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Hemodynamic effects of Ivabradine in addition to dobutamine in patients with severe systolic dysfunction
International Journal of Cardiology 176 (2014) 450–455
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Hemodynamic effects of Ivabradine in addition to dobutamine in patients with severe systolic dysfunction☆ Romain Gallet ⁎, Julien Ternacle, Thibaud Damy, Soulef Guendouz, Camille Bremont, Aurélien Seemann, Pascal Gueret, Jean-Luc Dubois-Rande, Pascal Lim AP-HP — University Hospital Henri Mondor, Cardiovascular Department, INSERM U955 Team 3, Creteil, France
a r t i c l e
i n f o
Article history: Received 17 December 2013 Received in revised form 23 May 2014 Accepted 26 July 2014 Available online 1 August 2014 Keywords: Heart failure Dobutamine Ivabradine Oxygen consumption Cardiogenic shock
a b s t r a c t Background: Dobutamine induced tachycardia increases myocardial oxygen consumption and impairs ventricular filling. We hypothesized that Ivabradine may be efficient to control dobutamine induced tachycardia. Methods: We assessed the effects of Ivabradine in addition to dobutamine in stable heart failure (HF) patients (LVEF b 35%, n = 22, test population) and validated its effects in refractory cardiogenic shock patients (n = 9, validation population) with contraindication to cardiac assistance or transplant. In the test population (62 ± 17 years, LVEF = 24 ± 8%), systolic and diastolic function were assessed at rest and under dobutamine [10γ/min], before and after Ivabradine [5 mg per os]. In the validation population (54 ± 11 years, LVEF = 22 ± 7%), Ivabradine [5 mg twice a day] was added to the dobutamine infusion. Results: In the test population, Ivabradine decreased heart rate [HR] at rest and during dobutamine echocardiography (−9 ± 8 bpm, P = 0.0004). The decrease in HR was associated with a decrease in cardiac power output and an increase in diastolic duration at rest (+ 74 ± 67 ms, P = 0.0002), and during dobutamine infusion (+75 ± 67 ms, P b 0.0001). Change in LVEF during dobutamine was greater after Ivabradine treatment than before (+7.2 ± 4.7% vs. +3.6 ± 4.2%, P = 0.002). In the validation population, Ivabradine decreased HR (−18 ± 11 bpm, P = 0.008) and improved diastolic filling time (+67 ± 42 ms, P = 0.012) without decreasing cardiac output. At 24 h, Ivabradine improved systolic blood pressure (+9 ± 5 mm Hg, P = 0.007), daily urine output (+0.7 ± 0.5 L, P = 0.008), oxygen balance (ΔScv02 = +13 ± 15%, P = 0.010), and NT-pro BNP (−2270 ± 1912 pg/mL, P = 0.017). Finally, only 2/9 (22%) patients died whereas expected mortality determined from a historical cohort was 78% (P = 0.017). Conclusion: This pilot study demonstrates the safety and potential benefit of a HR lowering agent in cardiogenic shock. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Despite heart failure therapeutic innovations, cardiogenic shock mortality remains desperately high [1,2]. Symptomatic management of these patients mainly relies on diuretic and dobutamine infusion [3]. This sympathomimetic amine has dose dependent positive inotropic and chronotropic effects which lead to an increase in cardiac output and a decrease in left ventricle filling pressures. However, tachycardia induced by this treatment may be deleterious because it increases myocardial oxygen consumption and impairs left ventricle filling [4–8], thus limiting its beneficial impact. This tachycardia is usually not controlled because it is considered as an adaptive way to maintain cardiac output. ☆ No grant support was received and all authors have reported that they have no relationships relevant to the contents of this paper to disclose. ⁎ Corresponding author at: APHP Henri Mondor University Hospital, Department of Cardiovascular Medicine, 51 Av de Lattre de Tassigny, 94100 Creteil, France. Tel.: +33 1 49 81 28 04; fax: +33 1 49 81 28 05. E-mail address: [email protected] (R. Gallet).
http://dx.doi.org/10.1016/j.ijcard.2014.07.093 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
However this common belief is challenged by some recent data indicating that heart rate is an independent risk factor in several acute conditions including multiple organ dysfunction syndrome and hypertensive emergencies [9,10]. Ivabradine is strictly a heart rate lowering agent which acts on sinoatrial node without direct effects on cardiac function and cardiac output [11,12]. It decreases cardiovascular mortality and total mortality in chronic heart failure patients with elevated heart rate [13]. In the setting of acute heart failure, case reports demonstrated that Ivabradine may improve hemodynamic status and facilitate dobutamine weaning in patients referred for cardiogenic shock by controlling dobutamine induced tachycardia [14–16]. The primary hypothesis of this study is that Ivabradine is efficient to control dobutamine induced tachycardia. The second hypothesis is that this heart rate reduction is associated with left ventricle diastolic improvement. 2. Methods In this single center, prospective, non-randomized pilot study, hemodynamic effects of Ivabradine during dobutamine infusion were first assessed in 22 patients with stable
R. Gallet et al. / International Journal of Cardiology 176 (2014) 450–455 heart failure (test population) before validation in 9 patients with refractory cardiogenic shock (validation population). The study complies with the declaration of Helsinki. All patients provided informed consent before inclusion and the protocol was approved by our local ethics committee. The study flowchart is shown in Fig. 1.
2.1. Test population This population was composed of stable heart failure patients who underwent baseline and dobutamine stress echocardiography without and then with Ivabradine treatment. All patients admitted for acute heart failure with LVEF b 35% were screened for inclusion. After heart failure stabilization, and before beta-blocker re-introduction, patients with sinus rhythm were included. Exclusion criteria were cardiogenic shock requiring catecholamine support, heart rate (HR) b70 bpm, recent acute coronary syndrome, previous ventricular arrhythmia, pregnancy and age under 18 years old. Rest and dobutamine stress echocardiography in the test population was first performed without Ivabradine. After stress echocardiography, Ivabradine administration was started (5 mg twice a day per os). Rest and dobutamine stress echocardiography were performed again 24 h after Ivabradine administration (flowchart in Fig. 1). The initial rate of dobutamine [5 μg/kg/min] was increased every 3 min [incremental rate of 2.5 μg/kg/min] until the maximal rate of 10 μg/kg/min. The test was conducted under continuous ECG and non-invasive blood pressure monitoring. Echocardiography data acquired at rest and during peak dose of dobutamine [10 μg/kg/min] included standard apical views [with and without color Doppler], pulse Doppler LV outflow tract (LVOT) velocity, pulse Doppler E/A mitral flow velocities and tissue Doppler velocities of the lateral and septal wall.
