Article, Cardiology

Comparison of the therapeutic effect between sodium bicarbonate and insulin on acute propafenone toxicity

a b s t r a c t

Purpose: Unlike other sodium-channel-blocking antiarrhythmic agents, propafenone has ?-blocking effects and calcium-channel-blocking effects. Yi et al recently studied insulin’s treatment effect on Acute propafenone toxicity in rats. However, because the degree of effectiveness of insulin compared to the previously known antidote sodium bicarbonate (NaHCO3) was not studied, the 2 treatment methods were compared for propafenone intoxication in rats.

Methods: Rats received intravenous propafenone (36 mg/[kg h]) for 12 minutes. After the induction of toxicity, rats (n = 10 per group) received normal saline solution (NSS), NaHCO3, or insulin with glucose as treatment. Animals in the NSS, NaHCO3, and Insulin groups received an intravenous infusion of 36 mg/(kg h) propafenone until death occurred. For each animal, the mean arterial pressure (MAP, heart rate, PR interval, QRS duration, total hemoglobin, sodium, potassium, potential of hydrogen, bicarbonate, glucose, lactate, and Central venous oxygen saturation (ScvO2) were measured and compared among the groups.

Results: Survival of the Insulin group was greater than that of the NSS group by log-rank test (P = .021).

Sodium bicarbonate prevented the decline of MAP for 55 minutes. In comparison, insulin prevented the decline of MAP and heart rate, and the elongation of the PR interval and QRS duration for 55 minutes (P b .05). Propafenone toxicity led to decreased Ca2+, potential of hydrogen, and ScvO2 and increased lactate levels. Insulin prevented the decrease of Ca2+ and ScvO2, whereas NaHCO3 prevented the increase in lactate.

Conclusion: Insulin treatment was more effective than NaHCO3 on acute propafenone toxicity in rat. Therefore, when propafenone-induced cardiotoxicity occurs, which is unresponsive to current Treatment methods, glucose-Insulin infusion may be considered.

(C) 2014

Introduction

Propafenone is classified as a class Ic antiarrhythmic that blocks sodium channels [1]. Yet, unlike other sodium-channel-blocking agents, propafenone is structurally similar to propranolol and thus also has ?-blocking effects and calcium-channel-blocking effects [1-3].

Ingestion of an excessive amount of propafenone can lead to

cardiotoxic symptoms such as hypotension, arrhythmias, and death [4-6]. Sodium bicarbonate (NaHCO3) is the treatment of choice for toxicity due to sodium-channel-blocking agents. Theoretically, upon administration of NaHCO3, blood potential of hydrogen (pH) and sodium concentrations increase and thus prevent sodium-channel blockers from binding to the channels. This alkalization facilitates the cell membrane hyperpolarization, and it results in the substitution of the tissue receptor due to the increased nonionized fraction [7].

? Funding sources/disclosures: The authors have no relevant financial information or potential conflicts of interest to disclose.

* Corresponding author. Tel.: +82 42 259 1119; fax: +82 42 611 3889.

E-mail address: [email protected] (J.Y. Lee).

However, there are no reports to date clearly showing the efficacy of NaHCO3 in acute propafenone toxicity.

Recently, there have been reports which state that insulin is effective in acute propafenone toxicity [8,9]. Yi et al [8] studied hyperinsulinemia- euglycemia therapy on acute propafenone toxicity in rats after observing a case of propafenone self-poisoning, in which the patient recovered with an intravenous glucose-insulin infusion. However, because the degree of effectiveness of insulin compared to the previously known antidote NaHCO3 was not studied, the 2 treatment methods were compared for propafenone intoxication in rats.

Methods

Preparation of animals

The use of animals in this study was approved by the institutional animal care and use committee.

