electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine...

ARTICLE

Electrophysiologic and Hemodynamic Effects of Sodium Bicarbonatein a Canine Model of Severe Cocaine Intoxication#

Lance D. Wilson, M.D.,1,2,* and Chandresh Shelat, M.D.2

1MetroHealth Medical Center, Cleveland, Ohio, USA2PHS–Mt. Sinai Medical Center, Cleveland, Ohio, USA

ABSTRACT

Objective. Cocaine toxicity causes myocardial depression, malignant dysrhythmias, and

sudden death, partially due to cocaine-related myocardial sodium channel blockade. Because

of cocaine’s ability to block cardiac sodium channels, sodium bicarbonate (NaHCO3) has been

proposed as an antidote. The hypothesis of this study was that NaHCO3 would correct

cocaine-induced conduction abnormalities and resultant hemodynamic compromise in an

animal model simulating severe cocaine intoxication. Methods. Design: Prospective, con-

trolled, experimental study in which 15 anesthetized dogs were given three successive boluses

of cocaine (7 mg=kg) and then randomized to receive NaHCO3, 2 mEq=kg (n¼ 8) or placebo

(n¼ 7). Measurements: Arterial, left ventricular, and pulmonary artery pressures; cardiac

output (CO); electrocardiogram (ECG); blood gases; and serum concentrations of cocaine

were measured at baseline, at fixed time intervals after each bolus of cocaine, and then after

administration of NaHCO3 or placebo. Statistical significance was determined by analysis of

variance (ANOVA) for repeated measures. Results. Seven dogs experienced significant

arrhythmias, including VT, pulseless electrical activity, and third-degree atrioventricular

block; 2 of these dogs expired prior to receiving NaHCO3 and were excluded. Immediately

after administering NaHCO3, QRS duration decreased by 30% ( p< 0.001), returning to

baseline more quickly than in the control group. This effect was associated with a brief 30%

decrease in MAP ( p¼NS). After NaHCO3, CO increased 78% and remained increased for

5 min ( p< 0.007). One dog converted from complete heart block to sinus rhythm shortly after

NaHCO3 administration. Conclusions. NaHCO3 improved ECG changes secondary to

cocaine toxicity and improved myocardial function.

#Previously presented at the Society for Academic Medicine Annual Meeting, Boston, Massachusetts, May 1999.*Corresponsence: Lance Wilson, M.D., Department of Emergency Medicine, MetroHealth Medical Center, Cleveland, OH 44109,

USA; Fax: (216) 778-5349; E-mail: [email protected].

DOI: 10.1081=CLT-120025342 0731-3810 (Print); 1097-9875 (Online)

Copyright # 2003 by Marcel Dekker, Inc. www.dekker.com

777

Journal of Toxicology

CLINICAL TOXICOLOGY

Vol. 41, No. 6, pp. 777–788, 2003

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INTRODUCTION

The abuse of cocaine has become a major medical,

social, and economic problem in the United States.

Approximately 50 million Americans have tried cocaine,

and almost 5 million Americans use it on a regular basis.

Cocaine abuse results in an estimated 64,000 emergency

department visits annually and the majority are related to

cardiovascular complaints (1). The cardiac effects of

cocaine include acute myocardial infarction, ventricular

dysrhythmias, and sudden cardiac death (2).

The pharmacological effects of cocaine on the car-

diovascular system are varied and dose dependent. At

low doses, the sympathomimetic effects of cocaine pre-

dominate resulting in tachycardia, vasoconstriction, and

hypertension (2). At higher doses, cocaine-related myo-

cardial sodium channel blockade predominates. Cocaine

is a potent blocker of fast sodium channels in cardiac

myocytes and conduction tissues, which has been postu-

lated to be the mechanism of cocaine-related dysrhyth-

mias, myocardial depression, and sudden death (3–5).

Currently, benzodiazepines are first-line therapy for

cocaine-related cardiac toxicity. Although they are effec-

tive in sedating cocaine-intoxicated patients and decrease

sympathetic outflow from the central nervous system,

they have no effect on the conduction abnormalities

associated with cocaine-related sodium channel blockade

(1,6). Sodium bicarbonate (NaHCO3) is a proposed

treatment for cocaine-related ventricular dysrhythmias.

