Knockdown of 11β-hydroxysteroid dehydrogenase type 1 alleviates LPS-induced myocardial dysfunction through the AMPK/SIRT1/PGC-1αpathway

Sepsis-induced myocardial dysfunction is primarily accompanied by severe sepsis,which is associated with high morbidity and mortality.11β-hydroxysteroid dehydrogenase type 1(11β-HSD1),encoded by Hsd11b1,is a reductase that can convert inactive cortisone into metabolically active cortisol,but the role of 11β-HSD1 in sepsis-induced myocardial dysfunction remains poorly understood.The current study aimed to investigate the effects of 11β-HSD1 on a lipopolysaccharide(LPS)-induced mouse model,in which LPS(10 mg/kg)was administered to wild-type C57BL/6J mice and 11β-HSD1 global knockout mice.We asscessed cardiac function by echocardiography,performed transmission electron microscopy and immunohistochemical staining to analyze myocardial mitochondrial injury and histological changes,and determined the levels of reactive oxygen species and biomarkers of oxidative stress.We also employed polymerase chain reaction analysis,Western blotting,and immunofluorescent staining to determine the expression of related genes and proteins.To investigate the role of 11β-HSD1 in sepsis-induced myocardial dysfunction,we used LPS to induce lentivirus-infected neonatal rat ventricular cardiomyocytes.We found that knockdown of 11β-HSD1 alleviated LPS-induced myocardial mitochondrial injury,oxidative stress,and inflammation,along with an improved myocardial function;furthermore,the depletion of 11β-HSD1 promoted the phosphorylation of adenosine 5′-monophosphate-activated protein kinase(AMPK),peroxisome proliferator-activated receptor gamma coactivator 1α(PGC-1α),and silent information regulator 1(SIRT1)protein levels both in vivo and in vitro.Therefore,the suppression of 11β-HSD1 may be a viable strategy to improve cardiac function against endotoxemia challenges.

Pathophysiology of sepsis-induced myocardial dysfunction

Sepsis-induced myocardial dysfunction is a common complication in septic patients and is associated with increased mortality.In the clinical setting,it was once believed that myocardial dysfunction was not a major pathological process in the septic patients,at least in part,due to the unavailability of suitable clinical markers to assess intrinsic myocardial function during sepsis.Although sepsis-induced myocardial dysfunction has been studied in clinical and basic research for more than 30 years,its pathophysiology is not completely understood,and no specific therapies for this disorder exist.The purpose of this review is to summarize our current knowledge of sepsis-induced myocardial dysfunction with a special focus on pathogenesis and clinical characteristics.

Gastrin attenuates sepsis-induced myocardial dysfunction by down-regulation of TLR4 expression in macrophages

Myocardial dysfunction is the most serious complication of sepsis.Sepsis-induced myocardial dysfunction(SMD)is often associated with gastrointestinal dysfunction,but its pathophysiological significance remains unclear.The present study found that patients with SMD had higher plasma gastrin concentrations than those without SMD.In mice,knockdown of the gastrin receptor,cholecystokinin B receptor(Cckbr),aggravated lipopolysaccharide(LPS)-induced cardiac dysfunction and increased inflammation in the heart,whereas the intravenous administration of gastrin ameliorated SMD and cardiac injury.Macrophage infiltration plays a significant role in SMD because depletion of macrophages by the intravenous injection of clodronate liposomes,48 h prior to LPS administration,alleviated LPSinduced cardiac injury in Cckbr-deficient mice.The intravenous injection of bone marrow macrophages(BMMs)overexpressing Cckbr reduced LPS-induced myocardial dysfunction.Furthermore,gastrin treatment inhibited toll-like receptor 4(TLR4)expression through the peroxisome proliferator-activated receptor a(PPAR-a)signaling pathway in BMMs.Thus,our findings provide insights into the mechanism of the protective role of gastrin/CCKBR in SMD,which could be used to develop new treatment modalities for SMD.

