Should furosemide be avoided in acute right ventricular myocardial infarction?

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www.sciencedirect.com Annales de Cardiologie et d’Angéiologie 62 (2013) 95–100

Original article

Should furosemide be avoided in acute right ventricular myocardial infarction? Le furosémide doit-il être évité dans l’infarctus aigu du myocarde touchant le ventricule droit ? J. Ternacle a , R. Gallet a , T. Cognet b , P. Gueret a , E. Teiger a , J.-L. Dubois-Randé a , P. Lim a,∗ a

Inserm U955, Team 3, Department of Cardiovascular Medicine, Henri Mondor University Hospital, AP–HP, 51, avenue de Lattre-de-Tassigny, 94100 Creteil, France b Cardiovascular department, CHU Rangueil, 31000 Toulouse, France Received 24 October 2012; accepted 15 February 2013 Available online 13 March 2013

Abstract Background. – Diuretics are conventionally prohibited in acute right ventricular myocardial infarction. Aims. – To assess the benefit of diuretics compared to fluid expansion in patients with inferior myocardial infarction extended to the right ventricule. Methods. – Of 295 patients admitted for inferior or posterior acute myocardial infarction between November 2008 and November 2010, 77 had a right ventricular extension. Among these 77 patients, 19 presented with oligoanuria (< 0.5 mL/kg per hour) and no criteria for cardiogenic shock. Overall, 11 patients were treated by low dose of furosemide (40 to 80 mg) and eight received fluid expansion using isotonic saline solution. Results. – Baseline right ventricular dilatation and dysfunction, systolic blood pressure and heart rate were similar between the groups. Twentyfour hours after treatment, urine output was similar between the two groups but only the patients in the diuretic group improved their blood pressure (103 ± 16 mmHg versus 127 ± 20 mmHg, P < 0.001), heart rate (71 ± 15 bpm versus 76 ± 13 bpm, P = 0.03), creatinin level and alanine aminotrasferase plasmatic level. Hospitalization duration and the need of inotropic support were similar in the two groups. Conclusions. – Diuretics and fluid expansion provide similar efficiency for triggering diuresis in patients with right ventricular infarction and oligoanuria but only diuretics seem to be associated with improvement in hemodynamic status and venous congestion. © 2013 Elsevier Masson SAS. All rights reserved. Keywords: Acute myocardial infarction; Right ventricular infarction; Diuretic; Fluid expansion

Résumé Contexte. – Les diurétiques sont habituellement contre-indiqués dans l’infarctus aigu du myocarde étendu au ventricule droit. Objectif. – Évaluer le bénéfice des diurétiques comparés au remplissage vasculaire chez les patients admis pour infarctus aigu du myocarde inférieur avec extension au ventricule droit. Méthode. – Sur les 295 patients admis pour infarctus aigu inférieur ou postérieur entre novembre 2008 et novembre 2010, 77 avaient une extension ventriculaire droite. Parmis ces 77 patients, 19 présentaient une oligoanurie (< 0,5/mL/kg par heure) sans critère de choc cardiogénique. Au total, 11 patients ont rec¸u de faibles doses de furosémide (40 à 80 mg) et huit ont rec¸u un remplissage vasculaire par une solution de sérum salé isotonique. Resultats. – À l’admission, la dilatation et la dysfonction ventriculaire droite, la pression artérielle systolique et la fréquence cardiaque étaient similaires dans les deux groupes. Vingt-quatre heures après le traitement, la diurèse était identique dans les deux groupes mais seuls les patients du groupe diurétiques amélioraient leur pression artérielle systolique (103 ± 16 mmHg versus 127 ± 20 mmHg, p < 0,001), leur fréquence cardiaque (71 ± 15 bpm versus 76 ± 13 bpm, p = 0,03), leur taux de créatinine et d’alanine aminotransférase. La durée d’hospitalisation et le besoin d’inotropes étaient similaires dans les deux groupes.

∗

Corresponding author. E-mail address: [email protected] (P. Lim).

