CARDIOLOGY/ORIGINAL RESEARCH
Complications Associated With Nitrate Use in Patients Presenting With Acute Pulmonary Edema and Concomitant Moderate or Severe Aortic Stenosis David Claveau, MD*; Adam Piha-Gossack, BSc; Sayuri N. Friedland, BSc; Jonathan Afilalo, MD, MSc; Lawrence Rudski, MD, FRCPC *Corresponding Author. E-mail: [email protected].
Study objective: We evaluate the incidence of complications associated with the use of nitrates in patients presenting with acute pulmonary edema and concomitant moderate or severe aortic stenosis compared with patients without aortic stenosis. Nitrates are contraindicated in severe aortic stenosis because of the theoretical yet unproven risk of precipitating profound hypotension. Methods: A cohort design with retrospective chart review study was conducted at two Canadian hospitals. Patients with aortic stenosis (moderate or severe) and without aortic stenosis were included if they presented with acute cardiogenic pulmonary edema, received intravenous or sublingual nitroglycerin, and had an echocardiography report available. The primary outcome was clinically relevant hypotension, defined as hypotension leading to any of the following predefined events: nitroglycerin discontinuation, intravenous fluid bolus, vasopressor use, or cardiac arrest. The secondary outcome was sustained hypotension, defined as a systolic blood pressure less than 90 mm Hg and lasting greater than or equal to 30 minutes. Results: The cohort consisted of 195 episodes of acute pulmonary edema, representing 65 episodes with severe aortic stenosis (N¼65) and an equal number of matched episodes with moderate aortic stenosis (N¼65) and no aortic stenosis (N¼65). Nitroglycerin was administered intravenously only in 70% of cases, intravenously and sublingually in 25%, and sublingually only in the remaining 5%. After adjustment for sex, initial systolic blood pressure, furosemide dose, and use of noninvasive ventilation, moderate and severe aortic stenosis were not associated with clinically relevant hypotension after receipt of nitroglycerin (adjusted odds ratio [OR] 0.97, 95% confidence interval [CI] 0.40 to 2.37 for moderate aortic stenosis; adjusted OR 0.99, 95% CI 0.41 to 2.41 for severe aortic stenosis). The incidence of clinically relevant hypotension was 26.2% for moderate and severe aortic stenosis and 23.1% in the no aortic stenosis reference group. The secondary outcome of sustained hypotension occurred in 29.2% of patients with severe aortic stenosis, 16.9% with moderate aortic stenosis, and 13.8% in the no aortic stenosis group (adjusted OR for severe aortic stenosis 2.34; 95% CI 0.91 to 6.01). Conclusion: In this retrospective study, neither moderate nor severe aortic stenosis was associated with a greater risk of clinically relevant hypotension requiring intervention when nitroglycerin was used for acute pulmonary edema. Future studies should investigate safety and efficacy of nitroglycerin for patients with aortic stenosis because this study was limited by a small sample size and design limitations. Cautious use of nitroglycerin in patients with moderate or severe aortic stenosis and presenting with acute pulmonary edema may be a safer strategy than traditionally thought. [Ann Emerg Med. 2015;-:1-8.] Please see page XX for the Editor’s Capsule Summary of this article. 0196-0644/$-see front matter Copyright © 2015 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2015.03.027
SEE EDITORIAL, P. XXX. INTRODUCTION Background Acute pulmonary edema is a problem frequently encountered in the emergency department (ED), for which the mortality risk is high and the therapeutic options Volume
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are limited.1 Patients with concomitant aortic stenosis represent the most challenging group because their risk is incrementally higher2 and one of the therapeutic cornerstones—nitroglycerin—is contraindicated. Nitrates are considered to be contraindicated in severe aortic stenosis because patients with aortic stenosis are unable to augment their stroke volume to maintain an adequate Annals of Emergency Medicine 1
Claveau et al
Complications Associated With Nitrate Use in Patients With Pulmonary Edema
Editor’s Capsule Summary
What is already known on this topic An international guideline based on expert opinion states that nitrates should be used with great caution in patients with severe aortic stenosis. What question this study addressed The authors used a retrospective cohort of 195 patients with acute pulmonary edema to investigate whether the risk of nitrate-induced hypotension was higher in patients with moderate or severe aortic stenosis. What this study adds to our knowledge Patients with aortic stenosis did not have more hypotension. Approximately 25% of patients, with and without aortic stenosis, required that the nitrates be stopped. How this is relevant to clinical practice This study provides some support that nitrates do not cause relevant hypotension and may be judiciously used in patients with aortic stenosis and pulmonary edema.