Effects of Shenfu Injection(参附注射液)on Inflammatory Response during Post-Resuscitation Myocardial Dysfunction after Cardiac Arrest in Swine

Objective:To investigate whether Shenfu Injection(SFI,参附注射液)can alleviate post-resuscitation myocardial dysfunction by inhibiting the inflammatory response.Methods:After 8 min of ventricular fibrillation and 2 min of basic life support,24 pigs were randomly divided into 3 groups(n=8),which were given intravenous bolus injections of SFI(1.0 mL/kg),epinephrine(EP,0.02 mg/kg)and normal saline(SA),respectively.The animals were sacrificed at 24 h after restoration of spontaneous circulation(ROSC),and serum interleuking-6(IL-6)and tumor necrosis factor-α(TNF-α)levels were measured by enzyme-linked immunosorbent assay(ELISA);expressions of Toll-like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)m RNAs and proteins were determined by RT-PCR and Western blot,respectively.Results:Compared with the EP and the SA groups,the ultrastructure of myocardial cells were slightly damaged and the systolic function of the left ventricle was markedly improved in the SFI group at 24 h after ROSC(P<0.05).In addition,compared with the EP and SA groups,the SFI group also showed significantly reduced levels of serum IL-6 and TNF-α,protein and mRNA levels of myocardial NF-κB and TLR4(P<0.05).Conclusions:Activation of TLR4/NF-κB signaling pathway may be involved in the pathological mechanisms of post-resuscitation myocardial dysfunction.SFI may block NF-κB-mediated inflammatory response by reducing the activity of NF-κB and the level of TNF-α,thus playing a protective role in post-resuscitation myocardial dysfunction.

Accelerated Autophagy of Cecal Ligation and Puncture-Induced Myocardial Dysfunction and Its Correlation with Mammalian Target of Rapamycin Pathway in Rats

Background：Recent studies have indicated that autophagy is involved in sepsis-induced myocardial dysfunction.This study aimed to investigate the change of autophagy in cecal ligation and puncture （CLP）-induced myocardium dysfunction and its relationship with mammalian target of rapamycin （mTOR） pathway.Methods：Totally,12 rats were randomly divided into CLP group or sham-operated （SHAM） group.Cardiac tissues were harvested 18 h after CLP or sham operation.Pathology was detected by hematoxylin and eosin staining,cardiac functions by echocardiography,distribution ofmicrotubule-associated protein light chain 3 type Ⅱ （LC3II） by immunohistochemical staining,and autophagic vacuoles by transmission electron microscopy.Moreover,phosphorylation of mTOR （p-mTOR）,phosphorylation of S6 kinase-1 （PS6K1）,and LC3II and p62 expression were measured by western blotting.Pearson＇s correlation coefficient was used to analyze the correlation of two parameters.Results：The results by pathology and echocardiography revealed that there was obvious myocardial injury in CLP rats （left ventricle ejection fraction：SHAM 0.76 ± 0.06 vs.CLP 0.59 ± 0.l l,P 〈 0.01;fractional shortening：SHAM 0.51 ± 0.09 vs.CLP 0.37 ± 0.06,P 〈 0.05）.We also found that the autophagy process was elevated by CLE the ratio of LC3II/LC3I was increased （P 〈 0.05） while the expression of p62 was decreased （P 〈 0.05） in the CLP rats,and there were also more autophagosomes and autolysosomes in the CLP rats.Furthermore,the mTOR pathway in CLP myocardium was inhibited when compared with the sham-operated rats;p-mTOR （P 〈 0.01） and PS6K 1 （P 〈 0.05） were both significantly suppressed following CLP challenge.Interestingly,we found that the mTOR pathway was closely correlated with the autophagy processes.In our study,while p-mTOR in the myocardium was significantly correlated with p62 （r=0.66,P =0.02）,PS6K1 was significantly positively correlated with p62 （r =0.70,P =0.01） and negatively correlated with LC31I （r =-0.71,P =0.01）.Conclusions：The autophagy process in the myocardium was accelerated in CLP rats,which was closely correlated with the inhibition of the mTOR pathway.

