Recovery of arterial blood pressure after chest compression pauses in patients with out-of-hospital cardiac arrest.

BACKGROUND AND AIMS: Chest compressions generating good perfusion during cardiopulmonary resuscitation (CPR) in cardiac arrest patients are critical for positive patient outcomes. Conventional wisdom advises minimizing compression pauses because several compressions are required to recover arterial blood pressure (ABP) back to pre-pause values. Our study examines how compression pauses influence ABP recovery post-pause in out-of-hospital cardiac arrest. METHODS: We analyzed data from a subset of a prospective, randomized LUCAS 2 Active Decompression trial. Patients were treated by an anesthesiologist-staffed rapid response car program in Oslo, Norway (2015-2017) with mechanical chest compressions using the LUCAS device at 102 compressions/min. Patients with an ABP signal during CPR and at least one compression pause >2 sec were included. Arterial cannulation, compression pauses, and ECG during the pause were verified by physician review of patient records and physiological signals. Pauses were excluded if return of spontaneous circulation occurred during the pause (pressure pulses associated with ECG complexes). Compression, mean, and decompression ABP for 10 compressions before/after each pause and the mean ABP during the pause were measured with custom MATLAB code. The relationship between pause duration and ABP recovery was investigated using linear regression. RESULTS: We included 56 patients with a total of 271 pauses (pause duration: median = 11 sec, Q1 = 7 sec, Q3 = 18 sec). Mean ABP dropped from 53 ± 10 mmHg for the last pre-pause compression to 33 ± 7 mmHg during the pause. Compression and mean ABP recovered to >90% of pre-pause pressure within 2 compressions, or 1.7 sec. Pause duration did not affect the recovery of ABP post-pause (R2: 0.05, 0.03, 0.01 for compression, mean, and decompression ABP, respectively). CONCLUSIONS: ABP generated by mechanical CPR recovered quickly after pauses. Recovery of ABP after a pause was independent of pause duration.

Automated external defibrillator electrode size and termination of ventricular fibrillation in out-of-hospital cardiac arrest.

Smaller electrodes allow more options for design of automated external defibrillator (AED) user interfaces. However, previous studies employing monophasic-waveform defibrillators found that smaller electrode sizes have lower defibrillation shock success rates. We hypothesize that, for impedance-compensated, biphasic truncated exponential (BTE) shocks, smaller electrodes increase transthoracic impedance (TTI) but do not adversely affect defibrillation success rates. METHODS AND RESULTS: In this prospective before-and-after clinical study, Amsterdam police and firefighters used AEDs with BTE waveforms: an AED with larger electrodes in 2016-2017 (113 cm2), and an AED with smaller electrodes in 2017-2020 (65 cm2). We analyzed 157 and 178 patient cases with an initial shockable rhythm where the larger and smaller electrodes were used, respectively. A single 200-J shock terminated ventricular fibrillation (VF) in 86% of patients treated with large electrodes and 89% of patients treated with smaller electrodes. Small electrodes had a non-inferior first shock defibrillation success rate compared to large electrodes, with a difference of 3% (95% CI: -3% -9%) with the lower confidence limit remaining above the defined non-inferiority threshold. TTI was significantly higher for the smaller electrodes (median: 100 Ω) compared to the larger electrodes (median: 88 Ω) (p < 0.001). CONCLUSIONS: For AEDs with impedance-compensating BTE waveforms, TTI was higher for smaller electrodes than the large electrode electrodes. Overall defibrillation shock success for AEDs with smaller electrodes was non-inferior to the AEDs with larger electrodes.

Prehospital Predictors of Atypical STEMI Symptoms.