blood pressure in the face of nitrate-induced vasodilation and decreased preload. Although an international guideline does in fact caution against nitrates’ use in significant aortic stenosis,3 we were unable to find any evidence supporting this contraindication. In fact, nitroglycerin has been reported to have favorable hemodynamic effects in aortic stenosis, namely, by improving the left ventricular supply/demand oxygen ratio.4,5 Sodium nitroprusside, once also considered contraindicated in aortic stenosis patients because of its vasodilatory effects, has been shown to be safe and effective in a small series of patients with decompensated severe aortic stenosis. However, its use was confined to the intensive care setting with invasive hemodynamic monitoring and thus cannot easily be implemented in the ED as an initial treatment strategy.6 There are numerous anecdotal reports of patients who presented with acute pulmonary edema and who, unknown to the treating team, also had moderate or severe aortic stenosis, receiving nitrates in the ED without any adverse clinical event. In the ED setting, physical examination can be unreliable and formal echocardiography may not be readily available, making the diagnosis
2 Annals of Emergency Medicine
of severe aortic stenosis difficult in the face of an undiagnosed murmur (focused echocardiography does not typically include assessment of aortic stenosis7). Therefore, emergency physicians often have to decide whether to administer nitroglycerin in a patient with an undiagnosed murmur. Importance With an aging population, the incidence of acute pulmonary edema as a presenting symptom has tripled during the past 3 decades, and the incidence of aortic stenosis has similarly increased, now affecting 2.5 million individuals in the United States and Canada. Therefore, clinicians are encountering an increasing number of patients with acute pulmonary edema and concomitant aortic stenosis. Given the lack of evidence to support the contraindication of nitrates in aortic stenosis and the paucity of alternative therapeutic options, there is a pressing need to reevaluate their safety profile. Goals of This Investigation The main goal of this study was to evaluate the complications associated with nitroglycerin use in patients with aortic stenosis and presenting with acute pulmonary edema. Specifically, we aimed to determine whether administration of sublingual and intravenous nitroglycerin was associated with a 20% increased risk of clinically relevant hypotension in patients with moderate or severe aortic stenosis compared with patients with no aortic stenosis. An additional goal was to determine which clinical factors were independently predictive of clinically relevant hypotension. MATERIALS AND METHODS Study Design and Setting A cohort design with retrospective chart review was assembled at two Canadian university-affiliated hospitals. The Jewish General Hospital is an urban tertiary-care teaching hospital with 76,000 annual ED visits. It has a comprehensive cardiology service with a coronary care unit, an echocardiography laboratory, and a catheterization laboratory. The Centre Hospitalier Affilié Universitaire Régional of the Centre de Santé et de Services Sociaux de Trois-Rivières is a large community hospital with a census of approximately 55,000 ED visits per year. It has a comprehensive cardiology service with a coronary care unit and echocardiography laboratory. Institutional review boards at both hospitals approved the study.
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Selection of Participants The administrative databases were searched for patients receiving a discharge diagnosis of congestive heart failure (diagnosis codes of I50.0, I50.1, I50.9, and J81 of the International Classification of Diseases, 10th Revision) between January 1, 2008, and December 31, 2013. Patients were selected from 2008 to 2013 to limit the search to computerized charts. Charts of each patient with a primary discharge diagnosis of heart failure were searched to identify other relevant admissions with congestive heart failure as a secondary diagnosis and ED visits with congestive heart failure not leading to admission. A patient could be included more than once if he or she met inclusion criteria on different ED visits or admissions. Patients who did not have an echocardiography performed within 12 months of the index visit were excluded. Patients were divided into three groups of aortic stenosis: moderate, severe, and none. Severity of aortic stenosis was graded according to the American College of Cardiology/ American Heart Association guidelines.8 Moderate aortic stenosis was defined as aortic valve area between 1.0 and 1.5 cm2, mean gradient between 25 and 40 mm Hg, or aortic jet velocity between 3 and 4 m/s. Severe aortic stenosis was defined as aortic valve area less than 1.0 cm2, mean gradient greater than 40 mm Hg, or aortic jet velocity greater than 4 m/s. No aortic stenosis was defined as absence of significant aortic valve calcification and aortic jet velocity less than 2 m/s. All patients with acute pulmonary edema and concomitant severe aortic stenosis who received at least one treatment of sublingual or intravenous nitroglycerin were included in the cohort until 65 patients were enrolled. An equal number of randomly sampled patients with acute pulmonary edema and moderate or no aortic stenosis were included in the cohort. Because patients with severe aortic stenosis were generally older and more frequently women, patients were matched for age (within 5 years), sex, and hospital to limit risk of bias and create similar groups based on demographics. Outcome Measures The primary outcome was clinically relevant hypotension, defined as hypotension requiring any of the following predefined events: nitroglycerin discontinuation, intravenous fluid bolus, vasopressor use, or cardiac arrest. The secondary outcome was sustained hypotension, defined as systolic blood pressure less than 90 mm Hg for greater than or equal to 30 minutes (same definition as that used in the Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock study).9 Other secondary Volume
