Hypertonic Saline Does Not Reverse the Sodium Channel Blocking Actions of Lidocaine: Evidence from Electrophysiologic and Defibrillation Studies

Summary: Studies have shown that increasing extracellular sodium concentration can partially reverse sodium channel blockade. However, there is conflicting in vitro evidence in this regard for lidocaine. The effects of lidocaine on cardiac electrophysiology and defibrillation were studied in a basal and hypernatremic state to determine reversibility of sodium channel blockade. Electrophysiologic studies measured right ventricular effective refractory period at 350 ms pacing cycle length and QRS interval, JT interval, and monophasic action potential duration during sinus rhythm and right ventricular pacing (350 ms cycle length) in 14 pentobarbital-anesthetized swine (25-30 kg). Defibrillation threshold (DFT) was measured by quantitating successful conversion of sustained ventricular fibrillation to normal sinus rhythm. Each pig was randomly assigned to a treatment group with three study phases; group 1 = baseline, lidocaine (20 mg/kg/h), and lidocaine plus placebo (D5W; n = 7); and group 2 = baseline, lidocaine, and lidocaine plus hypertonic saline (2-3 mM/kg/h; n = 7). In groups 1 and 2, lidocaine infused alone significantly (p < 0.01) increased DFT values from baseline (9.8 ± 3.9 to 15.7 ± 5.8 J and 8.9 ± 2.9 to 14.7 ± 5.4 J, respectively) and increased QRS duration from baseline during right ventricular pacing (89 ± 6 to 109 ± 10 ms; p < 0.01; and 87 ± 6 to 103 ± 12 ms; p < 0.01). Lidocaine alone reduced right ventricular action potential duration (APD) in groups 1 and 2 (214 ± 18 to 206 ± 20 ms; p < 0.10; and 228 ± 8 to 212 ± 8 ms; p < 0.05), respectively, and it reduced paced JT interval in both groups (194 ± 20 to 184 ± 18 ms; p < 0.10; and 200 ± 12 to 183 ± 16 ms; p < 0.05), respectively. When hypertonic saline was added to lidocaine, DFT and QRS duration values were unaffected (14.7 ± 5.4 to 16.1 ± 3.7 J and 103 ± 12 to 100 ± 11 ms, respectively). However, APD and JT intervals returned to basal values when hypertonic saline was added to lidocaine (212 ± 8 to 225 ± 13; p < 0.05; and 183 ± 16 to 192 ± 18; p < 0.05, respectively). When D5W was added in the control group, no changes occurred in DFT or electrophysiologic values. Lidocaine slowed ventricular conduction velocity and reduced APD. The administration of hypertonic saline to increase extracellular sodium concentrations failed to reverse the effect of lidocaine on conduction-velocity slowing or elevated DFT values. Hypertonic saline did reverse the effects of lidocaine on repolarization parameters. These data suggest that shortening of repolarization is not a mechanism by which lidocaine makes it more difficult to defibrillate the heart.

In vivo and in vitro models have shown that sodium channel blocking actions of several class IA and IC antiarrhythmic agents, cocaine and amitriptyline, can be reversed by either sodium bicarbonate or hypertonic saline and thus may be an antidote in toxicity cases ^(1-8). The mechanism responsible for this interaction is likely the competition between the drug ligand and extracellular Na⁺ for the drug-binding site ^(9,10). In vitro models indicate that increases in extracellular Na⁺ can decrease the association rate constant of the drugs propafenone and disopyramide to the open sodium channel ^(11,12). These studies with lidocaine, however, have yielded conflicting results. By using voltage-clamped atrial cells, one investigation indicated that lidocaine did not compete with extracellular Na⁺ for the open sodium channel ⁽¹¹⁾. This led the authors to conclude that lidocaine does not block along the ion-conduction pathway, and thus increases in extracellular sodium do not reverse the actions of lidocaine. On the other hand, a microelectrode study did show that an increase in extracellular Na⁺ can limit the effect of lidocaine on action potential upstroke velocity ⁽¹²⁾.

