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Cardiovascular effects of diazepam
Cardiovascular effects of diazepam Jesus A. Bianco, M.D., E. Anne Shanahan, M.B.B.S., Gerard W. Ostheimer, M.D., Robert A. Guy ton, B.A., Wm. John Powell, Jr., M.D., and Willard M. Daggett, M.D.,* Boston, Mass.
JLviazepam, a benzodiazepine derivative, has been advocated recently as an alterna tive to general anesthesia in patients under going cardioversion.1"3 Aside from a tend ency toward slight and transient lowering of blood pressure, no discernible effects on cardiovascular function were reported in these preliminary clinical studies. More re cently, Dalen and his co-workers4 failed to observe any effect on the heart when diaze pam was injected into the pulmonary artery of patients undergoing cardiac catheterization, regardless of whether heart failure was present or absent. We have recently ob served precipitous hypotension following ad ministration of diazepam, 2 to 5 mg. given intramuscularly, in 4 patients after openheart surgery. In an effort to clarify possible mechanisms of hypotension consequent to diazepam administration, the present investi gation was undertaken. Methods Experiments were carried out in mongrel dogs anesthetized intravenously with a From the General Surgical and Medical Services of the Massachusetts General Hospital, and the Departments of Surgery and Medicine, Harvard Medical School, Boston, Mass. This work has been supported in part by U . S. Public Health Service Grants H E 12322-01, HE 12777-01, HE 06664 ( H E P P ) , and HE 5196. Received for publication Oct. 29, 1970. Address for reprints: Willard M . Daggett, M.D., Depart ment of Surgery, Massachusetts General Hospital, Boston, Mass. 02114. •Established Investigator of the American Heart Asso ciation.
warmed mixture of chloralose (60 mg. per kilogram) and urethane (600 mg. per kilo gram). After intubation of the trachea, ventilation was controlled with an Emerson volume-limited respirator. Two experimental preparations were used. Right heart bypass preparation (RHBP). In previous publications from this labora tory, a detailed description of this prepara tion has been presented.5 Briefly, the systemic venous return is diverted through an oxygenator from which oxygenated blood is pumped at known flows into the pulmo nary artery. The isolated right heart per forms no work under these conditions, and its venous content—minus left ventricular Thebesian drainage—represents the effluent from the coronary veins. Cardiac input and heart rate were controlled; however, be cause of the transient and rapid effects of diazepam on blood pressure (see below), control of this variable was possible only to a limited degree. Coronary blood flow (CBF) was continuously monitored by means of a Shipley-Wilson rotameter as previously described.6 Rotameter readings were calibrated by means of timed col lections of the right heart drainage in a graduated cylinder. Coronary arteriovenous oxygen content difference was continuously monitored with an A-V 0 2 analyzer.* The analyzer was calibrated with oxygen con tent manometric determinations by the •Oxford Instrument Co., Jackson, Miss.
125
The Journal of
12 6
Bianco et aL
Thoracic and Cardiovascular Surgery
method of Van Slyke and Neill.6 Myocardial oxygen consumption (MV0 2 ) was expressed as the product of CBF and A-V 0 2 difference. Control of pH and Pco 2 was effected by appropriate infusion of sodium bicarbonate. Isovolumic left ventricle preparation (ILVP). This preparation has also been described at length previously.5 The load the ventricle faces in this preparation is in dependent of arterial pressure. Left ven tricular systolic and end-diastolic pressures are both functions of the ventricular (bal loon) volume, which is set at will. Heart rate was kept constant by atrial pacing as in the RHBP. To minimize reflex effects on the contrac tile state of the heart, ganglionic and betaadrenergic receptor blockades were effected with mecamylamine HC1 (Inversine), 10 mg. per kilogram,* and propranolol (Inderal), 0.5 mg. per kilogram, which were added to the extracorporeal reservoir. The effectiveness of autonomie blockade was checked by using a challenge dose of isoproterenol and by observing the absence of heart rate changes in the unpaced heart in response to sudden alterations in arterial pressure. Experimental protocol RHBP. Diazepamj was fed as a bolus of 2.5 mg. into the pulmonary artery. A total of six 2.5 mg. boluses were introduced cumulatively every 3 minutes into the pulmo nary artery in 5 animals. In order to ac count for possible variations in drug effect based on the base-line level of ventricular size and initial fiber length, these runs were conducted both at low left ventricular enddiastolic pressures (mean 14.8 cm. H 2 0 , range 10 to 15.5) and at high left ventric ular end-diastolic pressures (mean 19 cm. H 2 0 , range 15.5 to 22.5). In these experi mental runs it was possible to control car diac output, heart rate, and aortic pressure. »Merck Institute for Therapeutic Research, West Point, Pa. fRefers to the commercially available diazepam solution, Roche Laboratories, Nutley, N. J.
