ICU indicates intensive care unit.
Solid lines represent median values. The shaded areas bordered by dotted lines represent the
upper and lower quartiles by colors.
Solid lines represent median values. The shaded areas bordered by dotted lines represent the
upper and lower quartiles. MAP indicates mean arterial pressure.
Black lines represent median values for the esmolol group; blue, the control group. The shaded
areas represent the upper and lower quartiles. Patients receiving renal replacement therapy were
excluded from analysis.
A, unadjusted survival plots (Kaplan-Meier) of patients. B, multivariable adjusted survival (Cox)
at mean values of Simplified Acute Physiology Score II. Ordinate axis is scaled as
“1-survival” to depict the 0 intersection without breaking the axis.
eMethods. Randomization procedures, calculation of area under the curve, comparison
of heart rate between groups using a linear mixed effects model, impact of esmolol dose on
levosimendan requirements, and impact of esmolol dose on overall 28-day mortality
eTable 1. Acid base and oxygen transport variables of study patients
eTable 2. Organ function and inflammatory variables of study patients
eAppendix. Statistical output of Cox regression analysis for 28 day overall
Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, Orecchioni A, D’Egidio A, D’Ippoliti F, Raffone C, Venditti M, Guarracino F, Girardis M, Tritapepe L, Pietropaoli P, Mebazaa A, Singer M. Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in
Patients With Septic ShockA Randomized Clinical Trial. JAMA. 2013;310(16):1683-1691. doi:10.1001/jama.2013.278477
Copyright 2013 American Medical Association. All Rights Reserved. Applicable
FARS/DFARS Restrictions Apply to Government Use.
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.
To investigate the effect of the short-acting β-blocker esmolol in patients with severe
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
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.
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.
clinicaltrials.gov Identifier: NCT01231698
Septic shock is associated with excessive sympathetic outflow, high plasma catecholamine levels,
myocardial depression, vascular hyporeactivity, and autonomic dysfunction.1,2 Typically, patients have a low resistance, high-cardiac output
circulation with tachycardia and arterial hypotension that may be poorly or even nonresponsive to
exogenous catecholamine vasopressors. Although norepinephrine is the current recommended mainstay of
treatment for sepsis-related hypotension,3 excessive
adrenergic stress has multiple adverse effects including direct myocardial damage (eg, Takotsubo
[stress] cardiomyopathy and tachyarrhythmias), insulin resistance, thrombogenicity,
immunosuppression, and enhanced bacterial growth.4,5 High plasma catecholamine levels, the extent and duration of catecholamine therapy, and
tachycardia are all independently associated with poor outcomes in critically ill patients.2,6- 8
High sympathetic stress is also implicated in sepsis-induced myocardial depression.9 Patients with sepsis often remain tachycardic, even after
excluding common causes such as hypovolemia, anemia, agitation, and drug effects. β-Adrenergic
blockade may enable heart rate control and limit adverse events related to sympathetic
overstimulation.5 In animal models of sepsis,
β-blockade appears beneficial, particularly when given as pretreatment.10,11 Although heart rate control is likely to improve cardiovascular
performance,9 concerns that β-blocker therapy in human
septic shock may lead to cardiovascular decompensation must be considered. A good safety profile was
reported in patients in septic shock who were given oral metoprolol to achieve heart rates of less
than 95/min12; however, intravenous β-blocker therapy
has not been formally investigated.
We hypothesized that intravenous β-blockade titrated to achieve heart rate control in septic
shock represents an effective approach to enhance myocardial function and improve outcome without
increased complications. The present study aimed to determine whether the short-acting intravenous
β1-adrenoreceptor blocker, esmolol, could reduce heart rate to be lower than a
predefined threshold and measured subsequent effects on systemic hemodynamics, organ function,
adverse events, and 28-day mortality.
