despite major improvements in prevention and management strategies , patients with out - of - hospital cardiac arrest ( oohca ) continue to face an ominous prognosis , especially when focusing on the likelihood of long - term survival with satisfactory neurologic function . developments to improve the clinical outlook which have been recently introduced into mainstream practice include mechanical chest compression devices for cardiopulmonary resuscitation ( cpr ) , therapeutic hypothermia , and extra - corporeal membrane oxygenation ( ecmo ) . another interesting yet simple technology designed to improve the results of cpr is the impedance threshold device ( it d ) . it consists of a valve interconnected between the patient airways and the ventilation tools used during cpr ( i.e. endotracheal tube , supraglottic airway , or face mask ) , and aims to decrease intrathoracic pressure during the release phase of cpr , thus increasing venous return to the heart , yet without impeding ventilation . experimental studies in animals and humans have suggested that it can increase both myocardial and cerebral perfusion , passively exploiting the forces generated during cardiac massage , especially when combined with an active compression - decompression - cpr ( acd - cpr ) method [ 4 , 6,7,8 ] . most recent data suggest that it d could be beneficial even in conscious yet hypotensive patients , thus supporting its overall efficacy and safety profile . however , clinical evidence on the impact of it d for oohca remains heterogeneous . a prior meta - analysis published by our group in 2008 suggested that it d could improve the likelihood of short- and mid - term favorable outcomes , but most recently , two large studies have focused on the use of it d in the management of patients with oohca undergoing cpr , with disappointingly conflicting results . this is at odds with real - world observational data , which suggest that it d has a significant beneficial impact on patient prognosis . as systematic reviews of randomized trials represent a unique opportunity to summarize and appraise the clinical evidence on any given issue , we aimed to conduct an updated and comprehensive systematic review and meta - analysis on it d during cpr for oohca aiming to reconcile such differences and explore suitable moderators . design . this review was conducted in keeping with the cochrane collaboration recommendations and prisma guidelines . all reviewing activities were performed independently by two experienced reviewers , with divergences resolved after consensus . search . randomized trials were searched in medline / pubmed according to a strategy modified from biondi - zoccai et al , using as key - words : cardiac arrest , impedance threshold device , and random * trial * ( with * denoting a wildcard ) . citations were first screened at the title / abstract level , and retrieved as full articles if potentially pertinent . studies were finally included if reporting on a randomized clinical trial focusing on it d versus any control treatment in patients with oohca , excluding duplications . specifically , outcomes of interest were : return of spontaneous circulation ( rosc ) , favorable neurologic outcome ( modified rankin score 3 ) , and survival at the longest available follow - up . internal validity was appraised with established methods , detailed quantifying the risk of selection , performance , attrition and selection bias . in addition , the risk of potential conflicts of interest was explicitly adjudicated . analysis . meta - analysis was performed pooling odds ratios ( or ) , together with 95% confidence intervals , with both fixed - effects and random - effects models . statistical heterogeneity and inconsistency were appraised with chi - squared test and i - squared , respectively . in addition , the egger s linear regression test was used to appraise small study effects and meta - regression was performed preliminarily to identify potential effect modifiers ( distinguishing two separate groups of studies [ it d alone vs it d plus acd - cpr ] with a dummy variable ) . two - tailed statistical significance was set at the 0.05 level for hypothesis testing for effect , and at the 0.10 level for hypothesis testing for heterogeneity , with p values unadjusted for multiplicity reported throughout . computations were performed with comprehensive meta - analysis software ( biostat , englewood , nj , usa ) . a total of 4,548 citations were screened ( 56 from the cochrane library , 4,390 from google scholar , 68 from medline / pubmed , and 34 from scopus ) , leading to the eventual inclusion of 7 trials ( 11,254 patients ) . included studies were published between 2000 and 2011 [ 11,12 , 22,23,24,25,26 ] , varying in size between 21 and 8,718 subjects ( table 1 ) [ 12 , 22 ] , with follow - up limited to the emergency or hospital setting in all but three reports [ 11 , 22 , 25 ] . notably , all but one trial report was coauthored by one of the co - inventors of it d . patient and procedural features were largely similar ( table 2 ) , with average age ranging between 58 and 67 years , cpr duration between 28 and 45 minutes , and ventricular fibrillation or ventricular tachycardia as initial rhythm spanning from 0% to 40% . meta - analysis for rosc suggested an overall neural effect of it d ( or=1.02 [ 0.94 - 1.11 ] , p for effect=0.598 ; or=1.17 [ 0.96 - 1.43 ] , p for effect=0.114 ; p for heterogeneity=0.055 , i - squared=51% , using fixed- and random - effects models respectively ) , with evidence of small study effects ( p=0.071 ) ( figures 1 and 2 ) . forest plot for return of spontaneous circulation ( rosc ) , reporting individual and summary effect estimates based on fixed effects . acd = active compression - decompression ; ci = confidence interval ; cpr = cardiopulmonary resuscitation ; it d = impedance threshold device . funnel plot for return of spontaneous circulation ( rosc , p = 0.071 ) . accordingly , it d did not impact significantly on the likelihood of favorable neurologic outcome ( or=1.12 [ 0.95 - 1.30 ] , p for effect=0.172 ; or=1.56 [ 0.97 - 2.50 ] , p for effect=0.065 ; p for heterogeneity=0.011 , i - squared=67% , using fixed- and random - effects models respectively ) , or survival at the longest available follow - up ( or=1.09 [ 0.95 - 1.25 ] , p for effect=0.236 ; or=1.22 [ 0.94 - 1.58 ] , p for effect=0.127 ; p for heterogeneity=0.236 , i - squared=27% , using fixed- and random - effects models respectively ) , with some evidence for small study effects for both outcomes ( respectively p=0.107 and p=0.058 ) ( figures 3 , 4 , 5 and 6 ) . forest plot for favorable neurologic outcome , reporting individual and summary effect estimates based on fixed effects . acd = active compression - decompression ; ci = confidence interval ; cpr = cardiopulmonary resuscitation ; it d = impedance threshold device . funnel plot for favorable neurologic outcome ( p=0.107 ) . forest plot for survival at longest available follow - up , reporting individual and summary effect estimates based on fixed effects . acd = active compression - decompression ; ci = confidence interval ; cpr = cardiopulmonary resuscitation ; it d = impedance threshold device . funnel plot for survival at longest available follow - up ( p=0.058 ) . as some studies had combined it d with acd - cpr while others had not , and this association has been considered very important to maximize it d efficacy , we then performed an exploratory analysis stratifying trials according to the concomitant use of it d and acd - cpr . this subgroup analysis showed that use of both it d and acd - cpr was associated with a significant increase in the rate of rosc ( or=1.19 [ 1.00 - 1.40 ] , p for effect=0.045 , using the fixed - effects model ) , favorable neurologic outcome ( or=1.60 [ 1.14 - 2.25 ] , p for effect=0.006 , using the fixed - effects model ) , or overall survival ( or=1.52 [ 1.11 - 2.08 ] , p for effect=0.009 , using the fixed - effects model ) . conversely , it d alone was not beneficial for rosc , favorable neurologic outlook , or survival ( respectively or=0.98 [ 0.89 - 1.07 ] , p for effect=0.611 , 1.01 [ 0.85 - 1.21 ] , p for effect=0.903 , and 1.01 [ 0.86 - 1.17 ] , p for effect=0.950 , using the fixed - effects model ) . this interaction between treatment effect ( expressed as the logarithm of the or ) and use of acd - cpr together with it d was confirmed at meta - regression analysis ( b=0.195 , p=0.045 in favor of it d + acd - cpr vs it d alone for rosc ; b=0.500 , p=0.018 for favorable neurologic outcome ; and b=0.413 , p=0.021 for overall survival ) . this systematic review and meta - analysis , providing a comprehensive and updated appraisal of the current evidence base on the role of it d in patients with oohca undergoing cpr , has the following implications : a )   the totality of the evidence , including a mix of trials exploiting it d alone with studies in which it d was used together with acd - cpr , shows no meaningful impact of it d use on the likelihood of rosc , favorable neurologic outcome , or long - term mortality ; b )   the available data are highly skewed , with the largest and most recent trial greater than the sum of all the other trials , together with evidence of significant statistical heterogeneity and small study effects ; c )   exploratory analysis based on the combination of it d plus acd - cpr suggests that this combo strategy is associated with favorable clinical results in comparison to a strategy based on acd - cpr alone or standard cpr ; d )   conversely , exploratory subgroup analysis focusing on the use of it d only confirms overall results against a clinically beneficial effect of it d when used without acd - cpr . despite remarkable improvements in the primary prevention of the most common causes of oohca , both in witnessed and unwitnessed oohca several precious minutes are often wasted before effective bls is started , translating into unsatisfactory clinical results . several strategies have been proposed , tested in animal studies , and then trialed formally in humans , with the ultimate goal of saving lives and improving neurologic prognosis . these include mechanical chest compression devices , it d , acd - cpr , hypothermia , emergency extra - corporeal membrane oxygenation , vasopressor , inotropic and antiarrhythmic drugs , and emergency coronary angiography . the evidence base for these approaches is heterogeneous , with some procedures supported by a large and homogenous evidence base ( e.g. hypothermia ) and others still relying on observational evidence at best ( e.g. emergency coronary angiography ) . accordingly , decision - makers envisioning the adoption of any one of the above approaches face a difficult challenge , as they wish to maximize their chances to improve what is often a very dismal prognosis , and the ethical and clinical imperative to avoid useless or potentially harmful interventions . this may hold even truer for the decision of whether to use or not the it d . the it d is a rather simple and relatively inexpensive device consisting of a valve interconnected between the patient airways and the ventilation means used during cpr . beside potentially decreasing intrathoracic pressure during the release phase of a chest compression cycle , while improving venous return to the heart and thus cardiac output , it guides cpr by providing visual guidance on optimal ventilation timing to bls and als providers . the concept behind it d is intriguing and the experimental evidence base in