OBJECTIVES: To examine the effect of premorbid β-blocker exposure on mortality and organ dysfunction in sepsis. DESIGN: Retrospective observational study. SETTING: ICUs in Australia, the Czech Republic, and the United States. PATIENTS: Total of 4,086 critical care patients above 18 years old with sepsis between January 2014 and December 2018. INTERVENTION: Premorbid beta-blocker exposure. MEASUREMENTS AND MAIN RESULTS: One thousand five hundred fifty-six patients (38%) with premorbid β-blocker exposure were identified. Overall ICU mortality rate was 15.1%. In adjusted models, premorbid β-blocker exposure was associated with decreased ICU (adjusted odds ratio, 0.80; 95% CI, 0.66-0.97; p = 0.025) and hospital (adjusted odds ratio, 0.83; 95% CI, 0.71-0.99; p = 0.033) mortality. The risk reduction in ICU mortality of 16% was significant (hazard ratio, 0.84, 95% CI, 0.71-0.99; p = 0.037). In particular, exposure to noncardioselective β-blocker before septic episode was associated with decreased mortality. Sequential Organ Failure Assessment score analysis showed that premorbid β-blocker exposure had potential benefits in reducing respiratory and neurologic dysfunction. CONCLUSIONS: This study suggests that β-blocker exposure prior to sepsis, especially to noncardioselective β blockers, may be associated with better outcome. The findings suggest prospective evaluation of β-blocker use in the management of sepsis.

Centre for immunology and allergy research Westmead Millennium Institute Westmead NSW Australia

Department of Computer Science Yale University New Haven CT

Department of Intensive Care Medicine Nepean Hospital Kingswood NSW Australia

Medical Intensive Care Unit University Hospital and Biomedicine Centre Pilsen Charles University Prague Prague Czech Republic

Medistra Hospital Jakarta Indonesia

Nepean Clinical School Sydney Medical School University of Sydney Sydney NSW Australia

NHMRC Clinical Trials Centre The University of Sydney Sydney NSW Australia

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Singer M, Deutschman CS, Seymour CW, et al.: The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315:801–810

Kaukonen KM, Bailey M, Suzuki S, et al.: Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014; 311:1308–1316

Levy MM, Evans LE, Rhodes A: The surviving sepsis campaign bundle: 2018 update. Intensive Care Med 2018; 44:925–928

Annane D, Renault A, Brun-Buisson C, et al.; CRICS-TRIGGERSEP Network: Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 2018; 378:809–818

Hartmann C, Radermacher P, Wepler M, et al.: Non-hemodynamic effects of catecholamines. Shock 2017; 48:390–400

Dünser MW, Ruokonen E, Pettilä V, et al.: Association of arterial blood pressure and vasopressor load with septic shock mortality: A post hoc analysis of a multicenter trial. Crit Care 2009; 13:R181

Schmittinger CA, Dünser MW, Torgersen C, et al.: Histologic pathologies of the myocardium in septic shock: A prospective observational study. Shock 2013; 39:329–335

de Montmollin E, Aboab J, Mansart A, et al.: Bench-to-bedside review: Beta-adrenergic modulation in sepsis. Crit Care 2009; 13:230

Suzuki T, Suzuki Y, Okuda J, et al.: Sepsis-induced cardiac dysfunction and β-adrenergic blockade therapy for sepsis [Internet]. J Intensive Care 2017; 5:22

Singer M: Catecholamine treatment for shock–equally good or bad? Lancet 2007; 370:636–637

Lesur O, Delile E, Asfar P, et al.: Hemodynamic support in the early phase of septic shock: A review of challenges and unanswered questions. Ann Intensive Care 2018; 8:102

Morelli A, Donati A, Ertmer C, et al.: Microvascular effects of heart rate control with esmolol in patients with septic shock: A pilot study. Crit Care Med 2013; 41:2162–2168

Morelli A, Ertmer C, Westphal M, et al.: Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: A randomized clinical trial. JAMA 2013; 310:1683–1691

Plummer MP, Deane AM: Dysglycemia and glucose control during sepsis. Clin Chest Med 2016; 37:309–319

Rehman A, Setter SM, Vue MH: Drug-induced glucose alterations part 2: Drug-induced hyperglycemia. Diabetes Spectr 2011; 24:234–238

Vue MH, Setter SM: Drug-induced glucose alterations part 1: Drug-induced hypoglycemia. Diabetes Spectr 2011; 24:171–177

Novotny NM, Lahm T, Markel TA, et al.: beta-Blockers in sepsis: Reexamining the evidence. Shock 2009; 31:113–119

van Loon LM, van der Hoeven JG, Lemson J: Hemodynamic response to β-blockers in severe sepsis and septic shock: A review of current literature. J Crit Care 2019; 50:138–143

Chacko CJ, Gopal S: Systematic review of use of β-blockers in sepsis. J Anaesthesiol Clin Pharmacol 2015; 31:460–465

Sanfilippo F, Santonocito C, Morelli A, et al.: Beta-blocker use in severe sepsis and septic shock: A systematic review. Curr Med Res Opin 2015; 31:1817–1825

McLean AS, Taccone FS, Vieillard-Baron A: Beta-blockers in septic shock to optimize hemodynamics? No. Intensive Care Med 2016; 42:1610–1612

