Comparative effects of ionic and nonionic contrast materials on indexes of isovolumic contraction and relaxation in humans

METHODS

Comparative Effects of Ionic and NonionicContrast Materials on Indexes of lsovolumicContractionand Relaxation in Humans G. 6. JOHN MANCINI, MD, FRCP (C), J. EDWIN ATWOOD, MD, VALMIK BHARGAVA,

PhD, ROBERT A. SLUTSKY,

MD, MALEAH GROVER, MD,

and CHARLES B. HIGGINS, MD

The effects of contrast media on left ventricular (LV) relaxation as assessed by the time constant of isovolumic relaxation have not previously been studied. A new nonionic contrast agent (iohexol) has been shown to have fewer deleterious effects than standard ionic agents. Nineteen patients received iohexol and sodium meglumine diatrizoate (Renografin-76e) in a double-blind, crossover study during left and right coronary arteriography and with simultaneous high-fidelity micromanometer measurements of LV pressure. Neither agent induced significant changes in LV end-diastolic pressure afler right or left coronary arteriography. After right coronary arteriography, neither agent produced significant deterioration of peak positive dP/dt or (dP/dt)/DPdo (dP/dt at a developed pressure of 40 mm Hg). However, afler right coronary arteriography

both agents caused a transient deterioration in peak negative dP/dt and the time constant of isovolumic relaxation (p <0.05 at 20 seconds after arteriography). After left coronary arteriography, sodium meglumine diatrizoate induced deterioration of systemic blood pressure (p <0.05), peak positive dP/dt (p
Ionic contrast materials routinely used in diagnostic cardiac catheterization produce deleterious effects on myocardial function during coronary arteriography, left ventriculography, and even after i.v. injection.l-g These agents produce a depression of the contractile state and inhibition of both global and regional myocardial function, particularly in the presence of coronary stenoses.*Jc Less well documented is an impairment of myocardial relaxation as measured by the maximal rate of pressure decrease (peak negative dP/dt).7J1,12

However, true impairment of relaxation has not been shown definitively because the alterations in peak negative dP/dt generally parallel the characteristic decrease in aortic pressure that occurs after injection of these agents. Such a decrease in pressure depresses the measured peak negative dP/dt without implying an independent change in the process of relaxation.‘sJ4 The characterization of myocardial relaxation by measurement of the relaxation time constantI has not been previously investigated. Although this variable is somewhat affected by loading conditions, the directional change in the relaxation time constant with alterations in afterload are exactly opposite to those of the maximal negative dP/dt, and might therefore be useful in characterizing perturbations in isovolumic relaxation induced by contrast injections.16J5 The deleterious cardiac effects of ionic contrast materials have generally been ascribed to excessive amounts of single-valence cations such as sodium and meglumine in the media, contrast-induced hypocal-

From the Departments of Medicine and Radiology, Veterans Administration Medical Center and University Hospital, University of California, San Diego, California. This study was supported in pat-l by the Canadian Heart Foundation, Ottawa, Canada; SCOR Research Grant HL 17682 from the National Institutes of Health and Grant iK04HL2001 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland; and the Sterling-Winthrop Rsearch Institute, Rensselaer, New York. Manuscript received August 26, 1983, accepted September 22, 1983. Address for reprints: G. B. John Mancini, MD, Division of Cardiology (11 lA), Veterans Administration Medical Center, 2215 Fuller Road, Ann Arbor, Michigan 48105. 228

January

TABLE I be

1. 1984

53f

(yr)

11

3 1 4

s&3 6f2 6f2

Right coronary arteriography Sodium meglumine diatrizoate lohexol Concomitant medications (no. of patients) Digitalis glycosides Nitrates Beta-blocking agents Calcium antagonists Antiarrhythmic agents