It is important to know whether hypertonic saline can reverse the sodium channel blocking effects of lidocaine, because lidocaine toxicity can be life threatening. Lidocaine is known adversely to affect defibrillation efficacy ^(13-15). If the energy required for successful defibrillation is increased beyond the capacity of the defibrillator, patient resuscitation will fail. Studies have shown that lidocaine increases the energy required for successful defibrillation (defibrillation threshold; DFT) at concentrations >4 μg/ml in both humans and animals ^(16,17). Lidocaine concentrations >10 μg/ml have resulted in a 50-100% increase in the DFT ^(14,15). The mechanism by which lidocaine affects DFT values is thought to be related to its sodium channel blocking actions. Thus if hypertonic saline is able to reverse the sodium channel blocking actions of lidocaine, it may also have the potential to reverse elevated DFT values. The specific aims for our study were to determine whether hypertonic saline can reverse the effect of lidocaine on ventricular conduction velocity and on DFT.

METHODS

Animal preparation and surgical instrumentation

Domestic farm pigs weighing between 25 and 30 kg were used in this investigation. All procedures were approved by the University of Cincinnati Institution Animal Care and Use Committee before conducting this investigation. The animals were fasted overnight on the day before the procedure. On the morning of the investigation, the animals were premedicated with ketamine (15 mg/kg) administered intramuscularly. Subsequently, pentobarbital (25 mg/kg) was administered intravenously for initial anesthesia induction. After intubation with an endotracheal cuffed tube, the animals were mechanically ventilated by using a large-animal Harvard pump ventilator. A level plane of anesthesia was subsequently maintained throughout the study period by using pentobarbital (demonstrated not to affect the DFT) ⁽¹⁸⁾, 75-150 mg intravenously every 30-60 min as needed. The femoral vein, external jugular vein, and the femoral artery were cannulated for catheterization, drug infusion, and blood collection. A combination pacing and contact monophasic action potential catheter (EP Technologies, Mountain View, CA, U.S.A.) was placed via the external jugular vein into the right ventricular apex under fluoroscopic guidance, to record monophasic action potential duration (APD) and for right ventricular pacing. A 5F pigtail Millar pressure-sensing catheter was placed via the femoral artery for blood pressure monitoring. Surface electrocardio-graphic leads were placed on the four limbs for monitoring of leads II and avF. The chest was opened by using a mediastinotomy. One 14-cm² and one 28-cm² titanium mesh patch electrode (Models A and L 67, respectively; CPI-Guidant, St. Paul, MN, U.S.A.) were sutured onto the surface of the pericardium. The large electrode was placed over the anterior and lateral wall of the right ventricle, which was perpendicular to the small electrode placed over the lateral/posterior/apical wall of the left ventricle. The electrodes were interfaced with an external defibrillator where the right ventricular patch served as the anode. The defibrillator was capable of delivering a monophasic truncated waveform at a 65% fixed tilt with a pulse duration between 5 and 8 ms. The output of this device is determined by preset voltage adjustments (1 - V increments; Ventak ECD; Cardiac Pacemakers). The chest was closed after these procedures, and chest tubes were placed into the pleural space and drained by suction. Arterial blood gases were measured every 20-30 min to maintain an arterial pH between 7.37 and 7.45, Pao₂ between 80 and 120 mm Hg, and Paco₂ between 35 and 45 mm Hg. Sodium and potassium concentrations were measured every 30 min to maintain a serum sodium concentration between 135 and 144 mEq/L and a serum potassium concentration between 3.4 and 4.4 mEq/L (Nova 1; Baxter, Miami, FL, U.S.A.). Potassium concentrations remained >3.4 mEq/L after the initial instrumentation phase of the study. Body temperature was monitored via a rectal probe and maintained at 37-38°C by using a surgical thermal blanket. Adequate hydration was maintained by using lactated Ringer's solution, 2-5 ml/kg/h.