Introduction: Rapid prehospital identification of patients with ST-elevation myocardial infarction (STEMI) is a critical step to reduce time to treatment. Broad screening with field 12-lead ECGs can lead to a high rate of false positive STEMI activations due to low prevalence. One strategy to reduce false positive STEMI interpretations is to limit acquisition of 12-lead ECGs to patients who have symptoms strongly suggestive of STEMI, but this may delay care in patients who present atypically and lead to disparities in populations with more atypical presentations. We sought to assess patient factors associated with atypical STEMI presentation.Methods: We retrospectively analyzed consecutive adult patients for whom Los Angeles Fire Department paramedics obtained a field 12-lead ECG from July 2011 through June 2012. The regional STEMI receiving center registry was used to identify patients with STEMI. Patients were designated as having typical symptoms if paramedics documented provider impressions of chest pain/discomfort, cardiac arrest, or cardiac symptoms, otherwise they were designated as having atypical symptoms. We utilized logistic regression to determine patient factors (age, sex, race) associated with atypical STEMI presentation.Results: Of the 586 patients who had STEMI, 70% were male, 43% White, 16% Black, 20% Hispanic, 5% Asian and 16% were other or unspecified race. Twenty percent of STEMI patients (n = 117) had atypical symptoms. Women who had STEMI were older than men (74 years [IQR 62-83] vs. 60 years [IQR 53-70], p < 0.001). Univariate predictors of atypical symptoms were older age and female sex (p < 0.0001), while in multivariable analysis older age [odd ratio (OR) 1.05 per year, [95%CI 1.04-1.07, p < 0.0001] and black race (OR vs White 2.18, [95%CI 1.20-3.97], p = 0.011) were associated with atypical presentation.Conclusion: Limiting prehospital acquisition of 12-lead ECGs to patients with typical STEMI symptoms would result in one in five patients with STEMI having delayed recognition, disproportionally impacting patients of older age, women, and Black patients. Age, not sex, may be a better predictor of atypical STEMI presentation.

Alternating fast and slow chest compression rates during CPR improved hemodynamics.

INTRODUCTION: Mechanical chest compression devices allow for variation in chest compression (CCs) characteristics from moment to moment, enabling therapy that is not feasible for manual CCs. Effects of varying compressions over time have not been studied. In a randomized trial in an experimental model of prolonged cardiac arrest, we compared time-varying CPR (TVCPR), alternating between 100 and 200 compressions per minute (cpm) every 6 s, to guidelines CPR (Control). METHODS: Ventricular fibrillation (VF) was electrically induced in 20 anesthetized pigs (28.4-45.8 kg). Following 10 min of untreated VF, cardiopulmonary resuscitation (CPR) began, randomized to TVCPR or Control. Rate of return of spontaneous circulation (ROSC), 4-h survival, and hemodynamics during the first 5 min of CPR were compared between groups. Moment-to-moment hemodynamic effects of changing the CC rate were analyzed. RESULTS: TVCPR improved the proportion of ROSC over time compared to Control (p < 0.05) but ROSC (9/10 vs. 5/10) and 4-h survival (8/10 vs 5/10) did not differ significantly between groups. During CPR, coronary and cerebral perfusion pressures and femoral artery pressure did not differ between groups; however, end-tidal CO2 and mixed venous O2 saturation were higher, and pulmonary artery pressure was lower (p < 0.05) for TVCPR than Control. During TVCPR, switching to 100 cpm increased coronary perfusion pressure (p < 0.05), and switching to 200 cpm increased cerebral perfusion pressure (p < 0.05). CONCLUSIONS: Time-varying CPR significantly improved indicators of net forward blood flow and proportion of ROSC over time without negatively impacting perfusion pressures. Alternating CC rate alternates between perfusion pressures favoring the brain and those favoring the heart. Time-varying CPR represents a new avenue of research for optimizing CPR. INSTITUTIONAL PROTOCOL NUMBER: University of Alabama at Birmingham Institutional Animal Care and Use Committee (IACUC) Protocol Number 140406860.

An investigation of inter-shock timing and electrode placement for double-sequential defibrillation.

