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Systemic and Coronary Hemodynamic Effects ofDiazepam in Patients with Normal and Diseased

Coronary Arteries

By PIEnRRE COTEI, M.D., PASCAL GUE'RET, M.D., AND MARTIAL G. BOU-RASSA, M.D.

SUMMARYIn 12 patients with significant coronary artery disease (group I) and in eight patients with normal coronary

arteries (group II), 5 to 8.5 mg of diazepam was given intravenously before coronary angiography. Adequatesedation was obtained in 17 patients. Hypoventilation occurred in all patients but was without clinical cor-

relate. Coronary and cardiovascular effects were assessed before as well as 10 and 20 min after diazepam.Heart rate was unchanged and aortic pressure (AP) decreased significantly (P < 0.01) in most patients. Car-diac index decreased only in patients of group II (P < 0.01). Of particular interest was a constant fall in leftventricular end-diastolic pressure (LVEDP) in both groups, (P < 0.01) and (P < 0.05) at 10 and 20 minrespectively in group I and (P < 0.01) at 10 and 20 min in group II. Tension-time index and myocardial oxy-

gen consumption (MVO2) were also significantly decreased (P < 0.05) after diazepam in both groups. Sinceneither coronary blood flow nor coronary vascular resistance were modified by diazepam, the fall in LVEDPcould be due to a decrease in AP (afterload) and/or in venous return (preload). The combination of theseeffects could reduce intra-cavitary volume, myocardial wall tension and left ventricular MVO,. Our datatherefore suggest that, in addition to its central sedative effects, diazepam also has a nitroglycerin-like actionon the coronary and systemic circulation.

Additional Indexing Words:Coronary sinus blood flowNitroglycerin-like action

Left ventricular functionLeft ventricular end-diastolic pressure

Myocardial metabolism

AS A SEDATIVE-HYPNOTIC AGENT, diazepamhas been found very useful to induce analgesia

and amnesia during direct-current cardioversion.'`Although it is generally accepted that diazepamproduces less circulatory depression than morphine,other narcotics and barbiturates,'6 these agents arestill used much more commonly to alleviate apprehen-sion and pain in cardiac patients, be it during thecourse of an acute myocardial infarction or in the car-diovascular laboratory. In the latter clinical situation,this contrasts with the general acceptance of diazepamas an excellent mental relaxant prior to broncho-scopy,4 gastroscopy6 and other procedures. 7', 8On the other hand, diazepam is frequently

prescribed in the management of anginal patients.Since anginal pain is often related to stressful stimuli,the beneficial effects of this tranquilizing drug are

From the Montreal Heart Institute, and the Department ofMedicine, University of Montreal Medical School, Montreal,Quebec, Canada.

Supported by the Jean-Louis Levesque Foundation and ProjectMA-4747, Medical Research Council of Canada.

Address for reprints: Martial G. Bourassa, M.D., Montreal HeartInstitute, 5000 East Belanger Street, Montreal H1T 1C8, Quebec,Canada.

Received April 30, 1974; revision accepted for publication July 1,1974.

thought to be mediated through its action on the psy-che. However, recent studies have shown thatdiazepam increases coronary blood flow and thusenhances left ventricular contractility in dogs duringcardiopulmonary bypass.9 10 Hemodynamic studiesfollowing diazepam administration in humans havebeen few and fragmentary."1- For example, there areto our knowledge no available data on the effects ofthe drug on left ventricular end-diastolic pressure.

Therefore, the primary purpose of the present studywas to reassess the sedative and hemodynamic effectsof diazepam in patients undergoing cardiaccatheterization. Since measurements of coronaryblood flow are now easily feasible in the car-diovascular laboratory,'4 we have also attempted todetermine the coronary and metabolic effects ofdiazepam in patients with normal and diseased cor-onary arteries.