2.2. Validation population The safety and hemodynamic effects of Ivabradine were then validated in refractory cardiogenic shock patients in sinus rhythm [HR N 70 bpm] with definitive or temporary contraindication to cardiac assistance or heart transplant. Refractory cardiogenic shock was defined by two unsuccessful attempts of dobutamine withdrawal, or by persisting peripheral hypoperfusion despite maximal dobutamine infusion. Dobutamine withdrawal failure was defined by persistent peripheral hypoperfusion despite optimal volemia after two attempts of dobutamine decrease or withdrawal. All patients were treated with a high dose of furosemide until euvolemia was achieved according to clinical and echocardiographic measurements. Once dobutamine rate was constant, Ivabradine was started at 5 mg twice a day. Trans-thoracic echocardiography was performed before and 24 h after Ivabradine administration. Because of a different hemodynamic profile, potential reversible stunning, and a different management strategy, cardiogenic shock related to acute myocardial infarction was excluded.
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2.3. Hemodynamic measurement in validation population A radial arterial catheter was used for blood pressure measurement and blood sample collection. A venous catheter was placed in superior vena cava for dobutamine infusion and central venous oxygen saturation (ScvO2) measurements. Clinical characteristics and blood samples including ScvO2, NT-proBNP and natremia were collected before Ivabradine administration and 24 h later. Oxygen consumption (VO2) was estimated using Fick's simplified equation: VO2 = (SaO2 − SvO2) × 1.34 × Hb × CO where SaO2 and SvO2 are arterial and venous oxygen saturation, Hb is hemoglobin and CO is cardiac output. Cardiac power output was calculated using the following equation: CPO = (CO × MAP) × K where CO is cardiac output (L/min), MAP the mean arterial pressure (mm Hg) and K the conversion factor (=2.22 × 10−3). 2.4. Echocardiography analysis Cardiac output (CO) was derived from LVOT pulsed Doppler using Bernoulli's equation as previously validated [17–20]. Left ventricular volumes, stroke volume and ejection fraction were measured using Simpson's method. The correlation between stroke volume values derived from Doppler and from Simpson's method was good (R = 0.82, P b 0.0001). LV filling pressure was assessed using E/E′ ratio and diastolic function by E/A ratio, diastolic deceleration time and E–A duration measurement adjusted to RR duration. 2.5. Clinical follow-up in validation population In hospital cardiovascular events defined by dobutamine withdrawal, hospital death and recurrent cardiogenic shock were prospectively recorded. This population was compared to a matched (age, heart rate, CO and LVEF) control population of patients with severe cardiogenic shock (defined by ScvO2 b 60%) and who were contra-indicated for heart transplant or cardiac assistance. This cohort was obtained from a historic cohort previously published [21]. This control group was used for comparison of outcomes only because full echocardiographic data was not recorded at the same time points. 2.6. Statistical analysis Continuous variables were expressed as mean ± standard deviation, and nominal variables as percentages. To compare numerical data between groups, Wilcoxon signed rank test was used. Nominal variables were compared using the chi-square test. Twotailed P-value b 0.05 was considered as statistically significant. Based on preliminary data in healthy subjects and published studies with Ivabradine in heart failure, we assumed that Ivabradine treatment would lead to a 5 bpm decrease in heart rate at peak dobutamine. Twenty patients were needed in the test population to demonstrate this hypothesis with an alpha risk of 0.05 and a beta risk of 0.10.
Fig. 1. Study flowchart. Stable heart failure population corresponds to “test population” and refractory cardiogenic shock population to “validation population”.
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8%, P b 0.0001) than without (27 ± 8% vs. 24 ± 8%, P = 0.0005) Ivabradine treatment (+ 7.2 ± 4.7% vs. + 3.6 ± 4.2% for changes in LVEF with and without Ivabradine respectively, P = 0.004) (Fig. 3 and Table 2). Overall, cardiac work assessed by cardiac power output was reduced at rest and during dobutamine infusion after Ivabradine treatment, but only reduction at peak dobutamine was statistically significant (Table 2).
Table 1 Patients' baseline characteristics in the test population (stable heart failure patients). ARB: angiotensin receptor blocker; ACE: angiotensin converting enzyme; LVEDV: left ventricle end diastolic volume; LVESV: left ventricle end systolic volume; LVEF: left ventricle ejection fraction. Characteristics
Test population N = 22
Age (years) Gender, Male n (%) Ischemic/non-ischemic cardiomyopathy ARB or ACE inhibitor treatment, n (%) Aldosterone receptor antagonist, n (%) Loop diuretic, n (%) Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) LVEDV (mm) LVESV (mm) LVEF (%) Cardiac output (L min−1) E/A ratio E–A duration (ms) Diastolic deceleration time (ms)
62 ± 17 18 (81%) 8/14 13 (60%) 8 (36%) 18 (81%) 89 ± 14 111 ± 17 67 ± 11 197 ± 80 153 ± 70 24 ± 8 4.4 ± 1.1 1.6 ± 1.1 324 ± 93 151 ± 36
3.2. Validation population Validation population characteristics are summarized in Table 3. The nine patients (54 ± 11 years old, 8 men) included in the validation population had refractory cardiogenic shock with severe LV dysfunction (LVEF = 22 ± 7%), and impaired oxygen balance (ScvO2 = 46 ± 7%), and had been treated with dobutamine for 10 ± 8 days. The LV dysfunction was from ischemic origin in 4 patients and non-ischemic origin in 5. Contraindication to cardiac assistance or heart transplantation included advance age or severe comorbidities (n = 4), limited treatment compliance (n = 4) and unexplained fever (n = 1). All were treated by dobutamine (7.8 ± 2.7 μg kg− 1 min− 1) and none received beta-blockers. In addition to dobutamine, 2 patients remained treated with an aldosterone receptor antagonist and 1 with an angiotensin converting enzyme inhibitor. Refractory cardiogenic shock was defined by two failures to withdraw dobutamine (n = 7, dobutamine rate = 7.1 ± 2.7 μg kg− 1 min− 1) or by persistent signs of shock (oligoanuria, peripheral hypoperfusion) despite dobutamine maximal rate (n = 2). Similarly to test population, the decrease in heart rate after Ivabradine (98 ± 16 bpm vs. 79 ± 9 bpm, P = 0.008) was associated with an increase in diastolic filling time (307 ± 98 ms vs. 240 ± 83 ms, P = 0.012), while LVEF and cardiac output remained unchanged (Table 3). Interestingly, improvement in systolic blood pressure (101 ± 7 mm Hg vs. 92 ± 6 mm Hg, P = 0.007) and urine output (2.7 ± 1.1 L vs. 2.1 ± 1.6 L, P = 0.02) was rapidly observed (at 24 h) after Ivabradine addition (Table 3 and Fig. 4), as well as a decrease in NT-proBNP level (8618 ± 4143 pg/mL to 5103 ± 3525 pg/mL, P = 0.017). Cardiac power output and VO2 did not significantly change after Ivabradine addition (Table 3). However, ScvO2, which displays oxygen balance ratio, was significantly improved after Ivabradine addition (ScvO2 = 46 ± 7% to 59 ± 11%, P = 0.010) (Table 3 and Fig. 4).
