Human leucocyte antigen class I-redirected anti-tumour CD4+ T cells require a higher T cell receptor binding affinity for optimal activity than CD8+ T cells.

CD4+ T helper cells are a valuable component of the immune response towards cancer. Unfortunately, natural tumour-specific CD4+ T cells occur in low frequency, express relatively low-affinity T cell receptors (TCRs) and show poor reactivity towards cognate antigen. In addition, the lack of human leucocyte antigen (HLA) class II expression on most cancers dictates that these cells are often unable to respond to tumour cells directly. These deficiencies can be overcome by transducing primary CD4+ T cells with tumour-specific HLA class I-restricted TCRs prior to adoptive transfer. The lack of help from the co-receptor CD8 glycoprotein in CD4+ cells might result in these cells requiring a different optimal TCR binding affinity. Here we compared primary CD4+ and CD8+ T cells expressing wild-type and a range of affinity-enhanced TCRs specific for the HLA A*0201-restricted NY-ESO-1- and gp100 tumour antigens. Our major findings are: (i) redirected primary CD4+ T cells expressing TCRs of sufficiently high affinity exhibit a wide range of effector functions, including cytotoxicity, in response to cognate peptide; and (ii) optimal TCR binding affinity is higher in CD4+ T cells than CD8+ T cells. These results indicate that the CD4+ T cell component of current adoptive therapies using TCRs optimized for CD8+ T cells is below par and that there is room for substantial improvement.

T cell receptor binding affinity governs the functional profile of cancer-specific CD8+ T cells.

Antigen-specific T cell receptor (TCR) gene transfer via patient-derived T cells is an attractive approach to cancer therapy, with the potential to circumvent immune regulatory networks. However, high-affinity tumour-specific TCR clonotypes are typically deleted from the available repertoire during thymic selection because the vast majority of targeted epitopes are derived from autologous proteins. This process places intrinsic constraints on the efficacy of T cell-based cancer vaccines and therapeutic strategies that employ naturally generated tumour-specific TCRs. In this study, we used altered peptide ligands and lentivirus-mediated transduction of affinity-enhanced TCRs selected by phage display to study the functional properties of CD8(+) T cells specific for three different tumour-associated peptide antigens across a range of binding parameters. The key findings were: (i) TCR affinity controls T cell antigen sensitivity and polyfunctionality; (ii) supraphysiological affinity thresholds exist, above which T cell function cannot be improved; and (iii) T cells transduced with very high-affinity TCRs exhibit cross-reactivity with self-derived peptides presented by the restricting human leucocyte antigen. Optimal system-defined affinity windows above the range established for natural tumour-specific TCRs therefore allow the enhancement of T cell effector function without off-target effects. These findings have major implications for the rational design of novel TCR-based biologics underpinned by rigorous preclinical evaluation.

Multicenter study of principles-based waveforms for external defibrillation.

STUDY OBJECTIVE: The efficacy of a shock waveform for external defibrillation depends on the waveform characteristics. Recently, design principles based on cardiac electrophysiology have been developed to determine optimal waveform characteristics. The objective of this clinical trial was to evaluate the efficacy of principles-based monophasic and biphasic waveforms for external defibrillation. METHODS: A prospective, randomized, blinded, multicenter study of 118 patients undergoing electrophysiologic testing or receiving an implantable defibrillator was conducted. Ventricular fibrillation was induced, and defibrillation was attempted in each patient with a biphasic and a monophasic waveform. Patients were randomly placed into 2 groups: group 1 received shocks of escalating energy, and group 2 received only high-energy shocks. RESULTS: The biphasic waveform achieved a first-shock success rate of 100% in group 1 (95% confidence interval [CI] 95.1% to 100%) and group 2 (95% CI 94.6% to 100%), with average delivered energies of 201+/-17 J and 295+/-28 J, respectively. The monophasic waveform demonstrated a 96.7% (95% CI 89.1% to 100%) first-shock success rate and average delivered energy of 215+/-12 J for group 1 and a 98.2% (95% CI 91.7% to 100%) first-shock success rate and average delivered energy of 352+/-13 J for group 2. CONCLUSION: Using principles of electrophysiology, it is possible to design both biphasic and monophasic waveforms for external defibrillation that achieve a high first-shock efficacy.