Healthy 9-week-old male rats (Sprague-Dawley rat; Damul Science, Daejeon, Korea), weighing between 270 and 300 g, were used in this study. The animals were anesthetized with intraperitoneal injections of

http://dx.doi.org/10.1016/j.ajem.2014.07.010

0735-6757/(C) 2014

Table

Hemodynamic and electrocardiographic parameters at baseline

Group

P value

Control

NSS

NaHCO3

Insulin

Total

Weight (g)

282.5 +- 2.9

281.3 +- 1.9

281.2 +- 3.0

283.8 +- 2.4

282.1 +- 1.2

.750

MAP (mm Hg)

102.0 +- 2.4

99.4 +- 4.3

100.1 +- 3.5

102.5 +- 2.9

100.5 +- 1.6

.406

HR (beats per minute)

295.9 +- 7.0

277.8 +- 11.8

302.8 +- 20.0

296.9 +- 21.1

293.4 +- 7.9

.645

PR interval (ms)

51.9 +- 2.3

46.9 +- 1.9

47.1 +- 2.6

47.3 +- 3.1

48.3 +- 1.3

.503

QRS duration (ms)

52.7 +- 1.6

52.6 +- 1.4

54.0 +- 1.7

53.4 +- 1.7

53.2 +- 0.8

.954

THb (g/dL)

15.6 +- 0.3

15.2 +- 0.3

15.4 +- 0.3

15.4 +- 0.2

15.4 +- 0.1

.732

Na+ (mmol/L)

138.9 +- 0.7

139.2 +- 1.5

140.6 +- 1.8

138.6 +- 0.8

139.3 +- 0.6

.688

K+ (mmol/L)

4.28 +- 0.09

4.32 +- 0.21

4.22 +- 0.15

4.47 +- 0.17

4.32 +- 0.08

.698

Ca2+ (mmol/L)

1.31 +- 0.07

1.27 +- 0.04

1.25 +- 0.08

1.25 +- 0.05

1.27 +- 0.03

.862

HCO (mmol/L)

30.1 +- 0.6

29.9 +- 1.0

29.9 +- 1.1

30.9 +- 0.7

30.2 +- 0.4

.936

pH

7.28 +- 0.01

7.29 +- 0.01

7.28 +- 0.01

7.29 +- 0.01

7.28 +- 0.01

.805

Glucose (mg/dL)

270.5 +- 18.4

291.7 +- 33.8

242.9 +- 22.8

273.3 +- 29.7

261.3 +- 12.3

.542

Lactate (mmol/L)

0.75 +- 0.03

0.85 +- 0.09

0.75 +- 0.03

0.71 +- 0.05

0.77 +- 0.03

.358

ScvO2 (%)

69.2 +- 2.6

69.6 +- 2.2

69.0 +- 2.7

68.9 +- 3.1

69.2 +- 1.3

.998

3

75 mg/kg ketamine (Ketamine; Huons, Seoul, Korea) and 10 mg/kg xylazine (Rompun; Bayer, Seoul, Korea), repeated as required with 1/2 dose every 30 minutes. A thermal barrier (Harvard Apparatus, Holliston, MA) was used to maintain body temperature near 36?C.

Experimental protocol

Four groups of animals were studied: normal saline solution treated (NSS group, n = 10), NaHCO3 treated (NaHCO3 group, n = 10), glucose-insulin treated (Insulin group, n = 10), and control (Control group, n = 10). A polyethylene catheter (Portex PE-50, 0.58 mm inner diameter; Portex Ltd, Kent, UK) was inserted into the internal jugular vein of fasting rats to infuse NSS, glucose, insulin (Humulin; Eli Lilly and Company, Indianapolis, IN), NaHCO3, and propafenone (Sigma Aldrich Korea Ltd, Kyunggi, Korea) using a syringe pump (Model 11 Plus; Harvard Apparatus).

