Novel CaMKII-δ Inhibitor Hesperadin Exerts Dual Functions to Ameliorate Cardiac Ischemia/Reperfusion Injury and Inhibit Tumor Growth.

BACKGROUND: Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease, the leading cause of morbidity and mortality worldwide. At present, there is no effective therapy for reducing cardiac I/R injury. CaMKII (Ca2+/calmodulin-dependent kinase II) plays a pivotal role in the pathogenesis of severe heart conditions, including I/R injury. Pharmacological inhibition of CaMKII is an important strategy in the protection against myocardial damage and cardiac diseases. To date, there is no drug targeting CaMKII for the clinical therapy of heart disease. Furthermore, at present, there is no selective inhibitor of CaMKII-δ, the major CaMKII isoform in the heart. METHODS: A small-molecule kinase inhibitor library and a high-throughput screening system for the kinase activity assay of CaMKII-δ9 (the most abundant CaMKII-δ splice variant in human heart) were used to screen for CaMKII-δ inhibitors. Using cultured neonatal rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, and in vivo mouse models, in conjunction with myocardial injury induced by I/R (or hypoxia/reoxygenation) and CaMKII-δ9 overexpression, we sought to investigate the protection of hesperadin against cardiomyocyte death and cardiac diseases. BALB/c nude mice with xenografted tumors of human cancer cells were used to evaluate the in vivo antitumor effect of hesperadin. RESULTS: Based on the small-molecule kinase inhibitor library and screening system, we found that hesperadin, an Aurora B kinase inhibitor with antitumor activity in vitro, directly bound to CaMKII-δ and specifically blocked its activation in an ATP-competitive manner. Hesperadin functionally ameliorated both I/R- and overexpressed CaMKII-δ9-induced cardiomyocyte death, myocardial damage, and heart failure in both rodents and human embryonic stem cell-derived cardiomyocytes. In addition, in an in vivo BALB/c nude mouse model with xenografted tumors of human cancer cells, hesperadin delayed tumor growth without inducing cardiomyocyte death or cardiac injury. CONCLUSIONS: Here, we identified hesperadin as a specific small-molecule inhibitor of CaMKII-δ with dual functions of cardioprotective and antitumor effects. These findings not only suggest that hesperadin is a promising leading compound for clinical therapy of cardiac I/R injury and heart failure, but also provide a strategy for the joint therapy of cancer and cardiovascular disease caused by anticancer treatment.

Subcellular Compartmentalization of Cyclic Adenosine Monophosphate in Heart Failure and Inotropic Pharmacology.

Cyclic adenosine monophosphate (cAMP) is a second messenger downstream of many G-protein coupled receptors, including the ß1-adrenoceptor, which is the target of many clinically used inotropic agents. When the Gαs subunit of a heterotrimeric G-protein is activated, it causes a localized elevation of cAMP. The significance of the spatial distribution of the elevation in cAMP is increasingly recognized, as is the disturbance of these microdomains in diseased states. Herein, the spatial compartmentalization of inotropic signaling is explored, including from internalized receptors.

Vasoactive and/or inotropic drugs in initial resuscitation of burn injuries: A systematic review.

BACKGROUND: According to current guidelines, initial burn resuscitation should be performed with fluids alone. The aims of the study were to review the frequency of use of vasoactive and/or inotropic drugs in initial burn resuscitation, and assess the benefits and harms of adding such drugs to fluids. METHODS: A systematic literature search was conducted in PubMed, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, UpToDate, and SveMed+ through 3 December 2021. The search included studies on critically ill burn patients receiving vasoactive and/or inotropic drugs in addition to fluids within 48 h after burn injury. RESULTS: The literature search identified 1058 unique publications that were screened for inclusion. After assessing 115 publications in full text, only two retrospective cohort studies were included. One study found that 16 out of 52 (31%) patients received vasopressor(s). Factors associated with vasopressor use were increasing age, burn depth, and % total body surface area (TBSA) burnt. Another study observed that 20 out of 111 (18%) patients received vasopressor(s). Vasopressor use was associated with increasing age, Baux score, and %TBSA burnt in addition to more frequent dialysis treatment and increased mortality. Study quality assessed by the Newcastle-Ottawa quality assessment scale was considered good in one study, but uncertain due to limited description of methods in the other. CONCLUSION: This systematic review revealed that there is a lack of evidence regarding the benefits and harms of using vasoactive and/or inotropic drugs in addition to fluids during early resuscitation of patients with major burns.