External exponential biphasic versus monophasic shock waveform: efficacy in ventricular fibrillation of longer duration.

Ventricular fibrillation (VF) duration may be a factor in determining the defibrillation energy for successful defibrillation. Exponential biphasic waveforms have been shown to defibrillate with less energy than do monophasic waveforms when used for external defibrillation. However, it is unknown whether this advantage persists with longer VF duration. We tested the hypothesis that exponential biphasic waveforms have lower defibrillation energy as compared to exponential monophasic waveforms even with longer VF duration up to 1 minute. In a swine model of external defibrillation (n = 12, 35 +/- 6 kg), we determined the stored energy at 50% defibrillation success (E50) after both 10 seconds and 1 minute of VF duration. A single exponential monophasic (M) and two exponential biphasic (B1 and B2) waveforms were tested with the following characteristics: M (60 microF, 70% tilt), B1 (60/60 microF, 70% tilt/3 ms pulse width), and B2 (60/20 microF, 70% tilt/3 ms pulse width) where the ratio of the phase 2 leading edge voltage to that of phase 1 was 0.5 for B1 and 1.0 for B2. E50 was measured by a Bayesian technique with a total often defibrillation shocks in each waveform and VF duration randomly. The E50 (J) for M, B1, and B2 were 131 +/- 41, 57 +/- 18,* and 60 +/- 26* with 10 seconds of VF duration, respectively, and 114 +/- 62, 77 +/- 45,* and 72 +/- 53* with 1 minute of VF duration, respectively (*P < 0.05 vs M). There was no significant difference in the E50 between 10 seconds and 1 minute of VF durations for each waveform. We conclude that (1) the E50 does not significantly increase with lengthening VF durations up to 1 minute regardless of the shock waveform, and (2) external exponential biphasic shocks are more effective than monophasic waveforms even with longer VF durations.

Fully discharging phases. A new approach to biphasic waveforms for external defibrillation.

BACKGROUND: Phase-2 voltage and maximum pulse width are dependent on phase-1 pulse characteristics in a single-capacitor biphasic waveform. The use of 2 separate output capacitors avoids these limitations and may allow waveforms with lower defibrillation thresholds. A previous report also suggested that the optimal tilt may be >70%. This study was designed to determine an optimal biphasic waveform by use of a combination of 2 separate and fully (95% tilt) discharging capacitors. METHODS AND RESULTS: We performed 2 external defibrillation studies in a pig ventricular fibrillation model. In group 1, 9 waveforms from a combination of 3 phase-1 capacitor values (30, 60, and 120 microF) and 3 phase-2 capacitor values (0=monophasic, 1/3, and 1.0 times the phase-1 capacitor) were tested. Biphasic waveforms with phase-2 capacitors of 1/3 times that of phase 1 provided the highest defibrillation efficacy (stored energy and voltage) compared with corresponding monophasic and biphasic waveforms with the same capacitors in both phases except for waveforms with a 30-microF phase-1 capacitor. In group 2, 10 biphasic waveforms from a combination of 2 phase-1 capacitor values (30 and 60 microF) and 5 phase-2 capacitor values (10, 20, 30, 40, and 50 microF) were tested. In this range, phase-2 capacitor size was more critical for the 30-microF phase-1 than for the 60-microF phase-1 capacitor. The optimal combinations of fully discharging capacitors for defibrillation were 60/20 and 60/30 microF. Conclusions-Phase-2 capacitor size plays an important role in reducing defibrillation energy in biphasic waveforms when 2 separate and fully discharging capacitors are used.

Optimal small-capacitor biphasic waveform for external defibrillation: influence of phase-1 tilt and phase-2 voltage.

