Effects of Potassium/Lidocaine-induced Cardiac Standstill During Cardiopulmonary Resuscitation in a Pig Model of Prolonged Ventricular Fibrillation

Several studies in patients who underwent open heart surgery found that myocardial ischemic damage was reduced by potassium cardioplegia combined with lidocaine infusion. The authors evaluated the effects of potassium/lidocaine-induced cardiac standstill during conventional cardiopulmonary resuscitation (CPR) on myocardial injury and left ventricular dysfunction after resuscitation from prolonged ventricular fibrillation (VF) cardiac arrest in a pig model. Ventricular fibrillation was induced in 16 pigs, and circulatory arrest was maintained for 14 minutes. Animals were then resuscitated by standard CPR. Animals were randomized at the start of CPR to receive 20 mL of saline (control group) or 0.9 mEq/kg potassium chloride and 1.2 mg/kg lidocaine diluted to 20 mL (K-lido group). Seven animals in each group achieved return of spontaneous circulation (ROSC; p = 1.000). Four of the K-lido group animals (50%) achieved ROSC without countershock. Resuscitated animals in the K-lido group required fewer countershocks (p = 0.004), smaller doses of epinephrine (p = 0.009), and shorter durations of CPR (p = 0.004) than did the control group. The uncorrected troponin-I at 4 hours after ROSC was lower in the K-lido group compared with the control group (2.82 ng/mL, 95% confidence interval [CI] = 1.07 to 3.38 ng/mL vs. 6.55 ng/mL, 95% CI = 4.84 to 13.30 ng/mL; p = 0.025), although the difference was not significant after Bonferroni correction. The magnitude of reduction in left ventricular ejection fraction (LVEF) between baseline and 1 hour after ROSC was significantly lower in the K-lido group (26.5%, SD ± 6.1% vs. 39.1%, SD ± 6.8%; p = 0.004). In a pig model of untreated VF cardiac arrest for 14 minutes, resuscitation with potassium/lidocaine-induced cardiac standstill during conventional CPR tended to reduce myocardial injury and decreased the severity of postresuscitation myocardial dysfunction significantly. Varios estudios en pacientes en los que se llevó a cabo una cirugía a corazón abierto documentaron que el daño isquémico del miocardio se redujo por la infusión cardiopléjica de potasio combinada con lidocaína. Se evaluaron los efectos de la lidocaína y el potasio en la parada cardiaca inducida, durante la resucitación cardiopulmonar (RCP) convencional (RCP), en la lesión miocárdica y la disfunción ventricular izquierda tras la RCP de la parada cardiaca por fibrilación ventricular (FV) prolongada en un modelo de cerdo. Se indujo fibrilación ventricular en dieciséis cerdos, y se mantuvo la parada cardiorrespiratoria durante 14 minutos. Los animales fueron entonces resucitados mediante RCP convencional. Los animales se aleatorizaron a recibir 20 mL de salino (grupo control) o 0,9 mEq/kg de potasio clorhídrico y 1,2 mg/kg de lidocaína diluidos a 20 mL (grupo Lido-K), al inicio de la RCP. Siete animales en cada grupo consiguieron la recuperación de la circulación espontánea (RCE) (p = 1,000). Cuatro de los animales del grupo Lido-K (50%) alcanzaron la RCE sin choques eléctricos. Los animales resucitados del grupo Lido-K requirieron menor número de choques eléctricos (p = 0,004), menor dosis de adrenalina (p = 0,009), y menor duración de la RCP (p = 0,004) que el grupo control. La troponina-I a las 4 horas tras RCE fue menor en el grupo Lido-K en comparación con el grupo control (2,82 ng/mL [IC 95% = 1,07 a 3,38 ng/mL] frente 6,55 ng/mL [IC 95% = 4,84 a 13,30 ng/mL] p = 0,025), aunque la diferencia no fue significativa tras la corrección de Bonferroni. La magnitud de la reducción en la fracción de eyección del ventrículo izquierdo entre el momento inicial y una hora tras la RCE fue significativamente menor en el grupo Lido-K (26,5% [DE ±6,1%] vs. 39,1% [DE ±6,8%]; p = 0,004). En un modelo cerdo de parada cardiaca por FV en cerdos no tratada durante 14 minutos, el uso de lidocaína y potasio durante la RCP convencional tendió a reducir la lesión miocárdica y disminuyó la gravedad de la disfunción miocárdica tras la RCP de forma significativa. Ventricular fibrillation (VF) greatly increases myocardial energy demands relative to energy supply because the fibrillating heart continues to consume energy.1, 2 Coronary perfusion generated during conventional cardiopulmonary resuscitation (CPR) rarely exceeds 30% of normal and thus fails to meet the metabolic requirements of the fibrillating heart.3, 4 Consequently, unless VF is corrected rapidly, the magnitude of myocardial ischemic injury increases.5, 6 Several studies