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Effect of Dobutamine on Plasma Potassium in Congestive Idiopathic Heart or Ischemic Failure Secondary Cardiomyopathy

Effect

of Dobutamine

on Plasma

Potassium

in Congestive Idiopathic

Heart or Ischemic

Failure

Secondary

Cardiomyopathy

to

Irvin F. Goldenberg,

MD, Maria Teresa Olivari,

MD, T. Barry Levine,

MD,

and Jay N. Cohn,

MD

Dobutamine

pg/kg/min

to

was

administered

13 patients

with

in

a dose

of

idiopathic

10 f

severe

1

or

D obutamine is apotent, intravenously

administered

inotropic agent used for temporary circulatory support in patients with severe pump failure.’

ischemic

dilated

cardiomyopathy.

 

Acute

hemody-

Recent reports also have advocated its intermittent

use

namic

improvement

was

noted

in

all

patients.

All

on a long-term basis for treatment of refractory conges-

patients

had

a significant

decrease

in plasma

po-

tive heart failure (CHF).2,3 Dobutamine exerts signifi-

tassium

(4.6

f

0.1

to

4.2

f

0.2

mEq/liter,

p

cant /3r stimulatory effects, with only modest stimula-

<0.0001)

at

peak

infusion.

The

decrease

in potas-

tion of & receptors.1,4 Other /3 agonists (such as epi-

sium

persisted

for

at

least

45

minutes

 

after

discon-

nephrine, salbutamol) by a postulated ,&-receptor

tinuing

the

infusion.

Three

patients

 

had

exacerba-

 

mechanism have been shown to cause a significant de-

tion

of baseline

ventricular

arrhythmias

that

re-

crease in plasma potassium in normal

subjects.5-8 These

solved

with

infusion

discontinuation.

 

Changes

in

changes have not been reported in patients with CHF.

plasma norepinephrine

could

not

explain

the

potas-

However, patients with CHF have been shown to have

sium

decrease

or arrhythmia

production,

which

down-regulation of ,& and /32 receptors in some or-

also

significantly

decreased

in these

patients

(771

ganq9Jo and thus may not have clinically

significant

po-

f

123

to

524

f

73

pg/ml,

p <O.Ol).

It is concluded

 

tassium decreaseswhen given drugs with only modest 162

that

dobutamine

causes

a significant

decrease

in

effects. Ventricular arrhythmias are often present in pa-

plasma

potassium

 

and

that

the

decrease

persists

at

tients with CHF and probably contribute to the high

least

45

minutes

after

the

infusion

is discontinued.

 

incidence of sudden death in this syndrome.r1J2 Beta

 

(Am

J Cardiol

1989;63:643-646)

agonists like dobutamine have been reported to worsen or precipitate these ventricular arrhythmias. Because potassium shifts could potentially contribute to arrhyth- mia production, the present study was designed to de- termine whether dobutamine, a predominant fir agonist, could produce significant plasma potassium changes in patients with CHF.

METHODS

Thirteen

patients with chronic dilated cardiomyopa-

thy were studied before, during

infusion. Five patients were treated because of acute ex- acerbations of their chronic CHF and 8 were in chronic,

and 7

4

women, and the mean age was 56 f 5 years. Six were in New York Heart Association class IV and 7 in class III. The average left ventricular ejection fraction was 15 f 3%. All patients were taking digoxin and received their dose on the day of the study. No patient received diu- retics within 12 hours of the study. All patients under- went right-sided heart catheterization and arterial line placement. Measurements were made of mean arterial

stable CHF. Of the 13 patients, 6 had idiopathic

ischemic cardiomyopathy. There

and after dobutamine

were 9

men

and

pressure, pulmonary artery wedge pressure, right atria1 pressure and cardiac output (thermodilution). Cardiac index, stroke index and systemic vascular resistance [80 (mean arterial pressure - right atria1 pressure)/cardiac

output]

were calculated.

Heart

rate was monitored

con-

tinuously

from

an electrocardiographic

lead. Baseline

From

the Minneapolis

Heart

Institute

and the University

of Minnesota,

Minneapolis,

Minnesota.

Manuscript

received

September

26,

1988;

revised

manuscript

received

and accepted

January

3, 1989.

Address

for

reprints:

Irvin

F. Goldenberg,

MD,

Minneapolis

Heart

Institute

Foundation,

920

East

28th

Street,

Suite

160,

Minneapolis,

Minnesota

55407.