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outcomes included lowest systolic blood pressure during treatment and percentage change in systolic blood pressure during treatment. Clinical outcomes such as need for mechanical ventilation, hospital length of stay, and inhospital mortality were also collected. Data Collection and Processing Data abstraction was conducted by three trained investigators (D.C., A.P.-G., and S.N.F.) using a standardized medical record extraction form. The training included a set of practice charts to ensure consistency between data abstractors and periodic audits by D.C. We blinded two data abstractors (A.P.-G. and S.N.F.) but not D.C. to study hypotheses and outcomes until all data collection was completed. Data were collected for the entire hospital visit. Baseline demographics (sex and age), as well as patient comorbidities and usual medication, were collected. Administered treatments such as nitroglycerin (formulation, route of administration, maximal dosage, and duration of treatment), loop diuretics, and use of noninvasive or invasive positive pressure ventilation were also recorded. Outcome data were abstracted for the duration of nitroglycerin treatment. For an adverse event to be recorded, it had to occur during nitroglycerin treatment or immediately after its discontinuation for an adverse event. Outcome data were abstracted by all three abstractors on a random selection of 15% of charts to evaluate interobserver agreement. Conflicting data were recorded according to the abstractor’s interpretation of the most accurate reflection of reality, and missing data were left as such. Primary Data Analysis Descriptive statistics such as means (SDs), medians (interquartile ranges), and proportions were used to describe baseline characteristics. The patient population was patients presenting with acute pulmonary edema and receiving nitrates. The primary predictor variable was presence or severity of aortic stenosis (none, moderate, and severe). The core covariates of interest for which we adjusted in the multivariate model were sex, initial systolic blood pressure, left ventricular ejection fraction, use of a nitroglycerin intravenous bolus, maximal dose of nitroglycerin, furosemide dose, and use of noninvasive ventilation. We selected the covariates to include in the model according to common sense and previous literature. Common sense dictates that sex (categorical), left ventricular ejection fraction (continuous), and initial systolic blood pressure (continuous) can influence the occurrence of hypotension. Other variables included were based on known hypotensive effects of treatments or cotreatments: use of nitroglycerin bolus (dichotomous), maximal dose of nitroglycerin Annals of Emergency Medicine 3
Claveau et al
Complications Associated With Nitrate Use in Patients With Pulmonary Edema Table 1. Baseline characteristics stratified by aortic stenosis status.* Baseline Characteristics
No AS (N[65)
Age, y 83 (8) Women, No. (%) 40 (61.5) Hypertension, No. (%) 57 (87.7) Coronary artery disease, No. (%) 32 (49.2) Atrial fibrillation, No. (%) 28 (43.1) Home medication, No. (%) ACE inhibitor 38 (58.5) Calcium channel blocker 36 (55.4) b-Blocker 36 (55.4) Diuretic 48 (73.8) Nitroglycerin 22 (33.8) Initial SBP, mm Hg 166 (31) Initial DBP, mm Hg 85 (20) Initial pulse rate, beats/min 98 (22) LVEF, No. % 47 (16) Aortic valve area, cm2 Mean gradient, mm Hg Peak velocity, m/s
Moderate AS Severe AS (N[65) (N[65) 83 35 55 42 30
(8) (53.8) (84.6) (64.6) (46.2)
84 41 59 47 19
(8) (63.1) (90.7) (72.3) (29.2)
42 38 40 57 27 161 83 91 46 1.25 16 2.6
(64.6) (58.5) (61.5) (87.7) (41.5) (31) (24) (25) (18) (0.16) (7) (0.6)
36 50 47 47 20 151 80 98 48 0.77 35 3.7
(55.4) (76.9) (72.3) (72.3) (30.7) (34) (21) (20) (16) (0.15) (16) (0.6)
AS, Aortic stenosis; ACE, angiotensin-converting enzyme; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction. *Results are presented as mean (SD) unless stated otherwise.
administered (continuous), furosemide dose (continuous), and use of noninvasive ventilation (dichotomous). The analytic approach was a multivariate logistic regression model including the primary predictor variable and the core covariates of interest. Missing data were handled by casewise deletion. For the primary outcome of clinically relevant hypotension, the primary objective was to determine the effect of aortic stenosis presence or severity on clinically relevant hypotension in patients receiving nitroglycerin for acute pulmonary edema. The objective for the secondary outcome was to determine the effect of aortic stenosis presence or severity on the occurrence of sustained hypotension below 90 mm Hg for 30 minutes or more. A generalized k statistic, based on random review of 15% of charts by the three abstractors, was calculated to assess the interobserver agreement to ascertain the primary
and secondary outcome. In accordance with a previous study reporting a 10% incidence of hypotension in patients without aortic stenosis, the sample size necessary to have a power of 80% to detect a 20% absolute difference in clinically relevant hypotension was estimated to be 65 patients per group.10 Statistical analyses were performed with SAS (version 9.3; SAS Institute, Inc., Cary, NC). RESULTS Characteristics of Study Subjects We have surveyed 2,851 episodes occurring between January 2008 and December 2013, of which most did not include pulmonary edema. We found 572 episodes that matched our inclusion criteria (acute pulmonary edema, nitroglycerin use, and available echocardiography report.) We had 69 episodes with severe aortic stenosis, 75 with moderate aortic stenosis, and 428 without aortic stenosis. After matching for age, sex, and hospital, 65 episodes per group were retained, for a total of 195 episodes in the cohort. In the severe aortic stenosis group, there were 49 patients accounting for 65 episodes, with 11 of these patients accounting for two or more episodes each. More specifically, two patients accounted for three episodes each and a single patient accounted for five episodes, whereas the remaining eight patients accounted for two episodes each. In the moderate aortic stenosis group, 61 patients were included in the 65 episodes, with four patients accounting for two episodes each. Within the no aortic stenosis group, there were 64 patients accounting for 65 episodes, with only a single patient accounting for two episodes. Tables 1 and 2 summarize baseline characteristics and treatments received for the three groups. Groups were well matched for age, sex, hospital attended, and nitroglycerin treatment. The group with severe aortic stenosis had a higher prevalence of coronary artery disease, higher use of calcium channel blockers, slightly lower initial systolic blood pressure, and higher initial troponin levels. The group with
Table 2. Treatments received, stratified by aortic stenosis status.* Treatments Received Nitroglycerin sublingual, No. (%) Nitroglycerin IV, No. (%) Nitroglycerin IV bolus, No. (%) Nitroglycerin IV max dose, median (IQR), mg/min Nitroglycerin IV duration, median (IQR), h Furosemide initial dose, mean (SD), mg Morphine administration, No. (%) NIV, No. (%) Invasive ventilation, No. (%)
No AS (N[65) 20 62 1 57 16.2 43 17 31 3
(30.8) (95.4) (1.5) (33, 100) (5.25, 29.7) (28) (26.2) (47.7) (4.6)
Moderate AS (N[65) 22 62 4 50 14.6 56 9 38
Severe AS (N[65)
(33.8) (95.4) (6.1) (30, 100) (4.25, 28) (32) (13.9) (58.5) 0
16 62 3 39 10.6 46 11 37 5
(24.6) (95.4) (4.6) (24, 67) (4.1, 27.7) (36) (16.9) (56.9) (7.7)
IV, Intravenous; IQR, interquartile range; NIV, noninvasive ventilation. *Results are presented as mean (SD) unless stated otherwise.