MethodsSubjectsTwenty unpremedicated subjects undergoing cardiac

evaluation for coronary artery disease were studied after anovernight fast. Informed consent was obtained for the ad-ditional procedure; however, no information was given con-cerning the nature of the drug to be studied. Exclusioncriteria were as follows: diabetes, valvular heart disease,arterial hypertension (diastolic pressure greater than 105

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NITROGLYCERIN-LIKE ACTION OF DIAZEPAM

mm Hg), significant pulmonary disease, therapy with beta-blocking or other autonomic drugs as well as digitalis orother cardiotropic drugs.The study was undertaken after left heart and coronary

sinus catheterization, prior to left ventriculography and cor-onary arteriography. Patients were then divided into twogroups, according to the presence (group I: 12 patients) orabsence (group II: 8 patients) of coronary artery disease, asdetermined by cinecoronary arteriography. Table 1 sum-marizes the clinical and biological characteristics of the twogroups.

Treatments

The control measurements described below were notcarried out until at least 10 min after catheter manipulationsin order to achieve a stable basal state. The followingmeasurements were made over a 5 min period: bloodsamples were withdrawn from central aorta and mid-coronary sinus for biochemical determinations; all pressureswere recorded; cardiac output was determined and, finally,coronary sinus blood flow was measured. During the last 3min, expired air was collected for determination of body 02consumption. After completion of basal measurements,diazepam in a dosage of 0.1 mg/kg body weight was in-jected as a bolus into an arm vein through the side-arm of aninfusion tubing and was flushed immediately to avoidphlebitis.`5 The patient was unaware that the drug was be-ing administered. Measurements were repeated at 5 and 15

Table 1

Cliniical and Biological Data

Coronary artery Normal coironarxdisease: group I arteries: group fl

Clinical dlataN

Age: range (meais)Sex: male

femaleAniginiaOld myocar.dial inifarct.tionFuncetionial (lassificat-ioss*

I

II

III

IV

Other diseases:Mild essential hypertenssiollChr onie br.onichitis

Angiogqaphic data.Ves.sels with 751( obstr.uc toni]

or1 more

1 vessel disease2 vessel disease3 vessel disease

Abnior.mal left venitriculogr.an

1.2`7-62 (5`)

9

lit7

x27 54 (42)

.,

o)

it

it

.,17)

7

4

7

7

()4

*New Yoik Heart Associatioin.tA :37-yeai.-old male was.i,vtmnptomatic at the firnie of the

sttudy, bit, he had suffered an) acute myocardial itfar(tionW3 moniths befor e.tAn acuste myocardia.l iinfa.rctioni was well documnenited in

this 27-year-old female, .3 mnionths pr.iorl to the stuldy.Circulation, Volume 50, December 1974

min after diazepam over a 5 min period. Expired air wascollected once for determination of body 02 consumptionduring the 12th to 15th min. The drug study was completedwithin 30 min after diazepam injection. Left ven-triculography and selective coronary arteriography werethen carried out'6 and a precise diagnosis of the obstructionswas made.

Measurements

Systemic Hemodynamics and Derived Variables

Left ventricular and aortic pressures were measuredthrough an end-hole, 100 cm, size 7F, polyethylene catheter(USCI, Billerica, Mass.) passed percutaneously from thefemoral artery. A 100 cm, size 8F, Ganz thermodilutioncatheter* was inserted from the right or left antecubital veininto the main coronary sinus. Catheters were connected toStatham P23Db transducers, which were adjusted so thatthe zero pressure was at the mid-chest position. Pressureswere amplified and recorded on high and normal sensitivityand at paper speed of 100 mm/sec on a mul-tichannel San-born photographic recorder. Pressure readings were alwaysthe mean of 10 beats. Cardiac output was measured afterrapid injection of 5 mg of indocyanine green into the cor-onary sinus, followed immediately by a saline flush. Centralaortic blood was withdrawn by a Harvard infusion pump ata rate of 20 ml/min through a cuvette dye densitometer.Computation of the cardiac output was performed with theuse of the Williams formula.17

Systemic vascular resistance (SVR in dynes-cm - min)was calculated as follows:

SVR map X 80SR CO

where MAP indicates mean aortic pressure in mm Hg, CO iscardiac output in L/min, and 80 is the conversion factor toexpress resistance in absolute units.

