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Esmolol Administration to Control Tachycardia in an Ovine Model of Peritonitis

Hosokawa, Koji MD; Su, Fuhong MD, PhD; Taccone, Fabio Silvio MD, PhD; Post, Emiel Hendrik MD; Pereira, Adriano José MD; Herpain, Antoine MD; Creteur, Jacques MD, PhD; Vincent, Jean-Louis MD, PhD

doi: 10.1213/ANE.0000000000002196
Critical Care and Resuscitation: Original Laboratory Research Report
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BACKGROUND: Excessive adrenergic signaling may be harmful in sepsis. Using β-blockers to reduce sympathetic overactivity may modulate sepsis-induced cardiovascular, metabolic, immunologic, and coagulation alterations. Using a randomized ovine fecal peritonitis model, we investigated whether administration of a short-acting β-blocker, esmolol, could control tachycardia without deleterious effects on hemodynamics, renal perfusion, cerebral perfusion, cerebral metabolism, or outcome.

METHODS: After induction of fecal peritonitis, 14 anesthetized, mechanically ventilated, and hemodynamically monitored adult female sheep were randomly assigned to receive a continuous intravenous infusion of esmolol to control heart rate between 80 and 100 bpm (n = 7) or a saline infusion (control group, n = 7). Esmolol was discontinued when the mean arterial pressure decreased below 60 mm Hg. Fluid resuscitation was titrated to maintain pulmonary artery occlusion pressure at baseline values. Left renal blood flow and cerebral cortex perfusion and metabolism were monitored in addition to standard hemodynamic variables.

RESULTS: Esmolol was infused for 11 (9–14) hours; the target heart rate (80–100 bpm) was achieved between 3 and 8 hours after feces injection. In the first 5 hours after the start of the infusion, the decrease in heart rate was compensated by an increase in stroke volume index; later, stroke volume index was not statistically significantly different in the 2 groups, so that the cardiac work index was lower in the esmolol than in the control group. Hypotension (mean arterial pressure <60 mm Hg) occurred earlier (10 [8–12] vs 14 [11–20] hours; P= .01) in the esmolol group than in the control animals. Renal blood flow decreased earlier in the esmolol group, but there were no differences in urine output, cerebral cortex perfusion, metabolism, or survival between the groups.

CONCLUSIONS: In this ovine model of abdominal sepsis, early control of tachycardia by esmolol was associated with a transient increase in stroke volume, followed by earlier hypotension. There were no significant effects of esmolol on cerebral perfusion, metabolism, urine output, or survival.

Published ahead of print July 13, 2017.

From the Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium.

Published ahead of print July 13, 2017.

Accepted for publication April 3, 2017.

The authors declare no conflicts of interest.

Funding: Institutional.

Reprints will not be available from the authors.

Address correspondence to Jean-Louis Vincent, MD, PhD, Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium. Address e-mail to jlvincent@intensive.org.

Excessive β-adrenergic activation in sepsis, which is associated with marked catecholamine release, may contribute to detrimental myocardial, immunological, and metabolic effects.1–6 β-Blockers may mitigate these deleterious effects,7,8 possibly as a result of improved ventricular filling and ventricular-arterial coupling.5 A recent systematic review that included 21 animal and 10 clinical studies suggested that β-blocker therapy in sepsis and septic shock was associated with some improvement in cardiovascular, metabolic, immune, and coagulation disorders.6 However, there is still considerable controversy and many unanswered questions regarding the use of β-blockers in sepsis. Indeed, the reported effects of β-blockers in experimental sepsis are difficult to interpret, in view of the different animal species and models used, and the different β-blocker agents that were given at different times and at different dosages. In some of these studies, administration of a β-blocker maintained a constant cardiac index by increasing stroke volume9,10 or reducing myocardial oxygen demand11–13 without affecting tissue perfusion, as suggested by microvascular flow measurements.10 Several studies also showed that β-blocker administration during sepsis could improve overall outcome.11,13–15 Nevertheless, other studies reported opposite findings, with deleterious effects of β-blockers on tissue perfusion, organ function, and survival.12 An open-label randomized clinical phase 2 trial in 154 patients with septic shock showed that targeting a heart rate of 80 to 94 bpm with esmolol, a short-acting, selective β1-agonist, was associated with a lower 28-day mortality than standard treatment. Patients treated with esmolol had an increase in stroke volume and stroke work index, lower fluid and norepinephrine requirements, and no adverse effects on organ function.13 However, concerns were raised about the high mortality rate (80.5%) in the control group15 and the significant number of patients in both groups who also received the inodilator, levosimendan (49.4% in the esmolol group and 40.3% in the control group).14

More data are, therefore, needed to clarify the role of β-blockers in sepsis. Using an ovine model of lethal abdominal sepsis, which has previously been shown to have the typical hyperdynamic pattern of clinical sepsis and to be clinically relevant,16–18 we studied the effects of heart rate control with esmolol. Our primary aim was to investigate whether using esmolol to control tachycardia would result in hemodynamic compromise; our secondary aim was to examine whether using esmolol to control tachycardia would alter renal perfusion, cerebral perfusion, cerebral metabolism, or outcome.

