Experimental Study On Cardiac Arrest Induced By Adenosine Triphosphate And Interventional Effect Of Medication Thereof

Background and objectives:Cardiac arrest (CA) is an emergent incident and needs to be treated with cardiopulmonary resuscitation (CPR) immediately. Although CPR has been performed for many years, the rate of successful resuscitation is low, and searching for a better resuscitated technique and medication remains a challenge. A lot of similarities can be found between small animals, such as rabbit, rat, mouse and so on, and large animals even human being. Therefore, an increasing number of small animals have been used in CPR experimental study.To establish an animal model of CA is the key to conduct a CPR experimental study, and nowadays several resuscitation models have been made, such as ventricular fibrillation induced by alternating current delivered to right ventricular, asphyxy, intravenous injection of KC1, cross-clamping the ascending aorta, or transoesophageal cardiac pacing, and so on. Of the total, inducing CA with KC1 injection is a relatively simple and effective model, while its disadvantage is relatively difficult to control the dose and the accumulation in vivo. As the latter may result in electrolyte disturbance or arhythmia, and may interfere with the therapeutic efficacy of medication. Therefore, it is necessary to look for other kinds of drugs which may have relatively less side effect on electrolyte concentration in vivo to establish a more effective and convenient animal model of CA.Adenosine triphosphate (ATP), an adenine nucleotide with a very short half-life and its effects depending mainly on its conversion to adenosine, is generally uesed to terminate paroxysmal supraventricular tachycardia in clinical practice. However, ATP were administered with an excessive dose or injected too fast may easily result in serious cardiac arrhythmias, such as sinus arrest, atrioventricular block, and so on. And studies have indicated currently that, adenosine play many important protective roles in pretreament and myocardial ischemia/reperfusion injury, mainly ascribed to its specific action in adenosine A₁, A_2a, and A_2b and A₃ receptors, which evokes the patency of potassium channels and the inhibition of calcium overload. In addition, as one kind of energy composition, ATP could release energy for cytolergy accompanying with its degradation process, which may provide more profits during CPR.Due to the rapid efficacy, short half-life and side effect of inducing CA, one of the purposes of the study, therefore, is to establish a simpler and more convenient CA models in rats and rabbits with ATP. Furthermore, we attempt to identify whether atropine and dopamine used after restoration of spontaneous circulation(ROSC) could improve the rate of appearance of spontaneous breathing (AOSB) and prolong survival time in rats CA model.Methods:1. Establishing CA model in rats: fourty SD rats of male weighing 200～300g were randomized into two groups: ATP group(n=16) and KCl group(n=24), and the latter were further randomly allocated to two groups (n=12 each group) according to non-intervention interval which were 5 and 10 min: KCl-5min group and KCl-10min group. ATP group recevied 5% ATP solution 1ml intravenously and KCl group recevied 1% KCl solution 1ml intravenously. CA was confirmed by disappearance of the arteriopalmus as well MAP<10mmHg in monitoring of blood pressure, indication of asystole, ventricular fibrillation or electrical mechanical dissociation in electrocardiogram. After 4 minutes of CA in ATP group, CPR was begun and followed by epinephrin (0.04 mg/kg) injection. While in KCl-5min group and KCl-10min group, CPR was initiated 5min or 10min later respectively. The time from the initiation of ATP or KCl injection to CA, rate of ROSC, rate of AOSB, and 30 min of survival rate were compared among the 3 groups.2. Establishing CA model in rabbits: sixteen rabbits of male weighing 2.5～3.0kg were randomized into two groups (n=8 each): ATP group recevied 1% ATP parenteral solution 6ml intravenously and ATP+MgSO₄ group recevied 9% mixed liquor (ATP:MgSO₄=2:1) 6ml intravenously. CA was confirmed by disappearance of the arteriopalmus as well MAP<10mmHg in monitoring of blood