have indicated that inducing transient cardiac standstill by infusing a high concentration of potassium allows successful cardioversion of VF during cardiopulmonary bypass.7-9 In a study that included 8,456 adult patients undergoing cardiac operations on cardiopulmonary bypass, Almdahl et al.7 reported that 79% of patients with VF after aortic declamping were successfully treated with 20 mmol potassium infusion. Recently we showed in a pig model of prolonged VF that resuscitation with potassium-induced cardiac standstill was feasible even during conventional CPR.10 The concept of potassium-induced cardiac standstill came from potassium-based cardioplegia during cardiac surgery. Potassium depolarization is an essential component in most cardioplegic solutions. It induces total electrical and mechanical standstill, thus minimizing energy consumption and contributing to the maintenance of high-energy phosphate and substrate stores.11 However, several studies indicate that extracellular hyperkalemia alone may not provide optimal cardioprotection because of deleterious effects of potassium depolarization such as accumulation of intracellular sodium and calcium.12, 13 Thus, various cardioplegia additives have been explored to improve the protective effects of potassium-based cardioplegia. Lidocaine is one of the most widely used antiarrhythmic drugs for the treatment of ventricular tachyarrhythmias. In addition to its antiarrhythmic effect, lidocaine as a cardioplegia additive has been shown to ameliorate the deleterious effects of potassium cardioplegia and further improve myocardial protection.14-16 Based on the studies that showed improved cardioprotection with potassium-based cardioplegia combined with lidocaine,14-16 we hypothesized that potassium/lidocaine-induced cardiac standstill during conventional CPR will provide myocardial protection compared to conventional CPR alone. The purpose of this study was to evaluate the effects of potassium/lidocaine-induced cardiac standstill during conventional CPR on myocardial injury and left ventricular dysfunction after resuscitation from prolonged VF cardiac arrest in a pig model. This was a laboratory study of induced cardiac standstill in pigs. The Animal Care and Use Committee of Chonnam National University Hospital approved the protocol of this study. Animal care and experiments were conducted according to Institutional Animal Care and Use Committee guidelines. Sixteen male domestic pigs weighing 27.0 kg (standard deviation [SD] ± 2.4 kg) were used. After premedication (ketamine, 20 mg/kg; xylazine, 2.2 mg/kg; atropine, 0.04 mg/kg, intramuscular), anesthesia was induced with 50%:50% N2O:O2 and 2% to 5% sevoflurane via a mask. After tracheal intubation, pigs were mechanically ventilated at a tidal volume of 15 mL/kg. Anesthesia was continued with 70%:30% N2O:O2 and 0.5% to 2% sevoflurane titrated to prevent signs of pain. Ventilatory rates were adjusted to achieve normocapnia. A catheter was inserted into an ear vein and normal saline was administered to maintain a right atrial (RA) pressure of 8 to 10 mm Hg. A double-lumen catheter was advanced from the right femoral artery to the thoracic aorta to monitor aortic pressure and for blood sampling. The right external jugular vein was cannulated with an 8-French introducer sheath to monitor RA pressure and to insert a right ventricle (RV) pacing catheter. Electrocardiogram (ECG) leads were placed on limbs to monitor heart rhythm. Rectal temperature was monitored and maintained between 37.5 and 38.5°C. The experimental timeline is shown in Figure 1. After baseline measurements, VF was induced by passing 60 Hz of A/C current at 30 mA through the RV pacing catheter for 4 seconds, and the animals were disconnected from ventilatory support. Immediately after inducing VF, an investigator, otherwise uninvolved with this study, opened a sealed envelope that assigned animals to either the control group or the potassium/lidocaine (K-lido) group and prepared either a saline placebo or potassium/lidocaine solution in identical volume (20 mL). All other investigators involved in this study remained blinded to treatment allocation until analysis. After 14 minutes of untreated VF, closed-chest compressions were administered by two investigators (BKL and HYL) blinded to the randomization in all animals at a rate of 100 beats/min and a compression depth of 40 mm. Asynchronous positive-pressure ventilations with high-flow O2 (10 L/min) were provided at a rate of 8/min using a manual resuscitator bag. The tidal volume was maintained at 15 mL/kg by using a volume-marked bag