Association of poly(ADP-ribose) polymerase activity in circulating mononuclear cells with myocardial dysfunction in patients with septic shock

Background Severe sepsis and septic shock are the leading causes of morbidity and mortality in hospitalized patients.This study aimed to investigate the association of poly（ADP-ribose） polymerase-1 （PARP-1） activity in circulating mononuclear cells with myocardial dysfunction in patients with septic shock.Methods A total of 64 patients with septic shock were divided into the survival group （n=41） and the nonsurvival group （n=23） according to mortality at 28 days after enrollments.PARP-1 activity in circulating mononuclear cells,brain natriuretic peptide,Acute Physiology and Chronic Health Evaluation Ⅱ score,the cardiac index （CI）,the cardiac function index （CFI）,global ejection fraction （GEF）,and the left ventricular contractility index （dp/dt max） were measured after admission to the intensive care unit.Results PARP-1 activity in circulating mononuclear cells of nonsurvival patients with septic shock was significantly higher than that in survival patients.PARP-1 activity in circulating mononuclear cells was strongly,negatively correlated with the CI,the CFI,GEE and dp/dt max.Multiple Logistic regression analysis showed that PARP-1 activity in circulating mononuclear cells was an independent risk factor of myocardial dysfunction.The optimal cutoff point of PARP-1 activity for predicting 28-day mortality was 942 nmol/L with a sensibility of 78.2% and specificity of 65.1%.Conclusion PARP-1 activity in circulating mononuclear cells is significantly associated with myocardial dysfunction and may have prognostic value in patients with septic shock.

Prognosis evaluation of BNP combined with Ee＇ in patients with sepsis-induced myocardial dysfunction

Background Sepsis-induced myocardial dysfunction is a common complication and the main cause of mor- tality in patients with sepsis. At present, there is still lack of specific early diagnosis index of the disease. Our study was aimed to investigate the diagnosis and prognosis evaluation value of b-type natriuretic peptide （BNP） combined with the ratio of early diastolic transmitral inflow velocity （E） to early diastolic mitral annulus velocity （e＇） （Ee＇） in sepsis-induced myocardial dysfunction, so as to apply them as early warning indicators of the disease. Methods Sixty-six cases of patients with sepsis were selected and divided into disorder group （myocardial dys- function, n=28） and normal group （normal myocardial function, n=38）. Ee＇ of patients at the same time of LVEF detection, plasma BNP levels and APACHE ]l score and the 28 d survival rate of the two groups were also deter- mined and compared. The correlations of between plasma BNP levels and Ee＇ in sepsis patients with myocardial dysfunction with LVEF, APACHE l] score and 28 d survival rate were analyzed, and the value of them in combi- nation for predicting the 28 d survival rate was analyzed. Results Compared with the normal group, Plasma BNP levels, Ee＇ and APACHE 1] scores in the disorder group were increased （P 〈 0.05）. The 28 d survival rate of the patients in the disorder group was lower than that in the normal group （42.68% vs. 73.68%; P 〈 0.05）. Com- pared with the survival patients in the disorder group, plasma BNP levels, Ee＇ and APACHE I[ scores of the dead patients in disorder group were higher, while LVEF in the dead patient in disorder group was lower （P 〈 0.05）. Spearman unconditional correlation analysis and Logistic multiple regression analysis model results showed that plasma BNP levels and Ee＇ in sepsis patients with myocardial dysfunction were correlated with LVEF, 28d sur- vival rate and APACHE lI score. ROC curve analysis showed that values of plasma BNP levels and Ee＇ in sepsis patients with myocardial dysfunction were better in predicting the 28 d survival rate, while their combination was the best. Conclusions Plasma BNP levels and Ee＇ in sepsis patients with myocardial dysfunction are correlated with the severity and prognosis, therefore, provide reference indexes for the assessment of severity and prognosis of patients with sepsis and myocardial dysfunction.

Coronary microembolization induced myocardial contractile dysfunction through a p38 mapk pathway

Background Cathepsin S and its endogenous inhibitor cystatin C are implicated in the pathogenesis of atherosclerosis,especially in the plaque destabilization and rupture leading to acute coronary syndrome.However, whether circulating cathepsin S and cystatin C also change in association with coronary plaque morphology is unknown yet. Methods Sprague-Dawley rats were randomly divided into three groups;Sham group,CME group and SB203580 group (n=10 per group).CME rats were produced by injection of 42μm microspheres into the left ventricle with occlusion of the ascending aorta.SB203580,a p38 MAPK inhibitor,was injected into femoral vein after finishing the injection of microspheres in SB203580 group.Left ventricular Ejection Fraction was determined by echocardiography.The level of phosphorylated and total P38 MAPK in myocardium was assessed by Western Blot.Results Left ventricular(LV) Ejection Fraction was depressed at 3 hours and until up to 12 hours in CME group.The increased p38 MAPK activation was observed in CME group.The administration of SB203580 partly inhibited the p38 MAPK activity and preserved cardiac contractile function.Conclusions p38 MAPK is significantly activated by CME and the inhibition of p38 MAPK can partly preserve cardiac contractile function.