5f2 5f2

5 :; 12 3

cemia and the hyperosmolality of these solutions.1,2~fi~1s-26 Laboratory investigations and a recent clinical investigation have demonstrated that nonionic contrast agents are devoid of many of these toxic properties and thereby might be safer for use in clinical coronary arteriography.1°1z7 This investigation further extends our observations on the cardiac effects in man of iohexol, a new nonionic contrast material, and compares it to sodium meglumine diatrizoate (Renografin-76@), the most commonly used angiographic contrast medium. Furthermore, we attempted to define more definitively the effects of these ionic and nonionic agents on indexes of isovolumic contraction and relaxation and to examine the behavior of the relaxation time constant during coronary arteriography. Methods All patients referred for cardiac catheterization were eligible for this study except (1) those with a serum creatine level >3.0 mg/lOO ml, (2) those with known sensitivity to iodine, (3) pregnant or lactating women, and (4) patients who had received contrast media within 48 hours of the study. The study was terminated when 19 patients had been enrolled. Clinical features of these patients are summarized in Table I. Patients were studied by the Judkins technique after premeditation with oral diazepam, 5 to 10 mg, and diphenhydramine, 25 to 50 mg. A No. 8Fr high-fidelity

TABLE II

229

53

Physical Characteristics of Contrast Materials Viscosity Centipoise Iodine (mg/mf)

Sodium meglumine diatrizoate lohexol l

Volume

micromanometer catheter (Millar) with a pigtail configuration was advanced through a sheath in the left femoral artery and into the left ventricle. Size 8 Judkins coronary catheters were inserted through the right femoral artery by the Seldinger technique. Heparinization was maintained during the entire protocol and was subsequently reversed with protamine sulphate. Aside from a superficial hematoma in 3 patients at the site of the added arterial puncture, no untoward effects of the protocol occurred. Neither the patient nor the angiographer knew which contrast agent was being used. The order in which the agents were used was also randomized. Each patient received both sodium meglumine diatrizoate and iohexol (Table II) for both left and right coronary arteriography in a double-blind, crossover st.udy design. Arteriography was performed during quiet respiration so that the hemodynamic effects of deep inspiration and inadvertent Valsalva maneuvers could be excluded. The amounts of contrast material injected were recorded (Table I) and were equal for the paired injections in each coronary artery. Contrast was injected manually and the delivery rate was maintained as similar as possible for the paired injections. The variables of interest were the systolic blood pressure, left ventricular (LV) end-diastolic pressure, peak positive dP/dt, (dP/dt)/DPdo (dP/dt at a developed pressure of 40 mm Hg), peak negative dP/dt, and the time constant of isovolumic relaxation. All variables were measured during a control state and for 5 minutes after administration of each agent used for both left and right coronary arteriography. Small test injections were used to confirm proper engagement of the coronary ostia and 1 to 2 minutes were allowed to elapse after this before data was recorded. The second coronary injection was performed 8 to 10 minutes after the first. The high-fidelity LV micromanometer was calibrated against a Statham strain-gauge manometer just before each coronary injection. LV pressure measurements were acquired and digitized at 200 samples/s on-line and stored on computer tape. The first derivative of the pressure tracing was computed. LV end-diastolic pressure was defined as the pressure at which dP/dt reached 200 mm Hgls and the pressure increased monotonically thereafter. The peak positive and peak negative dP/dt and (dp/dt)/DP*o were determined. The interval of isovolumic relaxation was defined from the time of peak negative dP/dt to a point at which LV pressure was 10 mm Hg above end-diastolic pressure of that beat. LV isovolumic pressure (P) with respect to

Characteristics of the Study Group

Coronary artery disease (no. of patients) Normal 1 vessel 2 vessel 3 vessel Valvular disease (no. of patients) Trivial to mild mitral regurgitation Mild aortic regurgitation Ejection fraction (%) Volume of contrast injected (ml) Left coronary arteriogr?phy Fhdi!i; meglumlne dlatrlzoate

THE AMERICAN JOURNAL OF CARDIOLOGY

370 350

Calcium disodium edetate.