It is used as an antidote in a number of toxicological

emergencies, including cardiac toxicity secondary to

cyclic antidepressant and type I antidysrhythmics (7–9).

Sodium bicarbonate has been recommended for treat-

ment of the cocaine-induced dysrhythmias based on case

reports as well as a few animal studies (10–17). It has

never been demonstrated to improve the hemodynamic

effects of cocaine (13,14). Although NaHCO3 maybe

useful in treating conduction abnormalities and possibly

myocardial depression due to sodium channel blockade,

there is a paucity of evidence supporting its use. The

aim of this study was to create a model of cocaine

intoxication characterized by the sodium channel block-

ing effects of cocaine. The hypothesis of this study

was that NaHCO3 would correct cocaine-induced

conduction abnormalities and resultant hemodynamic com-

promise in an animal model simulating severe cocaine

intoxication.

METHODS

Experiments were performed on 15 mongrel dogs,

with a mean body weight of 16.3 kg (range 9.4–19.9 kg,

SD¼ 2.5 kg). The experiments conformed to the guide-

lines established by the National Institutes of Health for

animal care and were approved by the Animal Care and

Use Committee of our institution. Each dog was sedated

with an intramuscular injection of morphine sulfate,

1.5 mg=kg and anesthetized with an intravenous injection

of alpha-chloralose, 100 mg=kg, dissolved in polyethy-

lene glycol.

Each dog was intubated and ventilated on a respira-

tor (Harvard Apparatus, Holliston, MA). At the initiation

of each experiment, a 1-mL sample of arterial blood

was collected for blood gas analyses to ensure normal pH

and baseline values were present after surgical pre-

paration. Adjustments were made to the ventilator to

correct any abnormalities in ventilation prior to any data

collection.

The right femoral artery and vein and the right

external jugular vein were isolated by surgical dissection.

The right femoral vein was cannulated with polyethylene

tubing connected to 5% dextrose and lactated Ringer’s

solution. The right femoral artery of each dog was

cannulated with a catheter that was advanced into the

aorta to measure central arterial pressure and connected

to a fluid-filled P23 pressure transducer (Gould, Cleve-

land, OH). A second catheter with a microtip pressure

transducer (Millar, Houston, TX) was advanced from the

left femoral artery into the left ventricle to measure left

ventricular systolic and diastolic pressures.

The entire left ventricular pressure waveform of each

of the left ventricular beats recorded by the Millar

catheter was sampled 500 times=sec by an analog-to-

digital converter (Labview1

, National Instruments, Aus-

tin, TX), and the digital information was stored on the

hard disk of a PC (Gateway, San Diego, CA). In each

experiment, the maximal rate of left ventricular pressure

rise was determined as an index of left ventricular

contractile function [(dP=dt)max]. The maximal rate of

left ventricular pressure decline was determined as an

index of ventricular relaxation [(dP=dt)min]. Both

(dP=dt)max and (dP=dt)min were determined from the

average of 10 consecutive left ventricular pressure wave-

forms recorded at each time interval.

A fiberoptic, balloon-tip catheter (Oximetrix1

,

Abbott Laboratories, Mountain View, CA) was inserted

into the right jugular vein of each dog and advanced into

the pulmonary artery. The fiberoptic catheter was also

connected to a SO2=CO computer (Oximetrix) for con-

tinuous measurements of mixed venous blood oxygen

saturation and measurement of cardiac output (CO) (18).

Cardiac output was determined by thermodilution tech-

nique (19). An average of at least three measurements of

CO that agreed within 10% was used for the measure-

ment of the CO.

778 Wilson and Shelat

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An electrocardiogram (ECG) was obtained by

attaching leads to the anterior chest wall of each dog to

produce lead I of the standard ECG. Aortic pressure, left

ventricular pressure, and a surface ECG were continu-

ously monitored and recorded on a PC (Gateway).

Hemodynamic and electrocardiographic data were ana-

lyzed from an average of 10 consecutive waveforms.

After completion of the instrumentation, each dog

was allowed 30–60 min for the monitored variables to

achieve a steady state. Baseline hemodynamic and elec-

trocardiographic measurements were then performed.