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Table 3. Outcomes, stratified by presence of aortic stenosis.* Outcomes
No AS
Clinically relevant hypotension, No. (%) Stop nitroglycerin, No. (%) IV fluid bolus, No. (%) Vasopressor, No. (%) Cardiac arrest, No. (%) SBP or ¼ 62 years with unoperated severe valvular aortic stenosis. Am J Cardiol. 1993;72:846-848. 3. McMurray JJV, Adamopoulos S, Anker SD, et al; Authors/Task Force Members. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787-1847. 4. Grose R, Nivatpumin T, Katz S, et al. Mechanism of nitroglycerin effect in valvular aortic stenosis. Am J Cardiol. 1979;44:1371-1377. 5. Perloff JG, Ronan JA, De Leon AC. The effect of nitroglycerin on left ventricular wall tension in fixed orifice aortic stenosis. Circulation. 1965;32:204-213. 6. Khot UN, Novaro GM, Popovic ZB, et al. Nitroprusside in critically ill patients with left ventricular dysfunction and aortic stenosis. N Engl J Med. 2003;348:1756-1763. 7. Labovitz AJ, Noble VE, Bierig M, et al. Focused cardiac ultrasound in the emergent setting: a consensus statement of the American Society of Echocardiography and American College of Emergency Physicians. J Am Soc Echocardiogr. 2010;23:1225-1230. 8. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease. J Am Coll Cardiol. 2008;52:e1-e142. 9. Thiele H, Zeymer U, Neumann F-J, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012;367:1287-1296. 10. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet. 1998;351:389-393. 11. Worster A, Haines T. Advanced statistics: understanding medical record review (MRR) studies. Acad Emerg Med. 2004;11:187-192. 12. Gilbert EH, Lowenstein SR, Koziol-McLain J, et al. Chart reviews in emergency medicine research: where are the methods? Ann Emerg Med. 1996;27:305-308. 13. Gerson JI, Allen FB, Seltzer JL, et al. Arterial and venous dilation by nitroprusside and nitroglycerin—is there a difference? Anesth Analg. 1982;61:256-260. 14. Chadda K, Annane D, Hart N, et al. Cardiac and respiratory effects of continuous positive airway pressure and noninvasive ventilation in acute cardiac pulmonary edema. Crit Care Med. 2002;30:2457-2461. 15. Vital FMR, Ladeira MT, Atallah AN. Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema. Cochrane Database Syst Rev. 2013;(5):CD005351.
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Complications Associated With Nitrate Use in Patients With Pulmonary Edema 16. Gray A, Goodacre S, Newby DE, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med. 2008;359:142-151. 17. Sharon A, Shpirer I, Kaluski E, et al. High-dose intravenous isosorbidedinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema. J Am Coll Cardiol. 2000;36:832-837. 18. Felker GM, O’Connor CM, Braunwald E, for the Heart Failure Clinical Research Network Investigators. Loop diuretics in acute decompensated heart failure: necessary? evil? a necessary evil? Circulation. 2009;2:56-62.
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19. Hasselblad V, Stough WG, Shah MR, et al. Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial. Eur J Heart Fail. 2007;9:1064-1069. 20. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364:797-805. 21. De Berrazueta JR, González JP, de Mier I, et al. Vasodilatory action of loop diuretics: a plethysmography study of endothelial function in forearm arteries and dorsal hand veins in hypertensive patients and controls. J Cardiovasc Pharmacol. 2007;49:90-95.
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APPENDIX E1 Details of cases with clinically relevant hypotension
Nitro IV Duration of Nitroglycerin Adverse Events Age, Nitro Max Dose Treatment Before AS Status Years Sex Received (mg/min) Adverse Event, Hours Stop Nitroglycerin IV Fluid Bolus Vasopressor Use Cardiac Arrest Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS
84 84 79 82 77 75 78 54 81 91 89 87 92 86 86 87 86 82 82 81 62 84 79 88 84 85 76 89 74 93 69 97 94 94 74 75 79 93 92 83 84 90 81 71 87 90 94 88 93
F F M F F F F M F F F F F F F F F M F F F M M F F M F M M F M M F F M F F F F F M M F F M F F F F
SL, IV SL IV IV IV SL, IV IV IV IV SL, IV IV IV SL, IV IV SL, IV SL IV IV SL, IV SL, IV IV IV SL, IV IV IV SL, IV IV SL, IV SL, IV IV IV IV SL, IV IV IV IV SL, IV IV IV IV IV IV IV IV IV IV IV IV IV
100
27.5
17 60 47 36 100 73 37 77 10 50 173 333 10
7.4 6.8 1.6 1.5 112 25.9 8.7 3.6 0.5 2.5 47 12.5 16.4
12 87 57 17 57 77 100 16 53 27 33 167 15 23 5 20 33 100 57 43 60 53 37 16 17 75 200 Missing 33 Missing 10 3 27
9.5 43.3 3.2 0.6 137 10 6.8 0.8 3.5 1.0 1.1 6.4 6.3 0.7 5.8 4.0 2.3 4.3 3.7 2.7 3.2 21.3 1.3 0.1 2.5 111.8 4.5 1.8 5 0.3 49.3 6.8 22.2
X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X
X
X
X
X
X X X
X X X
X
X
X
X
F, Female; SL, Sublingual; M, male.