In 3 animals, cumulative dose-response runs were conducted by introducing in se quence 2.5, 5.0, 10.0, 20.0, and 40.0 mg. diazepam boluses into the pulmonary artery while cardiac output and heart rate were held constant. Since blood pressure could not be con trolled in these experiments, the effect of ad ministering a 10 mg. bolus of diazepam into the left ventricle in 2 animals was com pared to the effect of suddenly raising or lowering aortic afterload at constant cardiac output and heart rate. When blood pressure was artificially lowered, efforts were made to match the decrement of pressure ob served after administration of diazepam. In addition, the vehicle* in which diaze pam is contained was introduced into the pulmonary artery of 3 dogs in boluses whose volumes corresponded to the 20 and the 40 mg. volumes of the whole reconstituted diazepam solution. The pH of the latter was 6.5. To rule out any possible effects of the osmolality of the vehicle itself,7 a sucrose solution of the same volume and osmolality of the vehicle was administered as a bolus into the pulmonary artery, and the experi mental runs were again repeated. ILVP. In 6 animals, the effect of 10 mg. diazepam fed as a bolus into the arterial line was studied in terms of peak left ven tricular pressure and the maximal rate of change of left ventricular pressure at a constant heart rate. These experiments also allowed for detection of any influence of the agent on left ventricular end-diastolic distensibility by continuously following left ventricular end-diastolic pressure at a con stant ventricular volume. Similarly, the effects of diazepam on the arterial resistance could be followed since, in this preparation, arterial pressure is set at a higher level than the peak systolic ventricular pressure; at constant flow, any change in arterial pressure represents a change in arterial resistance. ♦Vehicle content: 40 per cent propylene glycol, 10 per cent ethyl alcohol, 5 per cent sodium benzoate, benzoic acid, and 1.5 per cent benzyl alcohol. It is approximately twice isotonic, and its pH is 6.8. The vehicle was supplied by Roche Laboratories, Nutley, N. J.
Volume 62
Cardiovascular effects of diazepam
Number Ί
12 7
-July, 1971
2.5 mg 5.0mg 10 mg
I
I I
20 mg 40 mg
Diazepam 10 mg LV
I I
i
EKG
CBF
I3£t
CBF
(ml/minj
200
/ΗΌ,
10
DIFFiVol
%)
AP
/"mm //o/* ^
'
(cmH20) LV dp/dt
(ml/min)
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I
200r-
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AP (mm Hg)
1001
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20 r
oL 0L
0L
LV dp/dt 1000[(mm Hg/sec)
3000r-
'"jMmAt&ÊÊËÊk
(mrnHg/sec) RHBP M - I RHBPm-2 HR 130/BPM
6/27/69 CI =1300 ce
Fig. 1. Hemodynamic responses to diazepam boluses given into the pulmonary artery. EKG, Electrocardiogram. CBF, Coronary blood flow. AV O,, Arteriovenous oxygen difference. AP, Aortic pressure. LVDP, Left ventricular diastolic pressure. LV dp/dt, Rate of change of left ven tricular pressure. RHBP, Right heart bypass. HR, Heart rale. CI, Cardiac index. Note the transient increase of CBF and of LVEDP and the fall of maximum dp/dt with larger doses.
Results RHBP. In 5 animals, cumulative doses of diazepam (2.5 mg. every 3 minutes, up to 15 mg.) were administered into the pul monary artery at constant cardiac output, aortic pressure, and heart rate; under these conditions, the drug did not modify mean aortic pressure (MAP), left ventricular enddiastolic pressure (LVEDP), or the maxi mal rate of left ventricular pressure develop ment (max. dp/dt), regardless of the initial level of LVEDP. In contrast, in 3 animals in which cumu lative boluses were introduced into the pul monary artery at doses of 2.5, 5.0, 10.0, 20.0, and 40.0 mg., diazepam lowered the arterial pressure and max. dp/dt while raising LVEDP, especially when the larger
HR
140/BPM
6/26/69 C 1 = 800 cc
Fig. 2. Hemodynamic response to diazepam, 10 mg., introduced into the left ventricle as compared to sudden release and subsequent sudden elevation of aortic pressure. F o r symbols, see Fig. 1. See text for discussion.
