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Guarracinoetal.J Anesth Analg Crit Care (2023)3:41 https:/doi.org/10.1186/s44158-023-00126-2ORIGINAL ARTICLEOpen Access The Author(s)2023.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons licence,and indicate if changes were made.The images or other third party material in this article are included in the articles Creative Commons licence,unless indicated otherwise in a credit line to the material.If material is not included in the articles Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use,you will need to obtain permission directly from the copyright holder.To view a copy of this licence,visit http:/creativecommons.org/licenses/by/4.0/.Journal of Anesthesia,Analgesia and Critical CareThe role ofbeta-blocker drugs incritically ill patients:aSIAARTI expert consensus statementFabio Guarracino1,Andrea Cortegiani2,3*,Massimo Antonelli4,Astrid Behr5,Giandomenico Biancofiore6,Alfredo Del Gaudio7,Francesco Forfori8,Nicola Galdieri9,Giacomo Grasselli10,11,Gianluca Paternoster12,Monica Rocco13,Stefano Romagnoli14,15,Salvatore Sardo16,Sascha Treskatsch17,Vincenzo Francesco Tripodi18 and Luigi Tritapepe19 Abstract Background The role of-blockers in the critically ill has been studied,and data on the protective effects of these drugs on critically ill patients have been repeatedly reported in the literature over the last two decades.However,consensus and guidelines by scientific societies on the use of-blockers in critically ill patients are still lacking.The purpose of this document is to support the clinical decision-making process regarding the use of-blockers in critically ill patients.The recipients of this document are physicians,nurses,healthcare personnel,and other profes-sionals involved in the patients care process.Methods The Italian Society of Anesthesia,Analgesia,Resuscitation and Intensive Care(SIAARTI)selected a panel of experts and asked them to define key aspects underlying the use of-blockers in critically ill adult patients.The methodology followed by the experts during this process was in line with principles of modified Delphi and RAND-UCLA methods.The experts developed statements and supportive rationales in the form of informative text.The overall list of statements was subjected to blind votes for consensus.Results The literature search suggests that adrenergic stress and increased heart rate in critically ill patients are associated with organ dysfunction and increased mortality.Heart rate control thus seems to be critical in the manage-ment of the critically ill patient,requiring careful clinical evaluation aimed at both the differential diagnosis to treat secondary tachycardia and the treatment of rhythm disturbance.In addition,the use of-blockers for the treatment of persistent tachycardia may be considered in patients with septic shock once hypovolemia has been ruled out.Intravenous application should be the preferred route of administration.Conclusion-blockers protective effects in critically ill patients have been repeatedly reported in the literature.Their use in the acute treatment of increased heart rate requires understanding of the pathophysiology and careful differ-ential diagnosis,as all causes of tachycardia should be ruled out and addressed first.Keywords-blockers,Critically ill patient,ICU,Tachyarrhythmia,Sepsis,Adults*Correspondence:Andrea Cortegianiandrea.cortegianiunipa.itFull list of author information is available at the end of the articlePage 2 of 9Guarracinoetal.J Anesth Analg Crit Care (2023)3:41 BackgroundCritically ill patients admitted to an intensive care unit(ICU)may be affected by different degrees of sympa-thetic overflow 14 secondary to the primary acute disease(i.e.,shock,trauma,infection)and often present with preexisting cardiovascular comorbidities.The role of-blockers in critically ill patients has been studied,and data on the protective effects of these drugs on the critically ill have been repeatedly reported in the litera-ture over the last two decades.-blockers exert their effects through several sub-types of G-protein-coupled-adrenergic receptors 5 expressed on the surface of cell membranes almost ubiq-uitously in the human body.Generally,-blockers interfere with catecholamines and sympathomimetics by preventing and/or modulating the-adrenergic responses.The clinical effects depend on the subtypes of receptors a-blocker binds to and their locations(Table1).Based on their pharmacodynamics,-blockers are cur-rently indicated for treating systemic arterial hyperten-sion,tachyarrhythmias,and heart failure 6.In addition,-blockers decrease blood pressure by reducing after-load.This in turn together decreases myocardial oxygen consumption and improves myocardial perfusion as well as stroke volume(SV).They also show effective control of sympathetic activation,and their proven efficacy for treating rhythm alterations 7 represents