Propafenone was infused at 36 mg/(kg h) for 12 minutes to induce toxicity while monitoring the mean arterial pressure (MAP), heart rate (HR) and electrocardiogram (ECG).7 For the experimental groups,

Fig. 1. Rat survival after acute propafenone toxicity induction followed by treatment with NSS, NaHCO3, or insulin. Survival was significantly greater in the Insulin group compared to the NSS group and NaHCO3 group by log-rank test (P = .001 and .021).

after toxicity induction, there was a 2-minute preparation time; and the starting point of treatment was defined as 0 minute.

Animals in the NSS, NaHCO3, and Insulin group received propafenone as an intravenous infusion of 36 mg/(kg h) propafenone until death occurred. In the NSS group, animals were treated with 3.6 mL/(kg h) NSS from the starting point of treatment. In the NaHCO3 group, animals were treated with 8.4% NaHCO3 at a rate of 2 mEq/(kg h), with additional NSS infusion of 1.6 mL/(kg h) to equalize the total injected volume of solution to that of the NSS group [10]. In the Insulin group, 100 U/(kg h) of insulin was injected with 50% glucose at 0.55 mL/h to prevent hypoglycemia and maintain euglycemia, along with NSS infusion of 0.77 mL/(kg h) to equalize the total injected volume of solution to that of the NSS group [8,11]. For the Control group, all preparation protocols were applied; and monitoring was equal to the treatment-receiving animals, except that the animals were given only NSS at a rate of 3.6 mL/(kg h) instead of propafenone and NSS given as “treatment.” Overall, all 4 groups were infused with equal volumes of respective solutions [8].

Monitoring and sampling

The right carotid artery was cannulated with a polyethylene catheter (Portex PE-50, 0.58 mm inner diameter; Portex Ltd) connected to a pressure transducer for continuous monitoring of MAP and heart rate (HR). Limb-lead-needle electrodes were used to record the ECG. Immediately after anesthesia induction, ECG recording was started in all groups and monitored continuously until animal death occurred. Rat survival time was defined as the interval between the starting point of treatment until the disappear- ance of the QRS wave [8].

The hemodynamic digital signal was captured by a 4-channel data acquisition system (iWorx214; CB Sciences, Dover, NH) and stored on a personal computer using the Labscribe 2 software (CB Sciences).

Blood samples were analyzed by a blood gas/electrolyte analyzer (GEM Premier 3000; Instrumentation Laboratory, Lexington, MA). Total hemoglobin (THb), sodium (Na+), potassium (K+), pH, bicarbonate (HCO), glucose, lactate, and central venous oxygen saturation were measured and compared among the groups. For each animal, the MAP, HR, PR interval, and QRS duration were measured manually prior to toxicity induction, immediately after toxicity induction, and at 5-minute intervals after starting respective treatments. In addition, the time point at which an arrhythmia, such as second-degree atrioventricular block, third-degree atrioventricular block, or loss of P wave, occurred was noted. Data values were compared among the treatment groups and to the Control group. Blood sampling was done prior to toxicity induction, immediately after toxicity induction, and then every 20 minutes.

3

Fig. 2. a, Changes in MAP during treatment. Treatment with insulin or NaHCO3 prevented further decreases in MAP compared to treatment with NSS (P = .001 and .008). b, Changes in HR during treatment. Treatment with insulin prevented further decreases in HR than treatment with NSS (P = .002). Treatment with NaHCO3 did not prevent further decreases in HR compared to treatment with NSS (P = .073).

Statistical analysis

Results were expressed as mean +- standard error of the mean except repeated-measures analysis of variance. The Kolmogorov- Smirnov test was performed to determine whether the results were within a normal distribution. The difference among the groups regarding the general characteristics of rats was analyzed using the Kruskall-Wallis test. Survival analyses and the appearance time of an arrhythmia were calculated using the Kaplan-Meier method with the log-rank test to assess the statistical significance. Comparisons of the MAP, HR, PR interval, QRS duration, THb, Na+, K+, pH, HCO, glucose, lactate, and ScvO2 among each group were made by repeated- measures analysis of variance supported multiple comparison procedures with Tukey post hoc test. In this experiment, missing values were values that occurred after the animal met the death criteria. For missing values of MAP and HR, a zero was entered in place. When a value for the PR interval and/or the QRS duration was missing, a simple Linear regression analysis was conducted; and the resulting value was entered in place. Data were analyzed using the

3

SPSS software (version 13.0; SPSS, Inc, Chicago, IL). Data values were considered significant when P b .05.