Each dog was randomized to one of two groups. In the

control group, each dog received 7 mg=kg of cocaine as

an intravenous bolus over 10 sec. Cocaine hydrochloride

was dissolved in normal saline and given in a volume of

10 cc for each bolus. Each dog received three total doses

of cocaine at 15-min intervals. These doses of cocaine

were chosen to produce serum concentrations in the

study animals that would be comparable to the serum

cocaine concentrations observed in individuals who have

used cocaine ‘‘recreationally.’’ These doses and also been

shown to create cardiovascular responses in which the

local anesthetic effects of cocaine predominate (5,20). At

3 min after the third cocaine bolus, NaHCO3 was given at

a dose of 2 mEq=kg as an intravenous bolus in the study

group, or 5% dextrose in water was given in an equal

volume, as placebo. We used D5W as a control medica-

tion rather than normal saline to avoid sodium loading in

the placebo group. Hemodynamic and electrocardio-

graphic measurements were made at 1, 2, 4, 6, 10, and

15 min after each cocaine bolus. Cardiac output measure-

ments were obtained at 2, 6, 10, and 15 min after each

cocaine bolus. Arterial blood gases were obtained at

baseline, prior to the third cocaine bolus, and 2 min

after the NaHCO3 bolus. Serum cocaine levels were

obtained at 15 min after each cocaine bolus. Each

blood sample was immediately placed in a chilled glass

tube that contained potassium oxalate and sodium

fluoride. The samples were frozen at �80�C until

chemical analyses were performed. Serum cocaine concen-

trations were determined by gas chromatography=mass

spectroscopy (21).

STATISTICAL ANALYSIS

Statistical significance was determined by repeated

measures of analyses of variance. Within any one data

set, when between-group, time, or group–time interac-

tions were significant, differences between specific means

were determined by a Newman–Keuls post hoc test. In

our analyses, a value of p< 0.05 was considered sig-

nificant. For comparison with baseline measurements,

each dog served as its own control. Levene’s test was

used to confirm homogeneity of variances between

groups for each variable. Only for mean arterial pressure

was there significant violation of this analysis of variance

(ANOVA) assumption at data points after the second and

third cocaine injection. Scatterplots of the variances

against the means for each outcome variable were per-

formed and did not reveal any correlation between the

means and the variances for any variables. To ensure

that our data were not subject to violations of the nor-

mality assumption, our ANOVA was repeated using the

Kruskal–Wallis one-way ANOVA. We discovered no

significant differences between the nonparametric and

parametric methods of analysis between the control or

study groups in the major outcome variables.

In previous studies of the hemodynamic effects of

cocaine, we were able to show significant differences

between groups with a total of six or fewer dogs per

group (5,20). In reviewing the data from the previous

study, directly examining the effects of NaHCO3 on

cocaine-related changes in cardiac conduction, we were

able to estimate mean changes before and after bicarbo-

nate administration and their standard deviations (14).

From this data, a sample size calculation was performed.

We found that statistically significant results could be

demonstrated with as little as three to five animals per

group. Mean values and 95% confidence intervals (95%

CIs) are presented in the text.

RESULTS

One dog in each group expired prior to receiving

bicarbonate or placebo and was excluded from analysis.

By ANOVA, there was no difference in serum cocaine

concentrations between the two study groups

( p< 0.285). Mean serum cocaine concentrations

increased after each bolus and were 2560 ng=mL (95%

CI 1535–3584), 3267 ng=mL (95% CI 2187–4346), and

4333 ng=mL (95% CI 2930–5736), at 15 min after the

first, second, and third cocaine boluses, respectively.

Hemodynamic Effects

Transient drops in MAP occurred similarly in both

groups after each cocaine boluse, which were followed

by statistically significant increases in MAP compared

with baseline (Fig. 1). However, after bicarbonate, there

was a transient, 30% decrease in MAP ( p¼NS). This

moderate drop, although statististically nonsignificant,

was observed in seven of seven dogs in the bicarbonate

group and none of the control animals.

Sodium Bicarbonate for Cocaine Intoxication 779

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The changes in heart rate (HR) were significant over

time by repeated measures of ANOVA ( p< 0.016), but

not significantly different between groups, and the

group–time interaction was nonsignificant. Baseline HR

was 99 and 122 in the control and bicarbonate groups,

respectively. There were nonsignificant increases in HR

in both groups after each cocaine bolus with a maximal

HR of 112 and 128 in the placebo and bicarbonate

groups, respectively, after the third cocaine bolus (not

shown).

