CORRESPONDENCE: RESEARCH CORRESPONDENCE
Levosimendan Improves Cardiopulmonary Resuscitation and Survival by KATP Channel Activation
Gianluca A.A.M. Cammarata, MD,
Max Harry Weil, MD, PhD, FACC*,
Shijie Sun, MD,
Lei Huang, MD,
Xiangshao Fang, MD and
Wanchun Tang, MD
* 35100 Bob Hope Drive, Rancho Mirage, California 92270 (Email: Weilm{at}911research.org).
To the Editor: Global myocardial ischemia during cardiac arrest accounts for post-resuscitation myocardial dysfunction (1). The new myofilament Ca++ sensitizer, levosimendan, is of potential benefit in this setting, for it improves myocardial contractility without increasing myocardial oxygen consumption (2). Experimentally, levosimendan produces dose-dependent increases in contractility without adverse effects on diastolic function (3,4).
Levosimendan is a KATP channel opener of both plasma membranes and mitochondria (2,5). Opening of adenosine triphosphate (ATP)-sensitive potassium channels in ventricular myocites contributes to the inotropic action of levosimendan (2). Activation of the K+ATP channels also mitigates myocardial ischemic injury, reminiscent of "ischemic preconditioning" during cardiopulmonary resuscitation (6), with improved survival. We therefore hypothesized that levosimendan would improve initial cardiac resuscitation, post-resuscitation myocardial function, and post-resuscitation survival resulting from KATP channel activation.
The study was approved by the Institutional Animal Care and Use Committee of the Weil Institute. Fifteen male Sprague-Dawley rats weighing between 450 and 550 g were fasted overnight. Anesthesia followed intraperitoneal injection of pentobarbital in an amount of 45 mg kg–1. The trachea was orally intubated. Left ventricular pressure, including both dP/dt40 and negative dP/dt, right atrial pressure, and aortic pressure were measured with polyethylene catheters (PE 50, Becton-Dickinson, Sparks, Maryland) and with a high-sensitivity pressure transducer (model 42584-01, Abbott Critical Care System, North Chicago, Illinois). A thermocouple microprobe (9030-12-D-34, Columbus Instrument, Columbus, Ohio) was advanced into the descending thoracic aorta for blood temperature measurements. For cardiac output measurements, 0.2 ml of isotonic saline, maintained at 10°C, was injected into the right atrium. Thermodilution curves were computed (CO-100, Weil Institute of Critical Care Medicine, Rancho Mirage, California). A pre-curved guide wire was advanced through a 4-F catheter into the right ventricle until an endocardial electrogram was observed. Forty-five minutes before the induction of cardiac arrest, five animals were randomized to pre-treatment with a bolus injection of glibenclamide into the right atrium (6). A 60-Hz direct current, to a maximum of 3.5 mA, was delivered to the right ventricular endocardium until ventricular fibrillation (VF) was induced. Current flow was then continued for 3 min such as to prevent spontaneous defibrillation. Ventricular fibrillation was untreated for 6 min. Pre-cordial compressions at a rate of 200/min were started after 6 min, with a pneumatically driven mechanical chest compressor, and animals were mechanically ventilated with a tidal volume of 0.65 ml/100 g animal body weight, a frequency of 100/min, and FiO2 of 1.0. Depth of compressions was adjusted to secure coronary perfusion pressure (CPP) of 23 ± 1 mm Hg. Levosimendan (Orion Corp., Espoo, Finland, for Abbott Laboratories, 2.5 mg/ml) or saline placebo was injected into the right atrium after 2 min of untreated VF. Resuscitation was attempted with up to two 2-joule biphasic shocks. Restoration of spontaneous circulation (ROSC) was defined as the return of supraventricular rhythm with a mean aortic pressure of 60 mm Hg. Electrocardiographic lead II was continuously recorded. ST-segment elevation was digitally measured at baseline and at 3 min after ROSC, utilizing WINDAQ software (DATAQ Instruments, Inc., Akron, Ohio) (1,7). Mechanical ventilation with oxygen was continued for 4 h after resuscitation. Animals were then allowed to recover and all catheters were removed. Post-resuscitation survival was observed for a total of 48 h.