Use of Outpatient Intravenous Calcitropes for Heart Failure in the United States.

BACKGROUND: Outpatient calcitrope infusions-that is, the cardiac inotropes milrinone and dobutamine-are often used for bridge to transplantation and palliation in advanced heart failure, but few data exist about the real-world use of these agents. METHODS AND RESULTS: We used the Symphony Integrated DataVerse of commercial, managed Medicare, and Medicaid insurance claims of approximately 280 million people (2012-2020) to determine the incidence and characteristics of ambulatory calcitrope use. Demographics were calculated, including geographic densities at the metropolitan statistical area level. A population projection normalized for age, sex, and location was extrapolated to the total US population. Ambulatory dispensing of milrinone was found in 10,533 outpatients, 1867 in 2019. Ambulatory dobutamine use was found in 4967 outpatients, 836 in 2019. The 2019 total US projection was 3411 for milrinone and 1281 for dobutamine. The mean age was 62 years for milrinone and 68 for dobutamine. Males represented 70% of use. There were differences between drugs in geographic distribution, with more milrinone use in the Northeast and South and more dobutamine use in the Midwest. Duration of use was 4.6 ± 7.2 months for milrinone and 1.8 ± 4.0 months for dobutamine. Of the patients receiving milrinone, 30.6% subsequently underwent cardiac transplantation or left ventricular assist device placement, whereas 10% receiving dobutamine went on to advanced therapies. Less than 0.5% of patients received calcitropes while enrolled in hospice care. CONCLUSIONS: More than 4000 patients receive outpatient infusion of calcitropes annually in the outpatient setting. Men are much more likely to receive these medications. A minority of the use is as a bridge to advanced therapies. Geographic variability in use suggests better evidence and consistent guidelines may be helpful.

Prehospital, post-ROSC blood pressure and associated neurologic outcome.

OBJECTIVE: To investigate the relationship between hypotension and neurologic outcome in adults with return of spontaneous circulation after out-of-hospital cardiac arrest. METHODS: Blood pressure and medication data were extracted from adult patients who had ROSC after OHCA in Alameda County and matched with neurologic outcome using the CARES database from January 1, 2018 through July 1, 2019. We used univariate logistic regression with p ≤ 0.2 followed by multivariate logistic regression and reported an odds ratio with 95% confidence intervals. RESULTS: Among the 781 adult patients who had ROSC after OHCA, 107 (13.7%) were noted to be hypotensive and 61 (57% of the hypotensive group) received vasopressors. Patients with a final prehospital blood pressure recording of <90 mmHg were more likely to have a poor neurologic outcome (adjusted odds ratio 2.13, adj p = 0.048). About twice as many patients who were not hypotensive had a good neurologic outcome compared to hypotensive patients who had a good neurologic outcome (23% to 10.3%). Additionally, patients who were hypotensive and did not receive vasopressors had a similar neurologic outcome compared to patients who did receive vasopressors. CONCLUSION: Prehospital post-ROSC hypotension was associated with worse neurologic outcome and giving hypotensive patients vasopressors may not improve neurologic outcome in the prehospital setting.

Comparison of dopamine versus norepinephrine in circulatory shock after cardiac surgery: A randomized controlled trial.

BACKGROUND AND AIM OF THE STUDY: Although dopamine and norepinephrine are recommended as first-line agents in the treatment of shock, it is unclear which is the optimal vasoactive inotropic agent (VIA) to manage postcardiotomy circulatory shock. This single-center, randomized clinical trial aimed to investigate the efficacy and safety of dopamine versus norepinephrine in postcardiotomy circulatory shock. METHODS: We randomly assigned the patients with postcardiotomy circulatory shock to receive either dopamine or norepinephrine. When shock persisted despite the dose of 20 µg/kg/min of dopamine or the dose of 0.2 µg/kg/min of norepinephrine, epinephrine or vasopressin could be added. The primary endpoint was new-onset tachyarrhythmic event during drug infusion. Secondary endpoints included requirement of additional VIAs, postoperative complications, and all-cause mortality within 30 days of drug initiation. RESULTS: At the planned interim analysis of 100 patients, the boundary for the benefit of norepinephrine has been crossed, and the study was stopped early. Excluding two patients withdrawing a consent, 48 patients were assigned to dopamine and 50 patients to norepinephrine. New-onset tachyarrhythmic event occurred in 12 (25%) patients in the dopamine and one (2%) patient in the norepinephrine group (p = .009). The requirement for additional VIAs was more common in the dopamine group (p < .001). Other secondary endpoints were similar between groups. CONCLUSIONS: Despite the limited study subjects with early determination, in patients with postcardiotomy circulatory shock, dopamine as a first-line vasopressor was associated with higher tachyarrhythmic events and greater need for additional VIAs compared with norepinephrine.