20 and 40 mg. doses were given. Under these conditions, CBF rose and A-V 0 2 narrowed as the dose of the agent was in creased. Calculated myocardial oxygen con sumption (milliliter per minute) changed little. A typical experiment of this kind is shown in Fig. 1, in which the paper speed was slow. In this group of experiments, myo cardial function and arterial pressure were both transiently decreased consequent to diazepam administration, but only at very high doses of diazepam (see below). That the effect on LVEDP and CBF under the above conditions was independent of a changing afterload is demonstrated in Fig. 2. It is noteworthy that the effects on LVEDP and on CBF were opposite when aortic pressure was lowered to match the fall observed with diazepam, whereas the fall of max. LV dp/dt was present under both interventions. In 3 animals, it was observed that all the effects seen with diazepam at the high doses
The Journal of Thoracic and Cardiovascular Surgery
12 8 Bianco et al.
Diazepam 20ma(4ml)
LVeDP
MAP (mm Hg) LV MAX dp/dt (mm Hg/sec)
1500r ή 'RHBP HR 1508PM
CI »1400«
Fig. 3. Hemodynamic effects of diazepam as compared with the effects of the vehicle in which diazepam is contained. See text for discussion. MAP, Mean aortic pressure.
were reproduced by introducing, into the pulmonary artery, a bolus of the vehicle in which diazepam is contained. An example of this kind of observation at a slow paper speed is depicted in Fig. 3. On the other hand, a sucrose solution which was isosmotic with the vehicle failed to reproduce these findings. ILVP. In 6 dogs, 10 mg. boluses of diazepam, introduced into the arterial line, produced a moderate fall in peak left ven tricular pressure (mean -6.6 mm. Hg, range -3 to -10 mm. Hg) and in max. dp/dt (mean -17 per cent from control, range -8 to -32.5 per cent) at constant heart rate. LVEDP was not changed in these experiments, while CBF and A-V 0 2 again changed in the same direction as observed during the RHBP experiments. MV0 2 changed little in these runs, while arterial pressure decreased at constant flow. A representative experi ment is shown in Fig. 4. Fig. 5 depicts the effect of 10 mg. of diazepam on max. LV dp/dt and left ventricular systolic pressure in 6 animals under isovolumic conditions at a constant heart rate. LVEDP remained unchanged in all experiments. Discussion These data indicate that diazepam solu tion has little effect on left ventricular func tion of the dog at doses comparable to those
Diazepam 10 mg -if i—Diozepam—) i—Cortrot-
Z -[W-W^
(mmHg)
o
190
CBF (ml/mini LVDP (cm HtO) AP (mmHg) AV On DIFF (Vol%)
20 0 150 0L
£ f r l ®m ψ?ψ "■■■' ; ■ £ "'.υ frig 3ii;di5
0L ΙιοΙ-ί 5/8/69 Βοϋοοη Volume 15cc
Fig. 4. Effect of diazepam in the isovolumic left ventricle preparation. For symbols, see Fig. 1. LVP, Left ventricular pressure.
\
-10
s> -20 v. -30 | -40 -j
■ ^ N^^ 5? X.
^
1
1
CONTROL DIAZEPAM CONTROL DIAZEPAM
Fig. 5. Effect of diazepam on max. LV dp/dt and on LVP in the six osovolumic left ventricle preparations. LVP, Left ventricular pressure.
