Beta-block the septic heart

Alain Rudiger, MD
Objectives: Cardiac depression is a well-described manifestation of the sepsis syndrome. An important underlying mechanism is the attenuation of the adrenergic response at the cardiomyocyte level. By reducing their cell-specic function (contractility), the cardiomyocytes reduce their energy expenditure. Consequently, the cardiac myocytes survive in a hibernation-like state as long as intracellular energy generation is limited. The objective of this study was to review -blocker therapy for the treatment of septic patients. Data Source: MEDLINE database. Data Synthesis: During established sepsis with organ failure, external adrenergic stimulation of the heart must be kept at a minimum. To blunt the adrenergic response, -blockers have been used in several preclinical and clinical studies. In septic animals, -blockers reduced heart rate, whereas stroke volume was maintained. Esmolol in vivo prevented the downregulation of adrenergic pathways, preserving full cardiac function ex vivo. In addition, -blockers reduced the inammatory response and the degree of lung injury. Some animal studies documented survival benets, particularly when -blockers were administered before the septic insult. In patients with septic shock, blood pressure increased and cardiac indices remained stable with metoprolol administration. Conclusions: Preclinical and clinical studies with -1 receptor blockers during sepsis show promising results. Future studies are needed to establish the optimal dose and timing of its administration. (Crit Care Med 2010; 38[Suppl.]:S608 S612) KEY WORDS: sepsis; shock; heart failure; cardiomyopathy; -blocker; adrenergic blockade; metoprolol; esmolol; multiple organ failure

epsis, the systemic inammatory response to infection, is a multisystem disorder (1). When pathogens invade the hosts, inammatory defense mechanisms are activated resulting in immune, hormonal, metabolic, bioenergetic, and autonomic nervous system modications. The time-dependent interplay between these systems ideally eradicates the invading organisms, but can also result in multiple organ dysfunction (2). Cardiac depression with impaired left ventricular ejection fraction is a well-described manifestation of this syndrome and can be diagnosed in up to 60% of patients with septic shock (3). However, sepsis-induced myocardial depression can be viewed as adaptive and, at least partially, protective process. The objectives of this article are 1) to discuss therapeutic measures with cardioprotective properties; and 2) to review studies on -blocker therapy during sepsis.

Sepsis-induced cardiac depression

Early sepsis is characterized by elevated catecholamine levels (4 6), which derive from the autonomous nervous system, the gut (7), lymphocytes (8, 9), macrophages (10), and neutrophils (11, 12). This adrenergic response augments cardiac contractility (13) and heart rate (14), hence increasing cardiac energy demands. As sepsis progresses, circulatory derangements and mitochondrial dysfunction lead to tissue hypoxia and dysoxia, respectively. On a subcellular level, this reduces adenosine-5-triphosphate formation and energy supply (15). When energy demand outstrips supply, the cardiac myocytes are at risk of cell death. Elevated troponin levels are indicative for such injury (16, 17). To prevent further damage, the cells have to reduce their energy requirements. It can be hypothesized that they do so by reducing their cell-specic functions, hence creating a new balance between energy production and demand (Fig. 1). Several underlying mechanisms of sepsis-induced myocardial depression have been identied (18). Of major importance is the attenuation of the adrenergic response at the cardiomyocyte level resulting from downregulation of -adrenergic receptors (19, 20) and depression of postreceptor signaling pathways (2124). These changes are me-

diated by cytokines from activated immune cells (25, 26). Clinically, this adrenergic downregulation leads to a reversible hyporesponsiveness to dobutamine in patients with septic shock for up to 10 days (27). These effects are probably enhanced by neuronal apoptosis in the cardiovascular autonomic centers (28) and by inactivation of catecholamines through reactive oxygen species (29). Although the overall cardiac function is markedly reduced, the cardiomyocytes survive in a hibernation-like state. Once the septic insult is overcome and cellular energy supply reestablished, the cardiomyocytes start contracting again. Clinicians will note a normalization of the cardiac function in sepsis survivors, typically occurring between days 7 and 10 (30).