After approval by the local institutional ethics committee, we performed the study in the 18-bed
multidisciplinary intensive care unit (ICU) of the University of Rome “La Sapienza”
Hospital, after written informed consent from the patients’ next of kin. Enrollment occurred
between November 2010 and July 2012. Inclusion criteria were the presence of septic shock requiring
norepinephrine to maintain a mean arterial pressure (MAP) of 65 mm Hg or higher despite appropriate
volume resuscitation (pulmonary arterial occlusion pressure ≥12 mm Hg and central venous
pressure ≥8 mm Hg),4 and a heart rate of 95/min or
Exclusion criteria were age younger than 18 years, β-blocker therapy prior to randomization,
pronounced cardiac dysfunction (ie, cardiac index ≤2.2 L/min/m2 in the presence of
a pulmonary arterial occlusion pressure >18 mm Hg), significant valvular heart disease, and
All patients were sedated with sufentanil and propofol and received mechanical ventilation using
a volume-controlled mode with targeted tidal volumes of 6 mL/kgor less of predicted body
Systemic hemodynamic monitoring included pulmonary artery catheterization (7.5F catheter, Edwards
Lifesciences) and a radial artery catheter. MAP, central venous, mean pulmonary arterial, and
occlusion pressures were measured at end-expiration. We monitored heart rate and ST segments
continuously by electrocardiography. We measured cardiac index using the continuous thermodilution
technique (Vigilance II, Edwards Lifesciences). We sampled arterial and mixed-venous blood
intermittently for blood gas analyses to determine oxygen tensions and saturations, carbon dioxide
tensions, pH, standard bicarbonate, and base excess. Left and right ventricular stroke work, oxygen
delivery, consumption indexed to body surface area, and oxygen extraction ratios were calculated
using standard formulae.
We analyzed arterial blood samples for lactate, standard hematology, biochemistry, kidney and
liver function, coagulation profile tests, amylase, lipase, antithrombin, cardiac troponin I,
creatine kinase MB isoenzyme (CK-MB), and C-reactive protein.
We designed the present study as a single-center, open-label, randomized 2-group phase 2 trial.
Our primary outcome was to determine whether esmolol could reduce heart rates to be lower than the
predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min for the duration
of the patients’ ICU stay. Secondary outcomes included the effect of esmolol on norepinephrine
requirements, cardiorespiratory and oxygenation indices, safety end points (including markers of
organ function and injury and rescue therapy with other drugs), and 28-day overall survival.
After 24 hours of hemodynamic optimization aimed at establishing an adequate circulating blood
volume (adjudged by pulmonary artery occlusion pressure of ≥12 mm Hg and central venous
pressures of ≥8 mm Hg), a mixed venous oxygen saturation higher than 65% and a MAP of 65 mm Hg
or higher,4 we enrolled patients if they were still
requiring norepinephrine and their heart rate persisted at 95/min or higher. Patients were randomly
assigned by a computer-based random-number generator to receive conventional management with or
without a continuous esmolol infusion titrated to maintain heart rate between 80/min and 94/min (see
eMethods in the Supplement for
additional details on randomization procedures).
The esmolol infusion commenced at 25 mg × h−1 and progressively
increased the rate at 20-minute intervals in increments of 50
mg × h−1, or more slowly at the discretion of the investigators,
to reach the predefined threshold rate within 12 hours. We continued infusing esmolol to maintain
the predefined heart rate threshold until either ICU discharge or death with an upper dose limit of
2000 mg × h−1. Participant study flow data are presented in Figure 1.