Results

At baseline, all hemodynamic and electrocardiographic parameters in the 4 groups did not differ significantly among groups (P N .05) (Table). Compared to the NSS group, the survival times of the NaHCO3 and Insulin group were significantly longer (P = .039 and P = .001, respectively). Furthermore, compared to the NaHCO3 group, the survival time of the Insulin group was significantly longer (P = .021). From the starting point of treatment until 46 minutes, 50% of the animals died in the NSS group, whereas 80% of animals in the NaHCO3 group and 100% in the Insulin group were still alive (Fig. 1). In addition, at 59 minutes since the start of treatment, 100% of the animals in the NSS group died, whereas 40% of the NaHCO3 group and

60% of the Insulin group were still alive (Fig. 1).

Based on the analysis using the Kolmogorov-Smirnov test, intervals from the starting point of treatment to 55 minutes were

Fig. 3. a, Changes in the PR interval during treatment. Treatment with insulin prevented the elongation of the PR interval more than treatment with NSS (P = .019). However, treatment with NaHCO3 did not prevent the elongation compared to treatment with NSS (P = .362). b, Changes in QRS duration during treatment. Treatment with insulin prevented the elongation of the QRS duration more than treatment with NSS (P = .002). However, treatment with NaHCO3 did not prevent the elongation more compared to treatment with NSS (P = .058).

Fig. 4. Blood pressure monitoring and ECG recording. a, The ECG of the Control group exhibited normal sinus rhythm. b, The ECG of the experimental groups with induced propafenone toxicity exhibited second-degree atrioventricular block. c, The ECG of the experimental groups with induced propafenone toxicity exhibited loss of P wave.

Fig. 5. Appearance of arrhythmia in treatment with NSS, NaHCO3, and insulin after acute propafenone toxicity by Kaplan-Meier survival analysis. Appearance of arrhythmia was significantly later in the Insulin group compared to the NSS and NaHCO3 groups by log-rank test (P = .001 and .003).

within a normal distribution in the MAP, HR, PR interval, and QRS duration. Therefore, the values until 55 minutes were compared.

In all of the experimental groups, the MAP showed significant change with time (P b .001). The total MAP values of the groups were as follows: Control group, 102.4 mm Hg; Insulin group, 79.8 mm Hg; NaHCO3 group, 75.9 mm Hg; and NSS group, 59.9 mm Hg. Compared to the NSS group, the decline in MAP of both the NaHCO3 and Insulin group was significantly less (P = .001 and P = .008, respectively) (Fig. 2A). The MAP of the Insulin group was 3.9 mm Hg higher than that of the NaHCO3 group, but this difference was statistically not significant (P = .839).

In all of the experimental groups, HR showed significant decrease with time (P b .001). The average HR values of the groups were as follows: Control group, 293.3 beats per minute; Insulin group, 160.0 beats per minute; NaHCO3 group, 142.3 beats per minute; and NSS group, 111.6 beats per minute. Compared to the NSS group, the decrease in HR was significantly less in the Insulin group (P = .002), whereas the NaHCO3 group’s decrease in HR was not significantly different (P = .073) (Fig. 2B). However, when comparing the data up to 40 minutes since the start of treatment, the decrease in MAP in the NaHCO3 group is significantly less than that in the NSS group with a P value of .023.