0003-3928/$ – see front matter © 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ancard.2013.02.001

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Conclusions. – Les diurétiques et le remplissage vasculaire offrent la même efficacité pour déclencher la diurèse chez les patients ayant un infarctus ventriculaire droit avec oligoanurie mais seuls les diurétiques semblent être associés à une amélioration de l’état hémodynamique et de la congestion veineuse. © 2013 Elsevier Masson SAS. Tous droits réservés. Mots clés : Infarctus aigu du myocarde ; Ventricule droit ; Diurétique ; Remplissage vasculaire

1. Background Right ventricular (RV) extension occurs in 20% to 50% of patients presenting with myocardial infarction [1,2], depending on the culprit lesion location. The prognosis of RV extension remains severe despite improvements in reperfusion therapy [2,3]. RV infarction is usually suspected when the triad hypotension, clear lungs and increased jugular distension appears during the hospitalization. Current guidelines recommend fluid expansion to maintain RV preload [4], while diuretics and vasodilatators are conventionally contraindicated [4,5]. The rationale of fluid expansion is based on the hypothesis that the Franck-Starling mechanism will compensate the RV dysfunction through a RV dilatation to maintain cardiac output. This therapy strategy has been challenged by experimental studies [6–8] demonstrating that RV enlargement increases RV wall stress and impairs cardiac output because of paradoxical septal wall motion [9]. Despite these controversial data, no study has evaluated the benefit of reducing RV load by diuretics to avoid paradoxical wall motion and the deleterious impact of venous congestion. The aim of this study was to compare the two strategies (diuretic versus fluid expansion) in patients admitted for inferior myocardial infarction with RV extension and preserved left ventricular function. 2. Methods 2.1. Population study Of the 295 patients admitted for inferior or posterior acute myocardial infarction between November 2008 and November 2010, 77 (26%) had a RV extension without LV dysfunction (LV ejection fraction < 45%, n = 15). Among the 77 patients with RV extension, 32% (n = 25/77) were symptomatic: 76% (n = 19/25) had only oligoanuria (< 0.5 mL/kg per hour) without systolic blood pressure less than 90 mmHg and 24% (n = 6/25) developed a cardiogenic shock. Cardiogenic shock was conventionally treated by fluid expansion and catecholamine support. Of the remaining 19 patients, 11 were treated by furosemide and eight by fluid expansion (Fig. 1). 2.2. Treatment protocol All patients were conventionally treated according to the current Guidelines. All patients were reperfused by percutaneous coronary intervention (PCI) and received a dual anti-platelet regimen. Betablockers and angiotensin converting enzyme inhibitors were avoided until hemodynamic stability. In the diuretic group, initial furosemide dose ranged between 40 or

80 mg and the same diuretic dose was repeated 4 hours later if oligoanuria persisted. In the fluid expansion group, 0.5 to 1 L of isotonic saline solution was delivered during 30 minutes and repeated if oligoanuria persisted. All patients had a bladder catheter and urine output was carefully quantified. The study was retrospective and not randomized. The choice between volume expansion and diuretics was based on the physician individual experience, but not on a specific criteria. 2.3. 2D-echocardiography All patients underwent a comprehensive echocardiography (Vivid 7 system, GE Vingmed, Horton, Norway) before furosemide infusion or fluid expansion to confirm the RV extension. Criteria to define RV extension included a RV dilatation (RV and LV end-diastolic diameter ratio > 0.6) associated with the presence of abnormal wall motion (hypokinesia or akinesia) located at the basal and mid segment of RV inferior wall. Global RV systolic function was assessed by M-mode using tricuspid annular plane systolic excursion (TAPSE) and by Tissue-Doppler imaging (TDI) using peak systolic velocity (S’-TDI). RV systolic dysfunction was defined when TAPSE was less than 16 mm or a S’ velocity less than 11 cm/s. Left ventricular ejection fraction (LVEF) was computed using the Simpson biplane method from 2C and 4C apical views. Left cardiac output was assessed by Doppler method using LV outflow tract time-velocity integral. Pulmonary artery systolic pressure was quantified from tricuspid regurgitation flow using Doppler method. Inferior vena cava diameter was measured by TM mode using the sub-costal view. 2.4. Clinical endpoints Primary endpoint was defined by changes in blood pressure and heart rate 24 hours after treatment. Secondary endpoints included cardiogenic shock and death. 2.5. Statistical analysis Continuous variables with a normal distribution are expressed as mean ± standard deviation (SD) and nominal variables as percentage. To compare numerical data between two groups, paired and unpaired Student t-tests were used as appropriate. Nominal variables were compared using either the ␹2 or Fisher tests. Twotailed P-values < 0.05 were considered statistically significant. Population sample size was not defined because of the lack of previous published data.

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Fig. 1. Flow chart of population study. LVEF: left ventricular ejection fraction, RV: right ventricular.

3. Results

3.3. Changes in hemodynamic status at 24 hours

3.1. Population study baseline characteristics

In the diuretic group, mean furosemide dose delivered the first day averaged 85 ± 45 mg (range 40 to 160 mg) and most of patients (78%, n = 8) received only one (n = 4) or two bolus (n = 4). In the fluid expansion group, isotonic saline solution volume averaged 1.0 ± 0.7 L and fluid expansion was less than or equal to 1 L in 63% (n = 5/8) of patients. Twenty-four hours after treatment, urine output was similar in the two groups (Fig. 2A) but the increase in systolic blood pressure (127 ± 20 mmHg versus 103 ± 16 mmHg, P < 0.001, Fig. 2B) and heart rate (76 ± 13 bpm versus 71 ± 15 bpm, P = 0.03, Fig. 2C) was only observed in patients treated by diuretics. No correlation was observed between diuretic dose and the changes in systolic blood pressure and heart rate.

