Microvascular Effects of Heart Rate Control With Esmolol in Patients With Septic Shock: A Pilot Study*

none14β-blocker therapy may control heart rate and attenuate the deleterious effects of β-stimulating catecholamines in septic shock. However, their negative chronotropy and inotropy may potentially lead to an inappropriately low cardiac output, with a subsequent compromise of microvascular blood flow. The purpose of the present pilot study was to investigate the effects of reducing heart rate to less than 95 beats per minute in patients with septic shock using the β-1 adrenoceptor blocker, esmolol, with specific focus on systemic hemodynamics and the microcirculation.Prospective, observational clinical study.Multidisciplinary ICU at a university hospital.After 24 hours of initial hemodynamic optimization, 25 septic shock patients with a heart rate greater than or equal to 95 beats per minute and requiring norepinephrine to maintain mean arterial pressure greater than or equal to 65 mm Hg received a titrated esmolol infusion to maintain heart rate less than 95 beats per minute. Sublingual microcirculatory blood flow was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 24 hours after esmolol administration. Heart rates targeted between 80 and 94 beats per minute were achieved in all patients. Whereas cardiac index decreased (4.0 [3.5; 5.3] vs 3.1 [2.6; 3.9] L/min/m; p < 0.001), stroke volume remained unchanged (34 [37; 47] vs 40 [31; 46] mL/beat/m; p = 0.32). Microcirculatory blood flow in small vessels increased (2.8 [2.6; 3.0] vs 3.0 [3.0; 3.0]; p = 0.002), while the heterogeneity index decreased (median 0.06 [interquartile range 0; 0.21] vs 0 [0; 0]; p = 0.002). PaO2 and pH increased while PaCO2 decreased (all p < 0.05). Of note, norepinephrine requirements were significantly reduced by selective β-1 blocker therapy (0.53 [0.29; 0.96] vs 0.41 [0.22; 0.79] µg/kg/min; p = 0.03).This pilot study demonstrated that heart rate control by a titrated esmolol infusion in septic shock patients was associated with maintenance of stroke volume, preserved microvascular blood flow, and a reduction in norepinephrine requirements.A. Morelli;A. Donati;C. Ertmer;S. Rehberg;T. Kampmeier;A. Orecchioni;A. D'Egidio;V. Cecchini;G. Landoni;P. Pietropaoli;M. Westphal;M. Venditti;A. Mebazaa;M. SingerA., Morelli; Donati, Abele; C., Ertmer; S., Rehberg; T., Kampmeier; A., Orecchioni; A., D'Egidio; V., Cecchini; G., Landoni; P., Pietropaoli; M., Westphal; M., Venditti; A., Mebazaa; M., Singe

Effects of vasopressinergic receptor agonists on sublingual microcirculation in norepinephrine-dependent septic shock.