-Blockers for the septic heart

In view of these adaptive and protective mechanisms, current treatment guidelines must be challenged and new algorithms proposed. With the Hippocratic Oath keep the sick from harm in mind, external cardiac stimulation with -1 agonists might be inappropriate in established organ dysfunction (31). Indeed, efforts to enhance oxygen delivery above supranormal values by dobutamine administration showed no benet and even harm during established sepsis with concurrent organ failure (32, 33). AdeCrit Care Med 2010 Vol. 38, No. 10 (Suppl.)

From the Intensive Care Unit, University Hospital Zurich, Zurich, Switzerland. Supported by departmental funds. The author has not disclosed any potential conicts of interest. For information regarding this article, E-mail: alain.rudiger@usz.ch Copyright 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e3181f204ca

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Figure 1. Balance between energy expenditure and energy generation. In conditions of reduced energy generation (such as sepsis), the cells are at risk for cell death. By reducing their cell-specic functions, the cells reduce their energy expenditure and create a new balance between energy supply and demand. This state with noncontracting but viable myocytes can be viewed as a form of hibernating myocardium. When the bioenergetic crisis is overcome, the surviving cells have the potential for full functional recovery.

quate analgesia and sedation as well as avoidance of exogenous stress keep adrenergic stimulation of the heart at a minimum (34). However, some authors pushed it further and tested the use of -blockers in preclinical and clinical studies (Table 1). -Blockers in Animal Models of Sepsis. Using an endotoxin model in dogs, Berk et al (35) assessed the effects of the nonselective -blocker propranolol. The -blocker signicantly improved survival, even when it was started 60 mins after lipopolysaccharide injection. Propranolol also prevented the second phase of hypotension, hence reducing uid requirements. Arterial PO2 values were better in propranolol-treated animals, and postmortem investigations showed less lung injury in these animals. In contrast, Schmitz et al (36) demonstrated a negative effect on outcome in propranololtreated mice undergoing cecal ligation and puncture. In this study, -blocker treatment was started at the time of surgery, potentially impairing the initial resuscitation phase. Another explanation for the negative result is that nonselective -blockers inhibit the activation of -2 receptors, which have cardioprotective properties (37).
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Suzuki and coworkers (38) infused the -1 selective adrenergic blocker esmolol into septic rats, which reduced heart rates, blood pressures, and tumor necrosis factor- plasma levels. Interestingly, lactate levels did not increase compared with controls, indicating no excessive anaerobic metabolism. Twenty-four hours later, hearts were removed and mounted on an isolated perfused heart preparation. Hearts from -blocker-treated animals developed higher stroke volumes and used oxygen more efciently. In separate immunohistochemistry experiments, the authors showed a signicant reduction of the -1 receptor density in septic animals. -blocker treatment blunted this response and increased the number of receptors. It can be concluded that -blockers in vivo prevented the downregulation of adrenergic pathways, preserving full cardiac function ex vivo where the circulating catecholamines and -blockers were excluded from the perfusion medium. Hagiwara and coworkers (39) administered a 24-hr infusion of landiolol, a highly selective -1 adrenergic receptor antagonist with a very short half-life, to lipopolysaccharide-treated rats. landiolol blunted the increases of tumor necrosis

factor-, interleukin-6, and high-mobility group box 1 plasma levels. Assessing the heart ex vivo using the Langendorff technique, the hearts from landiololtreated animals showed better systolic and diastolic performance. Postmortem analysis of the lungs showed less tissue injury with landiolol. Ackland et al (40) investigated the effects of the -1 antagonist metoprolol in a different rodent model of sepsis. The systemic administration of metoprolol improved survival signicantly only when the drug was given before the endotoxin injection. The intracerebral administration of metoprolol failed to improve survival, suggesting that peripheral mechanisms are important for attenuating lipopolysaccharide-induced inammation. In separate experiments using a uid-resuscitated, long-term model of fecal peritonitis, metoprolol signicantly reduced heart rate but not stroke volume. There was a trend for improved survival when metoprolol was continuously infused intravenously after the initial uid resuscitation phase. -Blockers in Septic Patients. Berk and colleagues (41) treated ve septic patients with propranolol infusions. These patients had prolonged and therapy-refractory shock before -blocker treatment was started. Two patients died, but the other three patients showed an increase in blood pressure and recovered. The results of this study are difcult to translate to current practice, because several antiquated sepsis therapies (glucagons, high-doses steroids, digitalis) were used. In addition, neither noradrenaline nor adrenaline was available at that time. Gore and Wolfe (42) treated six normotensive septic patients with a 3-hr infusion of esmolol, a short-acting -1 antagonist. The dose was chosen to reduce the heart rate by 20%, which decreased cardiac output accordingly. Importantly, this did not limit oxygen use, affect whole body energy expenditure, or alter adenosine-5-triphosphate availability. Schmittinger and colleagues (43) treated patients with septic shock with uids, noradrenaline, milrinone, and vasopressin. Metoprolol through an enteral route was added within 48 hrs after the onset of shock. Heart rate targets between 65 and 95 beats/min were achieved in 39 of 40 patients. Stroke volumes increased and cardiac indices remained stable in the study population. Overall, mean arterial blood pressures increased
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Table 1. Overview of animal and human studies investigating -blockers during sepsis -Blocker/Dose/Start Propranolol 0.15 to 1.5 mg/ kg, given 5 to 60 mins after endotoxin injection Main Results in -BlockerTreated Subjects Survival 1 from 27% to 72% In vivo: BP 1, uid requirements 2 In vivo: PaO2 1 Postmortem: lung injury 2 In vivo: HR 2, BP 2 In vivo: TNF 2, lactate Ex vivo: HR , SV 1, CO 1, cardiac efciency 1 Postmortem: -1 receptor density 1 In vivo: HR 2, BP In vivo: TNF 2, IL-6 2, HMGB1 2, NF-B activation 2 Ex vivo: LVEDP 2, dP/dt 1, -dP/dt 1 Postmortem: lung injury 2 In vivo: HR 2, SV , CO 2 In vivo: IL-6 2, TNF 2, IL18 2, MCP-1 2 Survival 1 HR2, BP 1 Study Limitations/ Adverse Events Propranolol-treated dogs required infusion of 50% dextrose to prevent hypoglycemia Administration of calcium chloride for contractility and atropine for bradycardia Esmolol and circulating catecholmines excluded from the perfusion medium ex-vivo No outcome data Landiolol and circulating catecholmines excluded from the perfusion medium ex-vivo No outcome data

Model Animal Studies Mongrel dogs Endotoxin injection

Reference

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Wistar rats Fecal peritonitis Isolated perfused heart preparation (ex vivo) 24 hrs after sepsis induction Wistar rats Endotoxin injection Isolated perfused heart preparation (ex vivo) 12 hrs and 24 hrs after LPS injection Sprague Dawley/Wistar rats Endotoxin injections/fecal peritonitis Patient Studies Septic patients (n 5) with refractory shock Mortality 40% Septic patients (n 6) without vasopressors Hospital mortality 16%

Esmolol infusion of 10 mg/ kg/hr or 20 mg/kg/hrs for 24 hrs (in vivo)

38

Landiolol infusion of 0.1mg/ kg/min for 24 hrs (in vivo)

39

Metoprolol pre- and posttreatment (various doses)

Signicant survival benets only with pre-treatment in endotoxin model No control group Use of antiquated sepsis therapies such as glucagon, high dose steroids, or digitalis Small study population No control group Short treatment duration

40

Propranolol 5 mg infusion over 23 hrs, repeated once after 612 hrs Esmolol infusion for 3 hrs 622 mg/min (goal: HR 2 20%)

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Patients with septic shock (n 40) SAPS II 53 28-day mortality 33%

Metoprolol via enteral route 4752 mg/day (goal: HR 95/min After hemodynamic stabilization Combination with NA, milrinone and vasopressin

HR2, SV , CO 2 Resting energy expenditure O2 consumption (calorimetry) ATP concentration in muscle HR2, SV 1, CO Overall, NA and milrinone doses 2 Lactate 2, CRP 2 Organ function variables unchanged

42

Retrospective study No control group NA and milrinone requirements 1 in 9 and 6 patients, respectively Asymptomatic HR 65/min in 2 patients

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ATP, adenosine-5-triphosphate; BP, blood pressure; CI, cardiac index; CO cardiac output; CRP, C-reactive protein; HMGB, high-mobility group box; HR, heart rate; IL, interleukin; LPS, lipopolysaccharide; LVEDP, left ventricular end diastolic pressure; MCP, monocyte chemotactic protein; NA, noradrenaline; NF, nuclear factor; SAPS, Simplied Acute Physiologic Scale; ScvO2, central-venous oxygen saturation; SV, stroke volume; TNF, tumor necrosis factor.

and noradrenaline and milrinone requirements decreased. However, noradrenaline and milrinone doses had to be increased in 22.5% and 15% of the patients, respectively. An overview of studies with -blocker treatments in septic patients is given in Table 1. Apart from their action on the cardiovascular system, -blockers have other profound effects during sepsis (44 46). Inammation, metabolism, and coagulation are all inuenced by -adrenergic modulation. Of note, -blockers have also been successfully used in critically ill patients
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with myocarditis (47), tako-tsubo cardiomyopathy (48, 49), head injury (50), and burns (51, 52).

Other (experimental) forms of cardioprotection during sepsis

Cardiac afterload must be kept at a minimum. The current recommendation of a mean arterial blood pressure 65 mm Hg (53) is likely to result in a critical high afterload for the dysfunctional left ventricle and should be reconsidered in future studies. Similarly, right ventricular afterload can be minimized using ven-

tilator settings with low plateau pressures (54). Levosimendan, a calcium sensitizer, might be a valuable alternative for the -1 agonists, particularly in patients treated with -blockers. It has been successfully used in animal models of sepsis (5557) and septic patients (58). Its main limitations are the vasodilating properties, which potentially decrease the already low blood pressure. Next, isolated heart rate reduction has the potential to considerably lower cardiac energy demands. In addition, a lower heart rate will allow for better ventricular lling during diastole, hence improving stroke volume.
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The novel If-channel inhibitor lvabradine leads to a heart rate-dependent heart rate reduction, and rst clinical studies in acute patients with heart failure are promising (59). When cardiac output is not supported or even therapeutically reduced to protect the heart, new devices or biomarkers are needed to monitor the perfusion and metabolism of vital organs (brain, heart, kidney, gut, liver). To reduce systemic cellular energy requirements, mild therapeutic hypothermia might be applied (60). Ultimately, if cardiac output falls below a critical threshold, mechanical assist devices could provide bridging to recovery (61).

properties. -blocker treatment ideally starts before the septic insult or after hemodynamic stabilization. Finally, all novel concepts discussed in this article necessitate rigorous testing before they can be implemented in clinical practice. Studies should rst investigate patients with preexisting -blocker treatment and/or evidence of acute cardiac injury. Thereby, -blocker titration and close attention to hemodynamic parameters should be applied. However, if the concept of -blocker therapy in sepsis proves successful, it might be usefully extended to other stress cardiomyopathies commonly encountered in the critically ill.

Roundtable discussion
The topic was discussed at the Roundtable conference Thinking Outside the Box before the 30th International Symposium on Intensive Care and Emergency Medicine (March 9 12, 2010) in Brussels, Belgium. Decatecholaminization, which is the reduction of endogenous and exogenous adrenergic stimulation, was agreed to be important in the management of the critically ill patient, particularly in the transition between acute and chronic critical illness. -blocker treatment was considered an interesting option in this respect. However, excessive -blocker dosing may have negative inotropic effects and cause pump failure in an already depressed heart, leading to inappropriately low cardiac output and pulmonary congestion. Hence, -blockers should be titrated in septic patients, and close hemodynamic monitoring is warranted for early detection of potential negative effects. Others commented on the ongoing debate on perioperative -blocker treatment (62). Recently, the American College of Cardiology Foundation and the American Heart Association limited the indication for perioperative -blocker therapy to patients already receiving -blockers (63). Similarly, -blockers in sepsis could be studied rst in patients with pre-existing -blocker therapy. Another patient group worth investigating is patients with elevated troponin levels indicative for acute cardiac injury.

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