During the first 96 hours of the intervention period, we gave fluid challenges, as necessary, to
maintain filling pressures as described above. We transfused packed red blood cells when hemoglobin
concentrations decreased to less than 7 g/dL−1, or if the patient exhibited
clinical signs of inadequate systemic oxygen supply.4 We
titrated norepinephrine to maintain MAP of 65 mm Hg or higher and gave all patients intravenous
hydrocortisone (300 mg/d−1) as a continuous infusion. If mixed venous oxygen
saturation decreased to less than 65% despite appropriate arterial oxygenation (≥95%) and
hemoglobin concentrations of 8 g/dL−1 or higher, arterial lactate concentrations
increased, or both, we administered the nonadrenergic calcium sensitizer levosimendan to improve
systemic oxygen delivery at a dose of 0.2 µg/kg/min (without a loading bolus dose) for 24
We recorded all hemodynamic measurements, laboratory variables, blood gas analyses, and
norepinephrine requirements at baseline and at 24, 48, 72, and 96 hours after randomization. We also
recorded adverse events, including death from any cause, occurring during the 28 days following
To detect a 20% change in heart rate (estimated standard deviation 40%) with a power of 80% and a
type I error rate of .05, by using a 2-sided t test, we calculated that 64 patients
per group would be required. Because data distribution was unknown a priori and data were analyzed
by nonparametric analysis, we assumed a worst-case scenario with a minimal asymptotic relative
efficiency of 0.864 for the Wilcoxon-Mann-Whitney test, resulting in a minimum required sample size
of 75 patients per group.13
We used SPSS version 20 (IBM Corp) for statistical analysis. Continuous data are summarized by
median (interquartile range [IQR]), if not otherwise specified. We performed all analyses according
to the intention-to-treat principle. We compared baseline and demographic data using the
Wilcoxon-Mann-Whitney or χ2 test, as appropriate. To avoid multiple comparisons, we
calculated areas under the curve (AUCs) relative to baseline values for continuous variables with
repeated measurements, as suggested by Matthews et al14 (see
eMethods in the Supplement for
details). We then compared AUCs between the 2 treatment groups with the Wilcoxon-Mann-Whitney test.
Binary 28-day mortality of the 2 groups was compared by a χ2 test. In addition, we
compared 28-day overall survival by means of a log-rank test and by fitting a multivariable Cox
regression model. We built this latter model by using stepwise forward inclusion based on likelihood
ratio P values for which study group assignment, sex, multidrug-resistant
Acinetobacter or Klebsiella infection, and levosimendan infusion
were considered as cofactors, and age, body mass index (BMI, calculated as weight in kilograms
divided by height in meters squared), Simplified Acute Physiology Score (SAPS) II, baseline values
of norepinephrine dosage, arterial lactate concentration, and platelet count were considered as
covariables.15,16 Survival plots for time-to-event
outcomes were designed as recommended by Pocock et al.17 We
initially estimated mortality risk from the SAPS II score.18
This is usually computed using the most extreme values collected over the first 24 hours following
ICU admission, whereas we used values measured at study entry, by which time patient stabilization
has usually generated a lower SAPS II score and thus underestimates mortality risk. Patients
requiring high-dose norepinephrine, a requirement in our study, have a very high mortality.19,20 The primary end point was confirmatory tested at a
2-sided significance level of α = .05. All other given P values
are exploratory. Additional and alternative statistical approaches are detailed in the eMethods in
After hemodynamic optimization, we screened 336 patients with 176 being excluded due to heart
rate values of less than 95/min (n = 166) or previous β-blocker therapy
(n = 10). In another 6 patients, we could not obtain informed consent. Thus, a total of
154 patients were included and randomly assigned to the 2 study groups in a 1:1 ratio (Figure 1).
Data on the primary end point were complete, whereas only 29 of 770 data sets (154 patients
× 5 time points) had at least 1 laboratory variable missing (eg, troponin). To account for
these missing data, calculation of AUC was based on the assumption that the missing value represents
the mean of the values before and after.
Baseline data were similar among study groups with respect to age, sex, BMI, comorbidities, SAPS
II score, focus of sepsis, pathogen spectrum, norepinephrine dose, and first 24-hour fluid input
(Table 1). The high SAPS II score and the high
norepinephrine requirement at study entry (Table 1)
are indicative of patients who are at high risk of mortality.17- 19
The median esmolol dosage was 100 mg/h (IQR, 50-300) without relevant trends over time (Figure 2). We did not exceed the maximum permitted dosage of
The target range for heart rate was 80/min to 94/min in all patients in the esmolol group, which
was significantly lower throughout the intervention period than what was achieved in the control
group. The median AUC over the first 96 hours was −28/min (IQR, −37 to −21) for
the esmolol group vs −6/min (−14 to 0) for the control group
(P < .001; Figure 3).