BACKGROUND: Double-Sequential Defibrillation (DSD) is the near-simultaneous use of two defibrillators to treat refractory VF. We hypothesized that (1) risk of DSD-associated defibrillator damage depends on shock vector and (2) the efficacy of DSD depends on inter-shock time. METHODS: Part 1: risk of defibrillator damage was assessed in three anaesthetized pigs by applying two sets of defibrillation electrodes in six different configurations (near-orthogonal or near-parallel vectors). Ten 360J shocks were delivered from one set of pads and peak voltage was measured across the second set. Part 2: the dependence of DSD efficacy on inter-shock time was assessed in ten anaesthetized pigs. Electrodes were applied in lateral-lateral (LL) and anterior-posterior positions. Control (LL Stacked Shocks; one vector, two shocks ∼10 s apart) and DSD therapies (Overlapping, 10 ms, 50 ms, 100 ms, 200 ms, 500 ms, 1000 ms apart) were tested in a block randomized design treating electrically-induced VF (n = ∼89 VF episodes/therapy). Shock energies were selected to achieve 25% shock success for a single LL shock. RESULTS: Part 1: peak voltage delivered was 1833 ± 48 V (mean ± 95%CI). Peak voltage exposure was, on average, 10-fold higher for parallel than orthogonal vectors (p < 0.0001). Part 2: DSD efficacy compared to Stacked LL shocks was higher for Overlapping, 10 ms, and 100 ms (p < 0.05); lower at 50 ms (p < 0.05); and not different at 200 ms or longer inter-shock times. CONCLUSION: Risk of DSD-associated defibrillator damage can be mitigated by using near-orthogonal shock vectors. DSD efficacy is highly dependent on the inter-shock time and can be better, worse, or no different than stacked shocks from a single vector. INSTITUTIONAL PROTOCOL NUMBER: University of Alabama at Birmingham Institutional Animal Care and Use Committee (IACUC) Protocol Number 06860.

Blockade of CaMKII depresses conduction preferentially in the right ventricular outflow tract and promotes ischemic ventricular fibrillation in the rabbit heart.

Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates the principle ion channels mediating cardiac excitability and conduction, but how this regulation translates to the normal and ischemic heart remains unknown. Diverging results on CaMKII regulation of Na+ channels further prevent predicting how CaMKII activity regulates excitability and conduction in the intact heart. To address this deficiency, we tested the effects of the CaMKII blocker KN93 (1 and 2.75 µM) and its inactive analog KN92 (2.75 µM) on conduction and excitability in the left (LV) and right (RV) ventricles of rabbit hearts during normal perfusion and global ischemia. We used optical mapping to determine local conduction delays and the optical action potential (OAP) upstroke velocity (dV/dtmax). At baseline, local conduction delays were similar between RV and LV, whereas the OAP dV/dtmax was lower in RV than in LV. At 2.75 µM, KN93 heterogeneously slowed conduction and reduced dV/dtmax, with the largest effect in the RV outflow tract (RVOT). This effect was further exacerbated by ischemia, leading to recurrent conduction block in the RVOT and early ventricular fibrillation (at 6.7 ± 0.9 vs. 18.2 ± 0.8 min of ischemia in control, P < 0.0001). Neither KN92 nor 1 µM KN93 depressed OAP dV/dtmax or conduction. Rabbit cardiomyocytes isolated from RVOT exhibited a significantly lower dV/dtmax than those isolated from the LV. KN93 (2.75 µM) significantly reduced dV/dtmax in cells from both locations. This led to frequency-dependent intermittent activation failure occurring predominantly in RVOT cells. Thus CaMKII blockade exacerbates intrinsically lower excitability in the RVOT, which is proarrhythmic during ischemia.NEW & NOTEWORTHY We show that calcium/calmodulin-dependent protein kinase II (CaMKII) blockade exacerbates intrinsically lower excitability in the right ventricular outflow tract, which causes highly nonuniform chamber-specific slowing of conduction and facilitates ventricular fibrillation during ischemia. Constitutive CaMKII activity is necessary for uniform and safe ventricular conduction, and CaMKII block is potentially proarrhythmic.

Causes of Prehospital Misinterpretations of ST Elevation Myocardial Infarction.