none15ABSTRACT: INTRODUCTION: The present study was designed to determine the effects of continuously infused norepinephrine (NE) plus (1) terlipressin (TP) or (2) arginine vasopressin (AVP) or (3) placebo on sublingual microcirculation in septic shock patients. The primary study end point was a difference of ≥ 20\% in the microvascular flow index of small vessels among groups. METHODS: The design of the study was a prospective, randomized, double-blind clinical trial. NE was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg after establishment of normovolemia in 60 septic shock patients. Thereafter patients (n = 20 per group) were randomized to receive continuous infusions of either TP (1 μg/kg/hour), AVP (0.04 U/minute) or placebo (isotonic saline). In all groups, open-label NE was adjusted to maintain MAP within threshold values if needed. The sublingual microcirculatory blood flow of small vessels was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 6 hours after randomization. RESULTS: TP and AVP decreased NE requirements at the end of the 6-hour study period. The data are medians (25th and 75th interquartile ranges (IQRs)): 0.57 μg/kg/minute (0.29 to 1.04) vs. 0.16 μg/kg/minute (0.03 to 0.37) for TP and 0.40 μg/kg/minute (0.20 to 1.05) vs. 0.23 μg/kg/minute (0.03 to 0.77) for AVP, with statistical significance of P < 0.05 vs. baseline and vs. placebo. There were no differences in sublingual microcirculatory variables, systemic hemodynamics, oxygen transport and acid-base homeostasis among the three study groups during the entire observation period. The proportions of perfused vessels increased in relation to baseline within all study groups, and there were no significant differences between groups. The specific data were as follows (median (IQR)): 9.7\% (2.6 to 19.8) for TP, 8.9\% (0.0 to 17.8) for AVP, and 6.9\% (3.5 to 10.1) for placebo (P < 0.05 vs. baseline for each comparison), as well as perfused vessel density 18.6\% (8.6 to 36.9) for TP, 20.2\% (-3.0 to 37.2) for AVP, and 11.4\% (-3.0 to 19.4) for placebo (P < 0.05 vs. baseline for each comparison). CONCLUSIONS: The present study suggests that to achieve a MAP of 65 to 75 mmHg in septic patients treated with NE, the addition of continuously infused low-dose TP or AVP does not affect sublingual microcirculatory blood flow. In addition, our results suggest that microcirculatory flow abnormalities are mainly related to other factors (for example, volume status, timing, hemodynamics and progression of the disease) rather than to the vasopressor per se. TRIAL REGISTRATION: ClinicalTrial.gov NCT00995839.A. Morelli;A. Donati;C. Ertmer;S. Rehberg;T. Kampmeier;A. Orecchioni;A. D. Russo;A. D'Egidio;G. Landoni;M. R. Lombrano;L. Botticelli;A. Valentini;A. Zangrillo;P. Pietropaoli;M. WestphalA., Morelli; Donati, Abele; C., Ertmer; S., Rehberg; T., Kampmeier; A., Orecchioni; A. D., Russo; A., D'Egidio; G., Landoni; M. R., Lombrano; L., Botticelli; A., Valentini; A., Zangrillo; P., Pietropaoli; M., Westpha

Effects of levosimendan on mitochondrial function in patients with septic shock: A randomized trial

Mitochondrial dysfunction is key feature of septic shock and contributes to the development of sepsis related organ dysfunction. It is characterized by a variable reduction of the respiratory chain (RC) activities, altered mitochondrial morphology and reactive oxygen species production. Recent data have reported the efficacy of levosimendan, a calcium sensitizer, in improving heart performance and organ perfusion in critically ill patients. Moreover, it has been demonstrated that Levosimendan has antioxidant properties. Nevertheless, the effects of levosimendan on mitochondrial function are not fully elucidated. The objective of this study was therefore to evaluate the effect of levosimendan on mitochondria performance. Five mitochondrial parameters were screened: the redox status; the amount of scavenging enzymes; the activities of the RC complexes; the mitochondrial content; the steady state levels of the RC subunits; the mitochondrial biogenesis. Our results show that patients treated with levosimendan had a significant reduction of glutathionylated proteins and an increase in the amount of the antioxidant enzyme MnSOD, underlining its antioxidant properties. The activities of the RC complexes I, II and III were unchanged in the mitochondria of patients treated with levosimendan compared to controls whereas the mitochondrial content was significantly higher in levosimendan vs. control patients. Finally, evaluation of mitochondrial biogenesis did not show any significant difference in the two groups, although an overall increase in the amount of the RC subunits was observed in the levosimendan group. In conclusion, our study demonstrated that in septic shock patients, Levosimendan exerts antioxidant action by increasing antioxidant defense and lowering oxidative damage. (C) 2014 Elsevier Masson SAS. All rights reserved.Mitochondrial dysfunction is key feature of septic shock and contributes to the development of sepsis related organ dysfunction. It is characterized by a variable reduction of the respiratory chain (RC) activities, altered mitochondrial morphology and reactive oxygen species production. Recent data have reported the efficacy of levosimendan, a calcium sensitizer, in improving heart performance and organ perfusion in critically ill patients. Moreover, it has been demonstrated that Levosimendan has antioxidant properties. Nevertheless, the effects of levosimendan on mitochondrial function are not fully elucidated. The objective of this study was therefore to evaluate the effect of levosimendan on mitochondria performance. Five mitochondrial parameters were screened: the redox status; the amount of scavenging enzymes; the activities of the RC complexes; the mitochondrial content; the steady state levels of the RC subunits; the mitochondrial biogenesis. Our results show that patients trea

Heart rate reduction with esmolol is associated with improved arterial elastance in patients with septic shock. A prospective observational study

