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INOTROPIC DRUGS IN

CLINICAL PRACTICE

J. COLTART & P. WILLICOMBE

Departm ents ofCardiology and Cardiac Research,

The Ra yne l nstitute, SI. Thoma s ' Hospital, London, SE.i, Eng land.

The treatment of a patient with a low cardiac output is often disappointing and the

approach to management controversial. The use of pharmacological and physical

agents to support and improve left ventricular function following low cardiac output

states is at present a subject of considerable reappraisal. G uidelines as to whether

in vasive methods such as balloon counterpulsation or medical ph armacological

th erapy should be em ployed, have not been clearl y defmed. In most hospitals,

medical management has th e ad vantage that it is readily applicable. With the introduction of peripheral vasod ilators - salb uta mol, nitroprusside, phentolamine (Wyse,

Gibson & Branthwait e, 1974: Palmer & Lasseter, 1975) for th is clinical situation, th e

rol e of inotropic agents - iso prena line , ad rena line , dop amine, has been criticised

(C ha tte rgee, Parmley, Gan z, Forrester , Wa len sk y, Crexel s & Swan , 1973) and

become less clear. To ob viate so me of the th eoret ica l d isad vantages of avai lable

inotropic agents, ne w compounds have bee n synthes ised.

Dobutamine hydrochloride is a recently introduced, cardiose lective, synthetic

ca techo la mi ne , with a structure similar to isop ren aline and dop amine. Earl y studies

(Jewitt, Birkhead , Mitchell & Dollery, 1974; Vatner, McRi chi e & Braunwald . 1974)

with th is drug revealed that it had pot ent inotropic ac tivity, but co m pa red with other

ca tec ho lamines it caused less increase in heart rat e. It had littl e eITec t on peripheral

ß-adren oceptors, and peripheral resistan ce was little alt ered . As a res ult of this, the

reducti on in diastol ic coro na ry perfusion pre ssure seen with isoprena line , and the

elevat ed systolic pre ssures frequ entl y ca used by adrenaline and dop amine, do not

occ ur with thi s drug.

Unlike dopamine , dobutamine does not rely for part of its acti on on the release of

stored catec ho la m ines, which may be severely depleted a fter cardiopulmonary

bypass when inotro pic therapy is often indi cated. An imal stud ies have shown that the

increase o f cardiac output produced by dobutamine improves flow to th e coronar y

and iliac bed s, but ca uses only a minimal cha nge in renal blood flow . Studies on

myoca rdi al infar ction in dog s (Turtl e, Pollock. Todd & Trust, 1973; Mar ok o, Swa in

& Vatner , 1974) ha ve dem on strated that dobutamine ca uses less increase in infarct

size th an other inotropic agents, a nd suggest that th is co uld be du e to a co mbina tion

of slower heart rate, co ro na ry vasodi lation, and ma int enan ce of aortic diastolic

coronary perfusion pr essure. Such studies suggest therefore, that dobutamine is a

potent iall y useful drug in th e treatment oflow out pur sta tes,

The ex pe riences co m pa ri ng dobutamine, iso prenaline , ad rena line a nd noradrenaline in patients after cardiopulmonar y bypass surgery will be reviewed.

INOTROPIC DRUGS IN CLiNICAL PRACTICE

Mcthods

189

Aorticflow measurement

The use of the Williams-Barefoot extractable aortic 110w probe, produced a

continuous display or aortic 110w trace, and its derived parameters (Bourne &

Williams, 1975). This 110w probe is placed around the ascending aorta during surgery,

with its cable being exteriorized through a small incision to the right ofthe sternum.

The probe can be left in place for up to a week , and when recording has been

completed, by cutting an external snare, the probe can be removed by gentle traction,

causing less discomfort to the patient than removal of a conventional drain . The 110w

probe is connected to a Carolina 6010 gated square wave flowmeter, which gives a

continuous display ofcardiac output.

The haemodynamic Imdings were obtained with equipment designed specifically

for precise circulatory monitoring of the critically ill patient after cardiac surgery.