OBJECTIVES: To determine the causes of software misinterpretation of ST elevation myocardial infarction (STEMI) compared to clinically identified STEMI to identify opportunities to improve prehospital STEMI identification. METHODS: We compared ECGs acquired from July 2011 through June 2012 using the LIFEPAK 15 on adult patients transported by the Los Angeles Fire Department. Cases included patients ≥18 years who received a prehospital ECG. Software interpretation of the ECG (STEMI or not) was compared with data in the regional EMS registry to classify the interpretation as true positive (TP), true negative (TN), false positive (FP), or false negative (FN). For cases where classification was not possible using registry data, 3 blinded cardiologists interpreted the ECG. Each discordance was subsequently reviewed to determine the likely cause of misclassification. The cardiologists independently reviewed a sample of these discordant ECGs and the causes of misclassification were updated in an iterative fashion. RESULTS: Of 44,611 cases, 50% were male (median age 65; inter-quartile range 52-80). Cases were classified as 482 (1.1%) TP, 711 (1.6%) FP, 43371 (97.2%) TN, and 47 (0.11%) FN. Of the 711 classified as FP, 126 (18%) were considered appropriate for, though did not undergo, emergent coronary angiography, because the ECG showed definite (52 cases) or borderline (65 cases) ischemic ST elevation, a STEMI equivalent (5 cases) or ST-elevation due to vasospasm (4 cases). The sensitivity was 92.8% [95% CI 90.6, 94.7%] and the specificity 98.7% [95% CI 98.6, 98.8%]. The leading causes of FP were ECG artifact (20%), early repolarization (16%), probable pericarditis/myocarditis (13%), indeterminate (12%), left ventricular hypertrophy (8%), and right bundle branch block (5%). There were 18 additional reasons for FP interpretation (<4% each). The leading causes of FN were borderline ST-segment elevations less than the algorithm threshold (40%) and tall T waves reducing the ST/T ratio below threshold (15%). There were 11 additional reasons for FN interpretation occurring ≤3 times each. CONCLUSION: The leading causes of FP automated interpretation of STEMI were ECG artifact and non-ischemic causes of ST-segment elevation. FN were rare and were related to ST-segment elevation or ST/T ratio that did not meet the software algorithm threshold.

Mitochondrial depolarization and asystole in the globally ischemic rabbit heart: coordinated response to interventions affecting energy balance.

Mitochondrial membrane potential (ΔΨm) depolarization has been implicated in the loss of excitability (asystole) during global ischemia, which is relevant for the success of defibrillation and resuscitation after cardiac arrest. However, the relationship between ΔΨm depolarization and asystole during no-flow ischemia remains unknown. We applied spatial Fourier analysis to confocally recorded fluorescence emitted by ΔΨm-sensitive dye tetramethylrhodamine methyl ester. The time of ischemic ΔΨm depolarization (tmito_depol) was defined as the time of 50% decrease in the magnitude of spectral peaks reflecting ΔΨm. The time of asystole (tasys) was determined as the time when spontaneous and induced ventricular activity ceased to exist. Interventions included tachypacing (150 ms), myosin II ATPase inhibitor blebbistatin (heart immobilizer), and the combination of blebbistatin and the inhibitor of glycolysis iodoacetate. In the absence of blebbistatin, confocal images were obtained during brief perfusion with hyperkalemic solution and after the contraction failed between 7 and 15 min of ischemia. In control, tmito_depol and tasys were 24.4 ± 6.0 and 26.0 ± 5.0 min, respectively. Tachypacing did not significantly affect either parameter. Blebbistatin dramatically delayed tmito_depol and tasys (51.4 ± 8.6 and 45.7 ± 5.3 min, respectively; both P < 0.0001 vs. control). Iodoacetate combined with blebbistatin accelerated both events (tmito_depol, 12.7 ± 1.8 min; and tasys, 6.5 ± 1.1 min; both P < 0.03 vs. control). In all groups pooled together, tasys was strongly correlated with tmito_depol (R(2) = 0.845; P < 0.0001). These data may indicate a causal relationship between ΔΨm depolarization and asystole or a similar dependence of the two events on energy depletion during ischemia. Our results urge caution against the use of blebbistatin in studies addressing pathophysiology of myocardial ischemia.

Does the combination of hyperkalemia and KATP activation determine excitation rate gradient and electrical failure in the globally ischemic fibrillating heart?