Left ventricular stroke work index (LVSWI ingm/beat/iM2) was determined as follows:

LVSWI = SI (MSAP - LVEDP) 13.61000

where SI indicates stroke index in ml/beat/m2, MSAP ismean systolic aortic pressure and LVEDP is left ventricularend-diastolic pressure, both in mm Hg.

Tension-time index (TTI in mm Hg/sec/min) was mea-sured as follows:

TTI = (HR)' (SEP). (MSAP),

where HR represents heart rate in beats/min, SEP is systolicejection period in sec/beat and MSAP is mean systolic aorticpressure in mm Hg.Mean systolic ejection rate (MSER in ml/sec/m2) was

calculated as follows:

MSER =-SISEP

where SI is the stroke index in ml/beat/m2 and SEP is thesystolic ejection period in sec/beat.Coronary Hemodynamics and MetabolismCoronary sinus blood flow was measured by the ther-

*Supplied through Wilton Webster Co., Altadena, California.

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COTE, GUERET, BOURASSA

modilution method.`4 Estimation of total coronary flow bythis simple method was found highly reproducible in our

laboratory, provided that certain technical requirementswere observed. The external thermistor or distal pacing elec-trode of the Ganz catheter was positioned just inside the cor-

onary sinus ostium and was maintained in that positionthroughout the study. Location of the coronary sinus ostiumwas acknowledged by a small hand injection of contrastmaterial. A physiological saline solution at 22-25°C was in-jected into the coronary sinus, using a calibrated Harvardpump and twin-syringes of 20 ml, at a constant rate of about35-40 ml/min for 20-30 sec. As previously indicated,14 thisrelatively high injection rate allows adequate mixing of theinjectate with blood and the short period of injectionprevents contamination for recirculation. Under these con-

ditions, variations between two successive measurements inour laboratory did not exceed 5%.

Coronary sinus blood flow (CSBF in ml/min) wascalculated using the following formula:

CSBF = F,( Tb -1 ) 1.19Tb Tm

where Fi represents the volume of injectate (ml/min), Tb,T1, Tm are temperatures of blood, injectate and mixture ofblood and injectate ('C); 1.19 is a constant derived from thedensity and specific heat of the saline solution and blood.

Blood samples were obtained simultaneously from thecentral aorta and the coronary sinus and immediatelyanalyzed for pH, pO2 and pCO2 by a Micro-Astrup analyzer.Hemoglobin saturation was obtained from the oxyhemo-globin dissociation curve with correction for pH andtemperature, as described by Severinghaus.'8 Samples ofarterial and coronary sinus blood were also taken for deter-minations of lactate concentration by the enzymatic methodof Hohorst.19The following calculations were made:

left ventricular oxygen and lactate extraction (%)

arterial- coronary sinus oxvgen or lactate;arterial

left ventricular oxygen consumption (ml/min)[arterial - coronary sinus 02 content (ml/100 ml)]

X coronary sinus blood flow (ml/min) X 10-2;

coronary vascular resistance (units)mean aortic pressure (mm Hg)

coronary sinus blood flow (ml/min)Ventilatory Indexes

Before the administration of diazepam and midwaythrough the drug study, expired gas was collected and

measured in a Tissot spirometer. From the composition ofexpired air, oxygen consumption (V02 in ml/min) andalveolar ventilation (VA in L/min) were calculated.Respiratorv rate was measured by visual inspection of thechest.

Statistical analysis was performed with the use of a pairedStudent's t-test for comparison of data within the same sub-jects in each group. Diazepam values at 10 and 20 min were

compared to control values. No statistical comparisonbetween the two groups of patients was attempted.