3. Results 3.1. In the test population The baseline characteristics of the test population are summarized in Table 1. Briefly, 22 patients (62 ± 17 years old, 18 men) with severe left ventricular (LV) dysfunction (24 ± 8%) from ischemic (8/22) or nonischemic cause (14/22) were included. Ivabradine treatment decreased baseline heart rate by 10 ± 7 points (89 ± 14 bpm to 79 ± 15 bpm, P b 0.0001) and the difference was maintained at peak dose dobutamine (94 ± 18 bpm to 85 ± 15 bpm, P = 0.0004) (Table 2). The decrease in heart rate was associated with improvement in diastolic deceleration time and an increase in absolute and relative E–A duration time (% of the whole cardiac cycle) (Fig. 2 and Table 2). These improvements were observed at rest and remained significant during peak dose dobutamine (50 ± 9% vs. 46 ± 8%, P = 0.014 for baseline, and 51 ± 9% vs. 45 ± 10%, P = 0.002 for dobutamine) (Fig. 2 and Table 2). We observed a decrease in rest cardiac output (4.4 ± 1.1 L/min/m2 to 4.0 ± 1.0 L/min/m2, P = 0.003) after Ivabradine addition, however, this difference in cardiac output (without and with Ivabradine) disappeared during peak dose dobutamine (5.6 ± 1.4 L/min/m2 vs. 5.4 ± 1.1 L/min/m2, P = 0.433). Importantly, the increase in LVEF from baseline to peak dose dobutamine was twice higher with (33 ± 9% vs. 26 ±
3.3. Clinical events in validation population and comparison to control group No symptomatic bradycardia was observed after Ivabradine treatment. The control group was made from patients referred for cardiogenic shock with low ScvO2 value after treatment initiation
Table 2 Clinical and echocardiographic data at rest and peak dobutamine, and delta between rest and peak dobutamine with and without Ivabradine in the test population (stable heart failure patients). LVEDV: left ventricle end diastolic volume; LVESV: left ventricle end systolic volume; LVEF: left ventricle ejection fraction. Rest echocardiography
Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) LVEDV (mL) LVESV (mL) Stroke volume (mL) LVEF (%) Cardiac output (L min−1) E/A ratio E–A duration (ms) Diastolic deceleration time (ms) % diastolic filling time (%) Cardiac power output (W)
Dobutamine echocardiography
Baseline
Ivabradine
P
Baseline
Ivabradine
89 ± 14 111 ± 17
79 ± 15 109 ± 17
10 ± 7 −2 ± 16
b0.0001 0.641
94 ± 18 110 ± 16
85 ± 15 105 ± 18
9±8 −5 ± 14
0.0004 0.266
5±9 −1 ± 10
6±7 −3 ± 12
0.614 0.587
67 ± 11
65 ± 9
−2 ± 12
0.169
66 ± 8
61 ± 8
−5 ± 7
0.004
−1 ± 9
−4 ± 7
0.392
197 153 44 24 4.4 1.6 324 151
± ± ± ± ± ± ± ±
80 70 17 8 1.1 1.1 93 36
46 ± 8 0.84 ± 0.21
202 152 50 26 4.0 1.8 398 177
± ± ± ± ± ± ± ±
85 67 22 8 1.0 0.9 117 43
50 ± 9 0.78 ± 0.22
Delta
Delta between rest and peak dobutamine
5 −2 6 2 −0.5 0.2 74 27
± ± ± ± ± ± ± ±
27 24 13 5 0.7 0.8 67 39
4±7 −0.06 ± 0.16
0.297 0.808 0.012 0.070 0.003 0.421 0.0002 0.012
198 145 53 26 5.6 1.8 298 142
± ± ± ± ± ± ± ±
85 70 23 8 1.4 1.5 93 43
0.014 0.098
45 ± 10 1.07 ± 0.31
203 140 63 33 5.4 1.4 373 178
± ± ± ± ± ± ± ±
92 72 27 9 1.1 0.8 101 51
51 ± 9 0.90 ± 0.25
Delta
5 5 10 6 −0.2 −0.4 75 36
P
± ± ± ± ± ± ± ±
5 33 23 5 1.2 1.2 67 42
6 ± 10 −0.17 ± 0.23
Baseline
± ± ± ± ± ± ± ±
Ivabradine
0.118 0.230 0.033 0.0005 0.433 0.435 0.0005 0.0007
0 −8 9 4 1.3 0.1 −25 −10
27 20 22 4 1.2 0.7 48 28
0.002 0.015
−1 ± 9 0.24 ± 0.29
2 −11 13 7 1.3 −0.4 −24 0
± ± ± ± ± ± ± ±
30 25 16 5 0.8 0.7 56 48
1±6 0.13 ± 0.15
P
0.867 0.715 0.223 0.004 0.444 0.077 0.783 0.393 0.140 0.234
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Fig. 2. Test population; left ventricular diastolic filling parameters at rest and at peak dose dobutamine, without and with Ivabradine. Individual evolution and box plot are shown. Full lines show individual improvement and dash lines show individual impairment.
(indicating a high risk of refractory cardiogenic shock [21]) and with contraindication to heart transplant or assistance. This control group was matched to the validation population for age, heart rate, LVEF and cardiac output (Table 4). During in-hospital follow-up, 2 (22%) patients among the Ivabradine treated population died from refractory cardiogenic
shock at days 9 and 10 respectively. The 7 remaining patients were successfully weaned from dobutamine infusion 9 ± 4 days following inclusion and discharged from the intensive care unit. This population outcome was unexpectedly good when compared to the control group. Indeed we observed 7/9 death (77%) in the control group (P = 0.017).
Fig. 3. Test population; LVEF at rest (A) and at peak dose dobutamine (B) without and with Ivabradine. Increase from baseline to peak dose dobutamine without and with Ivabradine (C). Individual evolution and box plot are shown. Full lines show individual improvement and dash lines show individual impairment.
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Table 3 Hemodynamic parameters before and after Ivabradine administration in patients with refractory cardiogenic shock. LVEF: left ventricle ejection fraction; ScvO2: venous central oxygen saturation; SaO2: arterial oxygen saturation.
Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean blood pressure (mm Hg) Daily urine output (L) LVEF (%) Stroke volume (mL) Cardiac output (L min−1) E/A ratio Diastolic deceleration time (ms) E–A duration (ms) SvO2 (%) SaO2 (%) Hemoglobin VO2 (L/min) Nt-pro-BNP (pg mL−1) Cardiac power output (W)
Dobutamine
Dobutamine and Ivabradine
P
98 92 59 70 2.1 22 37 4.0 2.3 103 240 46 97 10.4 2.5 8618 0.60
79 101 62 75 2.7 27 45 3.9 2.2 123 307 59 98 10.4 1.8 5301 0.64
0.008 0.007 0.284 0.050 0.008 0.091 0.062 0.944 0.499 0.028 0.012 0.010 0.157 0.734 0.216 0.017 0.327
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
16 6 8 6 1.6 7 9 1.2 1.2 23 83 7 2 1.0 1.1 4143 0.17
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
9 7 6 5 1.1 7 5 0.9 1.2 21 98 11 2 0.9 0.5 3525 0.14
4. Discussion This is the first study assessing the hemodynamic effects of dobutamine and Ivabradine association. In compensated and non-compensated heart failure populations, this study demonstrates that Ivabradine may be safely used to limit dobutamine induced tachycardia. In both compensated and uncompensated heart failure patients, heart rate reduction was associated with diastolic function improvement. In heart failure patients with refractory cardiogenic shock, we observed a dramatic improvement in hemodynamic status after Ivabradine addition that allowed progressive weaning from dobutamine support. Dobutamine is the cornerstone of cardiogenic shock treatment [1–3]. It is a sympathomimetic catecholamine that increases cardiac inotropism
with the deleterious effect of increasing heart rate [6,8]. This induced tachycardia increases myocardial oxygen consumption and reduces left ventricular filling period [4,5,7]. Previous animal studies demonstrated that If current inhibitor added to dobutamine improves dobutamine inotropic effect by limiting tachycardia [22,23]. In stable heart failure patients with severe LV dysfunction, De Ferrari et al. showed that heart rate reduction obtained with Ivabradine infusion increases LV stroke volume without decreasing cardiac output [24]. In our study, we also observed an increase in stroke volume in stable heart failure patients. This gain may be related to the Frank–Starling mechanism but also to an improvement of myocardial energy supply by prolonging coronary perfusion during diastole. Contrarily to previous studies, we observed a slight decrease in cardiac output at rest. This asymptomatic decrease in cardiac output may be a compensatory mechanism related to diastolic function and cardiac work improvement. Interestingly, we observed a greater increase in LVEF during dobutamine infusion after Ivabradine treatment that indicates an increase in contractile reserve, probably related to the subtend improvement in diastolic function during dobutamine infusion. In compensated heart failure patients, large randomized trials demonstrated that Ivabradine on top of beta-blocker therapy improves patient symptoms and outcome even in patients with severe heart failure [12, 25–28]. Underlying mechanisms include reversal of LV remodeling and improvement in diastolic function and arterial ventricular coupling [28, 29]. In acute heart failure population [especially in cardiogenic shock], Ivabradine has never been extensively tested because of the general belief that tachycardia is an adaptive way to maintain cardiac output. However, Tan et al. have reported a beneficial effect of Ivabradine administration following Dobutamine weaning in 2 patients, potentially related to an increase in cardiac reserve [30]. In our study, we observed similar changes in the cardiogenic shock population than in the stable heart failure population regarding heart rate and diastolic function after Ivabradine. Conversely, cardiac output remains stable despite a greater decrease in heart rate. These changes are consistent with a previous experimental study demonstrating that coupled pacing, a pacing algorithm used to reduce heart rate without modifying LV inotrope propriety, induced a
Fig. 4. Validation population; heart rate, systolic blood pressure, ScvO2 and daily urine output before and after Ivabradine addition in patients with refractory cardiogenic shock. Individual evolution, mean and standard deviation are shown. * indicates P value ≤ 0.01 for difference between baseline and Ivabradine treatment.
R. Gallet et al. / International Journal of Cardiology 176 (2014) 450–455 Table 4 Validation (refractory cardiogenic shock patients) and control population characteristics. All hemodynamic data have been recorded under dobutamine infusion. LVEF: left ventricle ejection fraction; ScvO2: venous central oxygen saturation.
Age (years) Gender (M/F) Ischemic/non-ischemic cardiomyopathy Dobutamine dose (μg/kg/min) Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean blood pressure (mm Hg) LVEF (%) Cardiac output (mL/min) Cardiac index (mL/min/m2) ScvO2 (%) Event n (%)
Ivabradine patients (n = 9)
Control population (n = 9)
P
54 ± 11 8/1 4/5
60 ± 16 7/2 3/6
0.353 0.527 0.629
7.8 ± 2.6 98 ± 16 92 ± 6 59 ± 8 70 ± 6 22 ± 7 4.0 ± 1.2 2.1 ± 0.6 46 ± 7 2 (22%)
8.4 ± 4.5 96 ± 24 107 ± 19 60 ± 10 76 ± 12 26 ± 11 3.8 ± 1.3 2.2 ± 0.8 53 ± 2 7 (78%)
0.707 0.820 0.029 0.899 0.223 0.445 0.815 0.869 0.007 0.017
decrease in cardiac work and oxygen consumption [31]. In our study changes in LV diastolic function were associated with improvements in hemodynamic status and oxygen balance, assessed by blood pressure, urine output and venous oxygen saturation. This overall hemodynamic improvement might be one explanation for the higher decrease in heart rate observed in this population compared to the stable heart failure population. In addition, dobutamine was successfully withdrawn in the majority of these patients after Ivabradine treatment whereas we observed a very high mortality in a control group of severe cardiogenic shock patients. However results on outcome must be interpreted with caution given the small non-randomized populations. Overall, these results underline the deleterious impact of tachycardia during cardiogenic shock and open new therapeutic perspectives in this setting. 4.1. Limitation One limitation of this study is that most of the hemodynamic parameters (especially cardiac output and left ventricle volumes) were measured using echocardiography. Thermodilution is the gold standard for cardiac output measurement but, pulmonary artery catheterization has become poorly used [32], and several studies reported a good correlation between Doppler derived cardiac output and thermodilution [17–20]. On the other hand, this pilot study included a limited number of patients with cardiogenic shock because only patients not withdrawn from dobutamine support who could not benefit from heart transplant or cardiac assistance were included. Future randomized study should extend inclusion criteria to all cardiogenic shock patients to demonstrate the benefit of Ivabradine in association with dobutamine. A study assessing heart rate reduction by Ivabradine in patients with multiple organ dysfunction syndrome is currently ongoing and will provide further information on the benefit of decreasing heart rate in patients with shock although this study is including shock from different etiology (i.e. septic and cardiogenic) [33]. 5. Conclusion In refractory cardiogenic shock patients, Ivabradine in association with dobutamine is safe and associated with an improvement in left ventricle diastolic filling, oxygen balance and hemodynamic status. Following Ivabradine delivery, most patients were withdrawn from dobutamine support. References [1] Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation 2008;117:686–97.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Hemodynamic effects of Ivabradine in addition to dobutamine in patients with severe systolic dysfunction☆ Romain Gallet ⁎, Julien Ternacle, Thibaud Damy, Soulef Guendouz, Camille Bremont, Aurélien Seemann, Pascal Gueret, Jean-Luc Dubois-Rande, Pascal Lim AP-HP — University Hospital Henri Mondor, Cardiovascular Department, INSERM U955 Team 3, Creteil, France