The CO also transiently decreased in both groups

after each cocaine bolus from baseline or precocaine

bolus CO (Fig. 2). When first measured at 3 min after the

bicarbonate administration, CO increased by 78% (95%

CI 27% to 130%, p< 0.0001 compared with its baseline

by post hoc testing) and remained significantly increased

for the remainder of the observation period (Fig. 2). The

changes in ventricular stroke volume were similar to the

changes observed in CO (not shown). The changes in

ventricular stroke volume were significant over time by

repeated measures of ANOVA ( p< 0.0001), but not

significantly different between groups, and the group–

time interaction was nonsignificant.

The changes in ventricular contractile function as

measured by changes in (dP=dt)max were similar

between groups after each cocaine bolus. The increase

in ventricular contractile function relative to the control

group occurring at 3 min after the bicarbonate bolus was

not statistically significant (Fig. 3). Changes in ventricu-

lar relaxation (not shown) mirrored the changes in

ventricular contractile function.

Left ventricular end-diastolic pressure (LVEDP)

increased in both groups after the first cocaine bolus,

reaching statistical significance after the second cocaine

bolus. LVEDP was maximally increased by 88% (95% CI

44% to 156%) in the control group, whereas it was

maximally increased by 92% in the study group (95%

CI 26% to 174%, both p< 0.0001 relative to their

respective baselines by post hoc testing, data not

shown). Changes in LVEDP were significant over time

by repeated measures of ANOVA ( p< 0.0001), but not

significantly different between groups, and the group–

time interaction was nonsignificant.

Effects on the EKG

In both groups, persistent and significant QRS

prolongation occurred after each cocaine bolus (Fig. 4).

Immediately after NaHCO3, QRS duration decreased by

Figure 1. Changes in mean arterial pressure are shown. In this and all subsequent figures, the standard error of the mean is shown

and the * symbol represents statistically significant changes from baseline by ANOVA post hoc testing. The small arrow represents the

time when the cocaine bolus was given and the large arrow when NaHCO3 was administered. The changes in mean arterial blood

pressure were significantly different over time by repeated measures ANOVA ( p< 0.0001). The ANOVA between groups and group–

time interactions were nonsignificant. The nonsignificant decrease in MAP relative to control at 8 to 15 min in the NaHCO3 groups

represents one dog, which after receiving NaHCO3 became profoundly hypotensive and did not recover by 15 min after the cocaine

bolus.


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30% (95% CI 21% to 40%, p< 0.0003) relative to

control. After bicarbonate administration, the QRS

duration returned to baseline for the remainder of the

observation period, with the exception of the 6-min

measurement (3 min after NaHCO3). Relative to control,

NaHCO3 administration resulted in a quicker return of

QRS duration to baseline. In the control group, QRS

duration was similar to baseline by the 7-min measure-

ment (4 min after NaHCO3), and after the 6-min mea-

surement, the QRS duration was similar in both groups

(Fig. 4).

In both groups, significant QTc interval prolongation

occurred after each cocaine bolus and returned toward,

but not back to, baseline (Fig. 5). There was no statisti-

Figure 2. The changes in CO were significant over time by repeated measures ANOVA ( p< 0.0001) and the group–time interaction

was also significant ( p< 0.007). In this and all subsequent figures, the { represents differences between group means at the data point

indicated by ANOVA post hoc testing.

Figure 3. The changes in ventricular contractile function as measured by changes in dP dt(max) are shown. These changes were

significant over time by repeated measures of ANOVA ( p< 0.0001). The between-groups and group-time interactions were

nonsignificant.


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cally significant difference in QTc interval duration after

bicarbonate administration in the study group relative to

the control group (Fig. 5).

Arrhythmias observed in both groups are shown in

Table 1. Two dogs expired due to arrhythmias prior to

receiving bicarbonate or placebo and were excluded from

analysis.

In 13 of 15 dogs, ST segment and T wave changes

consistent with myocardial ischemia or infarction were

observed. These changes were typically transient, lasting

between 30 sec to 6 min, and consisted of ST segment

elevation and depression as well as T wave inversion.

These changes occurred at times when QRS interval

widening and aberrant conduction was observed.