ResultsClinical and Respiratory Effects of Diazepam

The average diazepam dosage was 7.2 mg (range: 5

to 8.5 mg) and 6.4 mg (range 5 to 8 mg) in groups Iand II, respectively. Adequate sedation was achievedin 17 of the 20 patients. In 5 subjects, light sleep wasinduced within one to 3 min and lasted 5 to 15 min;the patients were easily arousable. Three patientsbecame euphoric and one was slightly agitated for ashort period, but not disoriented. A few patients ex-perienced transient drowsiness after a bolus injectionof diazepam. Six patients had venous irritation at theinjection site, manifested by local pain; however,none developed phlebitis in the subsequent days.

Detailed ventilatory effects, between 12 and 15 minafter diazepam, and blood gas data at 5 and 15 minare shown in table 2. Minute ventilation decreasedfrom 7.7 to 6.6 L/min (P < 0.05) in group I and 7.0 to5.4 L/min (P < 0.01) in group II. Respiratory rate wasunchanged and thus hypoventilation was dueprimarily to a decrease in tidal volume. Analysis ofarterial blood gases reflected the observed hypoven-tilation, more pronounced in group I. In this group,there was a significant (P < 0.001) mean decrease inPO2 of 14 mm Hg at 5 min. In group II, PO2 decreasedby 6 mm Hg at 5 min but this was not significant.PC02 increased significantly (P < 0.001) in bothgroups at 5 min. There was a corresponding decreasein arterial pH 5 min after diazepam: mean decrease of0.05 in group I (P < 0.001) and 0.03 in group II(P < 0.05). By 15 min, PO2, PCO2 and pH hadreturned to control values in both groups, with the ex-ception of PO2 in group II, which was still significantly(P < 0.05) lower than control.

Svstemic Hemodynamic Effects of Diazepam

These data are shown in table 3 for both groups.

Heart Rate

There was no change in cardiac rhythm. Only twosubjects, with heart rates over 100 beats per min,slowed down after diazepam, from 122 to 98 and 112to 104 beats/min, respectively.

Pressures

At 5 and 15 min after administration of diazepam,aortic pressures (systolic, diastolic and mean) weresignificantly lower (P < 0.01) than control values inboth groups. Aortic pressures were unchanged in only3 patients. The observed changes were withoutclinical correlates and did not require therapy.

Left ventricular end-diastolic pressure (LVEDP)fell significantly in the normal group (group II) from9.5 to 6.6 mm Hg at 5 min (P < 0.01) and to 6.8 mmHg at 15 min (P < 0.01). In the coronary artery dis-ease group (group I), LVEDP also decreased from13.3 to 9.8 mm Hg at 5 min (P < 0.01) and to 9.6 mmHg at 15 min (P < 0.05). In the latter group, 5


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Table 2

Respiratory Effects of Diazepan in Patients with Normal and Diseased Coronary Arteries

Coronary artery disease: Group 1 Normal coronary arteries: Group IIN = 12 N = 8

After diazepam After diazepamParameters Control 5 to 10 min* 15 to 20 min Control 5 to 10 min 15 to 20 min

Arterial blood gasespH 7.48 0.02t 7.43 - 0.01 7.47 - 0.02 7.45 - 0.02 7.42 - 0.02 7.43' -0.01

P < 0.001t NS P < 0.05 NSpO2(mm Hg) 77 4 63 - 2 71 87 10 81= 9 87 -10

P <0.001 P <0.(0.5 NS NSpCO2(mm Hg) 26 1 32 2 25 1 24 - 2 29 . 2 25

P < 0.001 NS P < 0.001 NS

Ventilatory effects 15 min§ 15 min§02 consumption 245 - 14 221 - 11 216 13 191 * 11

(cc/min) P < 0.Oa P < 0.05Alveolar ventilation 7.7 - 0.8 6.6- 0.6 7.0 - 0.7 3.4 - 0.a

(L/min) p < 0.05 P < 0.01IlRespiratory iate (mini) 18 17 16 16

*Data collected over a 5 min period.tMean - SEM.tPaired t-test; differenice from control values (NS indicates ino significance).§Air collected through the mid-period of the drug study.