Biased Agonism: The Future (and Present) of Inotropic Support.

Biased agonism, which is the concept that different ligands activate different downstream signalling partners in different ratios to cause different functional effects, is yet to gain appropriate appreciation in the field of inotropic pharmacology. Biased agonism has already proven to be a clinically translatable technology in analgesic pharmacology, but this development is yet to be translated into inotropes. A better appreciation of bias in clinically used inotropes and a focus on bias when developing novel inotropes has the potential to lead to more targeted, personalized, and cleaner inotropes.

[Cardiomyopathy in a 22-year-old man with a long history of methamphetamine abuse]. / Kardiomyopathie bei einem 22-Jährigen mit langjährigem Methamphetaminkonsum.

This article presents the case of a 22-year-old male patient with cardiomyopathy associated with a long history of methamphetamine abuse. Echocardiography revealed a dilated cardiomyopathy with highly reduced systolic pump function and severe mitral valve regurgitation. Inotropic treatment and MitraClip® (Abbott Vascular, Santa Clara, CA, USA) implantation resulted in enhancement of hemodynamics. The rising prevalence of methamphetamine abuse should give reason to raise awareness for the diagnostic work-up and patient history particularly in cases of unexplained cardiomyopathy in young patients.

The Effect of inotropes and vasopressors on mortality: a meta-analysis of randomized clinical trials.

BACKGROUND: Inotropes and vasopressors are frequently administered to critically ill patients in order to improve haemodynamic function and restore adequate organ perfusion. However, some studies have suggested a possible association between inotrope administration and increased mortality. We therefore performed a meta-analysis of randomized trials published in the last 20 yr to investigate the effect of these drugs on mortality. METHODS: BioMedCentral, PubMed, Embase and the Cochrane Central Register were searched (all updated April 8th, 2015). Inclusion criteria were: random allocation to treatment, at least one group receiving an inotropic or vasopressor drug compared with at least one group receiving a non-inotropic/vasopressor treatment, study published after 1st January 1994, and systemic drug administration. Exclusion criteria were overlapping populations, studies published as abstract only, crossover studies, paediatric studies and lack of data on mortality. RESULTS: A total of 28 280 patients from 177 trials were included. Overall, pooled estimates showed no difference in mortality between the group receiving inotropes/vasopressors and the control group [4255/14 036 (31.7%) vs. 4277/14 244 (31.8%), risk ratio=0.98 (0.96-1.01), P for effect=0.23, P for heterogeneity=0.30, I2=6%]. A reduction in mortality was associated with inotrope/vasopressor therapy use in settings of vasoplegic syndromes, sepsis and cardiac surgery. Levosimendan was the only drug associated with improvement in survival. Subgroup analysis did not identify any groups with increased mortality associated with inotrope/vasopressor therapy. CONCLUSIONS: Our systematic review found that inotrope/vasopressor therapy is not associated with differences in mortality in the overall population and in the majority of subsettings.

When can we start early enteral nutrition safely in patients with shock on vasopressors?