Cardiac arrest, stony heart, and cardiopulmonary resuscitation: An updated revisit

The post-resuscitation period is recognized as the main predictor of cardiopul-monary resuscitation(CPR)outcomes.The first description of post-resuscitation syndrome and stony heart was published over 50 years ago.Major manifestations may include but are not limited to,persistent precipitating pathology,systemic ischemia/reperfusion response,post-cardiac arrest brain injury,and finally,post-cardiac arrest myocardial dysfunction(PAMD)after successful resuscitation.Why do some patients initially survive successful resuscitation,and others do not?Also,why does the myocardium response vary after resuscitation?These ques-tions have kept scientists busy for several decades since the first successful resuscitation was described.By modifying the conventional modalities of resu-scitation together with new promising agents,rescuers will be able to salvage the jeopardized post-resuscitation myocardium and prevent its progression to a dismal,stony heart.Community awareness and staff education are crucial for shortening the resuscitation time and improving short-and long-term outcomes.Awareness of these components before and early after the restoration of circulation will enhance the resuscitation outcomes.This review extensively addresses the underlying pathophysiology,management,and outcomes of post-resuscitation syndrome.The pattern,management,and outcome of PAMD and post-cardiac arrest shock are different based on many factors,including in-hospital cardiac arrest vs out-of-hospital cardiac arrest(OHCA),witnessed vs unwitnessed cardiac arrest,the underlying cause of arrest,the duration,and protocol used for CPR.Although restoring spontaneous circulation is a vital sign,it should not be the end of the game or lone primary outcome;it calls for better understanding and aggressive multi-disciplinary interventions and care.The development of stony heart post-CPR and OHCA remain the main challenges in emergency and critical care medicine.

Evaluation of Ventricular-vascular Coupling in Patients with Type 2 Diabetes Mellitus Using 2-Dimensional Speckle Tracking Imaging

The elastic and functional coupling of heart and vessels makes the stroke work （SW） of the heart optimal. Speckle tracking imaging （STI） can evaluate the myocardial strain and function. We studied ventricular-vascular coupling in 80 diabetic patients with different systolic function using STI. The patients were divided into two groups according to ejection fraction （EF）： the diabetes mel- litus with normal EF （DMN） group and the diabetes mellitus with abnormal EF （DMA） group. Forty-two volunteers served as control group. The relative wall thickness （RWT）, left ventricular mass index （LVMI）, stroke volume （SV）, SW, rate-pressure product （RPP）, systemic vascular resis- tance index （SVRI）, left ventricular end-systolic elastance （Ees）, effective arterial elasticity （Ea） and ventricular-vascular coupling index （VVI） were measured and calculated by conventional echocardi- ography. The longitudinal strain （LS） at basement （LSBA）, papillary muscle （LSvM） and cardiac apex （LSAv） was assessed with STI. It was found： （A） compared with control group, in DMN and DMA groups, LSBA, LSvM and LSAp decreased, and they were lower in DMA group. （B） VVI, RPP and SVRI increased, and they were higher in DMN group; Ees decreased, and it was lower in DMA group. （C） LSBA, LSpM, and LSAv had negative correlation with VVI. LSAp, RWT, LVMI and SW were independent predictors for VVI. The area under the receiver operating characteristic （ROC） curves was used for identification of DMA and DMN with LSBA, LSpM, and LSAp, and the area under the ROC of LSAp was the largest. This study supports that myocardial LS could reflect the ventricu- lar-vascular coupling. Different segments had an order to “respond to” the state of the coupling, and the cardiac apex might be the earliest.