The Williams-Barefoot extractable electromagnetic 110w probe permits the

continuous display ofascending aortic 110w in the intensive care unit, and has proved

of great benefit in the assessment and management of patients after open heart

surgery. A more precise assessment of the effects of pharmacological and physical

interventions is possible than with the conventional pressure and cardiac output

measurements hitherto available. Electromagnetic 110w probe cardiac output

measurements are more accurate than dilutional techniques, especially in low output

states (Jacobs, Heydon, Williams, Schmidt & Schenk, 1970). Values measured with

the Williams-Barefoot 110w probe have been compared with rigid electromagnetic

110w probes, indocyanine green dilution cardiac output, and thermodilution cardiac

output. Good correlations with all methods have been obtained. A further advantage

ofthe technique is that it is possible to derive other indices ofaortic 110w. Peak aortic

110w and maximal acceleration of 110w, (Noble, Trenchard & Guz, 1966) and left

ventricular power (Benzing, Stockert, Nave, Tsuei & Idaplan, 1974) have been used

as ind ices ofmyocardial function , and may be readily obtained using this equipment.

Other measurements

Left and right atrial pressures and arterial pressure (radial or femoral artery) were

measured using Statham 23 Pd pressure recorded directly on to a Philips eightchannel tape recorder and were analysed down-stream by the St Thornas' postoperative monitoring trolley. This enables a continuous digital or meter display of

cardiac output, stroke volurne , stroke work, an index ofperipheral resistance , arterial

pressure, left and right pressure, and heart rate.

In so me patients a coronary sinus sampling line was left in place following surgery,

and coronary sinus and arterial sampies were taken and analysed for lactate,

pyruvate, and oxygen content.

The haemodynamic variables were calculated from the basic data as folIows :

Cardiac Index (CI) =Cardiac output/body surface area (litres min-I rrr-'),

Stroke Volume Index (SVI) =Stroke volume/body surface area (mi min-I m- 2).

Stroke Work Index (SWl) =SVI x (mean arterial pressure - right atrial pressure) x 0.0136 (g rn-I rrr-').

Systemic Vascular Resistance Index (SVRl) = (mean arterial pressure - mean atrial pressure)

Cardiac index

(mmHg litre! min-I m-2)

The 110w trace was passed through a differentiator, and the first differential,

maximal acceleration of 110w was measured. The percentage change was calculated,

using either the resting or initial stable isoprenaline value as control.

190 J. COLTART & P. WILLICOMBE

Drug infusion

The patients fell into two groups, I) those on no inotrope, and 2) those patients who

prior to the study had been stabilised on isoprenaline.

Patients on no drugs

After confirrning that the patient was in a haemodynamically stable state (relatively

constant cardiac output, blood pressure, left and right atrial pressure and heart rate

for I h), dobutamine 1.25,2.5, 5 and 10 Ilg kg-i min-I or isoprenaline 0.01, 0.02, 0.04

and 0.08 pg kg-I min-I were given, each dose level of 7-10 min, starting with either

drug in a random order with a I h equilibrium interval between the different drug

infusions. The dose range was judged, from previous reports, to be the concentration

of drugs producing identical increments in cardiac output in patients studied during

cardiac catheterisation (Jewitt et al.. 1974).

Patients on isoprenaline

These patients were similarly confirmed to be stable; the isoprenaline dose was then

doubled for 10 min and was then returned to the control level. Once restabilised, the

patient was switched to dobutamine at 125 times the dose of isoprenaline for 10-20

min; the dose was then doubled for ten min . The patient was then placed back onto

the initial isoprenaline dose , allowed to stabilise again ; the dose was double for 10

min . Either the isoprenaline data before or after the dobutamine infusion was

analysed, in a random order.

The ratio of the diastolic pressure-time index to the tension-time index

(DPTIITTI) reflects adequacy of subendocardial perfusion. The effects of three

inotropic agents on DPTIITTI in patients 12-48 h after cardiopulmonary bypass

were examined by this department. Inotropic effect was quantified by indices derived

from simultaneous arterial pressure and aortic flow measurements.

Isoprenaline (eight patients) was infused intravenously at 0.01, 0.02, and 0.04 Ilg

kg-I min-I

. Adrenaline (five patients) or noradrenaline (frve patients) was infused

intravenously at 0 .03 , 0.06, 0.12 and 0.24 Ilg kg! min-I. Results are group mean

percentage changes from pre-drug baseline with successive incremental doses.