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Annals of Emergency Medicine 8.e1
Complications Associated With Nitrate Use in Patients Presenting With Acute Pulmonary Edema and Concomitant Moderate or Severe Aortic Stenosis David Claveau, MD*; Adam Piha-Gossack, BSc; Sayuri N. Friedland, BSc; Jonathan Afilalo, MD, MSc; Lawrence Rudski, MD, FRCPC *Corresponding Author. E-mail: [email protected].
Study objective: We evaluate the incidence of complications associated with the use of nitrates in patients presenting with acute pulmonary edema and concomitant moderate or severe aortic stenosis compared with patients without aortic stenosis. Nitrates are contraindicated in severe aortic stenosis because of the theoretical yet unproven risk of precipitating profound hypotension. Methods: A cohort design with retrospective chart review study was conducted at two Canadian hospitals. Patients with aortic stenosis (moderate or severe) and without aortic stenosis were included if they presented with acute cardiogenic pulmonary edema, received intravenous or sublingual nitroglycerin, and had an echocardiography report available. The primary outcome was clinically relevant hypotension, defined as hypotension leading to any of the following predefined events: nitroglycerin discontinuation, intravenous fluid bolus, vasopressor use, or cardiac arrest. The secondary outcome was sustained hypotension, defined as a systolic blood pressure less than 90 mm Hg and lasting greater than or equal to 30 minutes. Results: The cohort consisted of 195 episodes of acute pulmonary edema, representing 65 episodes with severe aortic stenosis (N¼65) and an equal number of matched episodes with moderate aortic stenosis (N¼65) and no aortic stenosis (N¼65). Nitroglycerin was administered intravenously only in 70% of cases, intravenously and sublingually in 25%, and sublingually only in the remaining 5%. After adjustment for sex, initial systolic blood pressure, furosemide dose, and use of noninvasive ventilation, moderate and severe aortic stenosis were not associated with clinically relevant hypotension after receipt of nitroglycerin (adjusted odds ratio [OR] 0.97, 95% confidence interval [CI] 0.40 to 2.37 for moderate aortic stenosis; adjusted OR 0.99, 95% CI 0.41 to 2.41 for severe aortic stenosis). The incidence of clinically relevant hypotension was 26.2% for moderate and severe aortic stenosis and 23.1% in the no aortic stenosis reference group. The secondary outcome of sustained hypotension occurred in 29.2% of patients with severe aortic stenosis, 16.9% with moderate aortic stenosis, and 13.8% in the no aortic stenosis group (adjusted OR for severe aortic stenosis 2.34; 95% CI 0.91 to 6.01). Conclusion: In this retrospective study, neither moderate nor severe aortic stenosis was associated with a greater risk of clinically relevant hypotension requiring intervention when nitroglycerin was used for acute pulmonary edema. Future studies should investigate safety and efficacy of nitroglycerin for patients with aortic stenosis because this study was limited by a small sample size and design limitations. Cautious use of nitroglycerin in patients with moderate or severe aortic stenosis and presenting with acute pulmonary edema may be a safer strategy than traditionally thought. [Ann Emerg Med. 2015;-:1-8.] Please see page XX for the Editor’s Capsule Summary of this article. 0196-0644/$-see front matter Copyright © 2015 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2015.03.027
SEE EDITORIAL, P. XXX. INTRODUCTION Background Acute pulmonary edema is a problem frequently encountered in the emergency department (ED), for which the mortality risk is high and the therapeutic options Volume
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are limited.1 Patients with concomitant aortic stenosis represent the most challenging group because their risk is incrementally higher2 and one of the therapeutic cornerstones—nitroglycerin—is contraindicated. Nitrates are considered to be contraindicated in severe aortic stenosis because patients with aortic stenosis are unable to augment their stroke volume to maintain an adequate Annals of Emergency Medicine 1
Claveau et al
Complications Associated With Nitrate Use in Patients With Pulmonary Edema
Editor’s Capsule Summary
What is already known on this topic An international guideline based on expert opinion states that nitrates should be used with great caution in patients with severe aortic stenosis. What question this study addressed The authors used a retrospective cohort of 195 patients with acute pulmonary edema to investigate whether the risk of nitrate-induced hypotension was higher in patients with moderate or severe aortic stenosis. What this study adds to our knowledge Patients with aortic stenosis did not have more hypotension. Approximately 25% of patients, with and without aortic stenosis, required that the nitrates be stopped. How this is relevant to clinical practice This study provides some support that nitrates do not cause relevant hypotension and may be judiciously used in patients with aortic stenosis and pulmonary edema.