Table 3

Systemic Heniodynamnic Effects of Diazepam in Patients with Normal and Diseased Coronary Arteries

Coronary artery disease: Group I Normal coronary arteries: Group IIN = 12 N = 8

After diazepam After diazepamParameters Control 5 to 10 min* 15 to 20 min* Control 5 to 10 min 15 to 20 min

Heart rate (/miii) 77 - 3t 79 * 3 77 - 3 85 * 8 86 - 5 81 * 5Pressures (mm Hg) NSt NS NS NS

Aortic, systolic 147 7 136 7 13) 7 138 4 126 3 126 4P < 0.01 P <0.01 P < 0.01 P < 0.01

Aortic, diastolic 84 - 3 79 - 3 81 * 3 85 80 : -,81 3P < 0.01 P <0.01 P < 0.01 P < 0.01

Aortic, mean 112 - 5 105 - 5 105 * 5 107 - 4 99 - 4 100 - 4P <0.01 P <0.01 P < 0.01 P < 0.01

LV, end-diastolic 13.3 * 1.7 9.8 1.2 9.6 1.4 9.5 .9 6.6 .5 6.8 * .6P < 0.01 P < 0.05 P < 0.01 P < 0.01

SVR (dyiies, sec, eni-3) 1945 - 171 1818 - 170 1916 -186 1228 - 85 1290 - 107 1314 - 136NS NS NS NS

Cardiac index 2.7 - .2 2.8 .. 2.7 .2 4.4 * . 3.8 * .2 3.9(L/min/m2) NS NS P < 0.01 P < 0.05

Stroke index 36 3 36* 4 35* 4 .3* 3 44* 2 49* 4(cc/beat/m2) NS NS P < 0.01 P < 0.05

Tension time inidex 9981 *217 2741 * 206 2730 *175 2944 *04 586 129 2552 * 140(mm Hg/sec/min) P < 0.05 P < 0.05 P < 0.01 P < 0.01

LV' stroke-work index 54 * 5 .0 * 6 50 * 5 69 * 8 63 * 4 69 * 5

(gm/beat/m2) NS NS NS NSMean systolic ejectio 118 * 10 120 * 11 115 * 10 180 * 12 165- 10 174 * 14

rate (ml/see/m2) NS NS P < 0.001 NS

*Data collected over a 5 min period.+Mean * SEM.tPaired 1-test; difference from control values (NS indicates no significance).Abbreviations: LV = Left ventricular; SRV = Systemic vasculai resistances.


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patients had a resting LVEDP greater than 14 mm Hg(upper limit of normal for this laboratory) and all ex-

cept one had a substantial fall.Basal systemic vascular resistance was higher in

group 1 (1945 dynes - cm-5 - sec) than in group II

(1228 dynes - cm-5 - sec); there was no significantchange after diazepam in either group, although a

mean decrease of 127 dynes-cm-5-sec was en-

countered in group I.

Cardiac Output and Ventricular PerformanceAverage cardiac index and stroke index were higher

in group II; they fell significantly in this group at 5(P < 0.01) and 15 min (P < 0.05). This was probablydue to an elevated resting cardiac index in 4 patients(normal value for this laboratory is 2.5 to 4.5L/min/m2). In group I, patients with coronary arterydisease, cardiac index was lower at rest, and did notchange significantly after diazepamr, even in patientswith the lowest values.

Tension-time index decreased significantly at 5 and15 min in both groups (P < 0.05 in group I andP < 0.01 in group II). Left ventricular stroke work in-dex decreased slightly but not significantly in mostpatients. Mean systolic ejection rate (MSER) was

decreased significantly only in group II (P < 0.001)and only at 5 min. Basal MSER was 180 ml/sec/M2 ingroup II as compared to 118 ml/sec/m2 in group I.

Coronary and Metabolic Effects of Diazepam

Table 4 summarizes the coronary hemodynamicand metabolic data.

Coronary HemodynamicsA slight decrease in coronary sinus blood flow

occurred after diazepam in both groups (from 134 to124 and 126 ml/min at 10 and 20 min, respectively, ingroup I and from 123 to 112 and 110 ml/min at 10 and20 min in group II). These changes were not signifi-cant. Coronary vascular resistance was unaltered ineither group.