Cardiovascular impact of COVID-19 with a focus on children: A systematic review

BACKGROUND Since the beginning of the pandemic,coronavirus disease-2019(COVID-19)in children has shown milder cases and a better prognosis than adults.Although the respiratory tract is the primary target for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),cardiovascular involvement is emerging as one of the most significant and life-threatening complications of SARS-CoV-2 infection in adults.AIM To summarize the current knowledge about the potential cardiovascular involvement in pediatric COVID-19 in order to give a perspective on how to take care of them during the current pandemic emergency.METHODS Multiple searches in MEDLINE,PubMed were performed using the search terms“COVID-19”or“SARS-CoV-2"were used in combination with“myocardial injury”or"arrhythmia"or“cardiovascular involvement”or"heart disease"or"congenital heart disease"or“pulmonary hypertension”or"long QT"or“cardiomyopathies”or“channelopathies”or"Multisystem inflammatory system"or"PMIS"or“MIS-C”or”Pediatric multisystem inflammatory syndrome"or"myocarditis"or"thromboembolism to identify articles published in English language from January 1st,2020 until July 31st,2020.The websites of World Health Organization,Centers for Disease control and Prevention,and the Johns Hopkins Coronavirus Resource Center were reviewed to provide up to date numbers and infection control recommendations.Reference lists from the articles were reviewed to identify additional pertinent articles.Retrieved manuscripts concerning the subject were reviewed by the authors,and the data were extracted using a standardized collection tool.Data were subsequently analyzed with descriptive statistics.For Pediatric multisystemic inflammatory syndrome temporally associated with COVID-19(PMIS),multiple meta-analyses were conducted to summarize the pooled mean proportion of different cardiovascular variables in this population in pseudo-cohorts of observed patients.RESULTS A total of 193 articles were included.Most publications used in this review were single case reports,small case series,and observational small-sized studies or literature reviews.The meta-analysis of 16 studies with size>10 patients and with complete data about cardiovascular involvement in children with PMIS showed that PMIS affects mostly previously healthy school-aged children and adolescents presenting with Kawasaki disease-like features and multiple organ failure with a focus on the heart,accounting for most cases of pediatric COVID-19 mortality.They frequently presented cardiogenic shock(53%),ECG alterations(27%),myocardial dysfunction(52%),and coronary artery dilation(15%).Most cases required PICU admission(75%)and inotropic support(57%),with the rare need for extracorporeal membrane oxygenation(4%).Almost all of these children wholly recovered in a few days,although rare deaths have been reported(2%).Out of PMIS cases we identified 10 articles reporting sporadic cases of myocarditis,pulmonary hypertension and cardiac arrythmias in previously healthy children.We also found another 10 studies reporting patients with preexisting heart diseases.Most cases consisted in children with severe COVID-19 infection with full recovery after intensive care support,but cases of death were also identified.The management of different cardiac conditions are provided based on current guidelines and expert panel recommendations.CONCLUSION There is still scarce data about the role of cardiovascular involvement in COVID-19 in children.Based on our review,children(previously healthy or with preexisting heart disease)with acute COVID-19 requiring hospital admission should undergo a cardiac workup and close cardiovascular monitoring to identify and treat timely life-threatening cardiac complications.

Age-adjusted NT-proBNP could help in the early identification and follow-up of children at risk for severe multisystem inflammatory syndrome associated with COVID-19(MIS-C)

BACKGROUND Multisystem inflammatory syndrome in children(MIS-C) has emerged as a new disease associated with COVID-19 that presents in acute critically ill children with acute cardiovascular dysfunction.AIM To determine whether the age-adjusted N-terminal pro-brain natriuretic peptide(NT-proBNP) value(Z-log-NT-proBNP) is associated with severe MIS-C and myocardial dysfunction.METHODS A retrospective study was conducted which included children with MIS-C managed at our institution between April 1,2020,and February 28,2022.We divided the population into groups depending on severity based on pediatric intensive care unit(PICU) admission.We compared Z-log-NT-proBNP values across these groups and analyzed Z-log-NT-proBNP dynamics during the onemonth follow-up.RESULTS We included 17 participants [median age 3(2-9) years] and seven(41%) required PICU admission.All(100%) of these cases presented very high(Z-log > 4) levels of NT-proBNP at the time of admission compared to only 5(50%) patients with non-severe MIS-C(P = 0.025).NT-proBNP was significantly correlated with highsensitive Troponin I levels(P = 0.045),Ross modified score(P = 0.003) and left ventricle ejection fraction(P = 0.021).CONCLUSION Raised NT-proBNP,specifically very high values(Z-log-NT-proBNP > 4) could help in the early identification of MIS-C patients with myocardial dysfunction requiring inotropic support and PICU admission.