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METHODS

This prospective randomized controlled experimental study was approved by the local animal ethics committee (No. 509N) and local guidelines on the use of laboratory animals and the Animal Research: Reporting In Vivo Experiments (ARRIVE) guidelines for animal research19 were adhered to.

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Animal Preparation

Fourteen domestic female Ovis aries sheep (weight 25–35 kg) were fasted overnight with free access to water. After premedicating the animals with an intramuscular mixture of midazolam (2 mg/kg; B. Braun, Melsungen, Germany) and ketamine HCl (15 mg/kg; Ceva Santé Animal, Libourne, France), a peripheral venous line (14 gauge, Surflo IV Catheter; Terumo Medical Corporation, Leuven, Belgium) was inserted into the cephalic vein. Intravenous boluses of midazolam (0.6 mg/kg), ketamine HCl (8 mg/kg), fentanyl citrate (30 µg/kg; Janssen, Beerse, Belgium), and rocuronium bromide (0.1 mg/kg; Esmeron, Organon, Oss, the Netherlands) were given, followed by oral endotracheal intubation (8-mm endotracheal tube, Hi-Contour; Mallinckrodt Medical, Athlone, Ireland). Mechanical ventilation (Servo 300 Ventilator; Siemens-Elema, Solna, Sweden) was started, with a heat and moist exchanger (HMEF 750/S GE Healthcare, Helsinki, Finland) in the respiratory circuit. The rumen (stomach) was drained via an orally inserted tube (inner diameter 1.8 cm) to prevent distension. Urine was drained by a Foley catheter (14F; Beiersdorf AG, Hamburg, Germany). During surgery, the animals were anesthetized with a continuous intravenous infusion of midazolam (2.4–3.0 mg/kg/h), ketamine HCl (32–40 mg/kg/h), and morphine HCl (1.6–2 mg/kg/h; Sterop Laboratoria, Brussels, Belgium). Muscle relaxation was achieved using rocuronium (0.2 mg/kg/h).

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Surgical Procedures

The sterile surgical procedure was performed after skin disinfection with 10% povidone-iodine (iso-Betadine; Meda Pharma, Brussels, Belgium). An arterial catheter (4.5F; LeaderCath; Vygon, Ecouen, France) was introduced surgically into the right common carotid artery, connected to a pressure transducer (Edwards Lifesciences, Irvine, CA), and then zeroed at mid-thorax level. An introducer (Intro-Flex, 8.5F; Edwards Lifesciences) was inserted through the right jugular vein, through which a 7.5F Swan-Ganz CCO catheter (Edwards Lifesciences) was advanced into the pulmonary artery under monitoring of waveform.

A midline laparotomy (10 cm) was performed to expose the cecum. After making a double pouch suture, the cecum was perforated (2 mm) and the feces were collected in a syringe. The cecum was cleaned, disinfected with 10% povidone-iodine, and closed. A tube (cut to 20 cm; Beldico, Aye, Belgium) was placed in the abdomen for later injection of feces, and the abdominal wall was closed. The animal was turned to the prone position, and a lung recruitment maneuver (20 cm H2O of positive end-expiratory pressure for 30 seconds) performed. The left renal artery was surgically exposed, and a flow probe (4PS; Transonic Systems, Ithaca, NY) was positioned around it. Gel (Sigma Gel; Parker Laboratories, Fairfield, NJ) was applied to ensure signal quality.

A cross-incision was made on the scalp (2 × 2 cm, centered at 1 cm caudal from ear line) and 2 holes (1.2 mm) were drilled in the skull. After careful puncture of the dura mater with a 22-gauge needle, a laser Doppler flowmetry probe (OxyFlo XP Probe; Oxford Optronix, Oxford, UK) and microdialysis membrane catheter (CMA 20; CMA Microdialysis AB, Solna, Sweden) were introduced 0.5 cm deep into the cortex of the right front lobe. These probes were fixed with wax to avoid dislocation. The microdialysis catheter was connected to a CMA 402 syringe pump (CMA 402; CMA Microdialysis AB), infusing CNS liquid (148 mEq/L NaCl, 2.7 mEq/L KCl, 1.2 mEq/L CaCl2, and 0.85 mEq/L MgCl2; osmolality 305 mOsm/kg; pH 6, CMA CNS; Microdialysis AB) at a rate of 0.3 µL/min and analyzed for glucose, lactate, and pyruvate concentrations using a bedside analyzer (Iscus Flex, CMA Microdialysis).