a strong patho-physiological rationale to consider such treatment in the management of critically ill patients suffering from acute tachyarrhythmias.However,consensus and guidelines by scientific soci-eties on the use of-blockers in critical illness are still lacking,and guidelines on management of septic patients have never recommended their use in this setting.To fill this gap,a group of expert intensivists selected by the Italian Society of Anesthesia,Analgesia,and Intensive Care(SIAARTI)wrote this good clinical practice docu-ment on the use of beta-blockers in critically ill patients.MethodologyThe expert panel members were selected by the two pro-ject coordinators(F.G.,L.T.)based on evidence,clini-cal,and scientific experience on the subject on behalf of SIAARTI.After an initial meeting to define the meth-odology,the different topics were assigned to one or more panel members,based on their respective skills,as follows:Evaluate the available evidence.Produce statements and supporting rationales in the form of an explanatory text.The overall list of statements was submitted to a vote,according to the method,to express the degree of consensus.The methodological path of the document was outlined by a methodologist(A.C.)and was based on the auditing principles of scientific literature and the modified Del-phi method 8.More in detail,the literature review was conducted by two subject matter experts with no defined time limit,on PubMed,using MeSH words 1(E-Table1 Additional File 1).The panel of experts defined four clinical questions(CQ)that were presented and voted during an online scoping workshop.Following up the definition of the questions,the two subject matter experts defined a dedi-cated literature search strategy.The two experts then selected the relevant literature from the list generated by the search and correlated each chosen paper to one or more of the four clinical questions.The list of chosen papers was then submitted to the panel for review(Addi-tional File 2).The types of papers included in the search were as fol-lows:randomized controlled trials,systematic reviews,meta-analysis,guidelines,non-randomized controlled trials,narrative reviews,position papers,and experi-mental studies.Papers with a language different from English were excluded,as were conference proceedings,Table 1 Pharmacokinetics and pharmacodynamic properties of intravenous-blockersLegend:Max Maximum,min Minutes,HR Heart rate,MAP Mean arterial pressureDrugOnset(min)Max.elimination half-life(min)ReceptorsCardio-selectivity(12)MetabolizationHRMAPMetoprolol1342013Cytochrome P2D6(Leber)Labetalol25120480121NoBy the liver resulting in an inac-tive glucuronide conjugatePropanolol 536060012NoCytochrome P2D6Esmolol29130ERY esterasesLandiolol141250Pseudocholinesterases /Page 3 of 9Guarracinoetal.J Anesth Analg Crit Care (2023)3:41 case reports,and case series.The search was conducted,and the final reports were generated following the prin-ciples of PRISMA 2020 9(Fig.1 in the Additional File 1).The panelists,using the report from the subject mat-ter experts and their competencies,drafted a list of state-ments and rationales that they then put for vote on a secret ballot.The entire panel(with the exclusion of the search specialist and methodologist)took part in the blind vote.The methodology dictated a maximum of two possible rounds of voting online.The opinion was expressed using an ordinal Likert scale,according to the RAND-UCLA method(minimum score,1=completely disagree;maximum score,9=com-pletely agree).This scale was divided into 3 sections:13 implied refusal/disagreement(“inappropriate”),46 implied(“uncertainty”),and 79 implied agreement/sup-port(“appropriateness”)10.A consensus was reached when as follows:1)At least 75%of the respondents(excluding the meth-odologist and the search specialist)assigned a score between 13,46,or 79,which meant refusal,uncertainty,and agreement of the statement,respec-tively.2)The median score was within the same range.The type of consensus was determined by the positioning of the median.It was not necessary to run the second Delphi round,as all statements reached consensus at the first round.The results of the votes were reported in a tabulated form.The full version of the Italian document issued by the Italian Society of Anesthe-sia,Analgesia,Resuscitation,and Intensive Care(SIAARTI)was published in April 2023 and is freely available on the societys website in Italian(https:/www.siaar ti.it/news/15276 82).Question I.What istherationale forcorrecting tachycardia inthecritically ill patients?In critically ill patients,the acute state of illness often increases myocardial and tissue oxygen consumption (VO2)in general and causes profound adrenergic acti-vation.Adrenergic hypertonicity is one of the protag-onists of the complex neuroendocrine response that the patient exhibits when oxygen delivery (DO2)and his VO2 lose the optimal ratio 