Ventricular fibrillation (VF) in the globally ischemic heart is characterized by a progressive electrical depression manifested as a decline in the VF excitation rate (VFR) and loss of excitability, which occur first in the subepicardium (Epi) and spread to the subendocardium (Endo). Early electrical failure is detrimental to successful defibrillation and resuscitation during cardiac arrest. Hyperkalemia and/or the activation of ATP-sensitive K(+) (KATP) channels have been implicated in electrical failure, but the role of these factors in ischemic VF is poorly understood. We determined the VFR-extracellular K(+) concentration ([K(+)]o) relationship in the Endo and Epi of the left ventricle during VF in globally ischemic hearts (Isch group) and normoxic hearts subjected to hyperkalemia (HighK group) or a combination of hyperkalemia and the KATP channel opener cromakalim (HighK-Crom group). In the Isch group, Endo and Epi values of [K(+)]o and VFR were compared in the early (0-6 min), middle (7-13 min), and late (14-20 min) phases of ischemic VF. A significant transmural gradient in VFR (Endo > Epi) was observed in all three phases, whereas a significant transmural gradient in [K(+)]o (Epi > Endo) occurred only in the late phase of ischemic VF. In the Isch group, the VFR decrease and inexcitability started to occur at much lower [K(+)]o than in the HighK group, especially in the Epi. Combining KATP activation with hyperkalemia only shifted the VFR-[K(+)]o curve upward (an effect opposite to real ischemia) without changing the [K(+)]o threshold for asystole. We conclude that hyperkalemia and/or KATP activation cannot adequately explain the heterogeneous electrical depression and electrical failure during ischemic VF.

Detection of mitochondrial depolarization/recovery during ischaemia--reperfusion using spectral properties of confocally recorded TMRM fluorescence.

Timing and pattern of mitochondrial potential (m) depolarization during no-flow ischaemia-reperfusion (I-R) remain controversial, at least in part due to difficulties in interpreting the changes in the fluorescence of m-sensitive dyes such as TMRM. The objective of this study was to develop a new approach for interpreting confocal TMRM signals during I-R based on spatial periodicity of mitochondrial packaging in ventricular cardiomyocytes. TMRM fluorescence (FTMRM) was recorded from Langendorff-perfused rabbit hearts immobilized with blebbistatin using either a confocal microscope or an optical mapping system. The hearts were studied under normal conditions, during mitochondrial uncoupling using the protonophore FCCP, and during I-R. Confocal images of FTMRM were subjected to spatial Fourier transform which revealed distinct peaks at a spatial frequency of ∼2 µm(-1). The area under the peak (MPA) progressively decreased upon application of increasing concentrations of FCCP (0.3-20 µm), becoming undetectable at 5-20 µm FCCP. During ischaemia, a dramatic decrease in MPA, reaching the low/undetectable level comparable to that induced by 5-20 µm FCCP, was observed between 27 and 69 min of ischaemia. Upon reperfusion, a heterogeneous MPA recovery was observed, but not a de novo MPA decrease. Both confocal and wide-field imaging registered a consistent decrease in spatially averaged FTMRM in the presence of 5 µm FCCP, but no consistent change in this parameter during I-R. We conclude that MPA derived from confocal images provides a sensitive and specific indicator of significant mitochondrial depolarization or recovery during I-R. In contrast, spatially averaged FTMRM is not a reliable indicator of m changes during I-R.

Metabolic determinants of electrical failure in ex-vivo canine model of cardiac arrest: evidence for the protective role of inorganic pyrophosphate.

RATIONALE: Deterioration of ventricular fibrillation (VF) into asystole or severe bradycardia (electrical failure) heralds a fatal outcome of cardiac arrest. The role of metabolism in the timing of electrical failure remains unknown. OBJECTIVE: To determine metabolic factors of early electrical failure in an ex-vivo canine model of cardiac arrest (VF+global ischemia). METHODS AND RESULTS: Metabolomic screening was performed in left ventricular biopsies collected before and after 0.3, 2, 5, 10 and 20 min of VF and global ischemia. Electrical activity was monitored via plunge needle electrodes and pseudo-ECG. Four out of nine hearts exhibited electrical failure at 10.1±0.9 min (early-asys), while 5/9 hearts maintained VF for at least 19.7 min (late-asys). As compared to late-asys, early-asys hearts had more ADP, less phosphocreatine, and higher levels of lactate at some time points during VF/ischemia (all comparisons p<0.05). Pre-ischemic samples from late-asys hearts contained ∼25 times more inorganic pyrophosphate (PPi) than early-asys hearts. A mechanistic role of PPi in cardioprotection was then tested by monitoring mitochondrial membrane potential (ΔΨ) during 20 min of simulated-demand ischemia using potentiometric probe TMRM in rabbit adult ventricular myocytes incubated with PPi versus control group. Untreated myocytes experienced significant loss of ΔΨ while in the PPi-treated myocytes ΔΨ was relatively maintained throughout 20 min of simulated-demand ischemia as compared to control (p<0.05). CONCLUSIONS: High tissue level of PPi may prevent ΔΨm loss and electrical failure at the early phase of ischemic stress. The link between the two protective effects may involve decreased rates of mitochondrial ATP hydrolysis and lactate accumulation.

