The impact of double sequential external defibrillation on termination of refractory ventricular fibrillation during out-of-hospital cardiac arrest.

BACKGROUND: Despite significant advances in resuscitation efforts, there are some patients who remain in ventricular fibrillation (VF) after multiple shocks during out-of-hospital cardiac arrest (OHCA). Double sequential external defibrillation (DSED) has been proposed as a treatment option for patients in refractory VF. OBJECTIVE: We sought to explore the relationship between type of defibrillation (standard vs DSED), the number of defibrillation attempts provided and the outcomes of VF termination and return of spontaneous circulation (ROSC) for patients presenting in refractory VF. METHODS: We performed a retrospective review of all treated adult OHCA who presented in VF and received a minimum of three successive standard defibrillations over a three-year period beginning on January 1, 2015 in four Canadian EMS agencies. Using ambulance call reports and defibrillator files, we compared rates of VF termination (defined as the absence of VF at the rhythm check following defibrillation and two minutes of CPR) and VF termination to ROSC for patients who received standard defibrillation and those who received DSED (after on-line medical consultation). Cases with public access defibrillation, those with do not resuscitate orders, and those who presented in VF but terminated VF prior to three shocks were excluded. RESULTS: Of the 252 patients included, 201 (79.8%) received standard defibrillation only and 51 (20.2%) received at least one DSED. Overall, VF termination was similar between standard defibrillation and DSED (78.1% vs. 76.5%; RR: 1.0; 95% CI: 0.8-1.2). In our shock-based analysis, when early defibrillation attempts were considered (defibrillation attempt 4-8), VF termination was higher for those receiving DSED compared to standard defibrillation (29.4% vs. 17.5%; RR: 1.7; 95% CI: 1.1-2.6). Overall, VF termination to ROSC was similar between standard defibrillation and DSED (21.4% vs. 17.6%; RR: 0.8; 95% CI: 0.4-1.6). Additionally, when early defibrillation attempts were considered (defibrillation attempt 4-8), ROSC was higher for those receiving DSED compared to standard defibrillation (15.7% vs. 5.4%; RR: 2.9; 95% CI: 1.4-5.9). When late defibrillation attempts were considered (defibrillation attempt 9-17), VF termination was higher for those receiving DSED compared to standard defibrillation (31.2% vs. 17.1%; RR: 1.8; 95% CI: 1.1-3.0), but ROSC was rare regardless of defibrillation strategy. When DSED terminated VF into ROSC, it did so with a single DSED attempt in 66.7% of cases. CONCLUSIONS: Our observational findings suggest that while overall VF termination and ROSC are similar between standard defibrillation and DSED, earlier DSED may be associated with improved rates of VF termination and ROSC compared to standard defibrillation for refractory VF. A randomized controlled trial is required to assess the impact of early application of DSED on patient-important outcomes.

EPAC1 promotes adaptive responses in human arterial endothelial cells subjected to low levels of laminar fluid shear stress: Implications in flow-related endothelial dysfunction.

Blood flow-associated fluid shear stress (FSS) dynamically regulates the endothelium's ability to control arterial structure and function. While arterial endothelial cells (AEC) subjected to high levels of laminar FSS express a phenotype resistant to vascular insults, those exposed to low levels of laminar FSS, or to the FSS associated with oscillatory blood flow, are less resilient. Despite numerous reports highlighting how the cAMP-signaling system controls proliferation, migration and permeability of human AECs (HAECs), its role in coordinating HAEC responses to FSS has received scant attention. Herein we show that the cAMP effector EPAC1 is required for HAECs to align and elongate in the direction of flow, and for the induction of several anti-atherogenic and anti-thrombotic genes associated with these events. Of potential therapeutic importance, EPAC1 is shown to play a dominant role the in response of HAECs to low levels of laminar FSS, such as would be found within atherosclerosis-prone areas of the vasculature. Moreover, we show that EPAC1 promotes these HAEC responses to flow by regulating Vascular Endothelial Growth Factor Receptor-2 and Akt activation, within a VE-cadherin (VECAD)/PECAM1-based mechanosensor. We submit that these findings are consistent with the novel proposition that promoting EPAC1-signaling represents a novel means through which to promote expression of an adaptive phenotype in HAECs exposed to non-adaptive FSS-encoded signals as a consequence of vascular disease.

Adaptive phenotypic modulation of human arterial endothelial cells to fluid shear stress-encoded signals: modulation by phosphodiesterase 4D-VE-cadherin signalling.

Although cAMP-signalling regulates numerous functions of vascular endothelial cells (VECs), including their ability to impact vascular resistance in response to changes in blood flow dynamics, few of the mechanisms underlying these effects have yet to be described. In addition to forming stable adherens junctions (AJs) in static VEC cultures, VE-cadherin (VECAD) has emerged as a critical component in a key mechanosensor responsible for linking altered blood flow dynamics and the VEC-mediated control of vascular resistance. Previously, a cAMP phosphodiesterase, PDE4D, was shown to coordinate the VEC permeability limiting effects of cAMP-elevating agents in human arterial VECs (HAECs). Herein, we report that PDE4D acts to allow cAMP-elevating agents to regulate VECADs' role as a sensor of flow-associated fluid shear stress (FSS)-encoded information in HAECs. Thus, we report that PDE4 activity is increased in HAECs exposed to laminar FSS and that this effect contributes to controlling how FSS impacts the morphological and gene expression changes in HAECs exposed to flow. More specifically, we report that PDE4D regulates the efficiency with which VECAD, within its mechanosensor, controls VEGFR2 and Akt activities. Indeed, we show that PDE4D knockdown (KD) significantly blunts responses of HAECs to levels of FSS characteristically found in areas of the vasculature in which stenosis is prevalent. We propose that this effect may provide a new therapeutic avenue in modulating VEC behaviour at these sites by promoting an adaptive and vasculo-protective phenotype.

Cyclic nucleotide phosphodiesterases (PDEs): coincidence detectors acting to spatially and temporally integrate cyclic nucleotide and non-cyclic nucleotide signals.

The cyclic nucleotide second messengers cAMP and cGMP each affect virtually all cellular processes. Although these hydrophilic small molecules readily diffuse throughout cells, it is remarkable that their ability to activate their multiple intracellular effectors is spatially and temporally selective. Studies have identified a critical role for compartmentation of the enzymes which hydrolyse and metabolically inactivate these second messengers, the PDEs (cyclic nucleotide phosphodiesterases), in this specificity. In the present article, we describe several examples from our work in which compartmentation of selected cAMP- or cGMP-hydrolysing PDEs co-ordinate selective activation of cyclic nucleotide effectors, and, as a result, selectively affect cellular functions. It is our belief that therapeutic strategies aimed at targeting PDEs within these compartments will allow greater selectivity than those directed at inhibiting these enzymes throughout the cells.