Volume 62 Number 1 July, 1971
employed in clinical cardioversion. These findings support the recent clinical studies of Dalen and his co-workers.4 On the other hand, high doses of the agent, or compa rable volumes of the vehicle alone, depress ventricular performance transiently in the working heart, as evidenced by an increased LVEDP, despite a fall in aortic pressure at a constant cardiac output and heart rate. In other experiments in the same animals, deliberately produced decreases in arterial pressure of the same magnitude resulted in a fall in LVEDP. The finding of a myocardial depressant effect with the diazepam solution or the vehicle is at variance with the recent report of Abel and colleagues.8 That these authors did not find a cardiac depressant effect of the diazepam solution may have been related to the low doses employed or to reflexly induced augmenta tion of ventricular performance in their preparations. In the present experiments, the diazepam solution at high doses also diminished aortic pressure in both experimental preparations, suggesting a transient relaxing effect on the arterial resistance vessels. Furthermore, the effect of the diazepam solution or of the vehicle on the ventricular myocardium was accompanied by a transient substantial in crease in CBF. The increase in CBF, despite blood pressure lowering, and the narrowing of coronary arteriovenous oxygen difference indicate that the diazepam solution with the vehicle, and the vehicle alone, are primary coronary vasodilators.9 These latter observa tions are consonant with the findings of Abel and associates,8 who reported an in crease in CBF with low doses of diazepam in the fibrillating ventricle and in the nonworking paced ventricle. While the effects on the coronary circulation and on peripheral resist ance suggest a direct effect on vasomotor tone, this action was short-lived and, in the absence of reflex mechanisms, would in dicate the result of a vasodilatory substance, probably within the vehicle. The diazepam solution did not signifi cantly influence MV0 2 in either the working heart or the isovolumic left ventricle prep-
Cardiovascular effects of diazepam
12 9
aration. Therefore, even at high doses, the transient hemodynamic effects of the solu tion or the vehicle did not influence the oxygen requirements of the heart, nor was a direct metabolic effect of the drug evident. The data indicate, under the conditions described, that high doses of the diazepam solution, and of the vehicle itself, provoked a transient depression of ventricular per formance and at the same time a transient elevation of coronary blood flow, which in dicated primary coronary vasodilation. The data suggest caution in the use of larger doses of this solution with the presently used vehicle for patients with severely impaired ventricular function. The data also indicate that all the hemo dynamic results which were shown with the diazepam solution also were demonstrated with the vehicle in which the agent is con tained; therefore, they may be attributable to the vehicle alone. Summary In areflexic canine right heart bypass preparations (RHBP), the diazepam solu tion did not affect ventricular performance when given into the pulmonary artery in cumulative doses of up to 15 mg. However, when larger doses of the diazepam solution or comparable volumes of the vehicle in which it is contained were given, a transient depression of left ventricular performance ensued. Coronary blood flow increased under the same conditions, while coronary arterio venous oxygen difference narrowed and myocardial oxygen consumption remained unaffected. In addition, there was a fall in arterial pressure. In six isovolumic left ventricular prepara tions, peak left ventricular pressure and max. LV dp/dt were reduced by the diazepam solution, while its effects on coronary flow and oxygen consumption were comparable to those obtained in the RHBP. Left ven tricular end-diastolic distensibility was not affected by diazepam. At constant flow, diazepam produced a fall in peripheral re sistance. It is concluded that the presently avail-
The Journal of
13 0 Bianco et al.
able diazepam solution used in doses higher than those ordinarily employed for cardio version results in a transient depression of ventricular performance, an increase in cor onary flow, and a decrease in systemic vascular resistance. Furthermore, the data also indicate that all the hemodynamic effects demonstrated with the diazepam solu tion are attributable to the vehicle in which diazepam is contained. REFERENCES 1 Nutter, D. O., and Massumi, R. A.: Diazepam in Cardioversion, New Eng. J. Med. 273: 650, 1965. 2 Kahler, R. L., Burrow, G. N., and Felig, P.: Diazepam-Induced Amnesia for Cardioversion, J. A. M. A. 200: 997, 1967. 3 Hendrix, G. H.: Intravenous Use of Diazepam in Cardioversion, Southern Med. J. 62: 483, 1969. 4 Dalen, J. E., Evans, G. L., Banas, J. S., Jr., Brooks, H. L., Paraskos, J. A., and Dexter, L.: The Hemodynamic and Respiratory Effects of
Thoracic and Cardiovascular Surgery
5
6
7
8
9
Diazepam (Valium), Anesthesiology 30: 259, 1969. Bianco, J. A., Freedberg, L. E., Powell, W. J., Jr., and Daggett, W. M.: Influence of Vagal Stimulation on Ventricular Compliance, Amer. J. Physiol. 218: 264, 1970. Powell, W. J., Jr., Daggett, W. M., Magro, A. E., Bianco, J. A., Buckley, M. J., Sanders, C. A., Kantrowitz, A. R., and Austen, W. G.: Effects of Intra-Aortic Balloon Counterpulsation on Cardiac Performance, Oxygen Con sumption, and Coronary Blood Flow, Circ. Res. 26: 753, 1970. Wildenthal, K., Mierzwiak, D. S., and Mitchell, J. H.: Acute Effects of Increased Serum Osmolality on Left Ventricular Performance, Amer. J. Physiol. 216: 898, 1969. Abel, R. M., Staroscik, R. N., and Reis, R. L.: The Effects of Diazepam on Left Ventricular Contractility and Coronary Blood Flow, Circula tion 39-40: 33, 1969 (Suppl. 3). Sullivan, J. M., and Gorlin, R.: Effect of 1-Epinephrine on the Coronary Circulation in Human Subjects With and Without Coronary Artery Disease, Circ. Res. 21: 919, 1967.