The average PR interval during the time period between the starting

point of treatment to 55 minutes was the following for each group:

Control group, 49.3 milliseconds; NSS group, 106.2 milliseconds; NaHCO3 group, 88.4 milliseconds; and Insulin group, 72.8 milliseconds. Compared to the NSS group, the degree of prolongation of PR interval was significantly less in the Insulin group (P = .019). Compared to the NSS group, the prolongation of PR interval in the NaHCO3 group was less too; but it was not a significant difference (P = .362) (Fig. 3A).

The average QRS duration during the time period between the starting point of treatment and 55 minutes was the following for each group: Control group, 53.9 milliseconds; NSS group, 116.0 milliseconds; NaHCO3 group, 91.6 milliseconds; and Insulin group, 87.9 milliseconds. Compared to the NSS group, the degree of prolongation of QRS duration was significantly less in the Insulin group (P = .002). Compared to the NSS group, the prolongation of QRS duration in the NaHCO3 group was not significantly less (P = .058) (Fig. 3B). However, when analyzing the data only up to 40 minutes since starting treatment, the prolongation of QRS duration is significantly less in the NaHCO3 group compared to the NSS group with a P value of .034.

In all rats, various arrhythmias such as second-degree atrioven- tricular block, third-degree atrioventricular block, and loss of P wave occurred prior to death (Fig. 4). The appearance time of an arrhythmia was at a significantly later time point in both the NaHCO3 group and Insulin group compared to the NSS group (P = .001 and P b .001, respectively). When comparing between the NaHCO3 group and the Insulin group, arrhythmia appeared later into the experiment for the insulin group (P = .003) (Fig. 5).

Severe arrhythmias such as second-degree atrioventricular block, third-degree atrioventricular block, or loss of P wave occurred

21.9 +- 3.9 minutes after beginning the NSS-propafenone infusion; and animal death due to cardiac arrest occurred after 45.7 +- 10.2 minutes. The total amount of propafenone infused was 20.3 +- 7.4 mg/kg when arrhythmia occurred and 34.6 +- 6.1 mg/kg when cardiac arrest occurred. In this group, the time point at which 50% of the rats died was 46 minutes with a total infusion amount of 34.8 mg/kg.

The THb, Na+, and glucose levels in the central venous blood between the Control and experimental groups, and among the experimental groups, were not significantly different (P N .05). There was also no significant difference in the Na+ level at each time point within each group (P N .05).

There was significant difference in the HCO level between the NaHCO3 group and NSS group (P b .05) (Fig. 6). Ca2+, pH, and ScvO2 were significantly decreased, whereas lactate level was increased (P b .05) (Fig. 6). The Ca2+ and ScvO2 levels were less decreased in the Insulin group compared to the NSS group (P N .05) (Fig. 6). Compared to the NSS group, the HCO level in the NaHCO group was higher and the lactate level was lower (P b .05) (Fig. 6).

3

3 3

Discussion

This study demonstrates that the Therapeutic effect of an insulin- glucose infusion is much greater than that of NaHCO3 treatment in

Fig. 6. Central Venous blood analysis. a, In overall comparison, the K+ level in the central venous blood between the Control and experimental groups, and among the experimental groups, were not significantly different (P N .05). However, at 20 and 40 minutes since starting treatment, the K+ level in the Insulin group was significantly decreased compared to that in the NSS group (P = .013 and .007). b, The difference in Ca2+ level in the central venous blood was of significance in all of the groups except the Insulin group (P = .810). Compared to the NSS group, the decrease in the Ca2+ level of the Insulin group was of significance; however, the change in Ca2+ level in the NaHCO3 group was not of significance (P = .001 and .989). c, The HCO level was not significantly different between the Control and experimental groups (P N .05). Compared to the NSS group, the HCO level was

3 3

significantly higher in the NaHCO3 group; however, the Insulin group did not show any significant difference (P = .019 and .579). When comparing the HCO level at each time

3

point, at 20 and 40 minutes since starting treatment, the HCO level was significantly higher in the NaHCO group compared to the NSS group (P = .014 and b.001). At 40 minutes