MAP was maintained despite a marked reduction in norepinephrine requirements in the esmolol group
with a median AUC of −0.11 μg/kg/min (IQR, −0.46 to 0) vs −0.01
μg/kg/min (−0.2 to 0.44) in the control group (P = .003;
Figure 3). Stroke volume, systemic vascular
resistance, and left ventricular stroke work indices were increased in the esmolol group (Figure 3, Table
2). Although reductions in systemic oxygen delivery were greater in the esmolol group with a
median AUC of −100 mL/min/m2 (IQR, −211 to −38) vs −32
mL/min/m2 (IQR, −108 to 21) in the control group
(P < .001) and had reduced consumption with a median AUC of
−29 mL/min/m2 (IQR, −55 to 0) in the esmolol group vs −4
mL/min/m2 (IQR, −29 to 20) in the control group
(P < .001; eTable 1 in the Supplement), the need for levosimendan rescue therapy did not differ
between groups (49.4% of esmolol patients vs 40.3% control patients;
P = .39). Fluid requirements were reduced in the esmolol group with a
median AUC of 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h (IQR, 4038 to 4775) in the control
group (P < .001; Table
2). We could find no clinically relevant difference between treatment groups for any other
systemic or pulmonary hemodynamic variable.
The median AUCs were higher for arterial pH for the esmolol group: 0.28 units (IQR, −0.01
to 0.08) vs −0.02 units (IQR, −0.06 to 0.06) for the control group
(P = .003) and for base excess, 0.8 mmol/L(−1.2 to
3.6) for the esmolol group vs −0.5 mmol/L (IQR, −2.1 to 2.8) for the control group
(P = .03), whereas the median AUC for arterial lactate concentration
was lower for the esmolol group at −0.1 mmol/L (IQR −0.6 to 0.3) than for the control
group at 0.1 mmol/L (IQR, −0.3 to 0.6; P = .006). Partial gas
pressures and oxygen saturations did not differ between groups (eTable 1 in the Supplement).
Kidney function, assessed by the Modification of Diet in Renal Disease formula for estimating
glomerular filtration rate, was better maintained in the esmolol group: median AUC of 14 mL/min/1.73
m2 (IQR, 4 to 37) than in the control group vs 2 mL/min/1.73 m2 (IQR, −7
to 20; P < .001). The trend remained when excluding patients
receiving renal replacement therapy with a median AUC in the esmolol group of 10 mL/min/1.73 m2
(IQR, 1 to 35) vs −2 mL/min/1.73 m2 (IQR, −9 to 4) in the control group
(P < .001; Figure 4).
During ICU stay, the percentage of patients requiring renal replacement therapy did not differ
between groups: 40.3% in the esmolol group vs 41.6% in the control group. The arterial oxygen
partial pressure to inspired oxygen fraction ratio was higher in the esmolol group with a median AUC
of 38 mm Hg (IQR, −22 to 72) than in the control group 6 mm Hg (IQR, −46 to 59;
P = .03). Liver function tests did not differ between groups, whereas
markers of myocardial injury were lower in the esmolol group with the median AUC for troponin T in
the esmolol group being −0.01 (IQR, −0.05 to 0.00) vs 0.00 (IQR, −0.01 to 0.02)
for the control group (P = .002) and the CK-MB for the esmolol group
was −1 (IQR, −4 to 0) vs control 0 (IQR, −1 to 1) for the control group
(P = .02; eTable 2 in the Supplement).
The esmolol group had a 28-day mortality rate of 49.4% vs 80.5% in the control group
(P < .001). Overall survival was higher in the esmolol group (Figure 5). Multivariable Cox regression analysis revealed
that esmolol group allocation (hazard ratio [HR], 0.392; 95% CI, 0.261-0.590;
P < .001) and SAPS II score (HR, 1.033; 1.013-1.054;
P < .001) were the only variables to be included in the model for
optimal prediction of overall survival (eAppendix in the Supplement). However, the esmolol dose did not influence 28-day
mortality (odds ratio [OR], 1.000; 95% CI, 0.999-1.001; Table 3)
In a cohort of patients with septic shock and high risk of mortality, our open-label use of
esmolol after initial hemodynamic optimization resulted in maintenance of heart rate within the
target range of 80/min to 94/min. Compared with standard treatment, esmolol also increased stroke
volume, maintained MAP, and reduced norepinephrine requirements without increasing the need of
inotropic support or causing adverse effects on organ function. There was an associated improvement
in 28-day survival.