JLviazepam, a benzodiazepine derivative, has been advocated recently as an alterna tive to general anesthesia in patients under going cardioversion.1"3 Aside from a tend ency toward slight and transient lowering of blood pressure, no discernible effects on cardiovascular function were reported in these preliminary clinical studies. More re cently, Dalen and his co-workers4 failed to observe any effect on the heart when diaze pam was injected into the pulmonary artery of patients undergoing cardiac catheterization, regardless of whether heart failure was present or absent. We have recently ob served precipitous hypotension following ad ministration of diazepam, 2 to 5 mg. given intramuscularly, in 4 patients after openheart surgery. In an effort to clarify possible mechanisms of hypotension consequent to diazepam administration, the present investi gation was undertaken. Methods Experiments were carried out in mongrel dogs anesthetized intravenously with a From the General Surgical and Medical Services of the Massachusetts General Hospital, and the Departments of Surgery and Medicine, Harvard Medical School, Boston, Mass. This work has been supported in part by U . S. Public Health Service Grants H E 12322-01, HE 12777-01, HE 06664 ( H E P P ) , and HE 5196. Received for publication Oct. 29, 1970. Address for reprints: Willard M . Daggett, M.D., Depart ment of Surgery, Massachusetts General Hospital, Boston, Mass. 02114. •Established Investigator of the American Heart Asso ciation.
warmed mixture of chloralose (60 mg. per kilogram) and urethane (600 mg. per kilo gram). After intubation of the trachea, ventilation was controlled with an Emerson volume-limited respirator. Two experimental preparations were used. Right heart bypass preparation (RHBP). In previous publications from this labora tory, a detailed description of this prepara tion has been presented.5 Briefly, the systemic venous return is diverted through an oxygenator from which oxygenated blood is pumped at known flows into the pulmo nary artery. The isolated right heart per forms no work under these conditions, and its venous content—minus left ventricular Thebesian drainage—represents the effluent from the coronary veins. Cardiac input and heart rate were controlled; however, be cause of the transient and rapid effects of diazepam on blood pressure (see below), control of this variable was possible only to a limited degree. Coronary blood flow (CBF) was continuously monitored by means of a Shipley-Wilson rotameter as previously described.6 Rotameter readings were calibrated by means of timed col lections of the right heart drainage in a graduated cylinder. Coronary arteriovenous oxygen content difference was continuously monitored with an A-V 0 2 analyzer.* The analyzer was calibrated with oxygen con tent manometric determinations by the •Oxford Instrument Co., Jackson, Miss.