devised by Cho et al.17 Coinciding with the start of chest compressions, 20 mL of saline placebo (control group) or 0.9 mEq/kg potassium chloride and 1.2 mg/kg lidocaine diluted to 20 mL (K-lido group) was administered into the RA. After 2 minutes of CPR, defibrillation was attempted with a single biphasic 150-J electric shock if indicated. If an organized cardiac rhythm with a mean aortic pressure of >60 mm Hg persisted for an interval of at least 1 minute, the animals were regarded as successfully resuscitated. If return of spontaneous circulation (ROSC) was not achieved, an additional 2 minutes of CPR was given before the next 10-second hands-off pause for rhythm analysis. If the cardiac rhythm was shockable, defibrillation was reattempted. At the start of CPR, all animals received 0.6 U/kg vasopressin intravenously as an initial vasopressor. After 5 minutes of CPR, 0.02 mg/kg epinephrine was administered every 3 minutes if required. This procedure was continued until ROSC was attained, or until 12 minutes had elapsed since the start of CPR, when resuscitation efforts were discontinued. Animals that achieved ROSC received mechanical ventilation with 100% O2 at prearrest settings and then underwent a 4-hour period of intensive care. Five minutes after achieving ROSC, the oxygen concentration was reduced to 40% and the ventilatory rate and/or tidal volumes were adjusted to achieve normocapnia. Mean arterial pressure was maintained at >65 mm Hg with norepinephrine infusion. Antihyperkalemic treatments including calcium, insulin and glucose, albuterol, and furosemide were not given during the intensive care period. Throughout the intensive care period, titrated doses of sevoflurane were administered to maintain adequate anesthesia. At the end of the 4-hour period, animals were euthanized by infusing potassium chloride. At the completion of each experiment, thoracic and abdominal cavities were opened and visceral organs were visually inspected for evidence of trauma. Aortic pressure, RA pressure, and standard lead II ECG were continuously monitored (CS/3 CCM, Datex-Ohmeda, Helsinki, Finland) and transferred to a personal computer by S/5 Collect software (Datex-Ohmeda). Coronary perfusion pressure (CPP) was calculated by subtracting RA end-diastolic pressure from simultaneous aortic end-diastolic pressure. Arterial blood gases (RapidLab865, Bayer Health Care, Fernwald, Germany) and lactate (Unicel DXC 800, Beckman Coulter, Brea, CA) were measured at prearrest baseline, at 5 minutes, and at 4 hours after ROSC. Troponin-I (Dimension RXL Max, Siemens Healthcare Diagnostics, Deerfield, IL) was measured at prearrest baseline and at 4 hours after ROSC. Serum potassium (Unicel DXC 800, Beckman Coulter) was measured from blood obtained from the aortic catheter at prearrest baseline, at 3 minutes after the start of CPR, and at 4 hours after ROSC. Transthoracic echocardiogram (Vivid S5, GE Healthcare, Buckinghamshire, UK) was obtained by a researcher blinded for the treatment allocation at prearrest baseline, and at 1 and 4 hours after ROSC. Left ventricular ejection fraction (LVEF) was calculated with the Teicholz method from a right parasternal approach with standard M-mode measurements obtained from a midventricular short-axis view. The primary outcomes were postresuscitation myocardial damage as assessed by troponin-I, and postresuscitation left ventricular function as assessed by LVEF. Secondary outcomes included hemodynamic variables during CPR, the ROSC rate, and the ease of resuscitation. Sample size was calculated based on the data from our previous study,10 where the difference in troponin-I between the control group and the potassium-induced cardiac standstill group was 19.81 ng/mL, and the pooled SD was ±12.37 ng/mL. We calculated that seven animals would be required per group, with an effect size 19.81, an alpha level of 0.05, and a power of 0.80. To minimize any effect of data loss, eight animals per group were needed. Categorical variables were shown as numbers of cases with percentages. Comparisons of categorical variables were performed using Fisher's exact test. Continuous variables were investigated for normality using the Shapiro-Wilk test. Normally distributed variables were summarized as mean (±SD) and independent t-test was performed, whereas nonnormally distributed variables were summarized as medians with interquartile ranges (IQR) and Mann-Whitney U-test was conducted. Bonferroni corrections were used to correct for multiple comparisons. Cohen's d (95% confidence interval [CI]) was calculated to investigate the effect size. Mixed randomized