a r t i c l e
i n f o
Article history: Received 17 December 2013 Received in revised form 23 May 2014 Accepted 26 July 2014 Available online 1 August 2014 Keywords: Heart failure Dobutamine Ivabradine Oxygen consumption Cardiogenic shock
a b s t r a c t Background: Dobutamine induced tachycardia increases myocardial oxygen consumption and impairs ventricular filling. We hypothesized that Ivabradine may be efficient to control dobutamine induced tachycardia. Methods: We assessed the effects of Ivabradine in addition to dobutamine in stable heart failure (HF) patients (LVEF b 35%, n = 22, test population) and validated its effects in refractory cardiogenic shock patients (n = 9, validation population) with contraindication to cardiac assistance or transplant. In the test population (62 ± 17 years, LVEF = 24 ± 8%), systolic and diastolic function were assessed at rest and under dobutamine [10γ/min], before and after Ivabradine [5 mg per os]. In the validation population (54 ± 11 years, LVEF = 22 ± 7%), Ivabradine [5 mg twice a day] was added to the dobutamine infusion. Results: In the test population, Ivabradine decreased heart rate [HR] at rest and during dobutamine echocardiography (−9 ± 8 bpm, P = 0.0004). The decrease in HR was associated with a decrease in cardiac power output and an increase in diastolic duration at rest (+ 74 ± 67 ms, P = 0.0002), and during dobutamine infusion (+75 ± 67 ms, P b 0.0001). Change in LVEF during dobutamine was greater after Ivabradine treatment than before (+7.2 ± 4.7% vs. +3.6 ± 4.2%, P = 0.002). In the validation population, Ivabradine decreased HR (−18 ± 11 bpm, P = 0.008) and improved diastolic filling time (+67 ± 42 ms, P = 0.012) without decreasing cardiac output. At 24 h, Ivabradine improved systolic blood pressure (+9 ± 5 mm Hg, P = 0.007), daily urine output (+0.7 ± 0.5 L, P = 0.008), oxygen balance (ΔScv02 = +13 ± 15%, P = 0.010), and NT-pro BNP (−2270 ± 1912 pg/mL, P = 0.017). Finally, only 2/9 (22%) patients died whereas expected mortality determined from a historical cohort was 78% (P = 0.017). Conclusion: This pilot study demonstrates the safety and potential benefit of a HR lowering agent in cardiogenic shock. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Despite heart failure therapeutic innovations, cardiogenic shock mortality remains desperately high [1,2]. Symptomatic management of these patients mainly relies on diuretic and dobutamine infusion [3]. This sympathomimetic amine has dose dependent positive inotropic and chronotropic effects which lead to an increase in cardiac output and a decrease in left ventricle filling pressures. However, tachycardia induced by this treatment may be deleterious because it increases myocardial oxygen consumption and impairs left ventricle filling [4–8], thus limiting its beneficial impact. This tachycardia is usually not controlled because it is considered as an adaptive way to maintain cardiac output. ☆ No grant support was received and all authors have reported that they have no relationships relevant to the contents of this paper to disclose. ⁎ Corresponding author at: APHP Henri Mondor University Hospital, Department of Cardiovascular Medicine, 51 Av de Lattre de Tassigny, 94100 Creteil, France. Tel.: +33 1 49 81 28 04; fax: +33 1 49 81 28 05. E-mail address: [email protected] (R. Gallet).
http://dx.doi.org/10.1016/j.ijcard.2014.07.093 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
However this common belief is challenged by some recent data indicating that heart rate is an independent risk factor in several acute conditions including multiple organ dysfunction syndrome and hypertensive emergencies [9,10]. Ivabradine is strictly a heart rate lowering agent which acts on sinoatrial node without direct effects on cardiac function and cardiac output [11,12]. It decreases cardiovascular mortality and total mortality in chronic heart failure patients with elevated heart rate [13]. In the setting of acute heart failure, case reports demonstrated that Ivabradine may improve hemodynamic status and facilitate dobutamine weaning in patients referred for cardiogenic shock by controlling dobutamine induced tachycardia [14–16]. The primary hypothesis of this study is that Ivabradine is efficient to control dobutamine induced tachycardia. The second hypothesis is that this heart rate reduction is associated with left ventricle diastolic improvement. 2. Methods In this single center, prospective, non-randomized pilot study, hemodynamic effects of Ivabradine during dobutamine infusion were first assessed in 22 patients with stable
R. Gallet et al. / International Journal of Cardiology 176 (2014) 450–455 heart failure (test population) before validation in 9 patients with refractory cardiogenic shock (validation population). The study complies with the declaration of Helsinki. All patients provided informed consent before inclusion and the protocol was approved by our local ethics committee. The study flowchart is shown in Fig. 1.
2.1. Test population This population was composed of stable heart failure patients who underwent baseline and dobutamine stress echocardiography without and then with Ivabradine treatment. All patients admitted for acute heart failure with LVEF b 35% were screened for inclusion. After heart failure stabilization, and before beta-blocker re-introduction, patients with sinus rhythm were included. Exclusion criteria were cardiogenic shock requiring catecholamine support, heart rate (HR) b70 bpm, recent acute coronary syndrome, previous ventricular arrhythmia, pregnancy and age under 18 years old. Rest and dobutamine stress echocardiography in the test population was first performed without Ivabradine. After stress echocardiography, Ivabradine administration was started (5 mg twice a day per os). Rest and dobutamine stress echocardiography were performed again 24 h after Ivabradine administration (flowchart in Fig. 1). The initial rate of dobutamine [5 μg/kg/min] was increased every 3 min [incremental rate of 2.5 μg/kg/min] until the maximal rate of 10 μg/kg/min. The test was conducted under continuous ECG and non-invasive blood pressure monitoring. Echocardiography data acquired at rest and during peak dose of dobutamine [10 μg/kg/min] included standard apical views [with and without color Doppler], pulse Doppler LV outflow tract (LVOT) velocity, pulse Doppler E/A mitral flow velocities and tissue Doppler velocities of the lateral and septal wall.