Shock is a common critical illness characterized by microcirculatory disorders and insufficient tissue perfusion. Patients with shock and hemodynamic instability generally require vasopressors to maintain the target mean arterial pressure. Enteral nutrition (EN) is an important therapeutic intervention in critically ill patients and has unique benefits for intestinal recovery. However, the initiation of early EN in patients with shock receiving vasopressors remains controversial. Current guidelines make conservative and vague recommendations regarding early EN support in patients with shock. Increasing studies demonstrates that early EN delivery is safe and feasible in patients with shock receiving vasopressors; however, this evidence is based on observational studies. Changes in gastrointestinal blood flow vary by vasopressor and inotrope and are complex. The risk of gastrointestinal complications, especially the life-threatening complications of non-occlusive mesenteric ischemia and non-occlusive bowel necrosis, cannot be ignored in patients with shock during early EN support. It remains a therapeutic challenge in critical care nutrition therapy to determine the initiation time of EN in patients with shock receiving vasopressors and the safe threshold region for initiating EN with vasopressors. Therefore, the current review aimed to summarize the evidence on the optimal and safe timing of early EN initiation in patients with shock receiving vasopressors to improve clinical practice.

Early Serial Assessment of Aggregate Vasoactive Support and Mortality in Cardiogenic Shock: Insights From the Critical Care Cardiology Trials Network Registry.

BACKGROUND: Associations of early changes in vasoactive support with cardiogenic shock (CS) mortality remain incompletely defined. METHODS: The Critical Care Cardiology Trials Network is a multicenter registry of cardiac intensive care units. Patients admitted with CS (2018-2023) had vasoactive dosing assessed at 4 and 24 hours from cardiac intensive care unit admission and quantified by the vasoactive-inotropic score (VIS). Prognostic associations of VIS at both time points, as well as change in VIS from 4 to 24 hours, were examined. Interaction testing was performed based on mechanical circulatory support status. RESULTS: Among 3665 patients, 82% had a change in VIS <10, with 7% and 11% having a ≥10-point increase and decrease from 4 to 24 hours, respectively. The 4 and 24-hour VIS were each associated with cardiac intensive care unit mortality (13%-45% and 11%-73% for VIS <10 to ≥40, respectively; Ptrend <0.0001 for each). Stratifying by the 4-hour VIS, changes in VIS from 4 to 24 hours had a graded association with mortality, ranging from a 2- to >4-fold difference in mortality comparing those with a ≥10-point increase to ≥10-point decrease in VIS (Ptrend <0.0001). The change in VIS alone provided good discrimination of cardiac intensive care unit mortality (C-statistic, 0.72 [95% CI, 0.70-0.75]) and improved discrimination of the 24-hour Sequential Organ Failure Assessment score (0.72 [95% CI, 0.69-0.74] to 0.76 [95% CI, 0.74-0.78]) and the clinician-assessed Society for Cardiovascular Angiography and Interventions shock stage (0.72 [95% CI, 0.70-0.74] to 0.77 [95% CI, 0.75-0.79]). Although present in both groups, the mortality risk associated with VIS was attenuated in patients managed with versus without mechanical circulatory support (odds ratio per 10-point higher 24-hour VIS, 1.36 [95% CI, 1.23-1.49] versus 1.84 [95% CI, 1.69-2.01]; Pinteraction <0.0001). CONCLUSIONS: Early changes in the magnitude of vasoactive support in CS are associated with a gradient of risk for mortality. These data suggest that early VIS trajectory may improve CS prognostication, with the potential to be leveraged for clinical decision-making and research applications in CS.

[Initial diagnosis and treatment of shock]. / Initiale Diagnostik und Therapie des Schocks.

BACKGROUND: Structured procedures have been established internationally for the initial clinical care of patients with traumatic injuries. Comparable concepts have not yet been applied to the initial clinical care of life-threatening nontraumatic emergencies. In 2022, a working group of the German Society for Acute and Emergency Medicine (DGINA) presented the Advanced Critical Illness Life Support (ACiLS) concept for the care of nontraumatic emergencies and offers corresponding training courses. OBJECTIVE: To present systematic clinical first aid for patients with the leading symptom of shock according to the ACiLS concept. RESULT: The (PR_E-)AUD2IT basic algorithm used in the ACiLS concept divides the initial care of a critically ill patient into the elements of preparation, resources, initial care, medical history, examination, differential diagnosis, diagnostics, interpretation and to do, interrupted by three team time-out elements for structured communication. The use of this concept is demonstrated here using the example of shock. CONCLUSION: The ACiLS concept has the potential to improve the quality of initial care of nontraumatic emergencies in emergency department shock rooms and intensive care units. Further evaluations in practice and training capacities are essential.

Repetitive ambulatory levosimendan as a bridge to heart transplantation.