Results

In both groups of patients, in the dose levels chosen, dobutamine appeared to

produce an equipotent inotropic effect when compared with isoprenaline.

Both drugs produced a dose-dependent increase in myocardial performance as

measured by maximum acceleration of aortic flow, and stroke work (left atrial

pressure changed little during the infusions). Though both drugs caused an increase

in heart rate, dobutamine produced its improvement in inotropic action as measured

by these two indices, at a heart rate 10-15% lower than isoprenaline (Figures land 2).

The stroke volume was only slightly altered by increasing doses of both drugs

(12.5% and 13.9% increase with the highest doses of dobutamine and isoprenaline,

respectively). As a result of this, in these patients following open heart surgery,

cardiac output is very dependent upon heart rate, and thus any difference in

chronotropic activity between the two drugs would not be revealed by a measurement

of cardiac output alone. Figures land 2 show that the increase in cardiac index with

dobutamine and isoprenaline was achieved at almost identical heart rates.

The effects of the drugs upon blood pressure differed considerably. Isoprenaline

caused little change in systolic pressure, but a fall in diastolic pressure (mean

diastolic pressure fall at the highest dose was (3 ± 1.5 mmHg, P < 0.05); in contrast

INOTROPIC DR UGS IN CLINICAL PRACTI CE 191

dobutamine ma intained diastol ic pr essure at co ntro l levels and there was a mod erat e

rise in systolic pressure (15.7 ± 2.9 mmHg, P < 0 .0 1 at th e highest do se). Both drugs

lead to a fall in peripheral resis ta nce, but thi s was more marked with isoprena line.

Cord ioc incex Maximal occelerot ion

(% changes frorn contro l) / / /

140 / 140 / /

/ Q) / Q) /

e_ / . / . / . / . 't:7 120 y. t :- l20 /, oe / 0, / . y Q) C

1? "E

"/' "E / / ... Q) Vl / ... c - - 0 100 .. 100 /~ J. E Q)

-x0 >:

.0 e/" • ~~ //.i : · . / ,, - " / . .0 / . .0 80 / 0 80 / ... 0 / .. 0 / 0 /

80 100 120 140

lsopr enotine heart rate

(bents rnin'")

Figure 1 The haemodynamic changes in one patient during isoprenaline and dobutamine

infusions, changes in cardiac index, and maximum percentage change from control in

acceleration for a given heart rate are compared.

110 ,

C

E100 Vl

Ci

8 90

o 80 Q)

I

Cordicc Index

9

/

/J

/

/

/

?

--

_ 110

,

C

E100 Vl

Ci 590

Q)

e

80 g

I

MaXimal occeteronon

,0

/ / /

0-/

/

/ /

/

o:

Cardiac index

(lit res mln- I m- 2)

2 2.5 3 3.5 100 110 120 130 140

MaXimal occelerot ion

(% changes trom controll

• Dobutamine

o Isoprenolme

Figure 2 A comparison of the chronotropic eflects of isoprenaline and dobutamine. The heart

rates produced by both drugs to achieve the same cardiac index (a), and maximal acceleration

(b), in the 14casesstudied are plotted.

A ll patients remained in sinus rh ythm du rin g th e infusio ns; in two pat ients th er e

was a slight inc rease in ventricular extras ystoles, but some ventricular extrasysto les

wer e evide nt during th e co ntro l period. The increase was sma ll (two to five

ventricular ectopics per m in), no infusion was stopped becau se ofthe development o f

arrh ythmias, and th er e were no cha nges in ST segments or T wave s wh ich were

monitored th roughout th e invest igati on.

In the five cases where sim ulta neous arter ial a nd coro nary sinus blood sa m pies

were taken , there appea rs to be little differen ce in th e metab oli e effects of both drugs.

Compa red to controllevels th ere was no differen ce in A- V ox ygen co nte nt difference,

and both drugs appeared to reduce th e lactate and pyruvat e uptak e of the

m yocardium. There thus app ea rs to be littl e ben efn in m yoca rd ial economy from

dobutamin e wh en compared with isopren aline in th ese pat ients.