Osmolality (mosmol/kg) 1680 880

2o”c

37OC

Sodium (mEq/liter)

13.8 23.3

8.4 10.6

190 Negligible

Calcium (mEq/liter)

Ne$gible

Sodium Citrate (mg/ml)

Disodium Edetate (mglml)

3.2

0.4 0.1’

230

CONTRAST-INDUCEDCHANGES IN ISOVOLUMIC INDEXES

TABLE III

Control Values Left Coronary Arteriography lohexol

Systolic blood pressure (mm Hg) Left ventricular end-diastolic pressure (mm Hg) Peak positive dP/dt (mm Hg/s) (dP/dt)/DPdo (mm Hg/s) Peak negative dP/dt (mm Hg/s) Relaxation time constant (ms)

130 f 19f8 1448 f 951 f -1664 f 54.1 f

Right Coronary Arteriography I?76

23

125 20 1411 951 -1556 54.2

291 187 554 5.2

Values represent mean f 1 standard deviation. (dP/dt)/DPdO = first derivative Hg; R76 = sodium meglumine diatrizoate (Renografin = 76).

f f f f f f

lohexol 22 7 249 183 423 6.3

127 20 1426 932 -1705 52.8

of left ventricular

f f f f f f

R76

21 7 292 176 525 6.8

130 22 1443 924 -1706 53.7

Results The preinjection control values are listed in Table III. No statistical difference at control was noted.

pressure at a developed pressure of 40 mm

RIGHT CORONARY ARTERIOGRAPHY

LEFT CORONARY AATERIOGRAPHY

1

!+iy++++ XI

*

.

fl76

0 *

IOM-XOL p< 05 “I

* p< 01 ++ p< 01

“I “I

c0Mrn01 c0ml01 IOHfXOl

lzz lo’

0’

’ IO

’ 20

FIGURE 1. Hemodynamic

’ 30

‘%iG+*S

20 8 255 208 475 7.1

Hemodynamic effects: Neither agent caused significant changes in LV end-diastolic pressure after coronary arteriography, and iohexol caused no significant changes in systolic blood pressure (Fig. 1). In contrast, sodium meglumine diatrizoate caused a significant decrease in systemic pressure at 20 and 30 seconds after both left and right coronary arteriography. Alterations in indexes of isovolumic contraction: Neither agent altered peak positive dP/dt significantly after right coronary arteriography (Fig. 2). However, after left coronary arteriography sodium meglumine diatrizoate caused a marked, transient depression in peak positive dP/dt (p
time (t) was fitted to an exponential curve of the form: P = PO exp (-t/T), where PO is the pressure at peak negative dP/dt and T is the relaxation time constant.15 T was calculated over the first 40 ms of the isovolumic pressure decline. 28,2gAll variables were automatically calculated on a beat-by-beat basis and averages were determined from 4 to 9 beats occurring during each time interval (0 to 10,lO to 20,20 to 30 and 50 to 60 seconds and 3 and 5 minutes). Statistics: All data were analyzed by repeated measures analysis of variance. Differences were considered significant if p <0.05. Tabular data are presented as mean f standard deviation and data in graphs represent mean f standard error of the mean. Two patients had a total proximal obstruction of the right coronary artery and 1 patient had an aberrant origin of the right coronary ostium that could not be directly intubated. Thus, the data presented for left coronary arteriography is based on paired data from 19 patients, whereas results for right coronary arteriography are based on paired data from 16 patients. Most patients had coronary disease or were ingesting medications not altered for this protocol, and statistical analysis of clinical subgroups was not attempted because of the small number of patients in each group. Nevertheless, because of the study design, each patient served as his own control.

'g

f f f f f f

min

%-k-+&+10

changes induced by contrast agents. R76 = Renografin-76.