pressure and indication of asystole, ventricular fibrillation or electrical mechanical dissociation in electrocardiogram. After 4 min of untreated CA, CPR was initiated following by injection of epinephrin (0.04 mg/kg) in both ATP group and ATP+MgSO₄ group. The time from the initiation of ATP or ATP+MgSO₄ injection to CA, rate of ROSC , rate of AOSB, and 30min of survival rate were compared between groups.3. Therapeutic efficacy of medication in rats CA model: thirty-six male SD rats weighing 200～300g were induced with ATP given in an intravenoue bolus, and animal model of CA was set up. Rats failed to be resuscitated were disengaging from the experiment, while those resuscitated rats were randomized into two groups: intervention group, which was administered with atropine (2.5～5mg/kg) and dopamine (10～20μg/kg.min) , and control group, which received aequale sodium chloride intravenously. The rate of AOSB and 30min of survival rate were compared between the two groups. Results:1. Results of induction of CA: immediately after ATP or KCl injection, spontaneous breathing arrest promptly in each group. The times from the initiation of ATP or KCl injection to CA were 210±55s (in ATP group), 47±11s (in KCl-5min group) and 51±12s (in KCl-10min group) respectively, and was significantly longer in ATP group than in KCl-5min group and KCl-10min group (P<0.005). Results of resuscitation: with regard to the rate of ROSC, no differences were observed among the 3 groups: ATP group(74.5%), KCl-5min group(100%) and KCl-10min group(100%). 30min of survival rate in ATP group (7.1%) were significantly lower than those in KCl-5min group (90%) and KCl-10min group (54.5%) respectively (P<0.0005 or <0.05), but no differences were noted between KCl-5min group and KCl-10min group. The rates of AOSB were 7.1%, 90% and 54.5% in ATP group, KCl-5min group and KCl-10min group respectively, and were significantly higher in KCl-5min group and KCl-10min group than in ATP group (P<0.0005 or <0.05). However, no statistically significant difference was observed between KCl-5min group and KCl-10min group.2. The times of spontaneous breathing termination and CA in ATP+MgSO₄ group (14±3s and 28±4s) were much shorter than those in ATP group (43±5s and 155±64s, P<0.005). The rate of ROSC in ATP+MgSO₄ group was significantly higher than that in ATP group (7/8 vs 2/8, P<0.05). There was an increasing tendency in ATP+MgSO₄ group compared with ATP group with regard to the rate of AOSB and 30min of survival rate (5/8 vs 2/8), even though the difference did not reach a statistical significance.3. The rate of ROSC was 26 of 36 (72.22%), and the time of ROSC was 160 (120,259)s. The times of AOSB were 16 (10.67,20) min, 18.6 (16,23) min in control group and intervention group respectively, and no differences were noted between this two groups. With regard to the rate of AOSB and 30min of survival rate, intervention group was significantly higher than that in control group (11/13 and 10/13 vs 3/13 and 3/13, P<0.01 or P<0.05 respectively).Conclusion:1. A significant inhibition of the respiration and circulation could be induced by ATP, which could resulte finally in the CA in rats. However, the time of induction of CA was relatively longer in this way compared with that induced by KC1. Furthermore, the blood pressure and heart rate were unstable after ROSC in the CA model induced by ATP, which eventually reduced the survival time substantially. Due to these disadvantage of the CA model, a great deal need to be improved and consummated.2. CA could be induced both by ATP alone and ATP plus magnesium sulfate in rabbits. However, administration of ATP plus magnesium sulfate could shorten the time of induction of CA and increase the rate of ROSC compared with ATP alone. Therefore, induction of CA with ATP plus magnesium sulfate could be more rapid, stable and yielded better outcomes of CPR than did ATP, which may become a new and reliable CA model in rabbits.3. In a rat CA model induced by ATP, administration of atropine and dopamine after ROSC may antagonize againist the side effect of ATP, keep the stableness of blood pressure and cardiac electricity, and consequently improve the rate of restoration of spontaneous breathing and prolong survival time as well.