blood pressure in the face of nitrate-induced vasodilation and decreased preload. Although an international guideline does in fact caution against nitrates’ use in significant aortic stenosis,3 we were unable to find any evidence supporting this contraindication. In fact, nitroglycerin has been reported to have favorable hemodynamic effects in aortic stenosis, namely, by improving the left ventricular supply/demand oxygen ratio.4,5 Sodium nitroprusside, once also considered contraindicated in aortic stenosis patients because of its vasodilatory effects, has been shown to be safe and effective in a small series of patients with decompensated severe aortic stenosis. However, its use was confined to the intensive care setting with invasive hemodynamic monitoring and thus cannot easily be implemented in the ED as an initial treatment strategy.6 There are numerous anecdotal reports of patients who presented with acute pulmonary edema and who, unknown to the treating team, also had moderate or severe aortic stenosis, receiving nitrates in the ED without any adverse clinical event. In the ED setting, physical examination can be unreliable and formal echocardiography may not be readily available, making the diagnosis
2 Annals of Emergency Medicine
of severe aortic stenosis difficult in the face of an undiagnosed murmur (focused echocardiography does not typically include assessment of aortic stenosis7). Therefore, emergency physicians often have to decide whether to administer nitroglycerin in a patient with an undiagnosed murmur. Importance With an aging population, the incidence of acute pulmonary edema as a presenting symptom has tripled during the past 3 decades, and the incidence of aortic stenosis has similarly increased, now affecting 2.5 million individuals in the United States and Canada. Therefore, clinicians are encountering an increasing number of patients with acute pulmonary edema and concomitant aortic stenosis. Given the lack of evidence to support the contraindication of nitrates in aortic stenosis and the paucity of alternative therapeutic options, there is a pressing need to reevaluate their safety profile. Goals of This Investigation The main goal of this study was to evaluate the complications associated with nitroglycerin use in patients with aortic stenosis and presenting with acute pulmonary edema. Specifically, we aimed to determine whether administration of sublingual and intravenous nitroglycerin was associated with a 20% increased risk of clinically relevant hypotension in patients with moderate or severe aortic stenosis compared with patients with no aortic stenosis. An additional goal was to determine which clinical factors were independently predictive of clinically relevant hypotension. MATERIALS AND METHODS Study Design and Setting A cohort design with retrospective chart review was assembled at two Canadian university-affiliated hospitals. The Jewish General Hospital is an urban tertiary-care teaching hospital with 76,000 annual ED visits. It has a comprehensive cardiology service with a coronary care unit, an echocardiography laboratory, and a catheterization laboratory. The Centre Hospitalier Affilié Universitaire Régional of the Centre de Santé et de Services Sociaux de Trois-Rivières is a large community hospital with a census of approximately 55,000 ED visits per year. It has a comprehensive cardiology service with a coronary care unit and echocardiography laboratory. Institutional review boards at both hospitals approved the study.
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Selection of Participants The administrative databases were searched for patients receiving a discharge diagnosis of congestive heart failure (diagnosis codes of I50.0, I50.1, I50.9, and J81 of the International Classification of Diseases, 10th Revision) between January 1, 2008, and December 31, 2013. Patients were selected from 2008 to 2013 to limit the search to computerized charts. Charts of each patient with a primary discharge diagnosis of heart failure were searched to identify other relevant admissions with congestive heart failure as a secondary diagnosis and ED visits with congestive heart failure not leading to admission. A patient could be included more than once if he or she met inclusion criteria on different ED visits or admissions. Patients who did not have an echocardiography performed within 12 months of the index visit were excluded. Patients were divided into three groups of aortic stenosis: moderate, severe, and none. Severity of aortic stenosis was graded according to the American College of Cardiology/ American Heart Association guidelines.8 Moderate aortic stenosis was defined as aortic valve area between 1.0 and 1.5 cm2, mean gradient between 25 and 40 mm Hg, or aortic jet velocity between 3 and 4 m/s. Severe aortic stenosis was defined as aortic valve area less than 1.0 cm2, mean gradient greater than 40 mm Hg, or aortic jet velocity greater than 4 m/s. No aortic stenosis was defined as absence of significant aortic valve calcification and aortic jet velocity less than 2 m/s. All patients with acute pulmonary edema and concomitant severe aortic stenosis who received at least one treatment of sublingual or intravenous nitroglycerin were included in the cohort until 65 patients were enrolled. An equal number of randomly sampled patients with acute pulmonary edema and moderate or no aortic stenosis were included in the cohort. Because patients with severe aortic stenosis were generally older and more frequently women, patients were matched for age (within 5 years), sex, and hospital to limit risk of bias and create similar groups based on demographics. Outcome Measures The primary outcome was clinically relevant hypotension, defined as hypotension requiring any of the following predefined events: nitroglycerin discontinuation, intravenous fluid bolus, vasopressor use, or cardiac arrest. The secondary outcome was sustained hypotension, defined as systolic blood pressure less than 90 mm Hg for greater than or equal to 30 minutes (same definition as that used in the Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock study).9 Other secondary Volume