3 3

since starting treatment, there was a significant difference in HCO level between the NaHCO and Insulin groups (P = .010). d, The difference in pH of the central venous blood

3 3

between the Control group and NaHCO3 group was not significant; however, the pH of the Insulin group was significantly lower (P = .756 and .010). Yet, compared to the NSS group, the pH values in the NaHCO3 and Insulin groups were not significantly different (P = .231 and .975). When comparing between time points, at 40 minutes since starting treatment, compared to the NSS group, the Insulin group did not exhibit significant difference, whereas the pH values in the NaHCO3 group were significantly higher (P = .598 and .006). e, The lactate levels of the central venous blood between the Control group and NaHCO3 group were not significantly different (P = .469). Compared to the NSS group, the lactate levels in the NaHCO3 and Insulin group were not significantly different (P N .05). f, Compared to the Control group, only the ScvO2 of the NSS group exhibited significant decrease (P = .001). However, at 40 minutes since starting treatment, the ScvO2 of the NaHCO3 group was significantly different compared to the Control group (P = .036). Furthermore, at the same time point, the ScvO2 value was significantly higher in the Insulin group compared to the NSS group (P = .024). *P b .05 compared to the NSS group.

the hemodynamics of the heart and cardiac conduction after propafenone toxicity.

Sodium bicarbonate has been used as treatment on acute propafenone toxicity because propafenone is a type of sodium- channel blocker [7,12]. There are reports that, for severe ventricular arrhythmias and hypotension and widened QRS interval due to sodium-channel blocker toxicity, administration of NaHCO3 may be of

benefit [1,13]. However, the therapeutic effect of NaHCO3 is not fully satisfactory. Thus, a more effective therapeutic measure is necessary. Our study supports previous study that glucose-insulin infusion increases the survival time, prevents the decrease in MAP and HR, and also prevents the prolongation of PR interval and QRS duration in acute propafenone toxicity [8]. The survival time of the Insulin group was 47% longer than that of the NSS group and 21% longer than that of

the NaHCO3 group. Compared to the control group, the decrease of MAP and HR was 22% and 45% in the Insulin group, 24% and 51% in the NaHCO3 group, and 42% and 62% in the NSS group, respectively. The glucose-insulin infusion significantly prevents the decrease in MAP and HR compared to the NSS group. Therefore, regarding the therapeutic effect on hemodynamics, glucose-insulin infusion is considered more effective than NaHCO3 in acute propafenone toxicity. The survival rates of NSS and Insulin groups appear to be worse in the previous study (there were 2 animals to survive more than 90 minutes in the Insulin group, whereas all animals of the Insulin group are dead at 90 minutes in this study) [8]. Although the study was designed to be conducted in the same environment with the previous study, the result came out to be different because of different

laboratory environment and experimenters’ technique.

Compared to the Control group, the percentage of increased prolongation of PR interval was 47% in the Insulin group, 79% in the NaHCO3 group, and 115% in the NSS group. The NaHCO3 treatment has no significant effect in preventing the prolongation of PR interval; however, glucose-insulin infusion exhibits a significant effect. Com- pared to the Control group, the percentage of increased prolongation of QRS duration was 65.8% in the Insulin group, 73% in the NaHCO3 group, and 119% in the NSS group. However, NaHCO3 treatment does not significantly prevent the increase in QRS duration beyond 45 minutes after start of treatment compared to the NSS group.

Compared to the Control group, the percentage of prolongation of QRS duration was the following: the NSS group, 119%; the NaHCO3 group, 73%; and the Insulin group, 65.8%. Thus, it appears that insulin prevents the prolongation of QRS duration. Furthermore, from 45 minutes since the start of treatment, the NaHCO3 group does not show significant difference in QRS duration prolongation compared to the NSS group, whereas in the Insulin group, there is significant difference until the end. From this, insulin is more effective than NSS, whereas NaHCO3 did not show a difference compared to NSS, in preventing the prolongation of QRS duration.

