BACKGROUND: The effect of premorbid β-blocker exposure on clinical outcomes in patients with sepsis is not well characterized. We aimed to examine the association between premorbid β-blocker exposure and mortality in sepsis. METHODS: EMBase, MEDLINE, and Cochrane databases were searched for all studies of premorbid β-blocker and sepsis. The search was last updated on 22 June 2019. Two reviewers independently assessed, selected, and abstracted data from studies reporting chronic β-blocker use prior to sepsis and mortality. Main data extracted were premorbid β-blocker exposure, mortality, study design, and patient data. Two reviewers independently assessed the risk of bias and quality of evidence. RESULTS: In total, nine studies comprising 56,414 patients with sepsis including 6576 patients with premorbid exposure to β-blockers were eligible. For the primary outcome of mortality, two retrospective studies reported adjusted odds ratios showing a reduction in mortality with premorbid β-blocker exposure. One study showed that premorbid β-blocker exposure decreases mortality in patients with septic shock. Another study showed that continued β-blockade during sepsis is associated with decreased mortality. CONCLUSION: This systematic review suggests that β-blocker exposure prior to sepsis is associated with reduced mortality. There was insufficient data to conduct a bona fide meta-analysis. Whether the apparent reduction in mortality may be attributed to the mitigation of catecholamine excess is unclear. TRIAL REGISTRATION: PROSPERO, CRD42019130558 registered June 12, 2019.

Centre for Immunology and Allergy Research Westmead Millennium Institute Westmead Australia

Department of Intensive Care Medicine Nepean Hospital Penrith Australia

Medical Intensive Care Unit Teaching Hospital and Biomedical Centre Charles University Alej Svobody 80 323 00 Pilsen Czech Republic

Nepean Clinical School Sydney Medical School University of Sydney Penrith Australia

Crit Care. 2020 Jan 3;24(1):3. doi: 10.1186/s13054-019-2699-8. PubMed

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Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA. 2016;315(8):801. doi: 10.1001/jama.2016.0287. PubMed DOI PMC

Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management. BMJ [Internet. 2016:i1585 [cited 2019 Mar 24]. Available from: http://www.bmj.com/lookup/doi/10.1136/bmj.i1585. PubMed DOI

Lesur O, Delile E, Asfar P, Radermacher P. Hemodynamic support in the early phase of septic shock: a review of challenges and unanswered questions. Ann Intensive Care. 2018;8(1) [cited 2019 Mar 24]. Available from: https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-018-0449-8. PubMed DOI PMC

Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–377. doi: 10.1007/s00134-017-4683-6. PubMed DOI

Suzuki T, Suzuki Y, Okuda J, Kurazumi T, Suhara T, Ueda T, et al. Sepsis-induced cardiac dysfunction and β-adrenergic blockade therapy for sepsis. J Intensive Care. 2017;5(1) [cited 2019 Mar 24]. Available from: http://jintensivecare.biomedcentral.com/articles/10.1186/s40560-017-0215-2. PubMed DOI PMC

Singer M. Catecholamine treatment for shock—equally good or bad? Lancet. 2007;370(9588):636–637. doi: 10.1016/S0140-6736(07)61317-8. PubMed DOI

de Montmollin E, Aboab J, Mansart A, Annane D. Bench-to-bedside review: β-adrenergic modulation in sepsis. Crit Care. 2009;13(5):230. doi: 10.1186/cc8026. PubMed DOI PMC

Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, 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(16):1683. doi: 10.1001/jama.2013.278477. PubMed DOI

Morelli A, Donati A, Ertmer C, Rehberg S, Kampmeier T, Orecchioni A, et al. Microvascular effects of heart rate control with esmolol in patients with septic shock: a pilot study*. Crit Care Med. 2013;41(9):2162–2168. doi: 10.1097/CCM.0b013e31828a678d. PubMed DOI

Macchia A, Romero M, Comignani PD, Mariani J, D’Ettorre A, Prini N, 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(10):2768–2772. doi: 10.1097/CCM.0b013e31825b9509. PubMed DOI

Singer KE, Collins CE, Flahive JM, Wyman AS, Ayturk MD, Santry HP. Outpatient beta-blockers and survival from sepsis: results from a national cohort of Medicare beneficiaries. Am J Surg. 2017;214(4):577–582. doi: 10.1016/j.amjsurg.2017.06.007. PubMed DOI PMC

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. doi: 10.1016/j.jcrc.2018.12.003. PubMed DOI

Chacko C, Gopal S. Systematic review of use of β-blockers in sepsis. J Anaesthesiol Clin Pharmacol. 2015;31(4):460. doi: 10.4103/0970-9185.169063. PubMed DOI PMC

Sanfilippo F, Santonocito C, Morelli A, Foex P. Beta-blocker use in severe sepsis and septic shock: a systematic review. Curr Med Res Opin. 2015;31(10):1817–1825. doi: 10.1185/03007995.2015.1062357. PubMed DOI

McLean AS, Taccone FS, Vieillard-Baron A. Beta-blockers in septic shock to optimize hemodynamics? No. Intensive Care Med. 2016;42(10):1610–1612. doi: 10.1007/s00134-016-4407-3. PubMed DOI

Stroup DF. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283(15):2008. doi: 10.1001/jama.283.15.2008. PubMed DOI

Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. doi: 10.1371/journal.pmed.1000100. PubMed DOI PMC

Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016:i4919 [cited 2018 Jul 30]. Available from: http://www.bmj.com/lookup/doi/10.1136/bmj.i4919. PubMed DOI PMC

Park S, Beretvas SN. Using total sample size weights in meta-analysis of log-odds ratios. J Exp Educ. 2018;1–15. [cited 2019 Mar 25]. Available from: https://www.tandfonline.com/doi/full/10.1080/00220973.2018.1451295 DOI

Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–1558. doi: 10.1002/sim.1186. PubMed DOI

Contenti J, Occelli C, Corraze H, Lemoël F, Levraut J. Long-term β-blocker therapy decreases blood lactate concentration in severely septic patients*. Crit Care Med. 2015;43(12):2616–2622. doi: 10.1097/CCM.0000000000001308. PubMed DOI

Alsolamy S, Ghamdi G, Alswaidan L, Alharbi S, Alenezi F, López-Rodríguez M, et al. 36th International Symposium on Intensive Care and Emergency Medicine: Brussels, Belgium. 15–18 March 2016. Crit Care. 2016;20(S2) [cited 2019 Mar 17]. Available from: http://ccforum.biomedcentral.com/articles/10.1186/s13054-016-1208-6. DOI

Charles DR, Jean-Francois L, Matthieu J, Charpentier J, Cariou A, Chiche J-D, et al. Proceedings of Réanimation 2018, the French Intensive Care Society International Congress. Ann Intensive Care. 2018;8(S1) [cited 2019 Mar 17]. Available from: https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-017-0345-7. DOI

Al-Qadi MO, O’Horo JC, Thakur L, Kaur S, Berrios RAS, Caples SM, et al. American Journal of Respiratory and Critical Care Medicine. San Diego: Conference: Ameriacn Thoracic Society International Conference, ATS 2014; 2014. Long-term use of beta blockers is protective in severe sepsis and septic shock; p. 189.

Sharma A, Vashisht R, Bauer S, Hanane T. Effect of preadmission beta-blocker use on outcomes of patients admitted with septic shock. United States: Critical Care Medicine; 2016. p. 413.

Fuchs C, Wauschkuhn S, Scheer C, Vollmer M, Meissner K, Kuhn S-O, 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(4):616–625. doi: 10.1093/bja/aex231. PubMed DOI

Hsieh M-S, How C-K, Hsieh VC-R, Chen P-C. Preadmission antihypertensive drug use and sepsis outcome: impact of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Shock. 2019;1 [cited 2019 Jun 22]. Available from: http://Insights.ovid.com/crossref?an=00024382-900000000-97629. PubMed

Sanfilippo F, Corredor C, Fletcher N, Landesberg G, Benedetto U, Foex P, et al. Diastolic dysfunction and mortality in septic patients: a systematic review and meta-analysis. Intensive Care Med. 2015;41(6):1004–1013. doi: 10.1007/s00134-015-3748-7. PubMed DOI

Sanfilippo F, Corredor C, Arcadipane A, Landesberg G, Vieillard-Baron A, Cecconi M, et al. Tissue Doppler assessment of diastolic function and relationship with mortality in critically ill septic patients: a systematic review and meta-analysis. Br J Anaesth. 2017;119(4):583–594. doi: 10.1093/bja/aex254. PubMed DOI

Kimmoun A, Louis H, Al Kattani N, Delemazure J, Dessales N, Wei C, et al. β1-adrenergic inhibition improves cardiac and vascular function in experimental septic shock*. Crit Care Med. 2015;43(9):e332–e340. doi: 10.1097/CCM.0000000000001078. PubMed DOI

Kohoutova M, Horak J, Jarkovska D, Martinkova V, Tegl V, Nalos L, et al. Vagus nerve stimulation attenuates multiple organ dysfunction in resuscitated porcine progressive sepsis. Crit Care Med. 2019;1 [cited 2019 Apr 19]. Available from: http://Insights.ovid.com/crossref?an=00003246-900000000-95985. PubMed

Chioléro R, Revelly JP, Tappy L. Energy metabolism in sepsis and injury. Nutr Burbank Los Angel Cty Calif. 1997;13(9 Suppl):45S–51S. doi: 10.1016/S0899-9007(97)00205-0. PubMed DOI

Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR. Reversal of catabolism by beta-blockade after severe burns. N Engl J Med. 2001;345(17):1223–1229. doi: 10.1056/NEJMoa010342. PubMed DOI

Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52(4):595–638. PubMed

Shaw SM, Coppinger T, Waywell C, Dunne L, Archer LD, Critchley WR, et al. The effect of beta-blockers on the adaptive immune system in chronic heart failure. Cardiovasc Ther. 2009;27(3):181–186. doi: 10.1111/j.1755-5922.2009.00089.x. PubMed DOI

Estrada LD, Ağaç D, Farrar JD. Sympathetic neural signaling via the β2-adrenergic receptor suppresses T-cell receptor-mediated human and mouse CD8 + T-cell effector function. Eur J Immunol. 2016;46(8):1948–1958. doi: 10.1002/eji.201646395. PubMed DOI PMC

Schouten M, Wiersinga WJ, Levi M, van der Poll T. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. 2008;83(3):536–545. doi: 10.1189/jlb.0607373. PubMed DOI

Hjemdahl P, Larsson PT, Wallén NH. Effects of stress and beta-blockade on platelet function. Circulation. 1991;84(6 Suppl):VI44–VI61. PubMed

Xu L, Yu W-K, Lin Z-L, Tan S-J, Bai X-W, Ding K, et al. Chemical sympathectomy attenuates inflammation, glycocalyx shedding and coagulation disorders in rats with acute traumatic coagulopathy. Blood Coagul Fibrinolysis. 2015;26(2):152–160. doi: 10.1097/MBC.0000000000000211. PubMed DOI

Johansson P, Stensballe J, Ostrowski S. Shock induced endotheliopathy (SHINE) in acute critical illness - a unifying pathophysiologic mechanism. Crit Care. 2017;21(1):25. doi: 10.1186/s13054-017-1605-5. PubMed DOI PMC

Correction to: The association between premorbid beta blocker exposure and mortality in sepsis-a systematic review