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Protocol

After a 2-hour stabilization period, peritonitis was induced by injection of the surgically collected autologous feces (1.5 g/kg of body weight) via the peritoneal tube (T0). Two hours after feces injection (T2), the animals were randomly assigned to 1 of 2 groups:

  • a. Esmolol group (n = 7)—animals received a continuous infusion of esmolol (Brevibloc; Baxter, Deerfield, IL) to target a heart rate (HR) of 80 to 100 bpm (Figure 1);
  • b. Control group (n = 7)—animals received a continuous infusion of saline solution (NaCl 0.9%) at a fixed rate of 5 mL/h.

In the 2 groups, the infusion of esmolol or saline solution was interrupted when mean arterial pressure (MAP) decreased to <60 mm Hg despite fluid administration (see below).

Figure 1.

Figure 1.

Both groups received fluid resuscitation with Ringer’s lactate solution (Hartmann; Baxter, Lessines, Belgium) and 6% hydroxyethyl starch solution (degree of substitution, 0.35–0.45: molecular weight, 130,000 Da: Voluven; Fresenius Kabi, Bad Homburg, Germany) in a 1:1 ratio to maintain pulmonary artery occlusion pressure at baseline levels. The adequacy of fluid resuscitation was assessed every 15 to 60 minutes. Fluid resuscitation was discontinued when MAP was <60 mm Hg for 45 minutes to avoid severe pulmonary edema.

The following respiratory settings were used: tidal volume 8 to 10 mL/kg; respiratory rate 14 to 24/min; positive end-expiratory pressure 5 cm H2O; inspired oxygen fraction <0.8; inspiratory:expiratory ratio 1:2; target Paco2 35 to 45 mm Hg. The doses of anesthetic agents (described above) were gradually decreased during the 5 hours after surgery to 0.6 mg/kg/h midazolam, 8 mg/kg/h ketamine, and 0.4 mg/kg/h morphine. Blood glucose and potassium concentrations were measured hourly. Blood glucose was maintained >50 mg/dL with 10-mL boluses of 50% glucose, and K+ was maintained >3.5 mEq/L by supplemental intravenous KCl. Antibiotics and vasopressors were not given.

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Measurements

Hemodynamic variables (HR, arterial pressure, mean pulmonary artery pressure, right atrial pressure, and pulmonary artery occlusion pressure) were collected hourly from a SC9000 monitor (Siemens, Munich, Germany). Cardiac output was estimated using an automatic thermodilution method or manually obtained using a bolus infusion of cold saline when the blood temperature was >41°C (Vigilance Monitor; Edwards Lifesciences). Derived variables (cardiac index, stroke volume index [SVI], pulse pressure, systemic vascular resistance [SVR] index, pulmonary vascular resistance index, left and right ventricular stroke work index, and static thoracopulmonary compliance) were calculated using standard formulas. Body surface area (BSA) was calculated using Meeh’s formula: BSA (m2) = k·W0.67 (k = 0.084, W = body weight, kg). Arterial and mixed venous blood gases, electrolytes, and lactate concentration were analyzed hourly (Cobas b-123; Roche, Rotkreuz, Switzerland). Fluid intake, urine output, glucose administration, and the doses of esmolol and anesthetics were recorded hourly.

Renal blood flow (TS420; Transonic Systems) and laser-Doppler flowmetry (OxyFlo 4000; Oxford Optronix) were recorded hourly and normalized to baseline values. Observations were continued until spontaneous cardiac arrest.