INTRODUCTION AND OBJECTIVES: Repetitive ambulatory doses of levosimendan are an option as a bridge to heart transplantation (HT), but evidence regarding the safety and efficacy of this treatment is scarce. The objective of the LEVO-T Registry is to describe the profile of patients on the HT list receiving levosimendan, prescription patterns, and clinical outcomes compared with patients not on levosimendan. METHODS: We retrospectively reviewed all patients listed for elective HT from 2015 to 2020 from 14 centers in Spain. RESULTS: A total of 1015 consecutive patients were included, of whom 238 patients (23.4%) received levosimendan. Patients treated with levosimendan had more heart failure (HF) admissions in the previous year and a worse clinical profile. The most frequent prescription pattern were fixed doses triggered by the patients' clinical needs. Nonfatal ventricular arrhythmias occurred in 2 patients (0.8%). No differences in HF hospitalizations were found between patients who started levosimendan in the first 30 days after listing and those who did not (33.6% vs 34.5%; P=.848). Among those who did not, 102 patients (32.9%) crossed over to levosimendan after an HF admission. These patients had a rate of 0.57 HF admissions per month before starting levosimendan and 0.21 afterwards. Propensity score matching analysis showed no differences in survival at 1 year after listing between patients receiving levosimendan and those who did not (HR, 1.03; 95%CI, 0.36-2.97; P=.958) or in survival after HT (HR, 0.97; 95%CI, 0.60-1.56; P=.958). CONCLUSIONS: Repetitive levosimendan in an ambulatory setting as a bridge to heart transplantation is commonly used, is safe, and may reduce HF hospitalizations.

[Fluid and vasopressor therapy in sepsis]. / Volumen- und vasoaktive Therapie bei Sepsis.

Sepsis is one of the most common and lethal conditions in intensive care medicine. Besides adequate treatment of the infection, timely hemodynamic management is essential to treat tissue hypoperfusion due to sepsis. Adequate fluid resuscitation plays a central role, and this should be carried out with dynamic monitoring of the hemodynamic response. However, a positive fluid balance is associated with poor outcome. Vasopressor therapy is required in case of inadequate response to fluid resuscitation, with norepinephrine considered the first choice. With increasing norepinephrine dose, addition of hydrocortisone or vasopressin may contribute to maintaining the hemodynamic state, although the prognostic advantage of these drugs has not been demonstrated. While dobutamine may be considered in patients with septic cardiomyopathy, the evidence for inotropic therapy in sepsis is limited.

Fluid Resuscitation and Inotropic Support in Patients With Septic Shock Treated in Pediatric Emergency Department: An Open-Label Trial.

Introduction Fluid resuscitation and inotropic support are essential interventions to improve cardiovascular function in patients with septic shock. However, the optimal volume of fluids and the timing of inotropic support to achieve the resolution of shock are controversial. They may depend on the availability of critical care support services.  Aims To compare early versus the delayed start of epinephrine administration after fluids bolus in children with septic shock.  Methods  We conducted an open-label randomized trial in which patients under 18 years of age diagnosed with septic shock and arterial hypotension were treated in two Pediatric Emergency Departments in Paraguay (Hospital de Clinicas of Universidad Nacional de Asunción and Instituto Privado del Niño) between 2015 and 2020. Septic shock was defined according to the American College of Critical Care Medicine (ACCM) guidelines. All patients received antibiotics and 40 ml/kg of fluids (two boluses of 20ml/kg if there were no signs of fluid overload) during the first hour. They were then divided into two groups: Group 1 received epinephrine infusion and maintenance fluids. Group 2 received an additional 20 ml/kg of fluids and then was started on epinephrine infusion.  Results Of 229 patients screened, 63 patients were included in the study. The mean age was 2.8±3.5 years. A total of 52% were female. Group 1 comprised 33 patients, and group 2 comprised a total of 30. Significant differences were found between group 1 and group 2 in the following: mortality (10% vs. 33%, p: 0.026, RR: 3.1, CI: 95%: 1-10), need for mechanical ventilation (10% vs. 41%, p: 0.006, RR: 4, CI: 95%: 1.3-12), and altered vascular hypoperfusion after one hour of interventions (7% vs. 59%, p<0,001, RR: 8.2, CI: 95%: 2-32). Conclusions Early administration of epinephrine infusion after initial fluid therapy was associated with better clinical outcomes than delayed administration.