BACKGROUND: Biphasic waveforms have been reported to be more efficacious than monophasic waveforms for external defibrillation. This study examined the optimal phase-1 tilts and phase-2 leading-edge voltages with small capacitors (60 and 20 microF) for external defibrillation. We also assessed the ability of the "charge-burping" model to predict the optimal waveforms. METHODS AND RESULTS: Two groups of studies were performed. In group 1, 9 biphasic waveforms from a combination of 3 phase-1 tilt values (30%, 50%, and 70%) and 3 phase-2 leading-edge voltage values (0.5, 1.0, and 1.5 times the phase-1 leading-edge voltage, V1) were tested. Phase-2 pulse width was held constant at 3 ms in all waveforms. Two separate 60- microF capacitors were used in each phase. The energy value that would produce a 50% likelihood of successful defibrillation (E50) decreased with increasing phase-1 tilt and increased with increasing phase-2 leading-edge voltage except for the 30% phase-1 tilt waveforms. In group 2, 9 waveforms were identical to the waveforms in group 1, except for a 20- microF capacitor for phase 2. E50 decreased with increasing phase-1 tilt. Phase-2 leading-edge voltage of 1.0 to 1.5 V1 appeared to minimize E50 for phase-1 tilt of 50% and 70% but worsened E50 for phase-1 tilt of 30%. There was a significant correlation between E50 and residual membrane voltage at the end of phase 2, as calculated by the charge-burping model in both groups (group 1, R2=0.47, P<0.001; group 2, R2=0.42, P<0.001). CONCLUSIONS: The waveforms with 70% phase-1 tilt were more efficacious than those with 30% and 50%. The relationship of phase-2 leading-edge voltage to defibrillation efficacy depended on phase-2 capacitance. The charge-burping model predicted the optimal external biphasic waveform.

Effects of respiration phase on ventricular defibrillation threshold in a hot can electrode system.

The impedance of defibrillation pathways is an important determinant of ventricular defibrillation efficacy. The hypothesis in this study was that the respiration phase (end-inspiration versus end-expiration) may alter impedance and/or defibrillation efficacy in a "hot can" electrode system. Defibrillation threshold (DFT) parameters were evaluated at end-expiration and at end-inspiration phases in random order by a biphasic waveform in ten anesthetized pigs (body weight: 19.1 +/- 2.4 kg; heart weight: 97 +/- 10 g). Pigs were intubated with a cuffed endotracheal tube and ventilated through a Drager SAV respirator with tidal volume of 400-500 mL. A transvenous defibrillation lead (6 cm long, 6.5 Fr) was inserted into the right ventricular apex. A titanium can electrode (92-cm2 surface area) was placed in the left pectoral area. The right ventricular lead was the anode for the first phase and the cathode for the second phase. The DFT was determined by a "down-up down-up" protocol. Statistical analysis was performed with a Wilcoxon matched pair test. The median impedance at DFT for expiration and inspiration phases were 37.8 +/- 3.1 omega, and 39.3 +/- 3.6 omega, respectively (P = 0.02). The stored energy at DFT for expiration and inspiration phases were 5.7 +/- 1.9 J and 6.0 +/- 1.0 J, respectively (P = 0.594). Shocks delivered at end-inspiration exhibited a statistically significant increase in electrode impedance in a " hot can" electrode system. The finding that DFT energy was not significantly different at both respiration phases indicates that respiration phase does not significantly affect defibrillation energy requirements.

Frequency and yield of postoperative fever evaluation.

OBJECTIVE: In women undergoing major gynecologic surgery, we wish to determine the frequency and yield of blood culture, urine culture, and chest X-ray evaluation of postoperative fever. METHODS: A retrospective review of 537 consecutive patients undergoing major gynecologic surgery was performed. In patients who developed postoperative fever, it was determined whether blood culture, urine culture, and/or chest X-ray were performed, and, if so, the frequency of positive results was evaluated. RESULTS: Two hundred eleven patients (39%) developed postoperative fever. Blood cultures were obtained in 77 of 211 (37%) febrile patients, urine cultures in 106 of 211 (50%) febrile patients, and chest X-ray in 54 of 211 (26%) febrile patients. Zero of 77 blood cultures were positive, 11 of 106 (10%) urine cultures were positive, and 5 of 54 (9%) chest X-rays were positive. Logistic regression revealed that late onset fever predicted for positive urine cultures and early onset fever and advanced age predicted for pneumonia. Eighty percent of patients with pneumonia were symptomatic. In 92% of patients with postoperative fever, no infections or pathologic process were diagnosed. CONCLUSION: Although postoperative fever is frequently evaluated by blood culture, urine culture, and chest X-ray, evaluation rarely yields positive results.