Metabolic Data

Myocardial extraction of oxygen, higher in group I,

was unchanged after diazepam in either group.

However, left ventricular oxygen consumption(LVO2) decreased significantly at 5 and 15 min in bothgroups. In group I, LVO2 decreased from 16.3 to 13.9(P < 0.001) and 14.2 ml/min (P < 0.05), and in groupII from 13.5 to 11.6 (P < 0.01) and 11.4 ml/min(P < 0.05).

Basal myocardial lactate extraction was low in 3patients with normal coronary arteries, and lactate ex-

traction increased in these subjects at 5 and 15 minafter diazepam. Of the 12 patients with coronary

artery disease, 4 had either a decrease of lactate ex-

traction or abnormal production of lactate at rest. Onepatient reversed myocardial lactate production to ex-

traction after diazepam and 3 remained unchanged.

Discussion

Diazepam has been widely used in patients withheart disease, either orally to relieve emotional ten-sion or parenterally to induce sedation, analgesia-amnesia and narcosis as a pre-anesthetic agent andduring electrocardioversion.1-8The present study was undertaken to determine 1)

whether diazepam was a safe and efficient premedi-cant agent for cardiac catheterization and coronary

able 4

Coronary and Metabolic Effects of Diazepam in Patients witth Normal and Diseased Coronary Arteries

Coronary artery disease: Group I Normal coronary arteries: Group IIN = 12 N = 8

After diazepam After diazepamParameters Control 5 to 10 min* 15 to 20 min Control 5 to 10 min 15 to 20 min

Coronary sinus blood 134 - 13t 124 i14 126 - 13 123 - 19 112 17 110 16flow (ml/min) NS$ NS NS NS

Coronary vascular 1.26 0.15 1.26 - 0.13 1.24 - 0.13 1.0.5 (0.16 1.03 0=0.15 1.13 - 0.19resistance NS NS NS NS(mnm Hg/ml/min)

Myoeardial oxygeni 67 -3 67 65 2 .51 f 8 61] 3 5X -- 4extraction (NO) NS NS NS NS

Left ventricular 16.3 - 1.2 13.9 - 1.2 14.2 - 1.3 13.5 - 2.1 11.6 - 1.9 11.4 - 1.9oxygen consumption P < 0.001 P < 0.05 P < 0.01 P < 0.05(ml/min)

Myocardical lactate 16 - 6 19 - 6 12 - 3 14 - .5 22 - 5 26 - 5extraction (%) NS NS P < (0.0 P < 0.05

*Data collected over a 55 mill period.tMean d SEM.tPaired t-test: difference from control values (NS iindicates no significance).


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angiography and 2) whether the drug would producesignificant cardiovascular alterations. We were par-ticularly interested to know whether drug-inducedacute depression or enhancement of the peripheraland coronary circulation could interfere with properevaluation of left ventricular function in the car-diovascular laboratory.The rapidly induced sedation was impressive and

was sufficient to keep the patient fully relaxedthroughout the catheterization and angiographicstudies. Significant changes in ventilation havepreviously been noted12 13 and were confirmed in ourstudy. The modest rise in PC02 that we have observedwas not different from that reported by Robin andassociates in normal individuals during physiologicalsleep,20 or by Dalen et al.12 and Rao et al.'3 in thecatheterization laboratory. Decreases in P02 and pHwere also consistently seen. This blood gas derange-ment was maximal within 5 min after diazepam ad-ministration and returned to near control values after15 min.12 This mild and transient respiratory depres-sion after diazepam suggests that the drug should beadministered cautiously to patients with severebronchopulmonary disease.

In contrast to the well documented respiratoryeffects of diazepam, few hemodynamic studies of thedrug are available. Moreover, there is still uncertaintyas to whether or not diazepam modifies the car-diovascular system directly, through reflex sym-pathetic or parasympathetic vasodilatation or via thecentral nervous system.