Tachycardia increases cardiac workload and myocardial oxygen consumption. In addition, shortening
of diastolic relaxation time and impairment of diastolic function further affect coronary perfusion,
contributing to a lower ischemic threshold.21 Excessive
sympathetic activation also leads to catecholamine-induced cardiomyocyte toxic effects characterized
by inflammation, oxidative stress, and abnormal calcium handling resulting in left ventricular
dilatation, apical ballooning, myocardial stunning, apoptosis, and necrosis.9,22,23 Taken together, these mechanisms contribute to
worsening of septic myocardial dysfunction and increased mortality.6- 8
Treating tachycardia in septic shock is controversial. The right timeframe for intervention and
the optimal heart rate threshold are currently undefined. In the early unresuscitated phase of
septic shock, tachycardia represents the main mechanism to compensate for any decrease in cardiac
output.21 In this case, heart rate reduction may derail this
adaptive physiologic response, leading to a decrease in oxygen delivery that may compromise organ
perfusion and function. Adequate volume resuscitation will often result in a concomitant decrease in
heart rate yet, in some septic patients, tachycardia persists despite excluding other causes such as
pain and agitation. Tachycardia may in such cases represent an expression of sympathetic
overstimulation, in part due to activation of peripheral afferent fibers by ischemia and
inflammation in peripheral tissues.21,24
Although reducing heart rate will decrease myocardial oxygen consumption and will improve
diastolic function and coronary perfusion, for patients with sepsis, an inadequate chronotropic
response may potentially negatively affect cardiac output and tissue perfusion. Predefining a
threshold value for heart rate is difficult because it must be individualized in the context of the
patient’s overall hemodynamic status and any preexisting comorbidities.21 In our study, we hypothesized that a heart rate range between 80/min to 94/min
was a sufficient compromise between improving cardiac performance and preserving systemic
hemodynamics. We found no obvious safety issues related to the use of esmolol, a finding reflected
in an open-label study of oral metoprolol given to patients with septic shock who had myocardial
depression for which heart rate control (targeted at 65/min-95/min) was successfully achieved in
97.5% of patients within a mean 12 (SD, 12) hours.12
Esmolol has the advantage of being ultrashort-acting with a half-life of approximately 2
minutes.25 This simplifies titration against a predefined
heart rate target and enables rapid resolution of any potential adverse effect after drug
discontinuation. Targeted heart rates between 80/min to 94/min were achieved safely within the first
24 hours of treatment. Importantly, the norepinephrine-sparing effect was not associated with a
higher need for inotropic support but rather by an increase in left ventricular stroke work. These
findings suggest that lowering of heart rate by esmolol allows better ventricular filling during
diastole, hence, improving stroke volume and thereby improving the efficiency of myocardial work and
oxygen consumption. Together with an amelioration in catecholamine-induced toxicity, myocardial
performance may be preserved during septic shock thereby facilitating survival. Administration of
esmolol improved markers of tissue perfusion and organ injury, with no obvious compromise of organ
Adverse effects of catecholamines may become manifest over the whole course of a patient’s
illness, affecting organs other than the heart. Examples include lung (pulmonary edema, pulmonary
hypertension), gastrointestinal tract (inhibition of peristalsis, bowel ischemia), coagulation
system (hypercoagulability, thrombus formation), immune system (immunomodulation, stimulation of
bacterial growth), metabolism (increases in cellular energy expenditure, hyperglycemia and impaired
glucose tolerance, muscle catabolism, increased lipolysis, and hyperlactatemia).5,6,26 Because noncardiac actions of
β-blocker therapy may also prove beneficial, we chose to continue esmolol therapy with
maintenance of the heart rate target range throughout the patient’s ICU stay.