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Statistical Analysis

Continuous variables are presented as mean ± SD, median (25%–75% interquartile range), or mean (95% confidence interval) as appropriate. All analyses were predefined. Mixed-effects polynomial regression models with restricted maximum likelihood estimation and first-order autoregressive (AR1) covariance structure were used to examine the differences in the measured variables between the esmolol and the control groups. When the trajectory of an analyzed variable was unlikely to be linear, we considered up to the second-degree polynomial models of time (hour) so that the effects of hour, hour 2, and hour 3 on that variable were tested as fixed effects. Interaction effects between groups and hour, hour 2, and hour 3 were also tested. Baseline values were included in the model as covariates, so that group comparisons at each particular point in time are adjusted for baseline values. No correction was performed for the multiple comparison tests made across the groups at each point in time. Model checking was performed by inspection of residual and normal plots. A t test was used to compare additional glucose between groups. The log-rank test was used to analyze differences between groups in time to hypotension (MAP <60 mm Hg) and survival. In this exploratory trial, we did not perform an a priori calculation of the sample size or power analysis, but selected the number of animals based on our extensive previous experience with this animal model.16–18 Assuming that a reduction of at least 30% in HR is necessary to achieve a HR between 80 and 100 beats/min, a sample size of 7 animals per group achieves 92% power to detect, during the first 6 hours after treatment administration, a difference of 45 in the esmolol group from a HR of 135 bpm in a repeated measurements design having a AR1 covariance structure when the SD is 25, the correlation between observations on the same subject is .8, and the α level is .05. Statistical analysis was performed using JMP (ver. 10; SAS Institute, Cary, NC) and SPSS version 23 (IBM Corporation, Somers, NY). All tests were 2-sided, and P< .05 was considered statistically significant.

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RESULTS

Table 1.

Table 1.

Table 2.

Table 2.

There were no significant differences in baseline characteristics between the esmolol and the control groups (Table 1) or in doses of anesthetics received during the study (Table 2). Blood temperature and arterial lactate increased and pH decreased over time in both groups without significant differences between groups, except for a slightly lower body temperature in esmolol animals at T16 (Table 2). Esmolol-treated animals needed more additional glucose than did the control animals (3.5 ± 1.6 g/h vs 3.1 ± 1.1 g/h; P = .03).

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Hemodynamics and Cardiac Function

Figure 2.

Figure 2.

In the esmolol group, the target HR (80–100 bpm) was achieved between 3 and 8 hours after feces injection (Figure 1). The dose of esmolol reached a maximum of 0.44 ± 0.38 mg/kg/h at 8 hours, and the infusion was interrupted at 11 (9–14) hours after sepsis induction (Figure 2). In the early phase of therapy (0–5 hours after start of study drug infusion), the decrease in HR in the esmolol group was compensated for by an increase in SVI, while in the later phase, SVI was not different in the 2 groups. Hypotension (MAP <60 mm Hg) occurred earlier (10 [8–12] vs 14 [11–20] hours after feces injection, P = .01) in the esmolol group than in the control animals (Figure 1). Cardiac work index was statistically significantly lower in the esmolol than in the control group between T6 and T10 (Figure 1). Oxygen consumption was statistically significantly lower in the esmolol group than in the control group from T0 to T12 (Table 2). There were no statistically significant differences in the amount of fluid administered over time in the 2 groups or in cardiac filling pressures (Table 2).

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Renal Blood Flow and Urine Output

Renal blood flow and urine output decreased over time in the 2 groups. Renal blood flow decreased earlier in the esmolol group than in the control group, but there were no statistically significant differences between groups in urine output (Table 2).

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Brain Regional Perfusion and Brain Metabolism

Table 3.

Table 3.

Brain cortex perfusion increased slightly in both groups for 5 hours, followed by a decrease thereafter with no statistically significant differences between the groups at any time point (Table 2). Interstitial lactate concentrations and the lactate/pyruvate ratio increased with development of septic shock in both groups (Table 3).

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Survival

There was no statistically significant difference in the survival time in the 2 groups (19 [18–21] hours for the esmolol group and 21 [19–24] hours for the control group; P= .26).

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DISCUSSION

This study tested the effects of HR control with esmolol on global hemodynamics, renal perfusion, and brain cortex perfusion and metabolism in an ovine model of septic shock. Esmolol administration effectively reduced HR, which was associated with a transient increase in stroke volume in this group, so that there were no differences in cardiac output and MAP between the groups in this early phase. However, hypotension developed earlier in the esmolol-treated animals and renal blood flow decreased earlier, although with little effect on urine output, right brain cortex perfusion, or metabolism. Glucose requirements were higher in the esmolol-treated animals. There were no differences in survival time.