Study design

The experiment consisted of three phases in which DFT and electrophysiologic parameters were measured initially during a baseline phase and then during lidocaine, which was followed by either hypertonic saline or placebo (D5W). Each pig was randomly assigned to a group; group 1, baseline followed by lidocaine, followed by lidocaine plus placebo (D5W infusion; n = 7); and group 2, baseline followed by lidocaine, followed by lidocaine plus hypertonic saline infusion (n = 7). The baseline phase was started 30 min after completion of instrumentation. The lidocaine phase began immediately after the completion of the baseline phase. This phase was followed by the last phase, in which the treatment (D5W or hypertonic saline) was administered as a 10-min loading dose (6 mM/kg NaCl, given as 14.7% solution) followed by a continuous infusion (2-3 mEq/kg/h, given as a 3% solution) to maintain serum sodium concentrations 10-15 mEq/L above baseline values. D5W served as placebo and was given in volume equal to the hypertonic saline infusion. Blood samples were obtained every 10 min during hypertonic saline to determine whole blood sodium and potassium concentrations.

Defibrillation threshold determination

Ventricular fibrillation was induced by delivering, to the right ventricle, a stimulus drive train at a 100-ms cycle length for 2 s with a stimulus amplitude of 10 V (Model S8800; Grass Instruments). Defibrillation shocks were applied by using truncated exponential waveform of preset energy levels. The time between defibrillation trials was ≥4 min but not until arterial blood pressure returned to within 10% of the preshock value. To quantitate DFT, a step-down step-up method was used as previously described ⁽¹⁴⁾. Energy, impedance, pulse width, and peak current delivered to the myocardium were measured by the defibrillator and subsequently printed. These values are accurate to within 10% of oscilloscopic measurements. The DFT response for each test was modeled based on response at each energy level within a treatment phase by using an iterative computer program (MERFFIT; Cardiac Pacemaker) ⁽¹⁴⁾.

Electrophysiology parameters

A global assessment of ventricular conduction velocity was determined by QRS duration by surface ECG leads II and avF during right ventricular pacing at 350-ms cycle length. Myocardial repolarization was assessed locally by right ventricular monophasic APD at 90% repolarization and globally by JT interval by surface ECG leads during right ventricular pacing at a pacing cycle length of 350 ms. Ventricular pacing was continued for 15 s before measuring these parameters. It is known that APD and refractoriness take ≈2 min to completely stabilize after a change in ventricular rate. However, 95% of change in these parameters occurs within the first 15 beats. Our protocol measured these variables after 35-40 beats (15 s) and took the average of five consecutive beats, which tends to smooth out the oscillations present after the onset of ventricular pacing. Right ventricular effective refractory period was determined by pacing the right ventricle for eight beats by using a stimulus intensity twice the diastolic threshold at a cycle length of 350 ms followed by one premature extra stimulus. The drive train was repeated after a 2-s pause, and the extra stimulus coupling interval was decremented by 2 ms until ventricular capture failed on two consecutive attempts. All electrophysiologic measurements were obtained at the start of DFT protocol, 30 min after the start of DFT protocol and at the end of DFT protocol during baseline and both drug-treatment phases. These values were then averaged for each study phase. During drug testing, electrophysiologic measurements were performed 20 min after beginning of the drug infusion to allow for tissue distribution. Electrophysiologic measurements were made by a blinded investigator using a digitizing pad interfaced with a computer program (Sigma Scan, Jandel Scientific, Corte Madera, CA, U.S.A.).

Data analysis

A multivariate repeated measures analysis of variance with contrast was used to test differences between groups. Within-group comparisons (measurements using the animal as its own control) were determined by using a paired t test looking at the comparisons of means for group and treatment phase (time). Data are presented as mean ± SD, and the significance level was set at p < 0.05.

RESULTS

Defibrillation threshold

In groups 1 and 2, DFT values were similar at baseline (9.8 ± 3.9 and 8.9 ± 2.9 J). When lidocaine was administered, DFT values increased significantly from baseline values in group 1 (9.8 ± 3.9 to 15.7 ± 5.8 J; p < 0.01) and group 2 (8.9 ± 2.9 to 14.7 ± 5.4 J; p < 0.01; Fig. 1). When D5W was added to lidocaine in group 1, DFT values did not change (15.7 ± 5 to 15.6 ± 6.6 J). Similarly, when hypertonic saline was added to lidocaine in group 2, DFT values did not change (14.7 ± 5.4 to 16.1 ± 3.7 J; Fig. 1).