repeated-measures analysis of variance (ANOVA) with Bonferroni post hoc test was used for comparison of time-based measurements, including aortic pressure, RA pressure, CPP, and LVEF. The sphericity assumption was assessed with Mauchly's test. Greenhouse-Geisser epsilon adjustments for nonsphericity were applied where appropriate. Data were analyzed by using PASW/SPSS software, version 18 (IBM Inc., Armonk, NY). A p-value of <0.05 was considered significant. There were no significant differences between groups in baseline measurements (Table 1). In the K-lido group, transient asystole was achieved in all animals at 30 ± after potassium/lidocaine was maintained for 1.2 minutes ± In animals the potassium/lidocaine-induced and ROSC was without at 2 minutes after the start of CPR, for one that not be resuscitated. animals in the K-lido group VF and were successfully resuscitated with CPR and at 4 minutes after the start of CPR. Serum potassium concentration at 3 minutes after the start of CPR was significantly in the K-lido group = to compared with the control group = to d = 95% CI = to p = Potassium after ROSC in and the potassium concentration at 4 hours after ROSC was between the control group ± and the K-lido group ± p = All resuscitated animals in groups were 1 and all the 4-hour intensive care period. variables and blood gases during the intensive care period shown in of primary and outcomes in this study is shown in The uncorrected troponin-I at 4 hours after ROSC was lower in the K-lido group (2.82 ng/mL, = 1.07 to compared with the control group ng/mL, to d = 95% CI = to p = 0.025), although the difference was not significant after Bonferroni correction. The of given in Figure The in the control group decreased in the hour after ROSC compared to the K-lido group and then at a rate to that in the K-lido group. The randomized repeated-measures on a significant between group and effect p = The of at 1 and 4 hours between the two groups showed no significant The difference of between prearrest baseline and 1 hour after ROSC was significantly in the control group SD ± compared to the K-lido group (26.5%, SD ± d = 95% CI = to p = 0.004). Figure 3 the of aortic pressure, RA pressure, and the 2 minutes of CPR. The randomized repeated-measures that aortic pressure, RA pressure, and in groups without a significant effect between group and effect p = p = and p = Seven animals in each group achieved ROSC (p = 1.000). Resuscitated animals in the K-lido group required fewer countershocks (p = 0.004), smaller doses of epinephrine (p = 0.009), and shorter durations of CPR (p = 0.004) than did the control group (Table In this study that evaluated the effects of potassium/lidocaine-induced cardiac standstill on myocardial injury and left ventricular dysfunction after resuscitation from prolonged VF cardiac the animals treated with potassium/lidocaine-induced cardiac standstill tended to lower troponin-I at 4 hours after ROSC and showed a significantly lower reduction in between the prearrest baseline and 1 hour after ROSC. a and of myocardial has been shown to myocardial Several studies indicate that the severity of myocardial injury cardiac arrest be by measurements of cardiac The lower uncorrected of troponin-I in the K-lido group after Bonferroni may indicate that animals damage and thus that potassium/lidocaine-induced cardiac standstill in our study myocardial injury cardiac The by potassium/lidocaine-induced cardiac standstill during CPR myocardial protection not and further study. minimizing energy consumption of the fibrillating heart through inducing cardiac studies that arrest during open cardiac surgery myocardial function after the ischemic period by inducing arrest and energy substrate Several studies the effects of during CPR that reduction of the oxygen requirements of the fibrillating heart myocardial injury during cardiac In this study, of CPR was significantly shorter in the K-lido group although CPP, a for myocardial perfusion during CPR, was between the two This may indicate that potassium/lidocaine-induced cardiac standstill ROSC by minimizing energy consumption of the fibrillating In addition to the minimizing energy consumption through inducing cardiac standstill, lidocaine protective effects on ischemic in addition to its antiarrhythmic effect, myocardial ischemic injury through its multiple effects on including In a study by et lidocaine reduced of a and myocardial size in a model of and Several studies indicate that lidocaine to a cardioplegic solution the protective effects of potassium-based In a study by et of lidocaine in potassium