In 2 dogs, T wave inversion and ST segment depress-

ion was more prolonged, lasting the entire 15-min

observation periods after the second and third cocaine

boluses.

Figure 4. Sodium bicarbonate administration resulted in a quicker return of QRS duration to baseline. The changes in the QRS

duration of the ECG were significant over time by repeated measures of ANOVA ( p< 0.0001) and the group–time interaction was also

significant ( p¼ 0.011).

Figure 5. The changes in the corrected QT interval duration of the ECG (QTc) were significant over time by repeated measures of

ANOVA ( p< 0.0001). The between-groups and the group–time interactions were nonsignificant.


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Ta

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Metabolic Effects

Sodium bicarbonate administration resulted in sig-

nificant increases in arterial pH, pCO2, and bicarbonate

by ANOVA (Table 2).

DISCUSSION

Cocaine and other drugs with type I antiarrhythmic

effects block the fast sodium channel, slowing conduc-

tion during the phase 0 upstroke of the action potential.

This effect is reflected primarily by QRS prolongation of

the ECG and was observed in the present experiments

(9). Cocaine-related myocardial sodium channel block-

ade is characterized by a greater affinity for rested Naþ

channels as well as impairment of sodium uncoupling

from the fast sodium channel (4). In these studies, the

transient improvement in cardiac conduction and sys-

temic hemodynamics after NaHCO3 are likely multi-

factorial. Severe cocaine intoxication has been

associated with metabolic and respiratory acidosis sec-

ondary to seizures, hypoventilation, and psychomotor

agitation. The resultant decrease in pH appears to play

a role in the development of cocaine-related dysrhyth-

mias (10–12). Increases in NaHCO3 concentration may

increase the gradient moving sodium across cardiac cell

membranes, overcoming cocaine-induced sodium chan-

nel blockade. In addition, alterations in pH may change

cocaine’s interaction with the sodium channel similarly to

CAs (22,23). The effects of NaHCO3 on pH are separate

and additive to those of sodium channel loading in the

setting of CA toxicity (7,8). Cocaine has a pKa of 8.8 so

alkalinization may transform more cocaine from its

ionized form to its neutral form, which may either

decrease cocaine’s affinity for the sodium channel or

cause more rapid dissociation from it (15). Recovery

from cocaine-related sodium channel blockade is mark-

edly improved by alkalinization in isolated myocytes

(23). Based on published studies and case reports,

alkalinization may be an important mechanism for the

effects of NaHCO3 in this setting. Sodium bicarbonate

was superior to equimolar sodium chloride in correcting

cocaine-related conduction abnormalities in one canine

study (16). There are case reports of NaHCO3 being used

effectively in patients exhibiting conduction abnormal-

ities related to cocaine use (10–12). These patients

suffered from profound metabolic acidosis associated

with cocaine toxicity, and NaHCO3 given to correct

acidosis resulted in improvement of cardiac conduction.

Changes in pH could also effect cocaine’s serum protein

binding, although this dose not appear to be a factor in

CA toxicity (24) and cocaine is approximately 90%

protein bound in human serum (22).

In this study, we did not directly investigate the

mechanism by which NaHCO3 caused improvement in

the ECG and systemic hemodynamics. Because this

study did not investigate equimolar sodium independent

of bicarbonate, we cannot discern if the effects observed

are predominately due to sodium loading rather than a

mechanism related to changes in arterial pH. Certainly

given what is known about cocaine’s effects on sodium

channels, our observations could be related to NaHCO3-

related improvement in conduction through myocardial

sodium channels. However, given the design of the study,

we cannot distinguish between the relative effects of

sodium loading vs. effects on serum pH.

Current recommendations for bicarbonate adminis-

tration in the setting of cocaine-induced ventricular

dysrhythmias are partially based on a previous canine

study that investigated the electrophysiological effects

cocaine (14). In this study the authors administered

NaHCO3 to some study animals. In these dogs, they

reported significant decreases in QRS duration and

resolution of ventricular tachycardia in one dog. No

changes in systemic hemodynamics secondary to

NaHCO3 administration were observed. They also used

high doses of cocaine, which produced serum cocaine

Table 2. NaHCO3 administration.a

Placebo Bicarbonate

Group Baseline Pre-HCO3 Post-HCO3 Baseline Pre-HCO3 Post-HCO3

PH 7.44 7.31 7.31 7.40 7.37 7.51*

PCO2 (mmHg) 33.3 33.8 31.7 38.8 34.5 46.8*

HCO3 (mEq=L) 21.6 21.8 18.3 23.3 19.8 34.5*

PO2 (mmHg) 130 142 145 113 134 106

aMean changes in arterial blood gases after NaHCO3 administration.