Fig. 1

Electrophysiologic parameters

The mean and SD of the electrophysiologic values are reported in Table 1 for both groups. Baseline values were similar between groups. Lidocaine increased QRS duration from baseline during right ventricular pacing in group 1 (89 ± 6 to 109 ± 10 ms; p < 0.01) and group 2 (87 ± 6 to 103 ± 12 ms; p < 0.01) by similar magnitudes, 18 and 22%, respectively. When D5W as added to lidocaine in group 1, QRS values did not change (109 ± 10 to 109 ± 14 ms). Similarly, when hypertonic saline was added to lidocaine in group 2, QRS values did not change (103 ± 12 to 100 ± 11 ms; Fig. 2). However, QRS duration did decrease from 113 to 92 ms in one subject when hypertonic saline was added to lidocaine (Figs. 2 and 3).

Table 1

Fig. 2

Fig. 3

Lidocaine reduced right ventricular APD during pacing in group 1 (214 ± 18 to 206 ± 20 ms; p < 0.10) and group 2 (228 ± 8 to 212 ± 8 ms; p < 0.05). Similar findings occurred with paced JT interval in group 1 (194 ± 20 to 184 ± 18 ms; p < 0.10) and group 2 (200 ± 12 to 183 ± 16 ms; p < 0.05), respectively. When D5W as added to lidocaine in group 1, APD and JT values did not change (206 ± 20 to 204 ± 20 ms; and 184 ± 18 to 179 ± 19 ms; p = NS), respectively. However, the addition of hypertonic saline to lidocaine in group 2 returned APD and JT values back to baseline values (212 ± 8 to 225 ± 13 ms; and 183 ± 16 to 192 ± 18 ms; p < 0.05, respectively; Fig. 4).

Fig. 4

Electrolyte and lidocaine concentrations

Mean whole blood sodium concentrations did not differ among groups during the baseline or lidocaine study phases (Fig. 5). Over time, however, sodium concentrations drifted downward. When D5W was added to lidocaine in group 1, sodium concentrations did not change. However, when hypertonic saline infusion was administered during lidocaine in group 2, serum sodium concentration increased significantly from baseline (137.8 ± 0.6 to 151.0 ± 2.2 mM, respectively; p < 0.0001). Potassium concentrations remained constant throughout each study phase, except in group 2 when there was a transient reduction in potassium concentrations related to the hypertonic saline bolus (Fig. 5).

Fig. 5

The dose of lidocaine achieved steady serum concentrations from the 20-min point onward, which was the time when the DFT study protocol started (Fig. 6). These concentrations ranged between 10 and 12 μg/ml in groups 1 and 2, which were not statistically different between groups when comparing area under the plasma concentration-time curve or differences between groups over time by using analysis of variance with repeated measures. Table 2

Table 2

Fig. 6

DISCUSSION

We showed that lidocaine increased QRS duration and DFT values by 18-22% and 60-65%, respectively. However, the administration of hypertonic saline did not reverse the effect of lidocaine on ventricular conduction velocity or DFT. Although we did not have a hypertonic saline control group, the lack of response to hypertonic saline in our study was similar to our previous data, which showed that hypertonic saline by itself does not affect ventricular conduction velocity, measures of ventricular repolarization, or DFT values ⁽¹⁹⁾. Our data help to clarify conflicting in vitro data between patch-clamp and microelectrode studies. The findings from this study support the conclusions from patch-clamp studies, which indicate that lidocaine does not compete with extracellular Na⁺ for the cardiac sodium channel ⁽¹¹⁾.