For measurements between groups, analysis of variance (ANOVA) and Scheffe’s multicomparision techniques were employed. Comparisons between time-based measurements within each group were performed with ANOVA repeated measurement. Categorical variables were analyzed with the Fisher exact test. Measurements are reported as mean ± SD. Values of p < 0.05 were considered significant.
Baseline hemodynamic and blood analysis did not differ significantly among the groups. Pre-cordial compression increased CPP to an average of 23 ± 1 mm Hg. Each animal, excepting only one pre-treated with glibenclamide, was resuscitated. A significantly lesser number of electrical shocks were required before resuscitation in levosimendan-treated animals (Table 1). Three minutes after ROSC, lesser ST-segment elevations were observed in the levosimendan group (Table 1). Significantly greater cardiac index and dP/dt40 were observed in comparison with glibenclamide-pre-treated and placebo control animals (Fig. 1). After levosimendan, each animal survived for more than 48 h. This contrasted with animals pre-treated with glibenclamide, a KATP-channel-blocking agent, in which duration of survival approximated placebo controls (27 ± 7 h and 28 ± 8 h, respectively).
Moderation of ischemic injury by K+-channel opening after levosimendan resulted in lesser myocardial dysfunction and prolonged the duration of survival. Pre-treatment with a non-selective K+-channel blocker abolished these benefits.
The capability of minimizing myocardial ischemic injury during cardiac arrest, like pre-conditioning, is possibly explained by its KATP-channel agonist effects. Lesser post-resuscitation ST-segment elevations provide additional evidence of levosimendan’s capability to minimize ischemic injury and thereby improve post-resuscitation myocardial function. Each of these effects would explain, at least in part, improvement in post-resuscitation myocardial function and outcomes.
We recognize limitations in the interpretation of our findings. The studies were performed on animals without cardiovascular disease. Accordingly, direct applicability to human patients remains to be proven. We conclude that the administration of levosimendan in experimental settings of VF facilitates resuscitation, significantly lessens post-resuscitation myocardial dysfunction, and improves post-resuscitation survival.
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1. Tang W, Weil MH, Sun S, Noc M, Yang L, Gazmuri R. Epinephrine increases the severity of postresuscitation myocardial dysfunction Circulation 1995;92:3089-3093.[Abstract/Free Full Text]2. Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. The novel calcium sensitizer levosimendan activates the ATP-sensitive K+ channel in rat ventricular cells J Pharmacol Exp Ther 1997;283:375-383.[Abstract/Free Full Text] 3. Haikala H, Nissinen E, Etemadzadeh E, Levijoki J, Linden IB. Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation J Cardiovasc Pharmacol 1995;25:794-801.[Web of Science][Medline] 4. Huang L, Weil MH, Sun S, Cammarata G, Cao L, Tang W. Levosimendan improves postresuscitation outcomes in a rat model of CPR J Lab Clin Med 2005;146:256-261.[CrossRef][Web of Science][Medline] 5. Kopustinskiene DM, Pollesello P, Saris NE. Levosimendan is a mitochondrial K(ATP) channel opener Eur J Pharmacol 2001;428:311-314.[CrossRef][Web of Science][Medline] 6. Tang W, Weil MH, Sun S, Pernat A, Mason E. KATP channel activation reduces the severity of postresuscitation myocardial dysfunction Am J Physiol Heart Circ Physiol 2000;279:H1609-H1615.[Abstract/Free Full Text] 7. Sun S, Weil MH, Tang W, Povoas H, Mason E. Combined effect of buffer and adrenergic agent on postresuscitation myocardial function Pharmacology 1999;291:773-777.
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