: supraventricular tachycardia.

a Moderate to severe respiratory distress with bilateral rales, a portable chest radiograph consistent with CPE, and no evidence of non-cardiogenic causes of pulmonary edema.

b Confirmed by chest radiograph and oxygen saturation of <90% prior to supplemental oxygen.

c Pulmonary edema on chest radiograph, presence of pulmonary rales, and >=1 of the following: history of heart failure, tachypnea (RR >30 breaths/min), significant dyspnea (use of accessory muscles of respiration or obvious air hunger), and hypoxia (SpO2 <= 90% on room air or <=95% on supplemental O2) or hypoxemia (PaO2 < 50 mmHg on room air).

d Final ED diagnosis of heart failure, left heart failure, or pulmonary edema.

e Final primary ED diagnosis of AHF and specific documentation of AHF as the reason for treatment with NTG.

f Acute CHF with pulmonary edema, markedly elevated blood pressure, severe dyspnea, and desaturation.

g SBP >=160 mmHg or MAP >=120 mmHg and respiratory distress defined by >=1 of the following: tachypnea (RR >30 breaths/min); significant dyspnea (use of accessory muscles of respiration or air hunger); hypoxia (SpO2 <= 90% on room air or <=95% on supplemental O2); pulmonary rales or B-lines over superior anterior lung fields on bedside ultrasound.

K. Wang, K. Samai / American Journal of Emergency Medicine 38 (2020) 132-137 135

Table 2

Adverse events.

Author, date, country

Nashed et al., 1995, USA

Nashed et al., 1997, USA

Cotter et al., 1998, Israel

Sharon et al., 2000, Israel

Levy et al., 2007, USA

Freund et al., 2011, France

Mallick et al., 2011, Kuwait

Wilson et al., 2017, USA

Hsieh et al., 2018, Taiwan

Paone et al., 2018, USA

Adverse events Successive NTG IVB

SVT: n = 1; treated with verapamil and continued to received NTG IVB

Symptomatic bradycardia: n = 1; HR 60 bpm, occurred after 3 NTG IVB doses, resolved spontaneously

NTG CIV vs. NTG CIV + NTG IVB

Hypotension: 1 vs. 0, described as uneventful HDISDN vs. furosemide IVB + ISDN CIV

MAP decrease >30%: 5 vs. 7, p = 1; none required intervention

Some sinus tachycardia and mild, transient episodes of Sinus bradycardia

HDISDN vs. BIPAP + ISDN CIV

Death: 0 vs. 2, p = 0.49

MI: 2 vs. 11, p = 0.006

Combined: 5 vs. 17, p = 0.0003 HDN vs. nonintervention

CV complications: n = 6 (MI: n = 5; symptomatic hypotension: n = 1, resolved with 500 mL fluid bolus) vs. n = 13 (all MI)

ISDN IVB vs. any other treatment

Minimum SBP in ED: 116 vs. 116 mmHg, p = 0.99 In-hospital mortality: 4 vs. 10%, p = 0.3

Repeated NTG IVB

SBP <100 mmHg: n = 2, no intervention required NTG IVB vs. CIV vs. combination

Hypotension: 2 vs. 2 vs. 5, p = 0.068

MI: 11 vs. 29 vs. 10, p = 0.49

24-h increase in SCr by >=0.5: 11 vs. 14 vs. 11, p = 0.59 48-h increase in SCr by >=0.5: 8 vs. 20 vs. 5, p = 0.13 None reported

None reported

and maximum rates of CIV NTG were 20 lg/min (IQR 10-40 lg/ min) and 60 lg/min (IQR 30-100 lg/min), respectively. The med- ian duration of CIV NTG therapy was similar between the infusion

and combination groups (16 vs. 16.5 h, respectively). Results for primary outcomes are presented in Table 1. Notably, requirement of BIPAP, need for intubation, and incidence of hypotension, myocardial injury, and worsening renal function were similar between groups. Authors concluded that HDN was associated with a lower ICU admission rate and a shorter hospital LOS compared with CIV NTG in patients with AHF.

Hsieh et al. presented three cases in which HDN and BIPAP were used successfully to treat SCAPE patients in the ED in Taiwan [22]. The patients were started on BIPAP and administered HDN 1 mg boluses every 2 min until dyspnea subsided; total doses ranged from 3-6 mg and one patient was initiated on low dose CIV NTG

at 40 lg/min following the HDN bolus doses. All patients were

described as having respiratory and vital sign improvement and did not require endotracheal intubation or ICU admission (Table 1). Authors conclude that HDN, in combination with BIPAP, may obvi- ate the need for endotracheal intubation and ICU admission.