Tan K, Harazim M, Tang B, et al.: The association between premorbid beta blocker exposure and mortality in sepsis-a systematic review. Crit Care 2019; 23:298

von Elm E, Altman DG, Egger M, et al.; STROBE Initiative: Strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies. BMJ 2007; 335:806–808

Pollard TJ, Johnson AEW, Raffa JD, et al.: The eICU collaborative research database, a freely available multi-center database for critical care research. Sci Data 2018; 5:180178

Wang T, Derhovanessian A, De Cruz S, et al.: Subsequent infections in survivors of sepsis: Epidemiology and outcomes. J Intensive Care Med 2014; 29:87–95

DeMerle KM, Royer SC, Mikkelsen ME, et al.: Readmissions for recurrent sepsis: New or relapsed infection? Crit Care Med 2017; 45:1702–1708

Singer KE, Collins CE, Flahive JM, et al.: Outpatient beta-blockers and survival from sepsis: Results from a national cohort of medicare beneficiaries. Am J Surg 2017; 214:577–582

Macchia A, Romero M, Comignani PD, et al.: Previous prescription of β-blockers is associated with reduced mortality among patients hospitalized in intensive care units for sepsis. Crit Care Med 2012; 40:2768–2772

Stortz JA, Cox MC, Hawkins RB, et al.: Phenotypic heterogeneity by site of infection in surgical sepsis: A prospective longitudinal study. Crit Care 2020; 24:203

Nachtigall I, Tafelski S, Rothbart A, et al.: Gender-related outcome difference is related to course of sepsis on mixed ICUs: A prospective, observational clinical study. Crit Care 2011; 15:R151

Finazzi S, Poole D, Luciani D, et al.: Calibration belt for quality-of-care assessment based on dichotomous outcomes. PLoS One 2011; 6:e16110

Ho DE, Imai K, King G, et al.: Matching as nonparametric preprocessing for reducing model dependence in parametric causal inference. Polit Anal 2007; 15:199–236

Zhang Z, Kim HJ, Lonjon G, et al.; written on behalf of AME Big-Data Clinical Trial Collaborative Group: Balance diagnostics after propensity score matching. Ann Transl Med 2019; 7:16

Al Harbi SA, Al Sulaiman KA, Tamim H, et al.: Association between β-blocker use and mortality in critically ill patients: A nested cohort study. BMC Pharmacol Toxicol 2018; 19:22

Al-Qadi MO, O’Horo JC, Thakur L, et al.: Long-term use of beta blockers is protective in severe sepsis and septic shock. Am J Respir Crit Care Med 2020; 189:A6655

Contenti J, Occelli C, Corraze H, et al.: Long-term β-blocker therapy decreases blood lactate concentration in severely septic patients. Crit Care Med 2015; 43:2616–2622

Alsolamy S, Ghamdi G, Alswaidan L, et al.: 36th international symposium on intensive care and emergency medicine: Brussels, Belgium. 15-18 March 2016 [Internet]. Crit Care 2016; 20:94

Fuchs C, Wauschkuhn S, Scheer C, et al.: Continuing chronic beta-blockade in the acute phase of severe sepsis and septic shock is associated with decreased mortality rates up to 90 days. Br J Anaesth 2017; 119:616–625

Hsieh M-S, How C-K, Hsieh VC-R, et al.: Preadmission antihypertensive drug use and sepsis outcome: Impact of Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs). Shock 2019; 53:407–415

Sharma A, Vashisht R, Bauer S, et al.: Effect of preadmission beta-blocker use on outcomes of patients admitted with septic shock. Crit Care Med 2016; 44:413

Liu P, Wu Q, Tang Y, et al.: The influence of esmolol on septic shock and sepsis: A meta-analysis of randomized controlled studies. Am J Emerg Med 2018; 36:470–474

Apple CG, Miller ES, Loftus TJ, et al.: Effect of beta-blockade on the expression of regulatory MicroRNA after severe trauma and chronic stress. J Am Coll Surg 2020; 230:121–129

Wong WT, Li LH, Rao YK, et al.: Repositioning of the β-Blocker carvedilol as a novel autophagy inducer that inhibits the NLRP3 inflammasome. Front Immunol 2018; 9:1920

Abdel Kawy HS: Low-dose carvedilol protects against acute septic renal injury in rats during the early and late phases. Can J Physiol Pharmacol 2015; 93:443–450

Stolk RF, van der Pasch E, Naumann F, et al.: Norepinephrine dysregulates the immune response and compromises host defense during sepsis. Am J Respir Crit Care Med 2020; 202:830–842

Uhel F, van der Poll T: Norepinephrine in septic shock: A mixed blessing. Am J Respir Crit Care Med 2020; 202:788–789

Silva IVG, de Figueiredo RC, Rios DRA: Effect of different classes of antihypertensive drugs on endothelial function and inflammation. Int J Mol Sci 2019; 20:3458

Grisanti LA, de Lucia C, Thomas TP, et al.: Prior beta blocker treatment decreases leukocyte responsiveness to injury. JCI Insight 2019; 4:e99485

Seymour CW, Kennedy JN, Wang S, et al.: Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA 2019; 321:2003–2017

Chan JZW, Tan JH, Lather KS, et al.: Beta-blockers’ effect on levels of lactate in patients with suspected sepsis - the BeLLa study. Am J Emerg Med 2020; 38:2574–2579

Lambden S, Laterre PF, Levy MM, et al.: The SOFA score-development, utility and challenges of accurate assessment in clinical trials. Crit Care 2019; 23:374