Propafenone toxicity has a greater effect on the PR interval compared to the QRS duration. Thus, because NaHCO3‘s preventative effect on the PR interval is fairly weak, it is not surprising to find that insulin is a more effective treatment.

The Na+ levels in the Control and experimental groups were not significantly different. In a study of another class IC antiarrhythmic agent, flecainide, toxicity, it was reported that the Na+ level in the NaHCO3 group was higher than that in the NSS group [14,15]. This difference between the studies can be explained to be due to the different amount of NaHCO3 injected and the different research models utilized. To note, in this study, the Na+ levels did not show significant difference before toxicity induction and among all of the groups at all time points throughout the experiment. And so, it seems that propafenone, unlike flecainide, does not affect Na+ levels and that NaHCO3 treatment in acute propafenone toxicity does not significantly change the Na+ levels. In fact, the Na+ levels remained constant; and so the effect of Na+ levels on the treatment effect could be excluded.

It is a known fact that serum K+ levels decrease upon insulin administration. In this study, in the Insulin group, K+ level was significantly lower than that in the Control group. Thus, if survival time becomes longer, K+ supplementation may need to be considered.

As for serum Ca2+ levels, compared to the Control group, the decrease in the NSS group was significant. Thus, it seems that acute propafenone toxicity causes lowering of serum Ca2+. Treatment with NaHCO3 did not prevent the decrease in serum Ca2+, but treatment with insulin seems to have prevented the decrease. The mechanism that prevents decrease in serum Ca2+ in the insulin group is uncertain; further evaluation is needed.

At 40 minutes since starting treatment, compared to the Control group, the NaHCO3 group’s HCO level was significantly higher. This is thought to be due to the substantial amount of NaHCO3 that was

3

infused. However, the variance in therapeutic effect depending on the concentration of NaHCO3 infusion needs to be studied.

In the Insulin group, glucose was infused with insulin and thus corrected any differences compared to the other groups.

Compared to the Control, the pH in the Insulin group was also significantly lower; and so insulin does not seem to be able to prevent the pH decrease. However, because the HCO level between the Insulin group and the Control group does not show significant difference, there must be another factor (ie, lactic acidosis, respiratory acidosis) that is affecting the pH. In particular, because the pH between the NaHCO3 group and the Control group did not show significant difference, it seems that increasing the amount of NaHCO3 can be considered.

3

In this study, we also analyzed the lactate levels and ScvO2, which are markers in shock treatment. We found that, compared to the Control group, lactate levels in the NSS and Insulin groups were significantly higher. It is thought that acute propafenone toxicity increases lactate levels; and whereas insulin treatment is unable to prevent the increase in lactate, NaHCO3 treatment is able to prevent the increase. As for the ScvO2, compared to the Control group, only the NSS group showed a significantly lower value. However, at 40 minutes since the start of treatment, compared to the Control group, the NaHCO3 group also showed significant decrease. Thus, insulin treatment seems to also prevent decrease in ScvO2.

The limitation to this study is that because the cardiotoxic dose of

propafenone in rats is unknown, only about 40% of the lethal dose 50 dose was used [8]. Also, because the treatment dose of NaHCO3 in rats is unknown, maximum infusion dosage of pediatric metabolic acidosis treatment was used [10]. More studies about treatment effect by methods and volume of NaHCO3 administration could be further evaluated. The appropriate concentration of propafenone that induces cardiac toxicity in rats was unknown. If Blood concentration and metabolites of propafenone were measured, the relationship with insulin could be further evaluated. We injected equal volume in all groups; but the isotonic effect of those volumes was different because saline and NaHCO3 were iso- or hypertonic, whereas glucose was hypotonic.

Conclusions

When acute propafenone intoxication symptoms appeared in the rats, NaHCO3 treatment and insulin treatment both increased the survival; but the increase was greater with insulin treatment.