Our model is characterized by a hyperdynamic state associated with increased HR and profound vasodilation. In this context, controlling tachycardia might optimize myocardial efficiency by reducing myocardial oxygen consumption and improving left ventricular filling.20 The results of our study agree with findings by Morelli et al,13 who showed that, in patients with septic shock, a reduction in HR to 80 to 95 bpm with esmolol was associated with an increase in SVI and left ventricular stroke work index. However, in the present study, the effect of esmolol on SVI was transient, lasting for approximately 5 hours only. Thereafter, SVI was not significantly different in the 2 groups, so that cardiac work was lower in the esmolol than in the control group. This may have been caused by depressed myocardial contractility due to the administration of increasingly higher doses of esmolol. Furthermore, high doses of esmolol are recognized to cause reflex tachycardia due to excessive hypotension.21 In healthy dogs, esmolol at 400 μg/kg/min was associated with reduced cardiac contractility,22 and we used doses of up to 800 μg/kg/min, higher than the usual dose in patients. These high doses were, however, necessary to achieve the target HR of 80 to 100 bpm while counteracting the diminishing effectiveness of the drug, possibly as a result of β1-receptor saturation or downregulation.23,24 This effect may be species specific; in addition, the response to esmolol by healthy young animals may be different than that of critically ill elderly patients with cardiovascular disease.

The administration of esmolol was associated with an earlier onset of shock. As there was a trend to lower cardiac output and SVR values in the esmolol-treated animals, it is likely that both these components contributed to the lower blood pressure in these animals. The inhibition of renin release25,26 and decreased renin activity23 via β1 blockade may have impaired angiotensin II formation, possibly explaining the trend toward a lower SVR.24 Findings on the effects of β-blockade on SVR in sepsis are variable9–11,21 and range from unchanged11 to transiently decreased,10 depending on the model used.

Despite the earlier and more severe hypotension with esmolol, brain cortex perfusion and metabolism were not statistically significantly different between groups at any time point. This observation suggests that esmolol may have caused an increase in the brain tolerance to hypotension. Indeed, such effects have been noted in the splanchnic circulation. In a rat septic shock model induced by fecal peritonitis, esmolol helped restore mesenteric vasoreactivity to norepinephrine.9 In a model of porcine endotoxemia, Jacquet-Lagrèze et al8 reported that esmolol improved the gut microcirculation, despite a lower MAP than in the control group. These findings may be helpful when considering that the earlier decrease in MAP in the esmolol group did not result in a corresponding alteration in renal function, as suggested by a lack of difference in urine output in the 2 groups.

Finally, animals receiving esmolol needed more glucose administration to maintain normal blood glucose levels. This finding could be explained by increased hepatic glucose uptake,25 inhibition of glycogenolysis,26 and reduced lipolysis driven by catecholamines.27 Blocking β1 (or β3) pathways increased hepatic extraction of glucose,25 as shown with propranolol in a gangrenous cholecystitis model.28 Blocking β1 receptors can also enhance insulin sensitivity.29

There are several limitations of our study. First, although our period of observation lasted for 24 hours, we cannot exclude a possible beneficial long-term effect of the use of esmolol in sepsis. Our acute and lethal sepsis model may limit the extrapolation of our findings to the more prolonged sepsis that typically occurs in a clinical setting. Second, the use of healthy young animals may not reflect the complex clinical population in which multiple comorbidities are usually present. The presence of coronary artery disease in clinical populations may, in particular, influence the results.13 Third, we avoided giving vasoactive and inotropic agents, because these would have complicated the interpretation of our results, especially because esmolol has been reported to upregulate α1-vascular adrenoceptors.9

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CONCLUSIONS

In this ovine model of abdominal sepsis, the administration of esmolol to control HR was associated with a transient increase in SVI, so that cardiac output and MAP were not affected in the early phase. Esmolol administration was associated with an earlier onset of hypotension, although urine output and cerebral metabolism were not adversely affected.

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DISCLOSURES

Name: Koji Hosokawa, MD.

Contribution: This author helped design the study, perform the experiments, analyze the data, draft the article, and read and approve the final manuscript.

Name: Fuhong Su, MD, PhD.

Contribution: This author helped design the study, perform the experiments, analyze the data, draft the article, and read and approve the final manuscript.

Name: Fabio Silvio Taccone, MD, PhD.

Contribution: This author helped design the study, interpret the data, critically revise the article, and read and approve the final manuscript.

Name: Emiel Hendrik Post, MD.

Contribution: This author helped coordinate the experiment, acquire the data, revise the article, and read and approve the final manuscript.

Name: Adriano José Pereira, MD.

Contribution: This author helped coordinate the experiment, acquire the data, revise the article, and read and approve the final manuscript.

Name: Antoine Herpain, MD.

Contribution: This author helped coordinate the experiment, acquire the data, revise the article, and read and approve the final manuscript.

Name: Jacques Creteur, MD, PhD.

Contribution: This author helped design the study, interpret the data, critically revise the article, and read and approve the final manuscript.

Name: Jean-Louis Vincent, MD, PhD.

Contribution: This author helped design the study, interpret the data, critically revise the article, and read and approve the final manuscript.

This manuscript was handled by: Avery Tung, MD, FCCM.

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