125
The Journal of
12 6
Bianco et aL
Thoracic and Cardiovascular Surgery
method of Van Slyke and Neill.6 Myocardial oxygen consumption (MV0 2 ) was expressed as the product of CBF and A-V 0 2 difference. Control of pH and Pco 2 was effected by appropriate infusion of sodium bicarbonate. Isovolumic left ventricle preparation (ILVP). This preparation has also been described at length previously.5 The load the ventricle faces in this preparation is in dependent of arterial pressure. Left ven tricular systolic and end-diastolic pressures are both functions of the ventricular (bal loon) volume, which is set at will. Heart rate was kept constant by atrial pacing as in the RHBP. To minimize reflex effects on the contrac tile state of the heart, ganglionic and betaadrenergic receptor blockades were effected with mecamylamine HC1 (Inversine), 10 mg. per kilogram,* and propranolol (Inderal), 0.5 mg. per kilogram, which were added to the extracorporeal reservoir. The effectiveness of autonomie blockade was checked by using a challenge dose of isoproterenol and by observing the absence of heart rate changes in the unpaced heart in response to sudden alterations in arterial pressure. Experimental protocol RHBP. Diazepamj was fed as a bolus of 2.5 mg. into the pulmonary artery. A total of six 2.5 mg. boluses were introduced cumulatively every 3 minutes into the pulmo nary artery in 5 animals. In order to ac count for possible variations in drug effect based on the base-line level of ventricular size and initial fiber length, these runs were conducted both at low left ventricular enddiastolic pressures (mean 14.8 cm. H 2 0 , range 10 to 15.5) and at high left ventric ular end-diastolic pressures (mean 19 cm. H 2 0 , range 15.5 to 22.5). In these experi mental runs it was possible to control car diac output, heart rate, and aortic pressure. »Merck Institute for Therapeutic Research, West Point, Pa. fRefers to the commercially available diazepam solution, Roche Laboratories, Nutley, N. J.
In 3 animals, cumulative dose-response runs were conducted by introducing in se quence 2.5, 5.0, 10.0, 20.0, and 40.0 mg. diazepam boluses into the pulmonary artery while cardiac output and heart rate were held constant. Since blood pressure could not be con trolled in these experiments, the effect of ad ministering a 10 mg. bolus of diazepam into the left ventricle in 2 animals was com pared to the effect of suddenly raising or lowering aortic afterload at constant cardiac output and heart rate. When blood pressure was artificially lowered, efforts were made to match the decrement of pressure ob served after administration of diazepam. In addition, the vehicle* in which diaze pam is contained was introduced into the pulmonary artery of 3 dogs in boluses whose volumes corresponded to the 20 and the 40 mg. volumes of the whole reconstituted diazepam solution. The pH of the latter was 6.5. To rule out any possible effects of the osmolality of the vehicle itself,7 a sucrose solution of the same volume and osmolality of the vehicle was administered as a bolus into the pulmonary artery, and the experi mental runs were again repeated. ILVP. In 6 animals, the effect of 10 mg. diazepam fed as a bolus into the arterial line was studied in terms of peak left ven tricular pressure and the maximal rate of change of left ventricular pressure at a constant heart rate. These experiments also allowed for detection of any influence of the agent on left ventricular end-diastolic distensibility by continuously following left ventricular end-diastolic pressure at a con stant ventricular volume. Similarly, the effects of diazepam on the arterial resistance could be followed since, in this preparation, arterial pressure is set at a higher level than the peak systolic ventricular pressure; at constant flow, any change in arterial pressure represents a change in arterial resistance. ♦Vehicle content: 40 per cent propylene glycol, 10 per cent ethyl alcohol, 5 per cent sodium benzoate, benzoic acid, and 1.5 per cent benzyl alcohol. It is approximately twice isotonic, and its pH is 6.8. The vehicle was supplied by Roche Laboratories, Nutley, N. J.
Volume 62
Cardiovascular effects of diazepam
Number Ί
12 7
-July, 1971
2.5 mg 5.0mg 10 mg
I
I I
20 mg 40 mg
Diazepam 10 mg LV
I I
i
EKG
CBF
I3£t
CBF
(ml/minj
200
/ΗΌ,
10
DIFFiVol
%)
AP
/"mm //o/* ^
'
(cmH20) LV dp/dt
(ml/min)
[ » ■ IU' 1 " I I » φ ΐ ϋ ΐ » ' '
i 0L
100 r i 0
''Sijfe'li
ί LLÏJ.«.·· J t i i r î - Ï
■■> I'I ίΐ^ΐνι&ΐ
20Γ
AVOz DIFFiVol %)
Sudden Releose
\
Sudden Elevation
I
200r-
6r 0L
AP (mm Hg)
1001
LVDP (cm HzO)
20 r
oL 0L
0L
LV dp/dt 1000[(mm Hg/sec)
3000r-
'"jMmAt&ÊÊËÊk
(mrnHg/sec) RHBP M - I RHBPm-2 HR 130/BPM
6/27/69 CI =1300 ce
Fig. 1. Hemodynamic responses to diazepam boluses given into the pulmonary artery. EKG, Electrocardiogram. CBF, Coronary blood flow. AV O,, Arteriovenous oxygen difference. AP, Aortic pressure. LVDP, Left ventricular diastolic pressure. LV dp/dt, Rate of change of left ven tricular pressure. RHBP, Right heart bypass. HR, Heart rale. CI, Cardiac index. Note the transient increase of CBF and of LVEDP and the fall of maximum dp/dt with larger doses.