In a recent experimental study,9 it wasdemonstrated that diazepam produces coronaryvasodilatation following administration to theneurally intact heart isolated from the circulation, butthat systemic administration does not produce cor-onary vasodilatation. With separate perfusion of thecoronary and systemic circulations in dogs, the sameauthors'0 have shown that intracoronary diazepamdecreases coronary vascular resistance, while systemicdiazepam does not.

In our study, heart rate was not altered bydiazepam and aortic pressures decreased significantlyin most patients, the average drop in mean aorticpressure being 7 and 8 mm Hg. Patients with lowbasal arterial pressures usually showed no decreaseafter diazepam administration, and this could possiblybe explained by variations in sympathetic or parasym-pathetic activity. None of our patients experienced ahypotensive reaction, thus making diazepam a safeagent to use. These changes are comparable to thoseobserved by Dalen and coworkers12 using the samedosage of diazepam under similar conditions. Otherworkers5 11 13 have found changes similar to ours or nochange, although the conditions of the studies were


often markedly different.Following a simultaneous drop in arterial pressure

and cardiac output in individuals with normal cor-onary arteries, systemic vascular resistances remainedunchanged. In patients with coronary artery disease,the basal cardiac output was lower and was un-changed following diazepam injection; the relativelysmall drop in arterial pressure did not alter systemicvascular resistances in these patients.Of particular interest was the constant fall in left

ventricular end-diastolic pressure (LVEDP). As far aswe know, this has not previously been investigated inman. This substantial fall was more obvious whenbasal LVEDP was elevated in some patients of thecoronary artery disease group. A diminution inpreload, possibly through a reduced venous return,associated with a fall, although moderate, in aorticpressure or a decrease in afterload could have con-tributed to the decrease in LVEDP in our patients.The fall in LVEDP could also be due to increase in

contractility and/or increase in coronary blood flow.This appears unlikely, however, since cardiac indexwas either decreased or unchanged, left ventricularstroke work index was unaltered and neither coronaryblood flow nor coronary vascular resistance weremodified by diazepam in this study.

As a result of its tendency towards a reduction incardiac output and aortic pressure, tension-time indexand myocardial oxygen consumption were signif-icantly decreased after diazepam. Since total coronaryblood flow was not increased, diazepam could mostlikely be regarded as a nitroglycerin-like agent.Nitroglycerin has been shown to lower arterialpressure, cardiac output, the rate of rise of left ven-tricular pressure and venous return.21 22 The combina-tion of these effects reduces intracavitary volume ofthe left ventricle, myocardial wall tension and oxygenrequirements. It is also possible that the sedative ac-tion of diazepam yielded a more basal resting state, asmanifested by a significantly decreased total bodyoxygen consumption.Mean myocardial extraction ratio of lactate was un-

changed in our patients; in a few individual subjects,lactate extraction was increased or even reversed fromproduction to extraction.

In conclusion, this study demonstrates thatdiazepam is the agent of choice to produce sedation inpatients with heart disease. It causes minimal depres-sion of respiration and has negligible side effects. Ithas no deleterious effect on the cardiovascular system;on the contrary, its effects tend to bring about an im-provement in cardiac function. This should be con-sidered when the drug is used as a premedicant in thecardiovascular laboratory. Although further studiesare needed in man, besides its central action,

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diazepam seems to act directly upon the circulation,its mode of action being similar to that ofnitroglycerin but of longer duration.

Acknowledgment

We thank Mrs. L. Begin, Miss D. Asselin, Mr. R. Cardinal, Mr. A.Gauthier and Mr. R. Pelletier for their technical assistance; we are

grateful to Drs. Claude Allard and Pierre Simard for their assistancein the biochemical determinations.

