Editorial<\/p>\n\n\n\n
Despite over 40 years of research, the search for an intervention that can alter clinical outcomes from septic shock remains elusive. Survival has improved, in part because of earlier recognition and treatment and in part because of reduced iatrogenic harm. However, mortality rates remain unacceptably high; most registry studies using the Sepsis-3 criteria for septic shock consistently report mortality rates of approximately 40%-50%. Over the decades, single-center studies using strategies such as early goal-directed therapy1<\/sup><\/a> and tight glycemic control2<\/sup><\/a> could not be subsequently replicated in large multicenter studies. Efficacy in motivated, experienced hands in a single hospital did not translate to effectiveness in the wider ICU community. The same seems to be happening to beta-adrenergic blockade in septic shock. In their 2013 landmark study,3<\/sup><\/a>Morelli et al demonstrated that the short-acting beta-blocker esmolol could be safely administered to tachycardic patients with septic shock. The major excitement attached to this study was generated by the secondary outcomes of a more rapid reduction in vasopressor dosing and, in particular, a dramatic reduction in 28-day mortality, from 80.5% in the control group to 49.4% in those receiving esmolol.<\/p>\n\n\n\n In this issue of CHEST<\/em>, Sato et al4<\/sup><\/a> report a systematic review and meta-analysis of trials of beta-blockade in 885 patients with septic shock. All studies were open-label as continuous infusions of either esmolol or landiolol were titrated to reduce tachycardia to a target heart rate range, usually between 80 and 95 beats\/min. No overall mortality benefit was seen, either at 28 days or later, albeit P<\/em> values and CIs were tantalizingly close to significance. However, there was a disparity between the single- and multicenter trials, with the latter failing to reproduce the benefit shown in the former.<\/p>\n\n\n\n The efficacy vs effectiveness debate once more rears its head. Did the multicenter studies suffer from a lack of both expertise and experience, especially ascending the learning curve that clinicians naive in beta-blocker use must go through to apply the intervention safely and successfully? Single-center studies are also usually driven by a local champion, leading a team trained in delivering the intervention, and the emotional investment into the study may not necessarily be replicated in multiple locations. Did a lack of advanced hemodynamic monitoring (a feature of many studies) fail to identify significant myocardial dysfunction or a major reduction in cardiac output with beta-blockade that was not identified by basic BP and heart rate monitoring? In the Morelli study,3<\/sup><\/a> all patients were monitored by pulmonary artery catheterization and the response to beta-blockade dose titration accurately assessed. A frequently overlooked feature of their paper was the addition of levosimendan in patients who had reduced oxygen delivery. Inclusion criteria for their study demanded a mixed-venous oxygen saturation > 65%, a pulmonary artery occlusion pressure \u2265 12 mm Hg, and a central venous pressures \u2265 8 mm Hg, thereby excluding a significant oxygen delivery-consumption mismatch and likely excluding significant hypovolemia.<\/p>\n\n\n\n Another important question that cannot appear in such metanalyses is the root cause of the tachycardia and homogeneity of the patient cohort. In how many patients was the tachycardia being targeted with beta-blockade because of a pathological excess of sympathetic drive, promoting diastolic dysfunction and cardiomyopathy where \u00df-blockade would arguably likely be beneficial? Conversely, was the tachycardia compensatory for a low stroke volume caused by significant myocardial depression or untreated hypovolemia, in which case the negative inotropic and chronotropic effects of the drug could be detrimental? A decrease in the systolic-dicrotic pressure difference (indicative of a lower rate of change of pressure with time [dP\/dtmax] and reflecting the degree of coupling between myocardial contractility and a given afterload) after 4 hours of esmolol treatment to patients with septic shock could discriminate between compensatory and noncompensatory tachycardia.5<\/sup><\/a><\/p>\n\n\n\n A genetic component to treatment responsiveness cannot be excluded. Sato et al4<\/sup><\/a>performed a sensitivity analysis, finding a significant reduction in mortality in studies published from non-English-language publications. However, this too may be confounded by health care delivery in different countries and long-standing use of beta-blockers in those ICUs.<\/p>\n\n\n\n A further issue is optimal timing. Septic shock is not a static disease. The cytokine profile differs between patients and changes over time. Adrenergic receptor sensitivity also changes temporally, and the relative influence, density, and activity of beta-1, beta-2 and, especially, beta-3 adrenoreceptors over the course of a septic illness are unknown, as is the impact of relatively specific beta blockade.<\/p>\n\n\n\n A final point is whether any possible benefits from beta blockade results from its immunomodulatory or cardioprotective effects.6<\/sup><\/a> The myocardial ischemia literature7<\/sup><\/a>suggests that the infarct-reducing effect of \u03b2-adrenergic antagonists may not be dependent on a decrease in heart rate but may involve modulation of neutrophil infiltration. Conversely, a cardioprotective effect has also been shown with \u03b2-adrenergic agonists mediated via kinase activation and reactive oxygen species production. Theranostic tools for better identification of patients with specific cardiophysiological and biological phenotypes who may benefit from either beta-blockade or activation, and in whom drug dosing is titrated to optimal effect, are sorely needed.<\/p>\n","protected":false},"excerpt":{"rendered":" Editorial Beta Blockers and Septic Shock: More Work to […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[24,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27775"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=27775"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27775\/revisions"}],"predecessor-version":[{"id":27776,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27775\/revisions\/27776"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=27775"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=27775"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=27775"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}