11,12.The continua-tion of this rapid compensation mechanism,even if the causes that may have triggered it are treated(e.g.,ane-mia,hypovolemia,pain,and hyperthermia),can favor hypoperfusion secondary to vasoconstriction and an inevitable increase in myocardial VO2 linked to tachy-cardia or heart failure 3,4.This scenario is commonly accompanied by an increase in heart rate,which can take the form of sinus tachy-cardia or lead to tachyarrhythmias possibly associated with hemodynamic instability(hypotension and/or hypoperfusion).This excessive adrenergic stress and increased heart rate have been associated with organ dysfunction and increased mortality 1315.In this pathophysiological scenario,in light of litera-ture data,heart rate control assumes an important role in the management of the critically ill patient,requiring careful clinical evaluation aimed at both the differential diagnosis of secondary tachycardia and the treatment of the rhythm alteration.Physiologically,the main compensation mechanisms involve the release of endogenous catecholamines with sympathetic hyperstimulation.The use of exogenous cat-echolamines may also be necessary for the treatment of hemodynamic instability.However,in both cases,exces-sive adrenergic stimulation is related to organ damage with worsening of the outcome and increased mortality.The diagnostic framework of tachycardia requires the analysis of the electrocardiographic tracing and the appropriate integration of this within an echocar-diographic examination 16.It is defined as a heart rate(HR)greater than 100bpm 12,17.It can originate as follows:At sinus node and is defined as sinus tachycardia;At the ventricular level and is defined as ventricular tachycardia,usually of short duration and accompa-nied by important hemodynamic alterations;From supraventricular origin and is generally rep-resented by an altered electrical activity in the atrial chambers and is due either to the re-entry mecha-nism or to an increase in automaticityIn the latter case,it can manifest itself as follows:Atrial flutter with regular sawtooth waves at a rate of 180250/min;Tachyarrhythmia absoluta with atrial fibrillation waves replacing P waves followed by abnormal QRS complexes;Ventricular tachycardia with irregular RR intervals and QRS complexes with abnormal duration and morphology and not associated with a previous P wave.Echocardiography performed in order to diagnose the origin of tachycardia and to guide the appropriateness of beta-blockers administration should focus on both sys-tolic and diastolic function,as well as on volume status.Page 4 of 9Guarracinoetal.J Anesth Analg Crit Care (2023)3:41 The calculation of the ventriculo-arterial coupling,a more complex evaluation,can be added to this echocar-diographic evaluation to understand the efficiency of the cardiovascular system 18 and to reassess the patients physiology after treatment.Question II.What istherationale forusing a-blocker tocorrect tachycardia incritical patients?In thecritically ill patient,tachycardia control should be achieved withtheuse ofblocking drugsA recent meta-analysis of 11 studies,including 2103 criti-cally ill patients,showed a significant reduction in mor-tality(risk ratio 0.65,95%CI 0.530.79;P 0.0001)in patients treated with-blockers compared to controls 12.However,it is important to note that this systematic review and meta-analysis included a diverse set of stud-ies,with the majority of them focusing on patients with myocardial ischemia or those undergoing cardiac sur-gery.As a result,it becomes challenging to make defini-tive conclusions regarding the observed differences in mortality.Another recent retrospective study of 204,981 patients undergoing major abdominal surgery,conducted with propensity score analysis,found no differences in the incidence of postoperative stroke among patients receiv-ing-blocker in chronic therapy(odds ratio,0.86;95%CI,0.65 to 1.15;P=0.901)and patients in whom the drug was started within 60 days before surgery(odds ratio,0.90;95%CI,0.31 to 2.04;P=0.757)19.Additionally,patients on chronic-blocker therapy had a lower risk of major cardiac events(odds ratio,0.81;95%CI,0.72 to 0.91;P=0.007)19.-blockers in the acute setting are only protective if there is“tachycardia.”They do not encounter a“self-effect”independent of the patients situation 20.To attribute confidence of recommendation to the use of these drugs in critically ill patients,further randomized controlled trials(RCTs)are needed to answer questions regarding patient selection,the choice of drug,timings,and optimal hemodynamics targets.In patients withseptic shock,theuse ofblockers fortreating persistent tachycardia may be consideredThe distinction between secondary(induced by a low SV)and non-secondary(generated by an excessive sym-pathetic response or arrhythmic disorder)tachycardia is therefore the
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