Paone et al. presented the case of a patient with SCAPE success- fully treated with HDN based on a local protocol for the use of HDN in SCAPE [23]. Inclusion criteria for use of this protocol required both respiratory distress and SBP >160 mmHg or MAP >120 mmHg.

High-dose NTG was administered as an infusion and was started at the maximum rate at 400 lg/min via the infusion pump. After 6 min of HDN, the patient met criteria for symptomatic resolution

and HDN was discontinued (Table 1). Authors concluded that uti- lization of the ”SCAPE-nitro” protocol allowed for safe and effective administration of HDN.

Literature discussion

Trial design, intervention, comparison arms

BIPAP: bi-level positive airway pressure; CIV: continuous intravenous infusion; CV: cardiovascular; ED: emergency department; HDISDN: high dose isosorbide dini- trate; HDN: high dose nitroglycerin; HR: heart rate; ICU: intensive care unit; ISDN: isosorbide dinitrate; IVB: intravenous bolus; MAP: mean arterial pressure; MI: myocardial infarction; MV: mechanical ventilation; NTG: nitroglycerin; SBP: sys- tolic blood pressure; SCr: serum creatinine; SVT: supraventricular tachycardia.

pulmonary edema patients. Subsequently, the anesthesia service placed the patients on NIPPV and administered HDN in repeated bolus doses. The mean number of HDN bolus doses received was four and mean total dose of IV NTG received was 1.588 mg. Results are presented in Table 1. Patients were reported to have marked improvement in respiratory parameters; however, specific mea- surements were not documented. Authors concluded that intuba- tion was avoided using a protocol combining NIPPV and HDN.

Wilson et al. performed a retrospective review of 395 patients who received NTG for the treatment of AHF in the ED at an urban, Inner city, academic institution in the U.S. [21]. Authors note there was no specific protocol for the treatment of AHF with IV NTG in place; however, they mention that it is typically utilized in patients at their institution with elevated BP and severe dyspnea. Patients were subsequently categorized into three groups: HDN (n = 124), CIV NTG (n = 182), or combination of HDN and CIV NTG (n = 89). Intravenous bolus doses were administered in increments up to 2 mg every 3 to 5 min, while CIV rates and titration parameters were dictated by physician discretion. initial BP was higher in the combination group, while patients in the HDN group more commonly had a history of atrial fibrillation, chronic heart failure, chronic obstructive pulmonary disorder, end-stage renal disease, and use of aspirin, beta-blockers, or Loop diuretics. In the HDN group, the median total dose of NTG was 2 mg (IQR 1-2 mg) with 79% of patients requiring only one dose. In the CIV NTG group, the

median initial and maximum rates of CIV NTG were 20 lg/min (IQR 10-30 lg/min) and 35 lg/min (IQR 20-50 lg/min), respec-

tively. In the combination group, the median dose of the boluses was 2 mg (IQR 2-4 mg), with most patients requiring one (40.5%) or two (28.1%) doses. In these patients, the median initial rate

Studies reviewed included two RCTs, three prospective studies, two retrospective studies, two case series and one case report (Table 1). Six studies compared HDN to a control group, while one was a single-arm study. Two RCTs studied HDISDN; however, intervention and comparison arms evaluated multiple combina- tions of treatments (e.g. CIV ISDN added to BIPAP group), which may have confounded the effect of HDISDN alone [17,18]. In the study by Levy et al., authors note this was a single-arm study; how- ever, results were compared to a nonintervention group [10]. There was no matched control group and it was unclear why patients in the nonintervention group were not screened and enrolled. Over- all, study designs and interventions were heterogeneous, and no trial was modeled as a RCT with HDN.

Patient population, Inclusion/exclusion criteria

Hypertensive AHF appears to be the patient population that may benefit most from HDN; however, has not been consistently represented in the literature. While patients with pulmonary edema and heart failure were included, hypertension was not an inclusion criterion in multiple studies [15,17-19,21]. Freund et al. studied elderly patients and relied on Diagnosis codes for identifi- cation of patients, which does not represent the target population of this review [19]. The patients in the prospective studies by Levy et al. and Mallick et al. and cases reported by Hsieh et al. and Paone et al. most closely align with H-AHF patients [10,20,22,23]. Inclu- sion criteria defining the patient population were variable across studies, which limits the generalizability and reproducibility to the target population of this review.