2.2. Validation population The safety and hemodynamic effects of Ivabradine were then validated in refractory cardiogenic shock patients in sinus rhythm [HR N 70 bpm] with definitive or temporary contraindication to cardiac assistance or heart transplant. Refractory cardiogenic shock was defined by two unsuccessful attempts of dobutamine withdrawal, or by persisting peripheral hypoperfusion despite maximal dobutamine infusion. Dobutamine withdrawal failure was defined by persistent peripheral hypoperfusion despite optimal volemia after two attempts of dobutamine decrease or withdrawal. All patients were treated with a high dose of furosemide until euvolemia was achieved according to clinical and echocardiographic measurements. Once dobutamine rate was constant, Ivabradine was started at 5 mg twice a day. Trans-thoracic echocardiography was performed before and 24 h after Ivabradine administration. Because of a different hemodynamic profile, potential reversible stunning, and a different management strategy, cardiogenic shock related to acute myocardial infarction was excluded.
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2.3. Hemodynamic measurement in validation population A radial arterial catheter was used for blood pressure measurement and blood sample collection. A venous catheter was placed in superior vena cava for dobutamine infusion and central venous oxygen saturation (ScvO2) measurements. Clinical characteristics and blood samples including ScvO2, NT-proBNP and natremia were collected before Ivabradine administration and 24 h later. Oxygen consumption (VO2) was estimated using Fick's simplified equation: VO2 = (SaO2 − SvO2) × 1.34 × Hb × CO where SaO2 and SvO2 are arterial and venous oxygen saturation, Hb is hemoglobin and CO is cardiac output. Cardiac power output was calculated using the following equation: CPO = (CO × MAP) × K where CO is cardiac output (L/min), MAP the mean arterial pressure (mm Hg) and K the conversion factor (=2.22 × 10−3). 2.4. Echocardiography analysis Cardiac output (CO) was derived from LVOT pulsed Doppler using Bernoulli's equation as previously validated [17–20]. Left ventricular volumes, stroke volume and ejection fraction were measured using Simpson's method. The correlation between stroke volume values derived from Doppler and from Simpson's method was good (R = 0.82, P b 0.0001). LV filling pressure was assessed using E/E′ ratio and diastolic function by E/A ratio, diastolic deceleration time and E–A duration measurement adjusted to RR duration. 2.5. Clinical follow-up in validation population In hospital cardiovascular events defined by dobutamine withdrawal, hospital death and recurrent cardiogenic shock were prospectively recorded. This population was compared to a matched (age, heart rate, CO and LVEF) control population of patients with severe cardiogenic shock (defined by ScvO2 b 60%) and who were contra-indicated for heart transplant or cardiac assistance. This cohort was obtained from a historic cohort previously published [21]. This control group was used for comparison of outcomes only because full echocardiographic data was not recorded at the same time points. 2.6. Statistical analysis Continuous variables were expressed as mean ± standard deviation, and nominal variables as percentages. To compare numerical data between groups, Wilcoxon signed rank test was used. Nominal variables were compared using the chi-square test. Twotailed P-value b 0.05 was considered as statistically significant. Based on preliminary data in healthy subjects and published studies with Ivabradine in heart failure, we assumed that Ivabradine treatment would lead to a 5 bpm decrease in heart rate at peak dobutamine. Twenty patients were needed in the test population to demonstrate this hypothesis with an alpha risk of 0.05 and a beta risk of 0.10.
Fig. 1. Study flowchart. Stable heart failure population corresponds to “test population” and refractory cardiogenic shock population to “validation population”.
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8%, P b 0.0001) than without (27 ± 8% vs. 24 ± 8%, P = 0.0005) Ivabradine treatment (+ 7.2 ± 4.7% vs. + 3.6 ± 4.2% for changes in LVEF with and without Ivabradine respectively, P = 0.004) (Fig. 3 and Table 2). Overall, cardiac work assessed by cardiac power output was reduced at rest and during dobutamine infusion after Ivabradine treatment, but only reduction at peak dobutamine was statistically significant (Table 2).
Table 1 Patients' baseline characteristics in the test population (stable heart failure patients). ARB: angiotensin receptor blocker; ACE: angiotensin converting enzyme; LVEDV: left ventricle end diastolic volume; LVESV: left ventricle end systolic volume; LVEF: left ventricle ejection fraction. Characteristics
Test population N = 22
Age (years) Gender, Male n (%) Ischemic/non-ischemic cardiomyopathy ARB or ACE inhibitor treatment, n (%) Aldosterone receptor antagonist, n (%) Loop diuretic, n (%) Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) LVEDV (mm) LVESV (mm) LVEF (%) Cardiac output (L min−1) E/A ratio E–A duration (ms) Diastolic deceleration time (ms)
62 ± 17 18 (81%) 8/14 13 (60%) 8 (36%) 18 (81%) 89 ± 14 111 ± 17 67 ± 11 197 ± 80 153 ± 70 24 ± 8 4.4 ± 1.1 1.6 ± 1.1 324 ± 93 151 ± 36
3.2. Validation population Validation population characteristics are summarized in Table 3. The nine patients (54 ± 11 years old, 8 men) included in the validation population had refractory cardiogenic shock with severe LV dysfunction (LVEF = 22 ± 7%), and impaired oxygen balance (ScvO2 = 46 ± 7%), and had been treated with dobutamine for 10 ± 8 days. The LV dysfunction was from ischemic origin in 4 patients and non-ischemic origin in 5. Contraindication to cardiac assistance or heart transplantation included advance age or severe comorbidities (n = 4), limited treatment compliance (n = 4) and unexplained fever (n = 1). All were treated by dobutamine (7.8 ± 2.7 μg kg− 1 min− 1) and none received beta-blockers. In addition to dobutamine, 2 patients remained treated with an aldosterone receptor antagonist and 1 with an angiotensin converting enzyme inhibitor. Refractory cardiogenic shock was defined by two failures to withdraw dobutamine (n = 7, dobutamine rate = 7.1 ± 2.7 μg kg− 1 min− 1) or by persistent signs of shock (oligoanuria, peripheral hypoperfusion) despite dobutamine maximal rate (n = 2). Similarly to test population, the decrease in heart rate after Ivabradine (98 ± 16 bpm vs. 79 ± 9 bpm, P = 0.008) was associated with an increase in diastolic filling time (307 ± 98 ms vs. 240 ± 83 ms, P = 0.012), while LVEF and cardiac output remained unchanged (Table 3). Interestingly, improvement in systolic blood pressure (101 ± 7 mm Hg vs. 92 ± 6 mm Hg, P = 0.007) and urine output (2.7 ± 1.1 L vs. 2.1 ± 1.6 L, P = 0.02) was rapidly observed (at 24 h) after Ivabradine addition (Table 3 and Fig. 4), as well as a decrease in NT-proBNP level (8618 ± 4143 pg/mL to 5103 ± 3525 pg/mL, P = 0.017). Cardiac power output and VO2 did not significantly change after Ivabradine addition (Table 3). However, ScvO2, which displays oxygen balance ratio, was significantly improved after Ivabradine addition (ScvO2 = 46 ± 7% to 59 ± 11%, P = 0.010) (Table 3 and Fig. 4).