 
Suite 160, Minneapolis, Minnesota 55407.   THE AMERICAN JOURNAL OF CARDIOLOGY APRIL 1, 1989 843
Suite 160, Minneapolis, Minnesota 55407.   THE AMERICAN JOURNAL OF CARDIOLOGY APRIL 1, 1989 843

THE AMERICAN

JOURNAL

OF CARDIOLOGY

APRIL

1,

1989

843

EFFECT

OF

BOBUTAMINE

ON

PLASMA

POTASSIUM

hemodynamic

utes until

measurements were taken every 1.5min-

varied by <lo%. by starting the infusion at

2 determinations

was titrated

Dobutamine

5.0 pg/kg/min

and increasing the infusion rate every 15

minutes

(by 2.5 to 5.0 pg/kg/min)

until

a dose of

15

pg/kg/min

was reached or the patient’s heart rate in-

creased by 15 beats/min,

creased by 20% or increasing ventricular ectopic activity

was noted. The peak dobutamine

maintained for 15 minutes and then the hemodynamic

the mean arterial

infusion

pressure in-

rate was

measurements were repeated. To avoid any potential ef-

fects of dextrose administration

levels, all dobutamine infusions were prepared with nor- mal saline. In all patients the cardiac rhythm was re- corded op continuous electrocardiographic strips for 60

minutes

strips

were analyzed and the number of ventricular premature complexes, couplets and ventricular tachycardia epi-

sodes every minute were determined. To classify the ar-

rhythmia

had to exhibit a mean increase of at least 5 ventricular premature complexes/min, or the dt+elopment of ven- tricular couplets or ventricular tachycardia. The in- crease in ventricular premature complexes had to be present for at least 15 minutes.

on plasma

potassium

before the infusion and during the entire infu-

sion period. The continuous electrocardiographic

as worsening during the infusion,

the patient

Central

venous blood was obtained for measurement

TABLE

I Changes

in Systemic

Hemodynamics

in Thirteen

Patients

with

Severe

Congestive

Heart

Failure

 

Baseline

Peak

p Value

Heart

rate (beats/min)

 

88f6

95f6

0.06

Mean

blood

pressure

(mm

Hg)

76f3

76f3

NS

Mean

right

atrial

pressure

lOf2

6f

2

<0.05

(mm

W

 

Pulmonary

artery

wedge

pressure

24f3

18f2

0.08

(mm

W

 

Cardiac

index (liters/min/m2)

 

2.1

fO.l

3.3 f0.2

<O.col

Stroke

volume

index (ml/m*)

25f3

35f3

<O.OOl

Systemic

vascular

(dynes-s-em-5)

resistance

NS = not s~@ficant.

1,429

f

113

955

f

76

<O.OOl

tained for the measurement of plasma renin activity by

the radioimmunoassay method of Sealey et all3 and plasma norepinephrine levels by the radioenzymatic as- say of Passon and Peuler,14 using a CAT-A-KIT device (Upjohn Company). Using this method, duplicate mea-

surements taken in our laboratory

variation of 8.4% for norepinephrine.

have a coefficient of

Statistical

analysis was performed

using paired

t

measurements and plas-

ma potassium at the different times stated. Data are expressed as mean values f standard error.

tests to compare hemodynamic

of plasma potassium at baseline (immediately before starting infusion), 15 minutes after peak infusion began and, in the last 7 patients, 45 minutes after the infusion was discontinued. In 9 patients, venous blood was ob-

5.5

r

.-

RESULTS

Dobutamine

was titrated

to a dose of 10 f

1 pg/kg/

min. The mean duration

dynamics

The most common reason for not reaching the target

dose of 15 pg/kg/

beats/min. Hemodynamic changes induced by peak

dobutamine

sium decreased significantly

infusion are listed in Table I. Plasma potas-

of infusion before peak hemo-

and potassium measurements was 60 minutes.

min was a heart rate increase >15

in all patients at peak infu-

sion, from

(Figure

p <O.OOOl

1). In 7 patients, plasma potassium was deter- again 45 minutes after the infusion was discon-

4.6 f

0.1 to 4.2 f

0.2 mEq/liter,

mined

tinued.

ter discontinuing

lower level than at baseline 4.3 f

liter, p <0.02 (Figure 1). There was no significant cor-

relation

plasma potassium changes. Plasma norepinephrine de- creased significantly at peak infusion (771 f 123 to 524

f

cant change in plasma ienin activity (35 f 10 to 32 f 9 ng/ml/hr, difference not significant).