Results RHBP. In 5 animals, cumulative doses of diazepam (2.5 mg. every 3 minutes, up to 15 mg.) were administered into the pul monary artery at constant cardiac output, aortic pressure, and heart rate; under these conditions, the drug did not modify mean aortic pressure (MAP), left ventricular enddiastolic pressure (LVEDP), or the maxi mal rate of left ventricular pressure develop ment (max. dp/dt), regardless of the initial level of LVEDP. In contrast, in 3 animals in which cumu lative boluses were introduced into the pul monary artery at doses of 2.5, 5.0, 10.0, 20.0, and 40.0 mg., diazepam lowered the arterial pressure and max. dp/dt while raising LVEDP, especially when the larger
HR
140/BPM
6/26/69 C 1 = 800 cc
Fig. 2. Hemodynamic response to diazepam, 10 mg., introduced into the left ventricle as compared to sudden release and subsequent sudden elevation of aortic pressure. F o r symbols, see Fig. 1. See text for discussion.
20 and 40 mg. doses were given. Under these conditions, CBF rose and A-V 0 2 narrowed as the dose of the agent was in creased. Calculated myocardial oxygen con sumption (milliliter per minute) changed little. A typical experiment of this kind is shown in Fig. 1, in which the paper speed was slow. In this group of experiments, myo cardial function and arterial pressure were both transiently decreased consequent to diazepam administration, but only at very high doses of diazepam (see below). That the effect on LVEDP and CBF under the above conditions was independent of a changing afterload is demonstrated in Fig. 2. It is noteworthy that the effects on LVEDP and on CBF were opposite when aortic pressure was lowered to match the fall observed with diazepam, whereas the fall of max. LV dp/dt was present under both interventions. In 3 animals, it was observed that all the effects seen with diazepam at the high doses
The Journal of Thoracic and Cardiovascular Surgery
12 8 Bianco et al.
Diazepam 20ma(4ml)
LVeDP
MAP (mm Hg) LV MAX dp/dt (mm Hg/sec)
1500r ή 'RHBP HR 1508PM
CI »1400«
Fig. 3. Hemodynamic effects of diazepam as compared with the effects of the vehicle in which diazepam is contained. See text for discussion. MAP, Mean aortic pressure.
were reproduced by introducing, into the pulmonary artery, a bolus of the vehicle in which diazepam is contained. An example of this kind of observation at a slow paper speed is depicted in Fig. 3. On the other hand, a sucrose solution which was isosmotic with the vehicle failed to reproduce these findings. ILVP. In 6 dogs, 10 mg. boluses of diazepam, introduced into the arterial line, produced a moderate fall in peak left ven tricular pressure (mean -6.6 mm. Hg, range -3 to -10 mm. Hg) and in max. dp/dt (mean -17 per cent from control, range -8 to -32.5 per cent) at constant heart rate. LVEDP was not changed in these experiments, while CBF and A-V 0 2 again changed in the same direction as observed during the RHBP experiments. MV0 2 changed little in these runs, while arterial pressure decreased at constant flow. A representative experi ment is shown in Fig. 4. Fig. 5 depicts the effect of 10 mg. of diazepam on max. LV dp/dt and left ventricular systolic pressure in 6 animals under isovolumic conditions at a constant heart rate. LVEDP remained unchanged in all experiments. Discussion These data indicate that diazepam solu tion has little effect on left ventricular func tion of the dog at doses comparable to those
Diazepam 10 mg -if i—Diozepam—) i—Cortrot-
Z -[W-W^
(mmHg)
o
190
CBF (ml/mini LVDP (cm HtO) AP (mmHg) AV On DIFF (Vol%)
20 0 150 0L
£ f r l ®m ψ?ψ "■■■' ; ■ £ "'.υ frig 3ii;di5
0L ΙιοΙ-ί 5/8/69 Βοϋοοη Volume 15cc
Fig. 4. Effect of diazepam in the isovolumic left ventricle preparation. For symbols, see Fig. 1. LVP, Left ventricular pressure.