Ventricular-arterial (V-A) decoupling decreases myocardial efficiency and is exacerbated by tachycardia that increases static arterial elastance (Ea). We thus investigated the effects of heart rate (HR) reduction on Ea in septic shock patients using the beta-blocker esmolol. We hypothesized that esmolol improves Ea by positively affecting the tone of arterial vessels and their responsiveness to HR-related changes in stroke volume (SV). After at least 24 h of hemodynamic optimization, 45 septic shock patients, with an HR aeyen95 bpm and requiring norepinephrine to maintain mean arterial pressure (MAP) aeyen65 mmHg, received a titrated esmolol infusion to maintain HR between 80 and 94 bpm. Ea was calculated as MAP/SV. All measurements, including data from right heart catheterization, echocardiography, arterial waveform analysis, and norepinephrine requirements, were obtained at baseline and at 4 h after commencing esmolol. Esmolol reduced HR in all patients and this was associated with a decrease in Ea (2.19 +/- A 0.77 vs. 1.72 +/- A 0.52 mmHg l(-1)), arterial dP/dt (max) (1.08 +/- A 0.32 vs. 0.89 +/- A 0.29 mmHg ms(-1)), and a parallel increase in SV (48 +/- A 14 vs. 59 +/- A 18 ml), all p < 0.05. Cardiac output and ejection fraction remained unchanged, whereas norepinephrine requirements were reduced (0.7 +/- A 0.7 to 0.58 +/- A 0.5 A mu g kg(-1) min(-1), p < 0.05). HR reduction with esmolol effectively improved Ea while allowing adequate systemic perfusion in patients with severe septic shock who remained tachycardic despite standard volume resuscitation. As Ea is a major determinant of V-A coupling, its reduction may contribute to improving cardiovascular efficiency in septic shock

Effects of vasopressinergic receptor agonists on sublingual microcirculation in norepinephrine-dependent septic shock

ABSTRACT: INTRODUCTION: The present study was designed to determine the effects of continuously infused norepinephrine (NE) plus (1) terlipressin (TP) or (2) arginine vasopressin (AVP) or (3) placebo on sublingual microcirculation in septic shock patients. The primary study end point was a difference of ≥ 20\% in the microvascular flow index of small vessels among groups. METHODS: The design of the study was a prospective, randomized, double-blind clinical trial. NE was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg after establishment of normovolemia in 60 septic shock patients. Thereafter patients (n = 20 per group) were randomized to receive continuous infusions of either TP (1 μg/kg/hour), AVP (0.04 U/minute) or placebo (isotonic saline). In all groups, open-label NE was adjusted to maintain MAP within threshold values if needed. The sublingual microcirculatory blood flow of small vessels was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 6 hours after randomization. RESULTS: TP and AVP decreased NE requirements at the end of the 6-hour study period. The data are medians (25th and 75th interquartile ranges (IQRs)): 0.57 μg/kg/minute (0.29 to 1.04) vs. 0.16 μg/kg/minute (0.03 to 0.37) for TP and 0.40 μg/kg/minute (0.20 to 1.05) vs. 0.23 μg/kg/minute (0.03 to 0.77) for AVP, with statistical significance of P < 0.05 vs. baseline and vs. placebo. There were no differences in sublingual microcirculatory variables, systemic hemodynamics, oxygen transport and acid-base homeostasis among the three study groups during the entire observation period. The proportions of perfused vessels increased in relation to baseline within all study groups, and there were no significant differences between groups. The specific data were as follows (median (IQR)): 9.7\% (2.6 to 19.8) for TP, 8.9\% (0.0 to 17.8) for AVP, and 6.9\% (3.5 to 10.1) for placebo (P < 0.05 vs. baseline for each comparison), as well as perfused vessel density 18.6\% (8.6 to 36.9) for TP, 20.2\% (-3.0 to 37.2) for AVP, and 11.4\% (-3.0 to 19.4) for placebo (P < 0.05 vs. baseline for each comparison). CONCLUSIONS: The present study suggests that to achieve a MAP of 65 to 75 mmHg in septic patients treated with NE, the addition of continuously infused low-dose TP or AVP does not affect sublingual microcirculatory blood flow. In addition, our results suggest that microcirculatory flow abnormalities are mainly related to other factors (for example, volume status, timing, hemodynamics and progression of the disease) rather than to the vasopressor per se. TRIAL REGISTRATION: ClinicalTrial.gov NCT00995839

Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial

β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects