Christian Ertmer

Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock A Randomized Clinical Trial

IMPORTANCE 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. OBJECTIVE To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock. DESIGN, SETTING, AND PATIENTS Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P < .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P < .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P < .001). CONCLUSIONS AND RELEVANCE For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01231698.

Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study.

IntroductionThe purpose of the present study was to investigate microcirculatory blood flow in patients with septic shock treated with levosimendan as compared to an active comparator drug (i.e. dobutamine). The primary end point was a difference of ≥ 20% in the microvascular flow index of small vessels (MFIs) among groups.MethodsThe study was designed as a prospective, randomized, double-blind clinical trial and performed in a multidisciplinary intensive care unit. After achieving normovolemia and a mean arterial pressure of at least 65 mmHg, 40 septic shock patients were randomized to receive either levosimendan 0.2 μg·kg-1·min-1 (n = 20) or an active comparator (dobutamine 5 μg·kg-1·min-1; control; n = 20) for 24 hours. Sublingual microcirculatory blood flow of small and medium vessels was assessed by sidestream dark-field imaging. Microcirculatory variables and data from right heart catheterization were obtained at baseline and 24 hours after randomization. Baseline and demographic data were compared by means of Mann-Whitney rank sum test or chi-square test, as appropriate. Microvascular and hemodynamic variables were analyzed using the Mann-Whitney rank sum test.ResultsMicrocirculatory flow indices of small and medium vessels increased over time and were significantly higher in the levosimendan group as compared to the control group (24 hrs: MFIm 3.0 (3.0; 3.0) vs. 2.9 (2.8; 3.0); P = .02; MFIs 2.9 (2.9; 3.0) vs. 2.7 (2.3; 2.8); P < .001). The relative increase of perfused vessel density vs. baseline was significantly higher in the levosimendan group than in the control group (dMFIm 10 (3; 23)% vs. 0 (-1; 9)%; P = .007; dMFIs 47 (26; 83)% vs. 10 (-3; 27); P < .001). In addition, the heterogeneity index decreased only in the levosimendan group (dHI -93 (-100; -84)% vs. 0 (-78; 57)%; P < .001). There was no statistically significant correlation between systemic and microcirculatory flow variables within each group (each P > .05).ConclusionsCompared to a standard dose of 5 μg·kg-1·min-1 of dobutamine, levosimendan at 0.2 μg·kg-1·min-1 improved sublingual microcirculatory blood flow in patients with septic shock, as reflected by changes in microcirculatory flow indices of small and medium vessels.Trial registrationNCT00800306.

Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial.

IntroductionPrevious findings suggest that a delayed administration of phenylephrine replacing norepinephrine in septic shock patients causes a more pronounced hepatosplanchnic vasoconstriction as compared with norepinephrine. Nevertheless, a direct comparison between the two study drugs has not yet been performed. The aim of the present study was, therefore, to investigate the effects of a first-line therapy with either phenylephrine or norepinephrine on systemic and regional hemodynamics in patients with septic shock.MethodsWe performed a prospective, randomized, controlled trial in a multidisciplinary intensive care unit in a university hospital. We enrolled septic shock patients (n = 32) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomly allocated to treatment with either norepinephrine or phenylephrine infusion (n = 16 each) titrated to achieve a mean arterial pressure between 65 and 75 mmHg. Data from right heart catheterization, a thermodye dilution catheter, gastric tonometry, acid-base homeostasis, as well as creatinine clearance and cardiac troponin were obtained at baseline and after 12 hours. Differences within and between groups were analyzed using a two-way analysis of variance for repeated measurements with group and time as factors. Time-independent variables were compared with one-way analysis of variance.ResultsNo differences were found in any of the investigated parameters.ConclusionsThe present study suggests there are no differences in terms of cardiopulmonary performance, global oxygen transport, and regional hemodynamics when phenylephrine was administered instead of norepinephrine in the initial hemodynamic support of septic shock.Trial registrationClinicalTrial.gov NCT00639015

Microvascular effects of heart rate control with esmolol in patients with septic shock: a pilot study.

Objective:&bgr;-blocker therapy may control heart rate and attenuate the deleterious effects of &bgr;-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 &bgr;-1 adrenoceptor blocker, esmolol, with specific focus on systemic hemodynamics and the microcirculation. Design:Prospective, observational clinical study. Setting:Multidisciplinary ICU at a university hospital. Measurements and Main Results: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/m2; p < 0.001), stroke volume remained unchanged (34 [37; 47] vs 40 [31; 46] mL/beat/m2; 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 &bgr;-1 blocker therapy (0.53 [0.29; 0.96] vs 0.41 [0.22; 0.79] µg/kg/min; p = 0.03). Conclusions: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.

Effects of short-term simultaneous infusion of dobutamine and terlipressin in patients with septic shock: the DOBUPRESS study†

BACKGROUND Terlipressin bolus infusion may reduce cardiac output and global oxygen supply. The present study was designed to determine whether dobutamine may counterbalance the terlipressin-induced depression in mixed-venous oxygen saturation (Svo) in patients with catecholamine-dependent septic shock. METHODS Prospective, randomized, controlled study performed in a university hospital intensive care unit. Septic shock patients requiring a continuous infusion of norepinephrine (0.9 microg kg(-1) min(-1)) to maintain mean arterial pressure (MAP) at 70 (sd 5) mm Hg were randomly allocated to be treated either with (i) sole norepinephrine infusion (control, n=20), (ii) a single dose of terlipressin 1 mg (n=19), or (iii) a single dose of terlipressin 1 mg followed by dobutamine infusion titrated to reverse the anticipated reduction in Svo2 (n=20). Systemic, pulmonary, and regional haemodynamic variables were obtained at baseline and after 2 and 4 h. Laboratory surrogate markers of organ (dys)function were tested at baseline and after 12 and 24 h. RESULTS Terlipressin (with and without dobutamine) infusion preserved MAP at 70 (5) mm Hg, while allowing to reduce norepinephrine requirements to 0.17 (0.2) and 0.2 (0.2) microg kg(-1) min(-1), respectively [vs1.4 (0.3) microg kg(-1) min(-1) in controls at 4 h; each P<0.001]. The terlipressin-linked decrease in Svo2 was reversed by dobutamine at a mean dose of 20 (8) microg kg(-1) min(-1) [Svo2 at 4 h: 59 (11)% vs 69 (12)%, P=0.028]. CONCLUSIONS In human catecholamine-dependent septic shock, terlipressin (with and without concomitant dobutamine infusion) increases MAP and markedly reduces norepinephrine requirements. Although no adverse events were noticed in the present study, potential benefits of increasing Svo2 after terlipressin bolus infusion need to be weighted against the risk of cardiovascular complications resulting from high-dose dobutamine.

Continuous versus bolus infusion of terlipressin in ovine endotoxemia.

In patients with sepsis, hemodynamic support is often complicated by a tachyphylaxis against conventional vasopressor agents. Bolus infusion of terlipressin, a vasopressin analog, has been reported to increase mean arterial pressure in patients with catecholamine-resistant septic shock. However, bolus infusion of terlipressin may be associated with severe side effects, including pulmonary vasoconstriction and impairment of oxygen delivery. We hypothesized that continuous low-dose infusion of terlipressin may reverse sepsis-related systemic arterial hypotension with reduced side effects as compared with the traditional concept of bolus administration. Twenty-seven adult sheep were instrumented for chronic study. After a baseline measurement, Salmonella typhosa endotoxin (10 ng·kg−1·min−1) was continuously administered for the next 40 h. After 16 h of endotoxemia, the surviving sheep (n = 24) were randomly assigned to be treated with either a continuous infusion of terlipressin (2 mg for 24 h), bolus injections of terlipressin (1 mg every 6 h), or placebo (normal saline; each n = 8). Continuous infusion of terlipressin permanently reversed endotoxin-induced systemic arterial hypotension (P < 0.001) and improved left ventricular stroke work index in all sheep (P < 0.05). Intermittent bolus injections of terlipressin were linked to decreases in heart rate and cardiac index and increases in pulmonary vascular resistance index (each, P < 0.001). These unwanted side effects were prevented by continuous low-dose infusion of the drug. In conclusion, continuous infusion of terlipressin stabilized hemodynamics and improved myocardial performance in endotoxemic ewes without obvious side effects. Continuous low-dose terlipressin infusion may represent a useful alternative treatment of arterial hypotension related to sepsis and systemic inflammatory response syndrome.

Methylprednisolone reverses vasopressin hyporesponsiveness in ovine endotoxemia

Tachyphylaxis against catecholamines often complicates hemodynamic support in patients with septic shock. Recent experimental and clinical research suggests that the hemodynamic response to exogenous arginine vasopressin (AVP) infusion may also be blunted. The purpose of the present study was therefore to clarify whether the efficacy of a continuous AVP infusion (0.04 U · min−1) decreases over time in ovine endotoxemia. An additional objective was to determine whether the anticipated hyporesponsiveness can be counteracted by corticosteroids. Fourteen adult ewes (37 ± 1 kg) were instrumented for chronic hemodynamic monitoring. All ewes received a continuous endotoxin infusion that contributed to a hypotensive-hyperdynamic circulation. After 16 h of endotoxemia, the sheep were randomized to receive either AVP (0.04 U · min−1) or the vehicle (normal saline; n = 7 each). After 6 h of AVP or placebo infusion, respectively, methylprednisolone (30 mg · kg−1) was injected. Arginine vasopressin infusion increased mean arterial pressure and systemic vascular resistance index at the expense of a reduced cardiac index (P < 0.05 each). Supraphysiologic AVP plasma levels in the treatment group (298 ± 15 pg · mL−1) were associated with increased surrogate parameters of liver, mesenterial, and myocardial dysfunction. After 6 h of continuous AVP infusion, the vasopressor effect was significantly reduced. Interestingly, a bolus infusion of methylprednisolone (30 mg · kg−1) reestablished mean arterial pressure by increasing both cardiac index and systemic vascular resistance index. The present study demonstrates that in endotoxemia, (a) the vasopressor effect of AVP infusion may be reduced, (b) corticosteroids may potentially be useful to increase the efficacy of AVP infusion, and (c) even moderate AVP doses may potentially impair myocardial and hepatic function.

Fluid resuscitation in multiple trauma patients.

Purpose of review Fluid resuscitation in trauma patients with hemorrhagic shock is controversially discussed in the literature. The coincidence of brain injury complicates management of these patients. This article summarizes the current knowledge on nonblood component fluid resuscitation and choice of fluids in patients with multiple trauma. Recent findings Whereas current evidence suggests the efficacy of fluid therapy in hemorrhagic shock without active bleeding, experimental and clinical data demonstrate that aggressive volume challenge may be futile or even deleterious in the setting of uncontrolled hemorrhage. Large amounts of isotonic crystalloids may be associated with hypothermia, acidosis and inflammation. In patients with traumatic brain injury hypertonic solutions may positively influence inflammation and intracranial pressure without affecting neurologic outcome or mortality. Summary To date no large-scale clinical studies exist to either support or refute the use of nonblood component fluid resuscitation of hemorrhagic shock in trauma patients. The optimal choice of fluid remains to be determined, but existing evidence suggests avoiding crystalloids in favor of hypertonic solutions. The role of modern, iso-oncotic colloids in the treatment of hemorrhagic shock has not yet been sufficiently defined. In patients with concomitant brain injury, arterial hypotension must be avoided and infusion of hypotonic solutions is obsolete, whereas administration of hypertonic solutions may exert beneficial effects beyond hemodynamic stabilization.

GLIBENCLAMIDE DOSE RESPONSE IN PATIENTS WITH SEPTIC SHOCK: EFFECTS ON NOREPINEPHRINE REQUIREMENTS, CARDIOPULMONARY PERFORMANCE, AND GLOBAL OXYGEN TRANSPORT

Adenosine triphosphate-sensitive potassium channels are important regulators of arterial vascular smooth muscle tone and are implicated in the pathophysiology of catecholamine tachyphylaxis in septic shock. The present study was designed as a prospective, randomized, double-blinded, clinical pilot study to determine whether different doses of glibenclamide have any effects on norepinephrine requirements, cardiopulmonary hemodynamics, and global oxygen transport in patients with septic shock. We enrolled 30 patients with septic shock requiring invasive hemodynamic monitoring and norepinephrine infusion of 0.5 μg·kg−1·min−1 or greater to maintain MAP between 65 and 75 mmHg. In addition to standard therapy, patients were randomized to receive either 10, 20, or 30 mg of enteral glibenclamide. Systemic hemodynamics, global oxygen transport including arterial lactate concentrations, gas exchange, plasma glucose concentrations, and electrolytes were determined at baseline and after 3, 6, and 12 h after administration of the study drug. Glibenclamide decreased plasma glucose concentrations in a dose-dependent manner but failed to reduce norepinephrine requirements. None of the doses had any effects on cardiopulmonary hemodynamics, global oxygen transport, gas exchange, or electrolytes. These data suggest that oral glibenclamide in doses from 10 to 30 mg fails to counteract arterial hypotension and thus to reduce norepinephrine requirements in catecholamine-dependent human septic shock.

Role of adenosine triphosphate-sensitive potassium channel inhibition in shock states: physiology and clinical implications.

Shock states are associated with an impaired tissue oxygen supply-demand relationship and perturbations within the microcirculation, leading to global tissue hypoxia, finally resulting in multiple-organ failure or even death. Two of the most frequent causes of shock are acute hemorrhage and sepsis. Although the origin and the pathophysiology of hemorrhagic and septic shock are basically different, the involvement of adenosine triphosphate-sensitive potassium (KATP) channels, as an important regulator of vascular smooth muscles tone, plays a pivotal role under both conditions. Because the excessive activation of vascular KATP channels is a major cause of arterial hypotension and vascular hyporesponsiveness to catecholamines, the pharmacological inhibition of KATP channels may represent a goal-directed therapeutic option to stabilize the hemodynamic situation in shock states. Despite promising results of preclinical studies, the efficacy of this innovative therapeutic approach remains to be confirmed in the clinical setting. The differences in the species, the comorbidity, and the difficulty in determining the exact onset of shock in clinical practice and, thus, any duration-related alterations in vascular responses and KATP channel activation may explain the discrepancy between the results obtained from experimental and clinical studies. Currently, two of the most relevant problems related to effective KATP blockade in shock states are represented by (1) the dose itself (benefit-risk ratio) and (2) the route of administration (oral vs. i.v.). This review article critically elucidates the published in vivo studies on the role of KATP channel inhibition in both described shock forms and discusses the advantages and the potential pitfalls related to the treatment of human shock states.