Our data differ from the findings of studies that used other sodium channel blockers such as quinidine, encainide, disopyramide, o-desmethyl encainide, and cocaine ^(1-8). These studies clearly showed that hypertonic sodium salts can reverse the measures of ventricular conduction-velocity slowing. The exact mechanism of how sodium can modulate the actions of some but not all sodium channel blockers is unknown. It is known that hypertonic saline by itself has no effect on global electrophysiology of canine and human myocardium ^(6,7,20). This is not surprising because a change in extracellular sodium concentration from 140 to 155 mM would increase the sodium potential slightly (60.3 to 62.9) based on the Nernst equation and assuming that intracellular sodium concentrations are kept constant by increased activity of the sodium-potassium ATPase pump and sodium-calcium exchanger ⁽⁶⁾. Thus hypertonic saline has little effect on sodium channel activity, but it appears to reverse the effects of some sodium channel blocking drugs. This suggest that increases in extracellular sodium must reverse sodium channel blockade by being able to modulate the binding of some drugs to the cardiac sodium channel ⁽⁸⁾. Lidocaine may have different binding properties on the cardiac sodium channel than other agents that are affected by hypertonic sodium. We know that lidocaine binds to the sodium channel principally during the inactivated state and not along the ion (sodium)-conduction pathway (open-channel state) ⁽²¹⁾. We speculate that this will prevent competition between extracellular sodium and lidocaine, because lidocaine binds to the sodium channel at a point in the action potential at which sodium ions are no longer conducting. Drugs such as quinidine and disopyramide are known to block sodium channels in the open state ^(11,22). Moreover, increases in extracellular sodium concentrations have been shown to reverse their sodium channel blocking effects ^(2,11). Thus the potential of increases in extracellular sodium to limit the effects of a sodium channel blocking drug appears to be dependent on the state in which the drug binds to the sodium channel.

It is possible also that the level of increase in extracellular sodium concentration was insufficient to compete with the high concentrations of lidocaine used in this study. However, others have shown that hypertonic sodium bolus can reverse high doses of o-desmethyl encainide, which is a more potent sodium channel blocker than lidocaine ⁽⁶⁾. Because we did not do concentration-effect studies with either lidocaine or extracellular sodium concentrations, we can not dismiss this possibility.

Decreasing cardiac ion conductance can affect defibrillation outcomes. This is evident from studies that have shown that decreased K⁺ conductance reduces DFT values (via D-sotalol), whereas decreases in Ca²⁺ (by verapamil) and Na⁺ conductance (by lidocaine) elevate DFT values ^(15,23-26). It is been proposed that lidocaine may increase DFT values either by slowing conduction velocity or by decreasing APD ⁽¹⁶⁾. Thus we proposed that reversing the sodium channel blocking actions of lidocaine could also reverse its effects on DFT values. We were unable to accomplish this by increasing extracellular sodium concentrations; thus DFT values were unaffected when hypertonic saline was added to lidocaine. Hypertonic saline administration, however, did reverse the effect of lidocaine on shortening APD. As mentioned, hypertonic saline by itself has no effect on repolarization indices. Thus reduction in APD is an unlikely mechanism by which lidocaine increases DFT values, because hypertonic saline reversed APD to baseline values without affecting DFT. Others have also shown that APD increased after hypertonic saline administration during o-desethyl-encainide toxicity ⁽⁶⁾. These investigators linked this change to transient reduction in plasma potassium concentrations. We also witnessed a transient reduction in potassium concentration at the initiation of hypertonic saline infusion. This reduction in potassium concentration, however, was so brief that it seems unlikely to have caused a prolonged reduction in APD. Thus other ionic mechanisms may be causative, such as increased intracellular sodium concentrations. This would require greater movements of outward potassium ions during repolarization to return membrane potential to resting diastolic values.

Conclusions

We have shown that increases in extracellular sodium concentrations, by the administration of hypertonic saline, do not reverse the sodium channel blocking actions of lidocaine as determined by a slowing of ventricular conduction velocity and did not reverse the lidocaine-induced increase in DFT. These data imply that other therapies may be needed to reverse the toxic effects of lidocaine. However, the reversal of the effect of lidocaine on repolarization without a change in DFT gives important insight into the mechanisms of the lidocaine-induced increase in DFT.

Acknowledgment: This work was supported by a Grant-In-Aid from the American Heart Association Ohio Affiliate (SW 92-22-1). Support of this study in the form of defibrillation equipment was provided by CPI-Guidant (St. Paul, MN, U.S.A.). The authors also are grateful of the technical support provided by Gary Flesher.