animals and in pilot human trials rather compelling [ 4,5 , 29 ] . there is a dark side of the moon , though . despite favorable results from smaller randomized trials , the two largest and most recent trials have provided patently conflicting evidence , with the largest trial ( roc primed , 8,717 patients ) evidently demonstrating that it d alone has no meaningful clinical effect in comparison to a sham device in patients with oohca undergoing cpr this is clearly at odds with the favorable results provided by the second largest trial , which combined it d with acd - cpr and compared it with standard cpr for oohca ( resq , 2,470 subjects ) . notably , a pooled summary effect estimate confirms ( and is dominated by ) the roc primed trial results , with it d appearing associated with non - significant changes on prognosis . conversely , pooled analysis of trials using both it d and acd - cpr suggest that this combo might be significantly beneficial . it is difficult to define which is the most appropriate attitude towards such clinical conundrum . one approach would be to disregard altogether it d as ineffective ( at least as long as the overall analysis is concerned ) . this decision could be revised in case a ( very unlikely ) future trial , larger than the roc primed one , shifts the balance of overall effect estimate in favor of it d . another approach would be to trust ( possibly too naively ) our subgroup analysis , and recommend routine use of both icd and acd - cpr to save lives and improve neurologic prognosis . a middle ground choice would be to envision a more selective and individualized use of it d and acd - cpr in specific patients with oohca , who are not deemed extremely unlikely to achieve rosc nor who quickly regain spontaneous circulation . the latter approach , based on a tailored use of it d and acd - cpr , would make sense given the extreme heterogeneity of patients with oohca . probably acd may allow to perform a more accurate number of chest compressions per minute , while standard rescuers may often perform too many and too shallow compressions per minute , without eliciting adequate thoracic elastic recoil . indeed , even minor improvements in rosc , neurologic prognosis and long - term survival in a subset of patients with oohca could have dramatic implications at a societal level , in keeping with the ominous impact that this condition still has . finally , in favor of the hypothesis that it d plus acd - cpr is clinically beneficial are also preliminary data on the role of it d in conscious but hypotensive patients . conversely , meta - analyses of trials focusing solely on acd - cpr do support their role during cardiac arrest , thus partially undermining the credibility of the favorable results hereby reported for it d combined with acd - cpr . limitations of this work include those inherent to any systematic review , and the risk of type i error and data mining , which is typical of subgroup analysis not based on hypotheses explicitly stated a priori . in addition , all included trials were performed in settings were operators and services were highly qualified and resourceful , thus results obtained in such scenarios can not be readily translated into different environments or healthcare contexts . the evidence base on it d in patients with oohca undergoing cpr is apparently inconclusive , with a neutral impact of clinically relevant outcomes . however , exploratory analysis focusing on the combined use of it d plus acd - cpr suggests that this combo may be useful to increase the likelihood of rosc , favorable neurologic outcome , and long - term survival .
introductionuncertainty persists on the clinical impact of impedance threshold devices in out - of - hospital cardiac arrest . 
 we conducted an updated systematic review on impedance threshold devices.methodsseveral databases were searched for studies testing the effectiveness of impedance threshold devices in patients with cardiac arrest . 
 the primary endpoint was long - term survival.resultsseven trials ( 11,254 patients ) were included . in 4 studies ( 2,284 patients ) 
 impedance threshold devices were used with active compression - decompression - cardiopulmonary resuscitation , and in the others alone . 
 overall , impedance threshold devices did not impact on the rate of return of spontaneous circulation ( odds ratio=1.17 [ 0.96 - 1.43 ] , p=0.114 ) , favorable neurologic outcome ( odds ratio=1.56 [ 0.97 - 2.50 ] , p=0.065 ) , or long - term survival ( odds ratio=1.22 [ 0.94 - 1.58 ] , p=0.127 ) . 
 these analyses were fraught with heterogeneity ( respectively , p=0.055 , p=0.236 , and p=0.011 ) and inconsistency ( respectively , i - squared=51% , i - squared=27% , and i - squared=67% ) . 
 exploratory analysis showed that combined use of impedance threshold devices with active compression - decompression significantly increased the likelihood of return of spontaneous circulation ( odds ratio=1.19 [ 1.00 - 1.40 ] , p=0.045 ) , favorable neurologic outcome ( odds ratio=1.60 [ 1.14 - 2.25 ] , p=0.006 ) , and long - term survival ( odds ratio=1.52 [ 1.11 - 2.08 ] , p=0.009 ) . the favorable impact of the interaction between impedance threshold devices and active compression - decompression was also confirmed at meta - regression analysis ( respectively , b=0.195 [ 0.004 - 0.387 ] , p=0.045 , b=0.500 [ 0.079 - 0.841 ] , p=0.018 , b=0.413 [ 0.063 - 0.764 ] , p=0.021).conclusionsthe evidence base on impedance threshold devices is apparently inconclusive , with a neutral impact on clinically relevant outcomes . 
 however , exploratory analysis focusing on the combined use of impedance threshold devices with active compression - decompression suggests that this combo treatment may be useful to improve patient prognosis .