Sodium bicarbonate treatment prevented the decrease in MAP and HR and the prolongation of PR interval and QRS duration, but the treatment effect of insulin was greater. In particular, only insulin treatment prevented the prolongation of PR interval statistically significantly. Arrhythmia was significantly prevented by both NaHCO3 and insulin treatment, but insulin treatment was more effective. Therefore, in propafenone toxicity related to the hemodynamics of the heart and cardiac conduction, insulin’s therapeutic effect is much greater than that of NaHCO3 treatment.

Insulin seems to prevent the decrease in Ca2+ and ScvO2, whereas NaHCO3 increases HCO levels and prevents the increase in lactate levels. Therefore, in a situation of propafenone toxicity, a combination of NaHCO3 and insulin is predicted to have an effective therapeutic effect; and this needs to be further investigated.

3

References

  1. Parker RB, McCollam PL, Bauman JL. Propafenone: a novel type Ic antiarrhythmic agent. DICP 1989;23:196-202.
  2. Satoh H, Hashimoto K. Effect of propafenone on the membrane currents of rabbit sino-atrial node cells. Eur J Pharmacol 1984;99:185-91.
  3. Hancox JC, Mitcheson JS. Inhibition of L-type calcium current by propafenone in single myocyte isolated from rabbit atrioventricular node. Br J Pharmacol 1997; 121:7-14.
  4. Clarot F, Goulle JP, Horst M, Vaz E, Lacroix C, Proust B. Fatal propafenone overdoses: case reports and a review of the literature. J Anal Toxicol 2003;27:595-9.
  5. Koppel C, Oberdisse U, Heinemeyer G. Clinical course and outcome in class IC antiarrhythmic overdose. J Toxicol Clin Toxicol 1990;28:433-44.
  6. Maxeiner H, Klug E. Lethal suicidal intoxication with propafenone, after a history of self-inflicted injuries. Forensic Sci Int 1997;89:27-32.
  7. Scanu P, Grollier G, Guilleman D, Iselin M, Bustany P, Hurpe JM, et al. Malignant ventricular tachycardia during propafenone treatment in a child with junctional automatic tachycardia: effectiveness of intravenous molar sodium lactate. Pacing Clin Electrophysiol 1991;14:783-6.
  8. Yi HY, Lee JY, Lee SY, Hong SY, Yang YM, Park GN. Cardioprotective effect of glucose-insulin on acute propafenone toxicity in rat. Am J Emerg Med 2012; 30:680-9.
  9. Bayram B, Dedeoglu E, Hocaoglu N, Gazi E. Propafenone-induced cardiac arrest: Full recovery with insulin, is it possible? Am J Emerg Med 2013;31:457.
  10. Wasserman J, Weiner D. Pediatric endocrine and Metabolic disorders. In: Aghababian RV, editor. Essentials of emergency medicine. Sudbury: Jones and Bartlett Learning; 2011. p. 592.
  11. Oubaassine R, Bilbault P, Roegel JC, Alexandre E, Sigrist S, Lavaux T, et al. Cardio protective effect of glucose-insulin infusion on acute digoxin toxicity in rat. Toxicology 2006;224:238-43.
  12. Brubacher J. bicarbonate therapy for unstable propafenone-induced wide complex

    tachycardia. CJEM 2004;6:349-56.

    Kerns II W, English B, Ford M. Propafenone overdose. Ann Emerg Med 1994;24: 98-103.

  13. Salerno DM, Murakami MM, Johnston RB, Keyler DE, Pentel PR. Reversal of flecainide-induced ventricular arrhythmia by hypertonic sodium bicarbonate in dogs. Am J Emerg Med 1995;13:285-93.
  14. Keyler DE, Pentel PR. Hypertonic sodium bicarbonate partially reverses QRS prolongation due to flecainide in rats. Life Sci 1989;45:1575-80.

Leave a Reply

Your email address will not be published. Required fields are marked *