References

1. NUwTEI DO, MASSLUIi RA: Diazepam in cardioversion. N EnglJ Med 273: 650, 1965

2. WAGNEii BC, MCINTOSH HD: The use of drugs in achievingsuccessful DC cardioversion. Prog Cardiovasc Dis 11: 431,1969

3. VINCE LN, WYANT GM, LOPEZ JF: Diazepam in cardioversion.Can Anaesth Soc J 18: 166, 1971

4. ROGERS WK, WATERMAN DH, Doximi SE, SUNIAY A: Efficacy ofa new psychotropic drug in bronchoscopy. Dis Chest 47:280, 1965

5. McLISH A: Diazepam as an intravenous agent for generalanaesthesia. Can Anaesth Soc J 13: 562, 1966

6. LULLA.M R, BENNETT JR: Comparison of diazepam andmorphine as premedication for gastrointestinal endoscopy.Lancet 8: 1397, 1971

7. TICKTIN HE, TRUJILLO NP: Evaluation of diazepam for pre-

endoscopy medication. Am J Dig Dis 10: 979, 19658. TOiANETTA FJ: Diazepam as pre-anaesthetic medication.

Anaesth Analg 44: 449, 19659. ABEL RM, REIS RL, STAROSCIK RN: Coronary vasodilatation

following diazepam (Valium). Br J Pharmacol 38: 620, 197010. ABEL RM, REIS RL, STAROSCIK RN: The pharmacological basis

of coronary and systemic vasodilator actions of diazepam(Valium). Br J Pharmacol 39: 261, 1970

11. KATZ J, FINESTONE SC, PAPPAS MT: Circulatory response totilting after intravenous diazepam in volunteers. AnaesthAnalg 46: 243, 1967

12. DALEN JE, EVANS GL, BANAS JS, BROOKS HL, PABASKOS JA,DEXTER L: The hemodynamic and respiratory effects ofdiazepam (Valium). Anesthesiology 30: 259, 1969

13. RAO S, SHERBAN1UK RW, PRASAD K, LEE SJK, SPROULE BJ:Cardiopulmonary effects of diazepam. Clin Pharmacol Ther14: 182, 1973

14. GANZ W, TAMURA K, MARCiuS HS, DONoso R, YOSHIDA S, SWANHJC: Measurement of coronary sinus blood flow by con-

tinuous thermodilution in man. Circulation 44: 181, 197115. LAN(GoDN DE, HARLAN JR, BALEY RL: Thrombophlebitis with

diazepam used intravenously. JAMA 223: 184, 197316. BOURASSA MG, LESPERANCE J, CANIPEAu L, Bois MA, SALTIEL J:

Selective coronary angiography using a percutaneousfemoral technique. Can Med Assoc J 102: 170, 1970

17. WILLIAXIS JCP, O'DONOVAN- TPB, WOOD EH: A method forcalculation of areas under indicator-dilution curves. J ApplPhysiol 21: 695, 1966

18. SEVERINGHAUS JW: Oxyhemoglobin dissociation curve

correction for temperature and pH variation in humanblood. J Appl Physiol 12: 485, 1958

19. HOHOBST HJ: L,, lactate: determination with lactic dehydro-genase and DPN. In Methods of Enzymatic Analysis, editedby BERGCMEYER HU. New York, Academic Press, 1965, p 266

20. ROBIN ED, WHALEY RD, CBLuNIP CH, TRAVIS DM: Alveolar gas

tension, pulmonary ventilation and blood pH duringphysiologic sleep in normal subjects. J Clin Invest 37: 981,1958

21. GOBLIN R, BRACHFELD N, MACLEOD C, BoPP P: Effect ofnitroglycerin on the coronary circulation in patients withcoronary artery disease or increased left ventricular work.Circulation 19: 705, 1959

22. ROBIN E, COWAN C, PuRi P, GANGULY S, DEBOYRIE E,MA.RTINEZ M, STOC K T, BING RJ: A comparative study ofnitroglycerin and propranolol. Circulation 36: 175, 1967


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PIERRE CÔTÉ, PASCAL GUÉRET and MARTIAL G. BOURASSADiseased Coronary Arteries

Systemic and Coronary Hemodynamic Effects of Diazepam in Patients with Normal and

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