3. Results 3.1. In the test population The baseline characteristics of the test population are summarized in Table 1. Briefly, 22 patients (62 ± 17 years old, 18 men) with severe left ventricular (LV) dysfunction (24 ± 8%) from ischemic (8/22) or nonischemic cause (14/22) were included. Ivabradine treatment decreased baseline heart rate by 10 ± 7 points (89 ± 14 bpm to 79 ± 15 bpm, P b 0.0001) and the difference was maintained at peak dose dobutamine (94 ± 18 bpm to 85 ± 15 bpm, P = 0.0004) (Table 2). The decrease in heart rate was associated with improvement in diastolic deceleration time and an increase in absolute and relative E–A duration time (% of the whole cardiac cycle) (Fig. 2 and Table 2). These improvements were observed at rest and remained significant during peak dose dobutamine (50 ± 9% vs. 46 ± 8%, P = 0.014 for baseline, and 51 ± 9% vs. 45 ± 10%, P = 0.002 for dobutamine) (Fig. 2 and Table 2). We observed a decrease in rest cardiac output (4.4 ± 1.1 L/min/m2 to 4.0 ± 1.0 L/min/m2, P = 0.003) after Ivabradine addition, however, this difference in cardiac output (without and with Ivabradine) disappeared during peak dose dobutamine (5.6 ± 1.4 L/min/m2 vs. 5.4 ± 1.1 L/min/m2, P = 0.433). Importantly, the increase in LVEF from baseline to peak dose dobutamine was twice higher with (33 ± 9% vs. 26 ±
3.3. Clinical events in validation population and comparison to control group No symptomatic bradycardia was observed after Ivabradine treatment. The control group was made from patients referred for cardiogenic shock with low ScvO2 value after treatment initiation
Table 2 Clinical and echocardiographic data at rest and peak dobutamine, and delta between rest and peak dobutamine with and without Ivabradine in the test population (stable heart failure patients). LVEDV: left ventricle end diastolic volume; LVESV: left ventricle end systolic volume; LVEF: left ventricle ejection fraction. Rest echocardiography
Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) LVEDV (mL) LVESV (mL) Stroke volume (mL) LVEF (%) Cardiac output (L min−1) E/A ratio E–A duration (ms) Diastolic deceleration time (ms) % diastolic filling time (%) Cardiac power output (W)
Dobutamine echocardiography
Baseline
Ivabradine
P
Baseline
Ivabradine
89 ± 14 111 ± 17
79 ± 15 109 ± 17
10 ± 7 −2 ± 16
b0.0001 0.641
94 ± 18 110 ± 16
85 ± 15 105 ± 18
9±8 −5 ± 14
0.0004 0.266
5±9 −1 ± 10
6±7 −3 ± 12
0.614 0.587
67 ± 11
65 ± 9
−2 ± 12
0.169
66 ± 8
61 ± 8
−5 ± 7
0.004
−1 ± 9
−4 ± 7
0.392
197 153 44 24 4.4 1.6 324 151
± ± ± ± ± ± ± ±
80 70 17 8 1.1 1.1 93 36
46 ± 8 0.84 ± 0.21
202 152 50 26 4.0 1.8 398 177
± ± ± ± ± ± ± ±
85 67 22 8 1.0 0.9 117 43
50 ± 9 0.78 ± 0.22
Delta
Delta between rest and peak dobutamine
5 −2 6 2 −0.5 0.2 74 27
± ± ± ± ± ± ± ±
27 24 13 5 0.7 0.8 67 39
4±7 −0.06 ± 0.16
0.297 0.808 0.012 0.070 0.003 0.421 0.0002 0.012
198 145 53 26 5.6 1.8 298 142
± ± ± ± ± ± ± ±
85 70 23 8 1.4 1.5 93 43
0.014 0.098
45 ± 10 1.07 ± 0.31
203 140 63 33 5.4 1.4 373 178
± ± ± ± ± ± ± ±
92 72 27 9 1.1 0.8 101 51
51 ± 9 0.90 ± 0.25
Delta
5 5 10 6 −0.2 −0.4 75 36
P
± ± ± ± ± ± ± ±
5 33 23 5 1.2 1.2 67 42
6 ± 10 −0.17 ± 0.23
Baseline
± ± ± ± ± ± ± ±
Ivabradine
0.118 0.230 0.033 0.0005 0.433 0.435 0.0005 0.0007
0 −8 9 4 1.3 0.1 −25 −10
27 20 22 4 1.2 0.7 48 28
0.002 0.015
−1 ± 9 0.24 ± 0.29
2 −11 13 7 1.3 −0.4 −24 0
± ± ± ± ± ± ± ±
30 25 16 5 0.8 0.7 56 48
1±6 0.13 ± 0.15
P
0.867 0.715 0.223 0.004 0.444 0.077 0.783 0.393 0.140 0.234
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Fig. 2. Test population; left ventricular diastolic filling parameters at rest and at peak dose dobutamine, without and with Ivabradine. Individual evolution and box plot are shown. Full lines show individual improvement and dash lines show individual impairment.
(indicating a high risk of refractory cardiogenic shock [21]) and with contraindication to heart transplant or assistance. This control group was matched to the validation population for age, heart rate, LVEF and cardiac output (Table 4). During in-hospital follow-up, 2 (22%) patients among the Ivabradine treated population died from refractory cardiogenic
shock at days 9 and 10 respectively. The 7 remaining patients were successfully weaned from dobutamine infusion 9 ± 4 days following inclusion and discharged from the intensive care unit. This population outcome was unexpectedly good when compared to the control group. Indeed we observed 7/9 death (77%) in the control group (P = 0.017).
Fig. 3. Test population; LVEF at rest (A) and at peak dose dobutamine (B) without and with Ivabradine. Increase from baseline to peak dose dobutamine without and with Ivabradine (C). Individual evolution and box plot are shown. Full lines show individual improvement and dash lines show individual impairment.
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Table 3 Hemodynamic parameters before and after Ivabradine administration in patients with refractory cardiogenic shock. LVEF: left ventricle ejection fraction; ScvO2: venous central oxygen saturation; SaO2: arterial oxygen saturation.
Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean blood pressure (mm Hg) Daily urine output (L) LVEF (%) Stroke volume (mL) Cardiac output (L min−1) E/A ratio Diastolic deceleration time (ms) E–A duration (ms) SvO2 (%) SaO2 (%) Hemoglobin VO2 (L/min) Nt-pro-BNP (pg mL−1) Cardiac power output (W)
Dobutamine
Dobutamine and Ivabradine
P
98 92 59 70 2.1 22 37 4.0 2.3 103 240 46 97 10.4 2.5 8618 0.60
79 101 62 75 2.7 27 45 3.9 2.2 123 307 59 98 10.4 1.8 5301 0.64
0.008 0.007 0.284 0.050 0.008 0.091 0.062 0.944 0.499 0.028 0.012 0.010 0.157 0.734 0.216 0.017 0.327
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
16 6 8 6 1.6 7 9 1.2 1.2 23 83 7 2 1.0 1.1 4143 0.17
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
9 7 6 5 1.1 7 5 0.9 1.2 21 98 11 2 0.9 0.5 3525 0.14
4. Discussion This is the first study assessing the hemodynamic effects of dobutamine and Ivabradine association. In compensated and non-compensated heart failure populations, this study demonstrates that Ivabradine may be safely used to limit dobutamine induced tachycardia. In both compensated and uncompensated heart failure patients, heart rate reduction was associated with diastolic function improvement. In heart failure patients with refractory cardiogenic shock, we observed a dramatic improvement in hemodynamic status after Ivabradine addition that allowed progressive weaning from dobutamine support. Dobutamine is the cornerstone of cardiogenic shock treatment [1–3]. It is a sympathomimetic catecholamine that increases cardiac inotropism
with the deleterious effect of increasing heart rate [6,8]. This induced tachycardia increases myocardial oxygen consumption and reduces left ventricular filling period [4,5,7]. Previous animal studies demonstrated that If current inhibitor added to dobutamine improves dobutamine inotropic effect by limiting tachycardia [22,23]. In stable heart failure patients with severe LV dysfunction, De Ferrari et al. showed that heart rate reduction obtained with Ivabradine infusion increases LV stroke volume without decreasing cardiac output [24]. In our study, we also observed an increase in stroke volume in stable heart failure patients. This gain may be related to the Frank–Starling mechanism but also to an improvement of myocardial energy supply by prolonging coronary perfusion during diastole. Contrarily to previous studies, we observed a slight decrease in cardiac output at rest. This asymptomatic decrease in cardiac output may be a compensatory mechanism related to diastolic function and cardiac work improvement. Interestingly, we observed a greater increase in LVEF during dobutamine infusion after Ivabradine treatment that indicates an increase in contractile reserve, probably related to the subtend improvement in diastolic function during dobutamine infusion. In compensated heart failure patients, large randomized trials demonstrated that Ivabradine on top of beta-blocker therapy improves patient symptoms and outcome even in patients with severe heart failure [12, 25–28]. Underlying mechanisms include reversal of LV remodeling and improvement in diastolic function and arterial ventricular coupling [28, 29]. In acute heart failure population [especially in cardiogenic shock], Ivabradine has never been extensively tested because of the general belief that tachycardia is an adaptive way to maintain cardiac output. However, Tan et al. have reported a beneficial effect of Ivabradine administration following Dobutamine weaning in 2 patients, potentially related to an increase in cardiac reserve [30]. In our study, we observed similar changes in the cardiogenic shock population than in the stable heart failure population regarding heart rate and diastolic function after Ivabradine. Conversely, cardiac output remains stable despite a greater decrease in heart rate. These changes are consistent with a previous experimental study demonstrating that coupled pacing, a pacing algorithm used to reduce heart rate without modifying LV inotrope propriety, induced a
Fig. 4. Validation population; heart rate, systolic blood pressure, ScvO2 and daily urine output before and after Ivabradine addition in patients with refractory cardiogenic shock. Individual evolution, mean and standard deviation are shown. * indicates P value ≤ 0.01 for difference between baseline and Ivabradine treatment.
R. Gallet et al. / International Journal of Cardiology 176 (2014) 450–455 Table 4 Validation (refractory cardiogenic shock patients) and control population characteristics. All hemodynamic data have been recorded under dobutamine infusion. LVEF: left ventricle ejection fraction; ScvO2: venous central oxygen saturation.
Age (years) Gender (M/F) Ischemic/non-ischemic cardiomyopathy Dobutamine dose (μg/kg/min) Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean blood pressure (mm Hg) LVEF (%) Cardiac output (mL/min) Cardiac index (mL/min/m2) ScvO2 (%) Event n (%)
Ivabradine patients (n = 9)
Control population (n = 9)
P
54 ± 11 8/1 4/5
60 ± 16 7/2 3/6
0.353 0.527 0.629
7.8 ± 2.6 98 ± 16 92 ± 6 59 ± 8 70 ± 6 22 ± 7 4.0 ± 1.2 2.1 ± 0.6 46 ± 7 2 (22%)
8.4 ± 4.5 96 ± 24 107 ± 19 60 ± 10 76 ± 12 26 ± 11 3.8 ± 1.3 2.2 ± 0.8 53 ± 2 7 (78%)
0.707 0.820 0.029 0.899 0.223 0.445 0.815 0.869 0.007 0.017
decrease in cardiac work and oxygen consumption [31]. In our study changes in LV diastolic function were associated with improvements in hemodynamic status and oxygen balance, assessed by blood pressure, urine output and venous oxygen saturation. This overall hemodynamic improvement might be one explanation for the higher decrease in heart rate observed in this population compared to the stable heart failure population. In addition, dobutamine was successfully withdrawn in the majority of these patients after Ivabradine treatment whereas we observed a very high mortality in a control group of severe cardiogenic shock patients. However results on outcome must be interpreted with caution given the small non-randomized populations. Overall, these results underline the deleterious impact of tachycardia during cardiogenic shock and open new therapeutic perspectives in this setting. 4.1. Limitation One limitation of this study is that most of the hemodynamic parameters (especially cardiac output and left ventricle volumes) were measured using echocardiography. Thermodilution is the gold standard for cardiac output measurement but, pulmonary artery catheterization has become poorly used [32], and several studies reported a good correlation between Doppler derived cardiac output and thermodilution [17–20]. On the other hand, this pilot study included a limited number of patients with cardiogenic shock because only patients not withdrawn from dobutamine support who could not benefit from heart transplant or cardiac assistance were included. Future randomized study should extend inclusion criteria to all cardiogenic shock patients to demonstrate the benefit of Ivabradine in association with dobutamine. A study assessing heart rate reduction by Ivabradine in patients with multiple organ dysfunction syndrome is currently ongoing and will provide further information on the benefit of decreasing heart rate in patients with shock although this study is including shock from different etiology (i.e. septic and cardiogenic) [33]. 5. Conclusion In refractory cardiogenic shock patients, Ivabradine in association with dobutamine is safe and associated with an improvement in left ventricle diastolic filling, oxygen balance and hemodynamic status. Following Ivabradine delivery, most patients were withdrawn from dobutamine support. References [1] Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation 2008;117:686–97.
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