* represents p< 0.05 between groups in the noted variable by ANOVA.


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concentrations that were greater than typically described

in clinical practice. We specifically attempted to produce

cocaine serum concentrations in the present experiments

within the range reported in patients who have complica-

tions from, or who have expired due to, cocaine toxicity.

In such patients, the range of serum cocaine levels are

variable, but typically average 5300 to 6000 ng=mL

(25,26). Maximal cocaine concentrations in this study

are consistent with those that cause significant cocaine-

related sodium channel blocking effects (5).

In another animal study, NaHCO3 reduced QRS

duration in rats suffering from cocaine toxicity. In this

study, NaHCO3 also reversed cocaine-induced QT inter-

val prolongation. Sodium bicarbonate did not reverse

cocaine-associated decreases in blood pressure (13). We

observed brief statistically insignificant decreases in

MAP associated with NaHCO3 administration. This has

been reported in other studies of NaHCO3 use not in the

setting of cocaine (27).

Recently, the revised ACLS guidelines have given

NaHCO3 a class IIa recommendation as first-line therapy

for cocaine-related ventricular tachycardia=VF, partially

based on the above studies and case reports. The authors

stated that there is no evidence of adverse effects of

NaHCO3 and that treating cocaine-related acidosis

appears important (17). Our data show significant

improvement in QRS duration after NaHCO3 although

its effects on the arrhythmias observed were equivocal

(Table 1). Our data does not conflict with these current

recommendations, nor does it suggest obvious antiar-

rhythmic benefit from NaHCO3 in our model, and we did

observe a potential adverse effect in one animal.

There are numerous potential adverse effects of

NaHCO3 treatment, including excessive alkalemia,

hypernatremia, hyperosomolarity, hypokalemia, and

hypocalcemia (27,28). Sodium bicarbonate administra-

tion results in rapid accumulation of carbon dioxide that

can rapidly be transported into myocardial cells, which is

both a negative ionotrope and causes a paradoxical

intracellular acidosis (28–31). Sodium bicarbonate-

related decreases in ionotropic function may be particu-

larly deleterious in patients suffering toxicity from the

myocardial depressant effects of cocaine (32). We

observed a brief 1- to 2-minute period of decreased

blood pressure relative to control and decreased contrac-

tile function, followed by a more prolonged period of

improved myocardial function. Although these changes

were statistically insignificant, they were observed in all

dogs that received NaHCO3.

We subsequently observed improved myocardial

function that was more prolonged than the relative

improvement in conduction. This is consistent with a

positive ionotropic effect of NaHCO3, independent of

improvement in cocaine-related conduction changes. The

authors note that one dog suffered refractory hypotension

that appeared to be temporally related to bicarbonate

administration. In this dog, MAP after the third cocaine

bolus was 27 mmHg, decreased to 15 mmHg 2 min after

the NaHCO3 was given, and remained significantly

hypotensive with a MAP between 10 and 15 mmHg for

the remainder of the observation period. It is difficult to

make definite conclusions based on an observation in a

single animal. This dog had a more pronounced hypo-

tensive response to cocaine administration than did other

animals studied, and we cannot say with certainty that the

effect was secondary to NaHCO3 or an effect of the

cocaine itself.

Sodium bicarbonate is theoretically harmful in treat-

ing some types of cocaine-induced dysrhythmias, such as

torsades de pointes. This dysrhythmia may be due to

cocaine’s blockade of cardiac potassium channels and

NaHCO3 administration would be expected to cause

resultant hypokalemia (6,33). Winecoff et al. reported

that bicarbonate increased JTc duration secondary to

cocaine in an isolated heart preparation (15). Some

authors suggest that delayed dysrhythmias due to cocaine

may be due to ischemic myocardium, and standard

treatment such as lidocaine would be indicated (6,34).

However, delayed arrhythmic effects of cocaine are

described, and may be due to cocaine metabolites,

which also may have sodium channel effects similar to

cocaine and may also be associated with myocardial

ischemia or systemic acidosis (4,35,36).