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outcomes included lowest systolic blood pressure during treatment and percentage change in systolic blood pressure during treatment. Clinical outcomes such as need for mechanical ventilation, hospital length of stay, and inhospital mortality were also collected. Data Collection and Processing Data abstraction was conducted by three trained investigators (D.C., A.P.-G., and S.N.F.) using a standardized medical record extraction form. The training included a set of practice charts to ensure consistency between data abstractors and periodic audits by D.C. We blinded two data abstractors (A.P.-G. and S.N.F.) but not D.C. to study hypotheses and outcomes until all data collection was completed. Data were collected for the entire hospital visit. Baseline demographics (sex and age), as well as patient comorbidities and usual medication, were collected. Administered treatments such as nitroglycerin (formulation, route of administration, maximal dosage, and duration of treatment), loop diuretics, and use of noninvasive or invasive positive pressure ventilation were also recorded. Outcome data were abstracted for the duration of nitroglycerin treatment. For an adverse event to be recorded, it had to occur during nitroglycerin treatment or immediately after its discontinuation for an adverse event. Outcome data were abstracted by all three abstractors on a random selection of 15% of charts to evaluate interobserver agreement. Conflicting data were recorded according to the abstractor’s interpretation of the most accurate reflection of reality, and missing data were left as such. Primary Data Analysis Descriptive statistics such as means (SDs), medians (interquartile ranges), and proportions were used to describe baseline characteristics. The patient population was patients presenting with acute pulmonary edema and receiving nitrates. The primary predictor variable was presence or severity of aortic stenosis (none, moderate, and severe). The core covariates of interest for which we adjusted in the multivariate model were sex, initial systolic blood pressure, left ventricular ejection fraction, use of a nitroglycerin intravenous bolus, maximal dose of nitroglycerin, furosemide dose, and use of noninvasive ventilation. We selected the covariates to include in the model according to common sense and previous literature. Common sense dictates that sex (categorical), left ventricular ejection fraction (continuous), and initial systolic blood pressure (continuous) can influence the occurrence of hypotension. Other variables included were based on known hypotensive effects of treatments or cotreatments: use of nitroglycerin bolus (dichotomous), maximal dose of nitroglycerin Annals of Emergency Medicine 3
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Complications Associated With Nitrate Use in Patients With Pulmonary Edema Table 1. Baseline characteristics stratified by aortic stenosis status.* Baseline Characteristics
No AS (N[65)
Age, y 83 (8) Women, No. (%) 40 (61.5) Hypertension, No. (%) 57 (87.7) Coronary artery disease, No. (%) 32 (49.2) Atrial fibrillation, No. (%) 28 (43.1) Home medication, No. (%) ACE inhibitor 38 (58.5) Calcium channel blocker 36 (55.4) b-Blocker 36 (55.4) Diuretic 48 (73.8) Nitroglycerin 22 (33.8) Initial SBP, mm Hg 166 (31) Initial DBP, mm Hg 85 (20) Initial pulse rate, beats/min 98 (22) LVEF, No. % 47 (16) Aortic valve area, cm2 Mean gradient, mm Hg Peak velocity, m/s
Moderate AS Severe AS (N[65) (N[65) 83 35 55 42 30
(8) (53.8) (84.6) (64.6) (46.2)
84 41 59 47 19
(8) (63.1) (90.7) (72.3) (29.2)
42 38 40 57 27 161 83 91 46 1.25 16 2.6
(64.6) (58.5) (61.5) (87.7) (41.5) (31) (24) (25) (18) (0.16) (7) (0.6)
36 50 47 47 20 151 80 98 48 0.77 35 3.7
(55.4) (76.9) (72.3) (72.3) (30.7) (34) (21) (20) (16) (0.15) (16) (0.6)
AS, Aortic stenosis; ACE, angiotensin-converting enzyme; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction. *Results are presented as mean (SD) unless stated otherwise.
administered (continuous), furosemide dose (continuous), and use of noninvasive ventilation (dichotomous). The analytic approach was a multivariate logistic regression model including the primary predictor variable and the core covariates of interest. Missing data were handled by casewise deletion. For the primary outcome of clinically relevant hypotension, the primary objective was to determine the effect of aortic stenosis presence or severity on clinically relevant hypotension in patients receiving nitroglycerin for acute pulmonary edema. The objective for the secondary outcome was to determine the effect of aortic stenosis presence or severity on the occurrence of sustained hypotension below 90 mm Hg for 30 minutes or more. A generalized k statistic, based on random review of 15% of charts by the three abstractors, was calculated to assess the interobserver agreement to ascertain the primary
and secondary outcome. In accordance with a previous study reporting a 10% incidence of hypotension in patients without aortic stenosis, the sample size necessary to have a power of 80% to detect a 20% absolute difference in clinically relevant hypotension was estimated to be 65 patients per group.10 Statistical analyses were performed with SAS (version 9.3; SAS Institute, Inc., Cary, NC). RESULTS Characteristics of Study Subjects We have surveyed 2,851 episodes occurring between January 2008 and December 2013, of which most did not include pulmonary edema. We found 572 episodes that matched our inclusion criteria (acute pulmonary edema, nitroglycerin use, and available echocardiography report.) We had 69 episodes with severe aortic stenosis, 75 with moderate aortic stenosis, and 428 without aortic stenosis. After matching for age, sex, and hospital, 65 episodes per group were retained, for a total of 195 episodes in the cohort. In the severe aortic stenosis group, there were 49 patients accounting for 65 episodes, with 11 of these patients accounting for two or more episodes each. More specifically, two patients accounted for three episodes each and a single patient accounted for five episodes, whereas the remaining eight patients accounted for two episodes each. In the moderate aortic stenosis group, 61 patients were included in the 65 episodes, with four patients accounting for two episodes each. Within the no aortic stenosis group, there were 64 patients accounting for 65 episodes, with only a single patient accounting for two episodes. Tables 1 and 2 summarize baseline characteristics and treatments received for the three groups. Groups were well matched for age, sex, hospital attended, and nitroglycerin treatment. The group with severe aortic stenosis had a higher prevalence of coronary artery disease, higher use of calcium channel blockers, slightly lower initial systolic blood pressure, and higher initial troponin levels. The group with
Table 2. Treatments received, stratified by aortic stenosis status.* Treatments Received Nitroglycerin sublingual, No. (%) Nitroglycerin IV, No. (%) Nitroglycerin IV bolus, No. (%) Nitroglycerin IV max dose, median (IQR), mg/min Nitroglycerin IV duration, median (IQR), h Furosemide initial dose, mean (SD), mg Morphine administration, No. (%) NIV, No. (%) Invasive ventilation, No. (%)
No AS (N[65) 20 62 1 57 16.2 43 17 31 3
(30.8) (95.4) (1.5) (33, 100) (5.25, 29.7) (28) (26.2) (47.7) (4.6)
Moderate AS (N[65) 22 62 4 50 14.6 56 9 38
Severe AS (N[65)
(33.8) (95.4) (6.1) (30, 100) (4.25, 28) (32) (13.9) (58.5) 0
16 62 3 39 10.6 46 11 37 5
(24.6) (95.4) (4.6) (24, 67) (4.1, 27.7) (36) (16.9) (56.9) (7.7)
IV, Intravenous; IQR, interquartile range; NIV, noninvasive ventilation. *Results are presented as mean (SD) unless stated otherwise.
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Table 3. Outcomes, stratified by presence of aortic stenosis.* Outcomes
No AS
Clinically relevant hypotension, No. (%) Stop nitroglycerin, No. (%) IV fluid bolus, No. (%) Vasopressor, No. (%) Cardiac arrest, No. (%) SBP or ¼ 62 years with unoperated severe valvular aortic stenosis. Am J Cardiol. 1993;72:846-848. 3. McMurray JJV, Adamopoulos S, Anker SD, et al; Authors/Task Force Members. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787-1847. 4. Grose R, Nivatpumin T, Katz S, et al. Mechanism of nitroglycerin effect in valvular aortic stenosis. Am J Cardiol. 1979;44:1371-1377. 5. Perloff JG, Ronan JA, De Leon AC. The effect of nitroglycerin on left ventricular wall tension in fixed orifice aortic stenosis. Circulation. 1965;32:204-213. 6. Khot UN, Novaro GM, Popovic ZB, et al. Nitroprusside in critically ill patients with left ventricular dysfunction and aortic stenosis. N Engl J Med. 2003;348:1756-1763. 7. Labovitz AJ, Noble VE, Bierig M, et al. Focused cardiac ultrasound in the emergent setting: a consensus statement of the American Society of Echocardiography and American College of Emergency Physicians. J Am Soc Echocardiogr. 2010;23:1225-1230. 8. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease. J Am Coll Cardiol. 2008;52:e1-e142. 9. Thiele H, Zeymer U, Neumann F-J, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012;367:1287-1296. 10. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet. 1998;351:389-393. 11. Worster A, Haines T. Advanced statistics: understanding medical record review (MRR) studies. Acad Emerg Med. 2004;11:187-192. 12. Gilbert EH, Lowenstein SR, Koziol-McLain J, et al. Chart reviews in emergency medicine research: where are the methods? Ann Emerg Med. 1996;27:305-308. 13. Gerson JI, Allen FB, Seltzer JL, et al. Arterial and venous dilation by nitroprusside and nitroglycerin—is there a difference? Anesth Analg. 1982;61:256-260. 14. Chadda K, Annane D, Hart N, et al. Cardiac and respiratory effects of continuous positive airway pressure and noninvasive ventilation in acute cardiac pulmonary edema. Crit Care Med. 2002;30:2457-2461. 15. Vital FMR, Ladeira MT, Atallah AN. Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema. Cochrane Database Syst Rev. 2013;(5):CD005351.
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Complications Associated With Nitrate Use in Patients With Pulmonary Edema 16. Gray A, Goodacre S, Newby DE, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med. 2008;359:142-151. 17. Sharon A, Shpirer I, Kaluski E, et al. High-dose intravenous isosorbidedinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema. J Am Coll Cardiol. 2000;36:832-837. 18. Felker GM, O’Connor CM, Braunwald E, for the Heart Failure Clinical Research Network Investigators. Loop diuretics in acute decompensated heart failure: necessary? evil? a necessary evil? Circulation. 2009;2:56-62.
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19. Hasselblad V, Stough WG, Shah MR, et al. Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial. Eur J Heart Fail. 2007;9:1064-1069. 20. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364:797-805. 21. De Berrazueta JR, González JP, de Mier I, et al. Vasodilatory action of loop diuretics: a plethysmography study of endothelial function in forearm arteries and dorsal hand veins in hypertensive patients and controls. J Cardiovasc Pharmacol. 2007;49:90-95.
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APPENDIX E1 Details of cases with clinically relevant hypotension
Nitro IV Duration of Nitroglycerin Adverse Events Age, Nitro Max Dose Treatment Before AS Status Years Sex Received (mg/min) Adverse Event, Hours Stop Nitroglycerin IV Fluid Bolus Vasopressor Use Cardiac Arrest Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Severe Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate Moderate No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS No AS
84 84 79 82 77 75 78 54 81 91 89 87 92 86 86 87 86 82 82 81 62 84 79 88 84 85 76 89 74 93 69 97 94 94 74 75 79 93 92 83 84 90 81 71 87 90 94 88 93
F F M F F F F M F F F F F F F F F M F F F M M F F M F M M F M M F F M F F F F F M M F F M F F F F
SL, IV SL IV IV IV SL, IV IV IV IV SL, IV IV IV SL, IV IV SL, IV SL IV IV SL, IV SL, IV IV IV SL, IV IV IV SL, IV IV SL, IV SL, IV IV IV IV SL, IV IV IV IV SL, IV IV IV IV IV IV IV IV IV IV IV IV IV
100
27.5
17 60 47 36 100 73 37 77 10 50 173 333 10
7.4 6.8 1.6 1.5 112 25.9 8.7 3.6 0.5 2.5 47 12.5 16.4
12 87 57 17 57 77 100 16 53 27 33 167 15 23 5 20 33 100 57 43 60 53 37 16 17 75 200 Missing 33 Missing 10 3 27
9.5 43.3 3.2 0.6 137 10 6.8 0.8 3.5 1.0 1.1 6.4 6.3 0.7 5.8 4.0 2.3 4.3 3.7 2.7 3.2 21.3 1.3 0.1 2.5 111.8 4.5 1.8 5 0.3 49.3 6.8 22.2
X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X
X
X
X
X
X X X
X X X
X
X
X
X
F, Female; SL, Sublingual; M, male.
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Annals of Emergency Medicine 8.e1