Study limitations include selection of an arbitrary predefined heart rate threshold rather than
an individualized approach titrated to specific myocardial characteristics or other biomarkers. We
adopted a heart rate threshold of less than 95/min because values persisting above this level are
associated with adverse cardiac events in ICU patients.7
Second, the study had to be nonblinded because titration of esmolol to achieve heart rate control
was the primary objective. Inactive placebo would be ineffective in lowering heart rate (unless
covert hypovolemia was present) and large volumes of fluid attempting to achieve this goal may prove
deleterious. Third, enrollment was performed in an environment of high-endemic rates of
multidrug-resistant Klebsiella and Acinetobacter baumannii strains
that may have led to secondary complications. Multivariable analysis was performed to account for
this infectious burden and other potential confounders. Fourth, we cannot conclude to what extent
noncardiac mechanisms of esmolol contributed to the observed improvement in mortality nor conclude
whether it was simply the reduction in heart rate alone. An ongoing study of heart rate control in
critically ill patients using the funny channel current inhibitor, ivabradine will help to address
Fifth, although mortality was not a primary end point, the unexpectedly large intergroup
difference does not exclude the possibility of a chance finding or a contribution from unknown
confounding factors. We did investigate a population in severe septic shock with sustained
tachycardia and requiring high-dose norepinephrine, all of which are indicative of a very poor
prognosis.6- 8,19,20 This high-risk subset would likely gain the greatest benefit from heart rate control by
β-blockade. Whether similar benefits are achieved in less sick patients requires further
investigation. Appropriately powered, randomized, controlled multicenter trials are required to
confirm our findings.
For patients in septic shock, the open-label use of esmolol was able to achieve reductions in
heart rate to target levels, without an increase in adverse outcomes compared with standard
treatment. Further investigation of the effects of esmolol on clinical outcomes is warranted.
Corresponding Author: Andrea Morelli, MD, Department of
Anesthesiology and Intensive Care, University of Rome, “La Sapienza,” Viale del
Policlinico 155, Rome 00161, Italy (firstname.lastname@example.org).
Published Online: October 9, 2013.
Author Contributions: Dr Morelli had full access
to all of the data in the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Morelli, Ertmer, Rehberg, Orecchioni, D’Egidio,
D’lppoliti, Raffone, Venditti, Guarracino, Pietropaoli, Singer.
Acquisition of data: Morelli, Rehberg, Orecchioni, D’Egidio,
D’lppoliti, Raffone, Venditti, Girardis, Tritapepe, Pietropaoli.
Analysis and interpretation of data: Morelli, Ertmer, Westphal, Rehberg,
Kampmeier, Ligges, Orecchioni, D’Egidio, Raffone, Venditti, Guarracino, Girardis, Pietropaoli,
Drafting of the manuscript: Morelli, Ertmer, Rehberg, Orecchioni,
D’Egidio, D’lppoliti, Raffone, Venditti, Pietropaoli, Singer.
Critical revision of the manuscript for important intellectual content: Morelli,
Ertmer, Westphal, Rehberg, Kampmeier, Ligges, Orecchioni, D’Egidio, Raffone, Venditti,
Guarracino, Girardis, Tritapepe, Pietropaoli, Mebazaa, Singer.
Statistical analysis: Ertmer, Kampmeier, Ligges.
Obtained funding: Morelli, Pietropaoli.
Administrative, technical, or material support: Morelli, Rehberg, Orecchioni,
D’Egidio, D’lppoliti, Raffone, Venditti.
Study supervision: Morelli, Westphal, Rehberg, Girardis.
Conflict of Interest Disclosures: All authors
have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr
Morelli reported receiving honoraria for speaking at Baxter symposia and Dr Singer reported serving
as a consultant and receiving honoraria for speaking and chairing symposia for Baxter. No other
disclosures were reported.
Funding/Support: This study was funded by an
independent research grant from the Department of Anesthesiology and
Intensive Care of the University of Rome “La Sapienza.”
Role of the Sponsor: The funders had no influence on the design and conduct of the
study; collection, management, analysis, and interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit the manuscript for publication.