Comparison of the effect of 1:1 and 1:2 frequencies of intra-aortic balloon pump on hemodynamics of the patients undergoing coronary artery bypass graft surgery.

BACKGROUND: Some patients require intra-aortic balloon pump (IABP) after coronary artery bypass graft (CABG) surgery. IABP can be adjusted to different frequencies such as 1:1, 1:2, or 1:3. In this study, we tried to compare the effect of 1:1 and 1:2 frequencies of IABP on hemodynamic status of the patients after CABG surgery. METHODS: In this experimental study, all patients using IABP after CABG surgery were entered the study as pretest and posttest groups. The study could not be blinded because of the clearness of posttest group for the same echocardiographist. The pretest group included patients using a 1:1 frequency of IABP device. The posttest group included patients in the pretest group who were exposed to a 1:2 frequency for 20 minutes. In both groups, on the moderate dose of inotropic support, hemodynamic parameters of patients including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), cardiac index (CI), stroke volume (SV), and velocity time integral (VTI) in the aorta during systole were measured. Both groups were compared using Wilcoxon signed rank test. SPSS software was used for analysis and P < 0.05 was considered to be statistically significant. RESULTS: Twelve patients were entered into the study. Three patients were excluded because of open chest and instability of vital signs. Nine patients completed the study. 3 patients were men and 6 were women. The mean age was 58.32 ± 13.18 years. MAP in 1:1 frequency was significantly higher than 1:2 (P = 0.043); however, there was no significant difference between 1:1 and 1:2 in other hemodynamic parameters, namely CO, CI, SV, HR, and VTI. CONCLUSION: In patients on moderate dose of inotropes, IABP frequencies of 1:1 and 1:2 have the same effect on hemodynamic parameters such as CI, SBP, DBP, HR, and left ventricular outflow tract (LVOT) VTI; meanwhile, MAP remains higher in 1:1 frequency.

[Resuscitation strategy for patients with sepsis and septic shock]. / Estrategia integral de reanimación del paciente con sepsis y shock séptico.

Fluid and vasopressor resuscitation is, along with antimicrobial therapy and control of the focus of infection, a basic issue of the treatment of sepsis and septic shock. There is currently no accepted protocol that we can follow for the resuscitation of these patients and the Surviving Sepsis Campaign proposes controversial measures and without sufficient evidence support to establish firm recommendations. We propose a resuscitation strategy adapted to the situation of each patient: in the patient in whom community sepsis is suspected, we consider that the early administration of 30mL/kg of crystalloids is effective and safe; in the patient with nosocomial sepsis, we must carry out a more in-depth evaluation before initiating aggressive resuscitation. In patients who do not respond to initial resuscitation, it is necessary to increase monitoring level and, depending on the hemodynamic profile, administer more fluids, a second vasopressor or inotropes.

Vasopressor and inotrope treatment for septic shock: An umbrella review of reviews.

PURPOSE: To review the characteristics, findings and quality of systematic reviews (SRs) on the effect of any vasopressor/inotrope on outcomes in adult patients with sepsis compared with either no treatment, another vasopressor or inotrope or fluids. MATERIALS AND METHODS: We systematically searched Cochrane Central Register of Controlled Trials, PubMed and Embase (January 1993-March 2021). Descriptive statistics were used. RESULTS: Among the 28 SRs identified, mortality was the primary outcome in most (26/28) and mortality was usually (23/28) studied using randomised controlled trials (RCTs). Fifteen SRs focused exclusively on patients with sepsis or septic shock. Sepsis and septic shock were always grouped for the analysis. Publication bias was consistently low when studied. The most consistent findings were a survival advantage with norepinephrine versus dopamine, which disappeared in analyses restricted to 28-day mortality, and more arrhythmias with dopamine. However, these analyses were dominated by a single study. Only 2 SRs were judged to be of moderate-high quality. Lack of blinding and attrition bias may have affected the outcomes. CONCLUSIONS: The quality of SRs on the effect of vasopressors/inotropes on the outcomes of adult patients with sepsis can be improved, but high-quality, multicenter, RCTs should be preferred to additional SRs on this topic.