STUDY LIMITATIONS

The electrocardiographic changes and hemodynamic

depression that occurred in the present experiments may

be due to cocaine-related myocardial ischemia. We

observed transient ECG ST segment changes consistent

with myocardial ischemia in the majority of dogs. How-

ever, the ST segment changes in these dogs occurred only

during increased HRs and when the QRS duration of the

ECG was significantly prolonged. Only two dogs devel-

oped persistent ST segment changes. We believe that

these ST changes observed were probably due to aberrant

impulse conduction related to sodium channel blockade

(37). If we had used more than one ECG lead, we may

have been able to better characterize these ECG changes.

In this regard, if we had performed additional leads, we

may have made both a more precise measure of QRS

duration as well as detected QRS prolongation, which

been underestimated in a single lead. Because we did not

directly examine coronary blood flow or myocardial

perfusion, we cannot rule out that myocardial ischemia


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caused some of the toxicity observed and cannot com-

ment on the role of NaHCO3 in the setting of cocaine-

induced myocardial ischemia.

We attempted to produce a model primarily exhibit-

ing the myocardial sodium channel blocking effects of

cocaine. We did observe transient myocardial depression

after each cocaine bolus as well as progressive slowing of

cardiac conduction; however, we also observed sym-

pathomimetic effects, including hypertension and

increased contractile function, after transient myocardial

depression. Thus, we did not create a model of isolated

sodium channel antagonism. Certainly these two effects

are antagonistic and seem to be dose dependent. In some

patients, it is possible that rapidly reversing cocaine-

related myocardial sodium channel blockade might

cause a greater preponderance of the sympathomimetic

effects, particularly if the sympathomimetic effects pre-

dominate in that patient. However, this study was not

designed to study possible deleterious or beneficial

effects of using NaHCO3 in the setting of cocaine-related

sympathomimetic toxicity. We did observe increases in

MAP and contractile function after NaHCO3 that was

greater than control. However, because these animals

were not hypotensive or exhibiting myocardial depres-

sion, the clinical importance of these observations to

patient suffering from cocaine-induced myocardial

depression is unclear.

These studies were performed under anesthesia.

Although cocaine-related hemodynamic effects are best

studied in unanesthetized animals, because of the inva-

siveness of the procedures, anesthesia was necessary.

Studies criticizing the use of anesthesia in animal models

of cocaine use have primarily criticized pentobarbital

anesthesia (38). Alpha-chloralose anesthesia was chosen

because of the drug’s ability to sustain autonomic reflex

control of the cardiovascular system and minimal effects

on left ventricular function (39,40).

We did not use a surgical control group to control for

effects of the experimental preparation; however, our

experience in similar canine models is that hemodynamic

and electrophysiologic variables are stable for approxi-

mately 5 hr (5,20). However, a longer observation period

would have been helpful to delineate any unexpected

delayed effects of bicarbonate and better characterize the

hypotensive effects observed in one dog.

Sodium, potassium, and osmolality were not mea-

sured. We cannot say if hypernatremia and increased

osmolality played a role in the brief hypotension and

myocardial dysfunction that followed sodium loading.

Volume or osmolar loading could precipitate ventricular

dysfunction in patients with an underlying cardiomyo-

pathy or cocaine-induced myocardial dysfunction. There

was no evidence that these canine hearts were diseased.

CONCLUSION

In this model of severe cocaine intoxication primar-

ily characterized by sodium channel blockade, NaHCO3

appeared to be effective in more rapidly returning

cocaine-induced conduction abnormalities to baseline

and created more prolonged improvement in myocardial

function. However, we observed no consistent beneficial

effects on the arrhythmias induced by cocaine. Our study

supports previous animal and case report data that in the

setting of cocaine-induced arrhythmias presumed sec-

ondary to cocaine-related myocardial sodium channel

blockade that NaHCO3 therapy may be indicated.

ACKNOWLEDGMENTS

This study was funded by a Haas Foundation Grant

from the Mt. Sinai Medical Center. The authors want to

thank Mike Zannoni for his technical assistance and

Mike Ritzenthaller for his support of the project. The

Department of Statistics, Case Western Reserve Univer-

sity, provided statistical support.

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electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine...

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