Astragaloside IV Attenuates Polymicrobial Sepsis-Induced Cardiac Dysfunction in Rats via IKK/NF-κB Pathway

Objective To evaluate the protective effects of Astragaloside IV(AST)in a rat model of myocardial injury induced by cecal ligation and puncture(CLP).Methods The model of sepsis-induced cardiac dysfunction was induced by CLP.Using a random number table,50 specific pathogen free grade of Sprague Dawley rats were randomized into 5 groups:the sham group(sham),the model group(CLP,18 h/72 h)and AST group(18 h/72 h).Except the sham group,the rats in other groups received CLP surgery to induce sepsis.CLP groups received intragastric administration with normal saline after CLP.AST groups received intragastric administration with AST solution(40 mg/kg)once a day.The levels of inflammatory mediators and oxidative stress markers in the serum of the septic rats were determined via enzyme-linked immunosorbent assay(ELISA)at different time point,such as interleukin 6(IL-6),IL-10,high mobility group box-1 protein B1(HMGB-1),superoxide dismutase(SOD),and malondialdehyde(MDA).Cardiac function was determined by echocardiography.Moreover,changes in myocardial pathology were evaluated using hematoxylin and eosin staining.The levels of lactate dehydrogenase(LDH)and creatine kinase-MB(CK-MB)were analysed to determine the status of CLP-induced myocardium.In addition,the apotosis of myocardial cells was analysed by terminal-deoxynucleoitidyl transferase mediated nick end labeling(TUNEL).The protein levels of B-cell lymphoma-2(Bcl-2),Bcl-2-associated X(Bax),IκB kinaseα(IKKα),nuclear factor kappa B p65(NF-κB p65)were detected by Western blot analysis.Moreover,survival rate was investigated.Results AST improved the survival rate of CLP-induced rats by up to 33.3%(P<0.05).The cardioprotective effect of AST was observed by increased ejection fraction,fractional shortening and left ventricular internal diameter in diastole respectively(P<0.01 or P<0.05).Subsequently,AST attenuated CLP-induced myocardial apoptosis and the ratio of Bcl-2/Bax in the myocardium,as well as the histological alterations of myocardium(P<0.01 or P<0.05);the generation of inflammatory cytokines(IL-6,IL-10,HMGB-1)and oxidative stress markers(SOD,MDA)in the serum was significantly alleviated(P<0.01 or P<0.05).On the other hand,AST markedly suppressed CLP-induced accumulation of IKK-αand NF-κB p65 subunit phosphorylation(P<0.01 or P<0.05).Conclusions AST plays a significant protective role in sepsis-induced cardiac dysfunction and survival outcome.The possible mechanism of cardioprotection is dependent on the activation of the IKK/NF-κB pathway in cardiomyocytes.

Effects of short-acting β-adrenergic blocker on B-type natriuretic peptide at early stage of postresuscitation in rabbits

Postresuscitation myocardial dysfunction is reversible heart failure and B-type natriuretic peptide （BNP） is a biochemical marker of ventricular disorders secreted from ventricle, which can be used to assess the status of left ventricular function. This study investigated the effect of β-adrenergic blocker on concentration of BNP and cardiac function after cardiopulmonary resuscitation in rabbits.

Septic cardiomyopathy: Diagnosis and management

There is an extensive body of literature focused on sepsis-induced myocardial dysfunction,but results are con-flicting and no objective definition of septic cardiomyopathy(SCM)has been established.SCM may be defined as a sepsis-associated acute syndrome of non-ischemic cardiac dysfunction with systolic and/or diastolic left ventricular(LV)dysfunction and/or right ventricular dysfunction.Physicians should consider this diagnosis in patients with sepsis-associated organ dysfunction,and particularly in cases of septic shock that require vasopres-sors.Echocardiography is currently the gold standard for diagnosis of SCM.Left ventricular ejection fraction is the most common parameter used to describe LV function in the literature,but its dependence on loading condi-tions,particularly afterload,limits its use as a measure of intrinsic myocardial contractility.Therefore,repeated echocardiography evaluation is mandatory.Evaluation of global longitudinal strain(GLS)may be more sensi-tive and specific for SCM than LV ejection fraction(LVEF).Standard management includes etiological treatment,adapted fluid resuscitation,use of vasopressors,and monitoring.Use of inotropes remains uncertain,and heart rate control could be an option in some patients.