3' min +-+mm

January 1.1984

THE AMERICAN

LEFTCORONARY ARTERIOGRAPHY

JOURNAL

OF CARDIOLOGY

Volume 53

RIGHTCORONARY ARTERIOGRAPHY

16OOr

F

. R76 0 IOHEXOL W p
1100' ;

' IO

I 20

FIGURE 2. Alterations

I 30

,,

’

I 60 set '

I 3 min '*

min

I1

I 0

10

I 20

I 30

.,

I 60 set"

’

I 3 min

'*

rnul

in peak positive dP/dt induced by contrast agents. R76 = Renografin-76.

LEFTCORONARY ARTERIOGRAPHY

RIGHTCORONARYARTERIOGRAPHY

105Or

‘.L*W? 20

30

FIGURE 3. Changes in (dP/dt)/DP,,

min

(dP/dt at a peak pressure of 40 mm Hg) caused by contrast agents. R76 = Renografin-76.

LEFTCORONARY ARTERIOGRAPHY 7

RlGHTCORONARYARTERlOGRAPHY

-1400 . 0 *

-1450 *

-1500

-1550

-1600 ; ", ‘, I -1650 z -1700

-1750

-1600

-1950 -1900

FIGURE 4. Temporal changes in peak negative dP/dt. R76 = Renografin76

1176 IOHEXOL p< 0.5 “S CONTRDl pc III “I CONTROI lO”EXOL

tt p<0,“S

231

232

CONTRAST-INDUCED

CHANGES

IN ISOVOLUMIC

INDEXES

The relaxation time constant was altered in a similar fashion to peak negative dP/dt (Fig. 5). That is, iohexol produced no significant change in isovolumic relaxation after left coronary arteriography, whereas sodium meglumine diatrizoate caused significant prolongation at 20 seconds compared with control (p
effect is somewhat blunted in the presence of coronary disease,10 as in most of our patients. Of the 4 patients with normal coronary arteries, 3 were taking &blocking or antiarrhythmic agents, which might also have blunted this positive inotropic effect. Our findings are therefore not at variance with these previous reports. Peak negative dP/dt deteriorated after left coronary arteriography with sodium meglumine diatrizoate but not with iohexol. Once again, this coincided with a decrease in arterial pressure, and this might itself produce a decrease in the peak negative dP/dt.‘“,14 A decrease in systemic pressure would be expected to cause shortening in the relaxation time constant;16k17 however, a prolongation was observed. Furthermore, this deterioration in LV relaxation variables induced by sodium meglumine might well have been underestimated in this study because of concomitant lowering of afterload. Thus, the current study showed a true impairment of myocardial relaxation in humans in response to ionic contrast media. This has not been shown previously. Both agents caused a similar, significant but slight depression of relaxation after right coronary arteriography. The reasons for the similar effects of the 2 contrast materials after right coronary arteriography are not clear, but may be related to a relatively higher volume, concentration, or rate of delivery of contrast into a smaller right coronary bed compared with the left coronary bed. This finding suggests that the disparate effects of these agents may, in part, be dose-related. An actual analysis of these factors is not provided in this investigation. In conclusion, in addition to fewer deleterious hemodynamic and electrocardiographic effects previously shown in humans,27 iohexol has the added advantages of causing less contractile depression and less impairment of relaxation. These findings, determined in a typical group referred for cardiac catheterization, are of potential importance because of the large number of patients undergoing angiographic procedures. Acknowledgment: We thank J. Neukam Bloomquist for help in recruiting patients and analyzing data and Elizabeth Gilpin for providing statistical analysis.

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.

RIGHT CORONARY ARTERIOGRAPHY

LEFT CORONARY ARTERIOGRAPHY

NT6

IotlExol x p< 05 YI %-#t p<.Ol vr t p<.OS M tt p<.OI M 0

.s

FIGURE

5. Transient

changes

in the relaxation

time

constant.

R76

= Renografin-76.

CONTROL CONTROL IOHEXOL IOHEXOL

January 1, 1984

3. 4.

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___.