Role of KATP channel in electrical depression and asystole during long-duration ventricular fibrillation in ex vivo canine heart.

Long-duration ventricular fibrillation (LDVF) in the globally ischemic heart is characterized by transmurally heterogeneous decline in ventricular fibrillation rate (VFR), emergence of inexcitable regions, and eventual global asystole. Rapid loss of both local and global excitability is detrimental to successful defibrillation and resuscitation during cardiac arrest. We sought to assess the role of the ATP-sensitive potassium current (I(KATP)) in the timing and spatial pattern of electrical depression during LDVF in a structurally normal canine heart. We analyzed endo-, mid-, and epicardial unipolar electrograms and epicardial optical recordings in the left ventricle of isolated canine hearts during 10 min of LDVF in the absence (control) and presence of an I(KATP) blocker glybenclamide (60 µM). In all myocardial layers, average VFR was the same or higher in glybenclamide-treated than in control hearts. The difference increased with time of LDVF and was overall significant in all layers (P < 0.05). However, glybenclamide did not significantly affect the transmural VFR gradient. In epicardial optical recordings, glybenclamide shortened diastolic intervals, prolonged action potential duration, and decreased the percentage of inexcitable area (all differences P < 0.001). During 10 min of LDVF, asystole occurred in 55.6% of control and none of glybenclamide-treated hearts (P < 0.05). In three hearts paced after the onset of asystole, there was no response to LV epicardial or atrial pacing. In structurally normal canine hearts, I(KATP) opening during LDVF is a major factor in the onset of local and global inexcitability, whereas it has a limited role in overall deceleration of VFR and the transmural VFR gradient.

Object discrimination with an artificial hand using electrical stimulation of peripheral tactile and proprioceptive pathways with intrafascicular electrodes.

Trans-radial amputee subjects were implanted with intrafascicular electrodes in the stumps of the median and ulnar nerves. Electrical stimulation through these electrodes was used to provide sensations of touch and finger position referred to the amputated hand. Two subjects were asked to identify different objects as to size and stiffness by manipulating them with a myo-electric hand without visual or auditory cues. Both subjects were provided with information about contact force with the objects via tactile sensations referred to their phantom hands. One subject, who was provided with information about finger position in the prosthetic hand via a different tactile sensation referred to his phantom hand, was unable to correctly identify the objects. The other subject, who received information about finger position via a proprioceptive sensation referred to his phantom hand, correctly identified the objects at a level statistically significantly above chance performance.

Complex structure of electrophysiological gradients emerging during long-duration ventricular fibrillation in the canine heart.

Long-duration ventricular fibrillation (LDVF) in the globally ischemic heart is a common setting of cardiac arrest. Electrical heterogeneities during LDVF may affect outcomes of defibrillation and resuscitation. Previous studies in large mammalian hearts have investigated the role of Purkinje fibers and electrophysiological gradients between the endocardium (Endo) and epicardium (Epi). Much less is known about gradients between the right ventricle (RV) and left ventricle (LV) and within each chamber during LDVF. We studied the transmural distribution of the VF activation rate (VFR) in the RV and LV and at the junction of RV, LV, and septum (Sep) during LDVF using plunge needle electrodes in opened-chest dogs. We also used optical mapping to analyze the Epi distribution of VFR, action potential duration (APD), and diastolic interval (DI) during LDVF in the RV and LV of isolated hearts. Transmural VFR gradients developed in both the RV and LV, with a faster VFR in Endo. Concurrently, large VFR gradients developed in Epi, with the fastest VFR in the RV-Sep junction, intermediate in the RV, and slowest in the LV. Optical mapping revealed a progressively increasing VFR dispersion within both the LV and RV, with a mosaic presence of fully inexcitable areas after 4-8 min of LDVF. The transmural, interchamber, and intrachamber VFR heterogeneities were of similar magnitude. In both chambers, the inverse of VFR was highly correlated with DI, but not APD, at all time points of LDVF. We conclude that the complex VFR gradients during LDVF in the canine heart cannot be explained solely by the distribution of Purkinje fibers and are related to regional differences in the electrical depression secondary to LDVF.