cardioplegic solution reduced troponin-I and improved in that underwent cardiopulmonary bypass, 2 hours of myocardial and 3 hours of et showed that lidocaine combined with potassium cardioplegia was with a reduction in ischemic damage and ventricular compared to potassium cardioplegia alone in a study of patients who underwent surgery. myocardial dysfunction has been in several experimental and and has been regarded as a contributing to and after successful In this study, the animals treated with potassium/lidocaine-induced cardiac standstill showed myocardial This to be to the of myocardial injury cardiac arrest by potassium/lidocaine-induced cardiac Several studies indicate that cardiac the severity of postresuscitation myocardial dysfunction and that minimizing myocardial ischemic injury postresuscitation myocardial 20 et reported a significant between troponin-I and of postresuscitation ventricular dysfunction in a without artery In this study, resuscitation was significantly in the K-lido group in of the of the of and the of CPR. with countershocks has been shown to myocardial Several studies that the severity of electrical myocardial injury is at least in to the of although perfusion during CPR, is to ischemic injury after resuscitation to its Several studies indicate that myocardial damage after resuscitation from cardiac arrest is to the of In a study of cardiac arrest patients who underwent CPR, et reported that the CPR was with cardiac Thus, the lower level of troponin-I in the K-lido group animals have from fewer the smaller of and the shorter of CPR. is to to myocardial injury is that in the of the of and the of CPR several studies have successful of VF during cardiopulmonary using successful of VF during conventional CPR has been of the K-lido group animals achieved ROSC without electrical in this study. In our previous study,10 VF potassium-induced asystole in of animals that received a potassium and one achieved ROSC without countershock. We that the addition of lidocaine to the potassium the of VF potassium-induced as as the of countershocks required to the Several studies in patients undergoing open heart surgery indicate that addition of lidocaine to the cardioplegic solution in a significant reduction in the of VF after and in the of 40 may to a of potassium in the that hyperkalemia may ROSC. However, in this study, the potassium/lidocaine-induced cardiac standstill did not the rate of ROSC, and did not significant after ROSC. In this study, although no treatment was potassium in the K-lido group animals after ROSC. This that potassium administered during CPR circulation is be before potassium/lidocaine-induced cardiac standstill be applied in to this study in the animals had normal potassium at the prearrest baseline, the of a of potassium in patients may successful resuscitation. studies animals with hyperkalemia at the prearrest baseline to this potassium/lidocaine-induced cardiac standstill be in a cardiac arrest model with a shorter Several studies indicate that the severity of postresuscitation myocardial dysfunction is to the of untreated cardiac Thus, effects of potassium/lidocaine-induced cardiac standstill on postresuscitation myocardial dysfunction may as the of untreated cardiac arrest In an to reduce the of animals used in this study did not the of potassium lidocaine to potassium alone. the of our previous study that potassium be that the addition of lidocaine to the potassium in this study the of VF potassium-induced However, is the addition of lidocaine to potassium to myocardial protection compared to the potassium alone. this study was conducted in pigs that were from any and its to of VF arrest to be VF was induced and was not by an ischemic This method of inducing VF may have from the experimental animals were and the effects of the were not the doses of potassium and lidocaine were study is required to the optimal doses of potassium and In a pig model of untreated ventricular fibrillation cardiac arrest for 14 minutes, resuscitation with potassium/lidocaine-induced cardiac standstill during conventional CPR tended to reduce myocardial and significantly decreased the severity of postresuscitation myocardial The potassium/lidocaine-induced cardiac standstill return of spontaneous circulation perfusion pressure between the two of the animals that received potassium/lidocaine-induced cardiac standstill spontaneous circulation without electrical countershock. In the of we that inducing cardiac standstill during CPR further The authors Cho for in the of this

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