Application of models of defibrillation to human defibrillation data: implications for optimizing implantable defibrillator capacitance.

BACKGROUND: Theoretical models predict that optimal capacitance for implantable cardioverter-defibrillators (ICDs) is proportional to the time-dependent parameter of the strength-duration relationship. The hyperbolic model gives this relationship for average current in terms of the chronaxie (t(c)). The exponential model gives the relationship for leading-edge current in terms of the membrane time constant (tau(m)). We hypothesized that these models predict results of clinical studies of ICD capacitance if human time constants are used. METHODS AND RESULTS: We studied 12 patients with epicardial ICDs and 15 patients with transvenous ICDs. Defibrillation threshold (DFT) was determined for 120-microF monophasic capacitive-discharge pulses at pulse widths of 1.5, 3.0, 7.5, and 15 ms. To compare the predictions of the average-current versus leading-edge-current methods, we derived a new exponential average-current model. We then calculated individual patient time parameters for each model. Model predictions were validated by retrospective comparison with clinical crossover studies of small-capacitor and standard-capacitor waveforms. All three models provided a good fit to the data (r2=.88 to .97, P<.001). Time constants were lower for transvenous pathways (53+/-7 omega) than epicardial pathways (36+/-6 omega) (t(c), P<.001; average-current tau(m), P=.002; leading-edge-current tau(m), P<.06). For epicardial pathways, optimal capacitance was greater for either average-current model than for the leading-edge-current model (P<.001). For transvenous pathways, optimal capacitance differed for all three models (P<.001). All models provided a good correlation with the effect of capacitance on DFT in previous clinical studies: r2=.75 to .84, P<.003. For 90-microF, 120-microF, and 150-microF capacitors, predicted stored-energy DFTs were 3% to 8%, 8% to 16%, and 14% to 26% above that for the optimal capacitance. CONCLUSIONS: Model predictions based on measured human cardiac-muscle time parameter have a good correlation with clinical studies of ICD capacitance. Most of the predicted reduction in DFT can be achieved with approximately 90-microF capacitors.

Optimized first phase tilt in "parallel-series" biphasic waveform.

INTRODUCTION: A biphasic defibrillation waveform can achieve a large second phase leading-edge voltage by a "parallel-series" switching system. Recently, such a system using two 30-microF capacitances demonstrated better defibrillation threshold than standard waveforms available in current implantable devices. However, the optimized tilt of such a "parallel-series" system had not been defined. METHODS AND RESULTS: Defibrillation thresholds were evaluated for five different biphasic "parallel-series" waveforms (60/15 microF) and a biphasic "parallel-parallel" waveform (60/60 microF) in 12 anesthetized pigs. The five "parallel-series" waveforms had first phase tilts of 40%, 50%, 60%, 70%, and 80% with second phase pulse width of 3 msec. The "parallel-parallel" waveform had first phase tilt of 50% with second phase pulse width of 3 msec. The defibrillation lead system comprised a left pectoral "hot can" electrode (cathode) and a right ventricular lead (anode). The stored energy at defibrillation threshold of the "parallel-series" waveform with first phase tilts of 40%, 50%, 60%, 70%, and 80% was 7.0 +/- 2.1, 6.1 +/- 2.8, 6.8 +/- 2.8, 7.2 +/- 2.9, and 8.4 +/- 3.1 J, respectively. The stored energy of the "parallel-series" waveform with a 50% first phase tilt was 16% less than the nonswitching "parallel-parallel" waveform (7.3 +/- 2.8 J, P = 0.006). CONCLUSIONS: A first phase tilt of 50% maximized defibrillation efficacy of biphasic waveforms implemented with a "parallel-series" switching system. This optimized "parallel-series" waveform was more efficient than the comparable "parallel-parallel" biphasic waveform having the same first phase capacitance and tilt.

Sawtooth first phase biphasic defibrillation waveform: a comparison with standard waveform in clinical devices.