Mean time between the onset of symptoms and PCI was 14 ± 12 hours. The culprit lesion was the right coronary atery in 79% of patients (n = 15/19) (Table 1). Admission systolic blood pressure and heart rate averaged 104 ± 13 mmHg [range, 90 to 138] and 70 ± 13 beats per minute, respectively. Of the 19 patients, seven patients had bradycardia (≤ 60 beat per minute [bpm]). No difference in blood pressure and heart rate was observed between those treated by diuretic and fluid expansion. 3.2. Baseline echocardiography characterics All patients had preserved LVEF (mean 52 ± 6%, [range, 45 to 65]). TAPSE and S’-TDI averaged 17 ± 4 mm and 11 ± 2 cm/s, respectively. No difference was observed between diuretics and fluid expansion groups for LVEF and RV function. All patients had a regional RV dysfunction and the mean RV/LV end-diastolic ratio was 0.8 ± 0.1. The severity of RV dilation was similar between those treated by diuretics or fluid expansion (0.83 versus 0.80, P = 0.47) and correlated with inferior vena cava diameter (r = 0.67, P = 0.003). Despite a RV dilatation and regional wall motion abnormality, global RV dysfunction was only observed in seven (three in fluid expansion group) according to S’-TDI and eight patients (three in fluid expansion group) according to TAPSE.

3.4. Biological markers of right ventricular congestive heart failure Alanine aminotrasferase (ALAT) and sodium plasma levels were similar at admission, while creatinin plasmatic level was greater in the diuretic group (94 ± 33 ␮mol/L versus 66 ± 13 ␮mol/L, P = 0.04). Natremia, ALAT and plasmatic creatinin (66 ± 13 ␮mol/L versus 75 ± 20 ␮mol/L, P = 0.02, Fig. 3) significantly improved at 24 hours in the diuretic group (Pvalue for interaction term < 0.05 for all), while ALAT and creatinin plasmatic levels increased in the fluid expansion group.

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Table 1 Patient’s baseline characteristics of patients with symptomatic right ventricular infarction. All patients

Furosemide

Fluid expansion

P

n = 19

n = 11

n=8

Age, years Female sex, No. (%) Smoker, No. (%) Diabetes, No. (%) Hypertension, No. (%) Dyslipidemia, No. (%)

60 ± 17 7 (37) 12 (63) 1 (5) 4 (21) 8 (42)

65 ± 19 5 (45) 5 (46) 1 (9) 4 (36) 4 (36)

52 ± 11 2 (25) 7 (87) 0 (0) 0 (0) 4 (50)

0.08 0.4 0.07 0.4 0.06 0.6

Right coronary thrombosis, No. (%) Circumflex thrombosis, No. (%) Left anterior thrombosis, No. (%) Coronary stenting, No. (%) Mean time before PCI, hours

15 (79) 4 (21) 1 (5) 18 (95) 14 ± 12

9 (82) 2 (18) 0 (0) 11 (100) 16 ± 13

6 (75) 2 (25) 1 (12) 7 (87) 13 ± 10

0.7 0.7 0.3 0.3 0.6

SBP, mmHg HR, bpm Hemoglobin, g/dL Natremia, mmol/L Uremia, mmol/L Creatinin, μmol/L Aspartate aminotransferase, UI/L Alanine aminotransferase, UI/L Bilirubin, μmol/L Troponina , UI/L

104 ± 13 70 ± 13 13 ± 1.8 136 ± 3 6.1 ± 3 82 ± 29 216 ± 259 41 ± 31 8.6 ± 3.8 3.2

103 ± 16 71 ± 15 12 ± 2 135 ± 3 7±4 94 ± 33 236 ± 247 45 ± 29 9±4 4.1

104 ± 11 67 ± 8 13 ± 1 137 ± 3 5±1 66 ± 13 187 ± 290 37 ± 36 8±4 1.6

0.9 0.5 0.3 0.3 0.08 0.04 0.7 0.6 0.7 0.1

Echocardiography LVEF (%) RV/LV ratio S’ tricuspid, cm/s TAPSE, mm PASP, mmHg IVC, mm

52 ± 6 0.8 ± 0.1 11 ± 2 17 ± 4 30 ± 5 21 ± 5

51 ± 5 0.8 ± 0.1 10 ± 2 17 ± 4 29 ± 5 21 ± 5

53 ± 7 0.8 ± 0.1 11 ± 3 18 ± 4 30 ± 3 20 ± 4

0.4 0.5 0.2 0.5 0.8 0.5

Plus-minus values are mean ± SD. PCI: percutaneous coronary intervention; SBP: systolic blood pressure; HR: heart rate; LVEF: left ventricular ejection fraction; S’: tricuspid velocity; TAPSE: tricuspid annular plane systolic excursion; PASP: pulmonary artery systolic pressure; IVC: inferior vena cava. a Expressed as median.