at

baseline (i.e., > 1 ventricular premature complex/min or couplets). Three of these patients had ventricular pre- mature complexes and 1 had couplets. No patient had ventricular tachycardia at baseline. The effects of dobu- tamine on the number of ventricular premature com- plexes in all 13 patients is shown in Figure 3. Three patients developed worsening of arrhythmias. One had an episode of nonsustained ventricular tachycardia and an increase in the frequency of ventricular premature complexes, 1 with no baseline arrhythmias developed frequent couplets and 1 had ventricular tachycardia re-

In these 7, the plasma potassium 45 minutes af-

the infusion was still at a significantly

0.1 vs 4.5 f

0.1 mEq/

between degree of hemodynamic

change and

p <O.Ol)

(Figure 2). There was no signifi-

arrhythmias

73 pg/ml,

Four of 13 patients had ventricular

 

3.0Pre

 

Post

flGURE

1.

Plasma

pdasdm

levels

before

dohtamine

 

infu-

sidn,

at

peak

infusion

and

45

minutes

after

infusion.

Thick

so&f

line

cenneets

means

f

standard

enws

of

all

13

patii

(bmeline

to peak

infusion).

Dashed lime commts

means

f

standard

errers

(basehe,

peak,

postinfusion)

 

in

7 patients

w

plasma

potatim

at

all

3

time

points.

*

p

<O.OWl

peak

vsbasetilM?inaH13patientq**p<o.o2postinfusionvs

 

basellne

in

7 patients.

844

THE AMERICAN

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63

  basellne in 7 patients. 844 THE AMERICAN JOURNAL OF CARDIOLOGY   VOLUME 63
quiring cardioversion. The latter had a history of recent cardiac arrest and myocardial infarction and

quiring cardioversion. The latter had a history of recent cardiac arrest and myocardial infarction and was being treated with dobutamine because of cardiogenic shock. Before starting dobutamine, this patient had not had any significant arrhythmias for 12 hours. Because dobu- tamine had to be discontinued, an intraaortic balloon pump was placed to maintain adequate perfusion. The other 10 patients had no notable change in the frequen- cy of their arrhythmias. The plasma potassium decrease in the 3 patients who developed worse arrhythmias (mean decrease = 0.4 mE!q/liter) was similar to the de-

crease found in the patients without

occurred at a similar

arrhythmias,

and it

dobutamine

dose (10 hg/kg/min).

DISCUSSION

Patients with idiopathic and ischemic dilated cardio-

myopathy

mias and sudden death.11J2 In addition

ing etiology of their disease (such as ischemia) predis- posing to arrhythmias, these patients are often given

drugs (e.g., diuretics,

mia production. l5 When patients with CHF are treated for severeexa- cerbations, they are often given additional diuretics and sometimes an infusion of dobutamine.‘J5 Because cer-

tain patients develop significant ventricular arrhythmias with dobutamine use, the dose must sometimes be de- creased or the infusion stopped. Occasionally, because the infusion must be discontinued, more aggressive measures are performed, such as intraaortic balloon placement, as was done in 1 of our patients.

are at increased risk for ventricular

digitalis)

arrhyth-

to the underly-

that facilitate arrhyth-

Whereas ,6 agonists may precipitate

ventricular

irri-

tability by multiple mechanisms, including ischemia, in- creased automaticity and decreased ventricular fibrilla- tion threshold, their effect on altering potassium fluxes

has only recently been stressed.16J7 Our study

deter-

mines if clinically significant decreases in plasma

potas-

sium occur when dobutamine

CHF. We found that patients given dobutamine in dos- ages producing the expected hemodynamic changes ex- hibited a significant acute decrease in plasma potassi- um. This decrease was present shortly after initiation of the infusion and persisted for at least 45 minutes after the infusion was discontinued. The decrease was associ- ated with the development or worsening of ventricular arrhythmias in 3 patients. A cause and effect relation

is given to patients with

A

T-

between the decreased potassium and arrhythmias,

however, was not established as these patients were not

retreated with dobutamine

um. In addition, lar arrhythmias

our sampling time long enough to adequately assessthe

true incidence of worsening of ventricular arrhythmias.

Although p agonist-induced

discovered phenomenon in normal subjects, this study does show that dobutamine, a relatively Pi-selective

drug with modest p2 effects, can produce significant changes in plasma potassium in patients with heart fail-

ure at clinically

Some p agonists have been reported to increase plas- ma norepinephrine during their infusion.* This increase

in plasma norepinephrine could potentially be responsi- ble for some of the arrhythmias produced by these

agents. In addition, norepinephrine has weak ,&-stimu- lating effects’* and can produce potassium decreases.6J9 In the present series, however, plasma norepinephrine decreased significantly during infusion of dobutamine.

after replacement

of potassi-

our criteria may not have

for worsening of ventricu-

been strict enough, nor

hypokalemia is not a newly

used dosages.

Not

all p agonists have been reported to cause the

same degree of plasma potassium decrease.7,8 Brown et al7 gave both epinephrine and isoproterenol to normal subjects. They found no change in plasma potassium

with isoproterenol, but a significant decrease in plasma potassium with epinephrine despite similar increases in heart rate (25 beats/mm) and pulse pressure with the 2 drugs. These investigators attributed the difference in

response of

lectivity of epinephrine. Other investigators8 have also shown differences between p agonists in their ability to cause hypokalemia, with /I2 agonists causing a greater decrease in plasma potassium than predominantly /3r agonists. Because the potassium decrease caused by these agents can be prevented by nonselective p antago- nism (such as propranolol) but not by selective pr an- tagonism (such as atenolol), a ,&-receptor mechanism for the decreased potassium has been suggested.* This

these 2 catecholamines to the relative p2 se-

lo T

This these 2 catecholamines to the relative p2 se- lo T I Baseline Peak Dobutamine FIGURE
This these 2 catecholamines to the relative p2 se- lo T I Baseline Peak Dobutamine FIGURE

I

Baseline

Peak

Dobutamine

FIGURE

2.

A,

plasma

norepinephrine

levels

at baseline

and

peak

dobutamine

infusion

(*

p <O.Ol).

B, plasma

renin

FIGURE

3.

Effect

of dobutamine

on

the

number

of

ventricular

activity

at

basehe

and

peak

dobutamine

infusion.

premature

complexes.

 
 

THE AMERICAN

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OF CARDIOLOGY

APRIL

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1989

845

premature complexes.     THE AMERICAN JOURNAL OF CARDIOLOGY APRIL 1, 1989 845

EFFECT

OF

DOBlJTAiVllNE

ON

Pi&MA

POTASSliJhi

&-receptor stimulation causes an increase in the sodi-

urn-potassium-adenosine triphosphatase activity in skel- etal muscle with subsequent potassium migration into the ~~11s.~The decrease in potassium appears to be related directly to &receptor stimulation and not to secondary changes in other hormone systems (e.g., re- nin, insulin, aldosterone) that regulate potassium changes.7J6 No change in plasma renin activity was not-

ed during infusion in the present study. In addition,

nary loss of potassium is not a likely mechanism for this

ap-

pears to further

duced hypokalemia.21

are

potassium

uri-

decrease,16v20but prior

use of diuretics

increase the risk of catecholamine-in-

with dilated

cardiomyopathy

Because patients

also often treated with diuretics

be at considerable risk for arrhythmias if hypokalemia develops. Because an inverse relation between plasma potassium levels and malignant ventricular arrhythmias has been demonstrated in patients with cardiac dis-

ease,22-24it would seem appropriate to monitor potassi- um levels closely in patients treated with dobutamine and to administer supplemental potassium when neces- sary.

have

been used to treat patients with chronic congestive car-

diomyopathy,2T3 the safety of this treatment has not been established. Dobutamine-induced hypokalemia could be harmful, leading to a worsening of ventricular arrhythmias and sudden death. A recently performed multicenter double-blind study comparing intermittent dobutamine infusions with placebo revealed a disturbing incidence of death during dobutamine infusions, partic- ularly if there were high grade ventricular arrhythmias on baseline Holter recordings. The relation of these findings to plasma potassium levels is not known,

and digoxin,

they may

Although

intermittent

dobutamine

infusions

Acknowledgment:

The authors would like to thank

Terri

tance in preparing

Hanson

and Nancy

Grunz for secretarial

this manuscript.

assis-

BS, Sutton FJ, Newman

KA, Reed WP. Intermittent dobutamine hydrochloride infusions in outpatients with chronic congestive heart failure. Chin Pharm 1985;4:195-199.

3. Berger

2. Roffman

DS, Applefeld

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MM,

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