INTRODUCTION: A major limitation in a conventional truncated exponential waveform is the rapid drop in current that results in short duration of high current or longer duration with a lower average current. We hypothesized that increasing the first phase average current by boosting the decaying waveform prior to phase reversal may improve defibrillation efficacy. METHODS AND RESULTS: To better simulate a "rectangular" waveform during the first phase, a "sawtooth" defibrillation waveform was constructed using "parallel-series" switching of capacitances (each 30 microF) during the first phase. This permitted a boost in the voltage late in the first phase. This sawtooth biphasic waveform (sawtooth) was compared to two clinical waveforms: a 135-microF capacitance (control-1) and a 90-microF capacitance (control-2) waveform. Defibrillation threshold (DFT) parameters were evaluated in 13 anesthetized pig models using a system consisting of a transvenous right ventricular apex lead (anode) and a left pectoral "hot can" electrode (cathode) system. DFT was determined by a "down-up down-up" protocol. The stored energy for sawtooth, control-1, and control-2 was 10.5 +/- 2.8 J, 12.3 +/- 3.7 J*, and 12.2 +/- 2.8 J*, respectively (*P < or = 0.01 vs sawtooth). The average current of the first phase for sawtooth, control-1, and control-2 was 7.6 +/- 1.3 A, 4.7 +/- 0.9 A*, and 6.2 +/- 0.9 A*, respectively (*P = 0.0001 vs sawtooth). CONCLUSION: A sawtooth biphasic waveform utilizing a "parallel-series" switching system of smaller capacitors can improve defibrillation efficacy. A higher average current in the first phase generated by such a waveform may contribute to more efficient defibrillation by facilitating myocyte capture.

Automated external defibrillators: design considerations.

Biphasic defibrillation waveforms are now the standard of care in clinical use for defibrillation with implantable cardioverter-defibrillators (ICDs), due to the superior performance demonstrated over that of comparable monophasic waveforms. To better understand these significantly different outcomes, ICD research has developed cardiac cell response models to defibrillation. Waveform design criteria have been derived from these first principles and have been applied to monophasic and biphasic waveforms to optimize their parameters. These principles-based design criteria have produced significant improvements over the current art of waveforms. Monophasic defibrillation waveforms remain the standard of care in clinical use for transthoracic defibrillation. Waveform design has not yet been influenced by the important gains made in ICD research. The limitations of present transthoracic waveforms may be due in part to a lack of application of these design principles to determine optimal waveform characteristics. To overcome these limitations, design principles based on cell response have recently been developed for external defibrillation waveforms. The transthoracic model incorporates elements into a cell response model that extends it to external defibrillation. External waveform design principles demonstrate reductions in capacitance, voltage, duration, and delivered energy. Therefore, design principles based on cardiac electrophysiology may provide a means to significantly reduce the energy required for safe and efficacious external defibrillation. Footnotes, formulae, and figures augment this presentation in order to clarify the defibrillation waveform theory.

Effects of polarity on defibrillation thresholds using a biphasic waveform in a hot can electrode system.

The polarity of a monophasic and biphasic shocks have been reported to influence DFTs in some studies. The purpose of this study was to evaluate the effect of the first phase polarity on the DFT of a biphasic shock utilizing a nonthoracotomy "hot can" electrode configuration which had a 90-microF capacitance. We tested the hypothesis that anodal first phase was more effective than cathodal ones for defibrillation using biphasic shocks in ten anesthetized pigs weighing 38.9 +/- 3.9 kg. The lead system consisted of a right ventricular catheter electrode with a surface area of 2.7 cm2 and a left pectoral "hot can" electrode with 92.9 cm2 surface area. DFT was determined using a repeated "down-up" technique. A shock was tested 10 seconds after initiation of ventricular fibrillation. The mean delivered energy at DFT was 11.2 +/- 1.7 J when using the right ventricular apex electrode as the cathode and 11.3 +/- 1.2 J (P = NS) when using it as the anode. The peak voltage at DFT was also not significantly different (529.0 +/- 41.3 and 531.8 +/- 28.6 V, respectively). We concluded that the first phase polarity of a biphasic shock used with a nonthroracotomy "hot can" electrode configuration did not affect DFT.

Dual level sensing significantly improves automatic threshold control for R wave sensing in implantable defibrillators. The Angeion Corporation.