3.5. Safety Hospitalization period in intensive care unit was similar in the two groups (3.4 ± 1 days, median = 3 days, range, 2 to 7 days) and no patient died or required inotropic support. After discharge, only one patient had stent thrombosis and died from refractory cardiogenic shock. 4. Discussion Fluid expansion is conventionally delivered to prevent cardiogenic shock in patients with RV infarction [4,10–12]. Diuretics are usually avoided [4,5] because of the fear of unbalancing the Franck-Starling mechanism that may worsen hemodynamic status. In the present study, we demonstrated that furosemide but not fluid expansion is associated with an increase in systolic blood pressure and reduced venous congestion. A cardiac magnetic resonance study showed that RV extension can be observed in 54% of patients with inferior necrosis and 11% of patients with anterior necrosis [13]. RV extension was usually associated with a poor outcome and a higher risk of cardiogenic shock and death despite improvements in reperfusion therapy [2,3,14]. The diagnosis is usually suspected in patients

with inferior myocardial infarction when they develop the triad hypotension, clear lung fields and raised jugular venous pressure [4]. The sensitivity of the diagnosis has been improved with the use of echocardiography which shows a RV dilatation with dilated hepatic veins and RV inferior wall motion abnormalities. On the pathophysiological point of view, RV dilatation reflects the Franck-Starling mechanism, allowing a preload reserve to maintain cardiac output when RV dysfunction occurs abruptly. In these patients, current guidelines recommend the use of fluid loading to maintain RV filling pressure and Franck-Starling mechanism [4]. Despite no study demonstrating their deleterious impact, diuretics are conventionally not recommended in patient with RV infarction because of the fear of unbalancing the FranckStarling mechanism [4]. In the present study, we demonstrate that both fluid loading and diuretics can activate diuresis but only low doses of furosemide improve systolic blood pressure and biological markers of venous congestion. In contrast, volume expansion seems to worsen liver and renal congestion. These paradoxical results are in agreement with experimental studies [7] demonstrating that RV overstretch aggravates RV wall stress and causes paradoxical septal motion that impairs LV compliance and decreases cardiac output [15–17]. Despite

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Fig. 2. Changes in urine output (A), systolic blood pressure (B) and heart rate (C) according to delivered treatment. BPM: beat per minute.

an initial hemodynamic benefit, RV dilatation becomes deleterious probably because a vicious cycle is established between RV enlargement and the decrease of cardiac output. These results are supported by Mercat’s study [18], which demonstrates an inverse correlation between cardiac output and RV dilatation.

Conversely, we believe that diuretics probably contribute to reverse the vicious cycle by restoring an adequate RV load. The supposed consequence is a decrease in venous congestion, RV wall stress and ischemia with a reduction of righ-left ventricular interdependence. Increase in heart rate in the diuretic group

Fig. 3. Changes in natremia (A), alanine aminotransferase plasma level (B) and in creatinin plasma level (C) according to delivered treatment.

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probably illustrates a decrease in right atrial ischemia and RV afferent vagal stimulation [19]. Overall, these results raise the need to carefully evaluate the real benefit of fluid expansion in patients with RV infarction. In patients with a RV dilatation, fluid expansion should be avoided to prevent aggration of venous congestion and diuretics may be preferred to warrant a better hemodynamic improvement. 5. Study limitations The study is restrospective and non-randomized with a small sample size, and potential bias may exist. Despite this limitation, our data raise the limitation of fluid expansion therapy and hightlight the need to evaluate the two strategies in a randomized multicentric study. We also believe that diuretic treatment should not be attempted in patients with cardiogenic shock or hypovolemic state. These patients should be managed conventionally with inotropic and/or mechanical support.

[5]

[6]

[7]

[8]

[9]

[10]

6. Conclusion [11]

Diuretics delivered in patients with RV acute myocardial infarction may improve hemodynamic status, while fluid expansion seems to aggravate RV congestion.

[12]

Disclosure of interest [13]

The authors declare that they have no conflicts of interest concerning this article. [14]

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