Setting

Five studies were performed in the United States, while others took place in countries around the world, including Israel, Kuwait, France, and Taiwan. The trials by Sharon et al. and Cotter et al. in Israel were prehospital studies in mobile emergency or intensive care units, which may not represent the resources available in pre- hospital or ED care in the United States [17,18]. Mallick and col- leagues’ study in Kuwait required consultation to the anesthesia

136 K. Wang, K. Samai / American Journal of Emergency Medicine 38 (2020) 132-137

service to perform emergent intubation in the ED; this practice may not be generalizable to the process in the United States, where intubations are more frequently performed by emergency physicians [20].

Dosing

Dosing differed considerably between studies and consisted of IV bolus and CIV administration of high-dose nitrates. Dose ranges, units of dose measurement (e.g. micromoles versus micrograms, weight-based versus nonweight-based), dose titration parameters, infusion durations, and goals of therapy were inconsistently reported. Additionally, evidence regarding the relative potency between ISDN and NTG is limited, which hinders the generalizabil- ity of studies utilizing ISDN in the United States. However, Paone et al. provided a protocol for HDN in SCAPE patients with clear indications for use, dosing, titration parameters, administration instructions, and goals of therapy, which would be easily repro- ducible in clinical practice [23].

Endpoints

The endpoints measured varied across studies and included both direct and indirect outcome measures. Interpretation of out- comes was limited in two studies due to use of unreproducible or unvalidated endpoints, such as physician judgment of clinical improvement and CSS, respectively [14,15]. Additionally, the case series by Nashed et al. was the first and only study to report a ben- efit of HDN in patients with acidemia, though limited by small sample size [16]. Cotter et al. used the incidence of mechanical ventilation as a surrogate marker of escalation of care to an inten- sive care setting; while Wilson et al. evaluated ICU admission rate, which would serve as a meaningful outcome if all titratable infu- sions, including NTG, did not require ICU admission per the institu- tion’s policy [17,21]. Incidence of hypotension, death, and myocardial infarction were the most commonly evaluated adverse events and represent relevant Safety outcomes. Evaluation of rele- vant efficacy and Safety endpoints is needed to ascertain the effects of high-dose nitrates.

Conclusion

The ability to draw strong conclusions regarding the use of HDN is limited due to heterogeneity and varying quality of studies; however, we have provided recommendations based on Level of evidence from available literature (Table 3). High-dose NTG appears to have an overall beneficial effect, including lower rates of mechanical ventilation, improvement in blood pressure, shorter LOS, and lower rates of ICU admission (moderate quality evidence). High-dose NTG may be appropriate in H-AHF patients presenting with severe respiratory distress and SBP >=160 mmHg or MAP

>=120 mmHg (moderate quality evidence). Consider initiation of high-dose NTG as IV bolus doses of 400 lg and up to 1 mg, though

doses up to 2 mg may be used; continuous infusion administration of HDN may also be considered (moderate quality evidence). Resolu- tion of respiratory distress should be used to determine treatment effectiveness (moderate quality evidence). Although hypotension is uncommon, blood pressure should be closely monitored due to potential risk of hypotension (moderate quality evidence). Future well-designed randomized controlled trials are needed to elucidate optimal dosing strategies and confirm safety and efficacy of HDN in patients with H-AHF.

Table 3

Level of evidence.

High Well-designed randomized controlled trials

Moderate Prospective, quasi-experimental, retrospective cohorts Low Case reports, case series, opinion of experts

Abbreviations

ACPE acute cardiogenic pulmonary edema AHF acute heart failure

BIPAP bi-level positive airway pressure BP blood pressure

CIV continuous intravenous infusion CSS clinical severity score

ED emergency department

H-AHF hypertensive acute heart failure HDISDN high-dose isosorbide dinitrate HDN high-dose nitroglycerin

HF heart failure

HR heart rate

ICU intensive care unit ISDN isosorbide dinitrate

IV intravenous

LOS length of stay

MAP mean arterial pressure

NIPPV non-invasive positive pressure ventilation NTG nitroglycerin

PCO2 partial pressure of carbon dioxide RCT randomized controlled trial

SBP systolic blood pressure

SCAPE sympathetic crashing acute pulmonary edema

Funding source

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

None.

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