ICDs must sense R waves over a range of amplitudes without sensing P or T waves. Automatic threshold control (ATC) is an accepted sensing method for that task. ATC sensing levels are from 25%-75% of the electrogram (EGM) peak, decreasing with an exponential decay. A high sensing level for a time after peak detection may better allow ATC to pass over a T wave, while a lower sensing level thereafter may better allow ATC to sense the next R wave. An ATC was designed with two sensing levels and time constants (tau), using a 58% level (tau = 1.75 s) for 325 ms after peak detection switching to 33% (tau = 1.1 s) thereafter, and was compared to a single level ATC (sensing level = 50%, tau = 1.4 s). The two ATC circuits were tested with 22 arrhythmia EGMs to determine sensitivity and specificity rates at +/-1-, 2-, 5-, 10-, and 20-mV amplitudes. It was confirmed that a dual level ATC significantly improves the sensitivity rate without degrading the high specificity rate of a standard sensing circuit.

Charge-burping theory correctly predicts optimal ratios of phase duration for biphasic defibrillation waveforms.

BACKGROUND: For biphasic waveforms, it is accepted that the ratio of the duration of phase 2 to the duration of phase 1 (phase-duration ratio) should be < or = 1. The charge-burping theory postulates that the beneficial effects of phase 2 are maximal when it completely removes the charge delivered by phase 1. It predicts that the phase-duration ratio should be < 1 when the time constant of the defibrillation system (tau s) exceeds the time constant of the cell membrane (tau m) but > 1 when tau s < tau m. This study tested the hypothesis that the optimal phase-duration ratio depends on tau s (the product of the defibrillator capacitance and pathway resistance). METHODS AND RESULTS: In a canine model of transvenous defibrillation (n = 8), we determined stored-energy defibrillation thresholds (DFTs) for biphasic waveforms from conventional capacitors (140 microF. tau s = 7.1 +/- 0.8 ms) and very small capacitors (40 microF. tau s = 2.0 +/- 0.2 ms). Each capacitance was tested with phase-duration ratios of 0.5, 1, 2, and 3. The duration of phase 1 approximated the optimal monophasic waveform, 6.3 +/- 0.7 ms for 140-microF waveforms and 2.8 +/- 0.2 ms for 40-microF waveforms. For 140-microF waveforms, the DFT was lower for phase-duration ratios < or = 1 than for phase-duration ratios > 1 (P = .0003). The reverse was true for 40-microF capacitors (P = .0008). There was a significant interaction between the effects of capacitance and phase-duration ratio on DFT (P = .0002). The lowest DFT for 40-microF waveforms was less than the lowest DFT for 140-microF waveforms (4.9 +/- 2.5 versus 6.4 +/- 2.4 J, P < .05). CONCLUSIONS: The optimal phase-duration ratio is < or = 1 for conventional capacitors and > 1 for small capacitors. This supports the predictions of the charge-burping theory.

Large change in voltage at phase reversal improves biphasic defibrillation thresholds. Parallel-series mode switching.

BACKGROUND: Multiple factors contribute to an improved defibrillation threshold of biphasic shocks. The leading-edge voltage of the second phase may be an important factor in reducing the defibrillation threshold. METHODS AND RESULTS: We tested two experimental biphasic waveforms with large voltage changes at phase reversal. The phase 2 leading-edge voltage was twice the phase 1 trailing-edge voltage. This large voltage change was achieved by switching two capacitors from parallel to series mode at phase reversal. Two capacitors were tested (60/15 microfarads [microF] and 90/22.5 microF) and compared with two control biphasic waveforms for which the phase 1 trailing-edge voltage equaled the phase 2 leading-edge voltage. The control waveforms were incorporated into clinical (135/135 microF) or investigational devices (90/90 microF). Defibrillation threshold parameters were evaluated in eight anesthetized pigs by use of a nonthoracotomy transvenous lead to a can electrode system. The stored energy at the defibrillation threshold (ion joules) was 8.2 +/- 1.5 for 60/15 microF (P < .01 versus 135/135 microF and 90/90 microF), 8.8 +/- 2.4 for 90/22.5 microF (P < .01 versus 135/135 microF and 90/90 microF), 12.5 +/- 3.4 for 135/135 microF, and 12.6 +/- 2.6 for 90/90 microF. CONCLUSIONS: The biphasic waveform with large voltage changes at phase reversal caused by parallel-series mode switching appeared to improve the ventricular defibrillation threshold in a pig model compared with a currently available biphasic waveform. The 60/15-microF capacitor performed as well as the 90/ 22.5-microF capacitor in the experimental waveform. Thus, smaller capacitors may allow reduction in device size without sacrificing defibrillation threshold energy requirements.

