We designed this study to observe the insulin effect on the recovery of cardiac hemodynamics and conduction during resuscitation after a bolus injection of bupivacaine in rabbits. The results showed that the recovery of ventricular contraction and conduction was enhanced after the insulin administration as compared with the control group during cardiac compression.
Bupivacaine blocks Na+
channel and thereby inhibits cardiac conductance by binding preferentially to the inactivated state of the sodium channel in ventricular muscle [3
]. Bupivacaine also inhibits transient outward potassium current (Ito
) which is associated with myocardial repolarization [4
] and depresses cardiac contractility by altering Ca++
release and Ca++
sequestration of the sarcoplasmic reticulum and decreases myofibrillar activation [13
]. In contrast, insulin increases Ca++
transport activity of sarcoplasmic reticulum [14
]. Transient outward K+
current is enhanced by insulin [15
]. Since cardiac depressant effects of bupivacaine can be attenuated by shortening the action potential duration [3
facilitated by insulin may promote depolarization, thus beneficial in reducing bupivacaine cardiotoxicity [4
Bupivacaine was continuously infused in the previous studies using a dog model; thus cardiac depression was gradually induced [5
]. In this study, the effect of insulin was compared after bupivacaine was injected as a bolus dose and CVC was induced suddenly. About 15 seconds were taken to reach MAP below 20
mmHg and HR lower than 65/min after the bolus injection. In clinical situation, accidental administration of bupivacaine into systemic circulation may occur in a drastic manner, therefore, resulting in a severe cardiotoxicity which needs prompt resuscitation including cardiac massage.
Bupivacaine increases the QRS duration in a dose-dependent manner, while this impairment in ventricular conduction by bupivacaine is rate dependent [12
]. Therefore, we tried to prove the insulin effect on the recovery of cardiac conduction in rabbits with higher baseline HR. In a pilot study, rabbits failed to recover spontaneously in the criteria of CVC (HR < 65/min and MBP below 20
mmHg) induced by a bolus injection of bupivacaine. In our experimental protocol, internal cardiac massage was continued till the time of ROSC and terminated thereafter. Myocardial blood flow is dependent on the aortic-to-right atrial pressure gradient during the relaxation phase of cardiac compression. CPP has been recommended more than 15 to 20
mmHg in cardiopulmonary resuscitation [16
]. By the similar changes of MAP and CPP between two groups, we believe that internal cardiac massage till ROSC was effective in producing cardiac output for all animals.
The decrease in contractility measured by the dP/dt max
is linearly correlated with the bupivacaine concentration [12
]. In this study, ROSC was reached faster with higher bupivacaine concentration in insulin-treated animals. The earlier recovery of arterial blood pressure at higher plasma bupivacaine level might be due to the positive inotropic effect of insulin [11
]. As expected, ROSR was slower than ROSC because bupivacaine impairs ventricular conduction more than contractility [12
ROSR appeared earlier in the insulin-treated group, but the bupivacaine concentrations on ROSR in both groups were not different significantly. This finding probably implies that insulin effect on cardiac conduction is mainly dependent on the change of plasma bupivacaine concentrations. Bupivacaine did not change cardiac automaticity but had a depressant effect on conduction at atrial, ventricular, and atrioventricular levels [17
]. Thus, the sinus rhythm can be generated at a lower bupivacaine concentration where atrial electrical impulse can reach ventricular purkinje fibers via the atrioventricular node, resulting in the synchronous contraction of ventricular myocardium. However, faster recovery of QRS complex duration in the insulin-treated group reveals that ventricular conduction was enhanced by the insulin, resulting in the reduction of action potential duration [15
Acidosis and hypoxia markedly potentiate cardiac toxicity [18
]. Hence, FI
was changed from initial 0.3 to 1.0 at the onset of CVC, and sodium bicarbonate was infused to maintain arterial pH. The values of pH were maintained equally normal in both groups. Despite the effect of insulin on lowering plasma potassium levels, potassium was not added to the insulin-treated group. Hypokalemia can increase resting membrane potential and action potential height [19
]. Thus, there might be a possibility that insulin-induced hypokalemia may enhance sodium inward current. However, hypokalemia may worsen toxicity by lengthening action potential duration [3
], which was not believed to play a major role in reversing bupivacaine-induced cardiotoxicity [5
]. Glucose was maintained above normal in both groups. The positive inotropic effects of insulin have been shown to be independent of the presence of glucose [11
]. Despite of significant decrease in calcium level in both groups, serum calcium was maintained within the normal range throughout the experiment.
The limitation of this study is that experimental animals were mechanically ventilated to keep normocapnia with 100% oxygen and pH was controlled with sodium bicarbonate from the beginning of CVC. Hypoxia and hyperkalemia, known to increase bupivacaine's depressive effects [3
], were prevented. These might reduce the occurrence of severe arrhythmia such as ventricular tachycardia. Though this study was not blindly performed, internal cardiac massage was so effective that all animals survived. Because hemodynamics and bupivacaine concentration changes were similar between both groups, insulin effect on the recovery of cardiac contractility and conduction could be compared while minimizing the investigator bias. In spite of the fact that bupivacaine seems to render myocardium refractory to defibrillation [21
], interaction or comparison of other treatment modalities with insulin therapy needs further investigations.
In conclusion, a single injection of insulin combined with open cardiac compression was helpful to restore spontaneous circulation and sinus rhythm after abrupt induction of CVC caused by a bolus injection of bupivacaine in rabbits. The result suggests that insulin therapy might be considered as a supplement to enhance cardiac contractility as well as to facilitate myocardial conduction for bupivacaine-induced cardiac toxicity.