A short duration, small capacitor, biphasic waveform has lower defibrillation thresholds than a clinically available biphasic waveform

A biphasic waveform delivered from an 85 uF capacitor was compared to a biphasic waveform delivered from a commercially available implantable defibrillator (ICD). The test waveform had a phase one (O1) duration of 4 ms, a phase two (O2) duration of 2.5 ms, and an innitial O2 voltage equal to the terminal O1 voltage. The control was delivered from a 150 uF capacitor, had adjustable pulse widths (O1, O2 = 8 ms for a 50 ohm load), and an initial O2 voltage equal to 50 por cento of the O1 terminal volge. The short duration, small capacitor waveform reduced stored energy defibrillation thresholds (DFT) by 18 por cento and increased O1 leading edge voltage by 20 por cento when compared to the control.

Defibrillation thresholds are lower with smaller storage capacitors.

Present implantable cardioverter defibrillators use a wide range of capacitance values for the storage capacitor. However, the optimal capacitance value is unknown. We hypothesized that a smaller capacitor, by delivering its charge in a time closer to the heart chronaxie, should lower the defibrillation threshold (DFT). We compared the energy required to defibrillate 10 open-chest dogs, after 15 seconds of ventricular fibrillation, with a monophasic, time-truncated waveform delivered from either a 85-microF or a 140-microF capacitor. Shocks were delivered through a pair of 14-cm2 epicardial patch electrodes: The two capacitors were randomly tested twice with each dog using a modified 3-reversal method for each DFT determination. The average stored and delivered DFT energies for the 85-microF capacitor were 6.0 +/- 1.7 joules and 5.2 +/- 1.5 joules, respectively, compared to 6.7 +/- 1.7 joules and 6.0 +/- 1.5 joules for the 140-microF capacitor (P = 0.01 and P = 0.004, respectively). The mean leading edge voltages were higher, the pulse duration shorter, and the mean impedance lower for the 85-microF capacitor. The impedance was inversely related to the pulse duration and the voltage decay suggesting that, at least in part, the mechanism of improved defibrillation could be accounted for by the waveform electrical characteristics. There was an equal number of episodes of postshock bradyarrhythmias and tachyarrhythmias following discharges from each capacitor. Moreover, there was no relationship between the likelihood of these arrhythmias and either the initial voltage or the delivered current nor there was a higher number of episodes of postshock hypotension following the smaller capacitor discharges.(ABSTRACT TRUNCATED AT 250 WORDS)

Low voltage shocks have a significantly higher tilt of the internal electric field than do high voltage shocks.

Typically, an implantable cardioverter defibrillator (ICD) uses a cardioversion shock that is a lower voltage pulse of the same morphology and tilt as its defibrillation pulse. We investigated the internal electric field resulting from an ICD low voltage shock to determine whether its field characteristics matched those of the internal electric field of a high voltage shock. We attached epicardial patch electrodes, for shock delivery, to five fresh pig hearts placed in a diluted, heparinized saline bath. We inserted two plunge electrodes into the myocardium to measure an internal voltage proportional to the electric field. Monophasic 20-msec shocks, from a 140-microF capacitor, ranging from 0.1-30 joules, were delivered through the patches. We measured the current, external voltage, and internal voltage every 0.1 msec throughout the duration of a shock. For each shock, we calculated the time point that represented the 65% tilt position as measured across the patch electrodes. At this 65% tilt time position, we measured the pulse widths and calculated the internal tilt from the internal voltage. We found that the initial internal voltage for the 30-joule shock was 173 +/- 40 volts compared to 10 +/- 2 volts for the 0.1-joule shock. Similarly, we found that the final internal voltage for the 30-joule shock was 56 +/- 14 volts compared to 2 +/- 1 volts for the 0.1-joule shock. Thus, the internal tilt for the 30-joule shock was 68 +/- 1% versus 82 +/- 3% for the 0.1-joule shock (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)