\
-10
s> -20 v. -30 | -40 -j
■ ^ N^^ 5? X.
^
1
1
CONTROL DIAZEPAM CONTROL DIAZEPAM
Fig. 5. Effect of diazepam on max. LV dp/dt and on LVP in the six osovolumic left ventricle preparations. LVP, Left ventricular pressure.
Volume 62 Number 1 July, 1971
employed in clinical cardioversion. These findings support the recent clinical studies of Dalen and his co-workers.4 On the other hand, high doses of the agent, or compa rable volumes of the vehicle alone, depress ventricular performance transiently in the working heart, as evidenced by an increased LVEDP, despite a fall in aortic pressure at a constant cardiac output and heart rate. In other experiments in the same animals, deliberately produced decreases in arterial pressure of the same magnitude resulted in a fall in LVEDP. The finding of a myocardial depressant effect with the diazepam solution or the vehicle is at variance with the recent report of Abel and colleagues.8 That these authors did not find a cardiac depressant effect of the diazepam solution may have been related to the low doses employed or to reflexly induced augmenta tion of ventricular performance in their preparations. In the present experiments, the diazepam solution at high doses also diminished aortic pressure in both experimental preparations, suggesting a transient relaxing effect on the arterial resistance vessels. Furthermore, the effect of the diazepam solution or of the vehicle on the ventricular myocardium was accompanied by a transient substantial in crease in CBF. The increase in CBF, despite blood pressure lowering, and the narrowing of coronary arteriovenous oxygen difference indicate that the diazepam solution with the vehicle, and the vehicle alone, are primary coronary vasodilators.9 These latter observa tions are consonant with the findings of Abel and associates,8 who reported an in crease in CBF with low doses of diazepam in the fibrillating ventricle and in the nonworking paced ventricle. While the effects on the coronary circulation and on peripheral resist ance suggest a direct effect on vasomotor tone, this action was short-lived and, in the absence of reflex mechanisms, would in dicate the result of a vasodilatory substance, probably within the vehicle. The diazepam solution did not signifi cantly influence MV0 2 in either the working heart or the isovolumic left ventricle prep-
Cardiovascular effects of diazepam
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aration. Therefore, even at high doses, the transient hemodynamic effects of the solu tion or the vehicle did not influence the oxygen requirements of the heart, nor was a direct metabolic effect of the drug evident. The data indicate, under the conditions described, that high doses of the diazepam solution, and of the vehicle itself, provoked a transient depression of ventricular per formance and at the same time a transient elevation of coronary blood flow, which in dicated primary coronary vasodilation. The data suggest caution in the use of larger doses of this solution with the presently used vehicle for patients with severely impaired ventricular function. The data also indicate that all the hemo dynamic results which were shown with the diazepam solution also were demonstrated with the vehicle in which the agent is con tained; therefore, they may be attributable to the vehicle alone. Summary In areflexic canine right heart bypass preparations (RHBP), the diazepam solu tion did not affect ventricular performance when given into the pulmonary artery in cumulative doses of up to 15 mg. However, when larger doses of the diazepam solution or comparable volumes of the vehicle in which it is contained were given, a transient depression of left ventricular performance ensued. Coronary blood flow increased under the same conditions, while coronary arterio venous oxygen difference narrowed and myocardial oxygen consumption remained unaffected. In addition, there was a fall in arterial pressure. In six isovolumic left ventricular prepara tions, peak left ventricular pressure and max. LV dp/dt were reduced by the diazepam solution, while its effects on coronary flow and oxygen consumption were comparable to those obtained in the RHBP. Left ven tricular end-diastolic distensibility was not affected by diazepam. At constant flow, diazepam produced a fall in peripheral re sistance. It is concluded that the presently avail-
The Journal of
13 0 Bianco et al.
able diazepam solution used in doses higher than those ordinarily employed for cardio version results in a transient depression of ventricular performance, an increase in cor onary flow, and a decrease in systemic vascular resistance. Furthermore, the data also indicate that all the hemodynamic effects demonstrated with the diazepam solu tion are attributable to the vehicle in which diazepam is contained. REFERENCES 1 Nutter, D. O., and Massumi, R. A.: Diazepam in Cardioversion, New Eng. J. Med. 273: 650, 1965. 2 Kahler, R. L., Burrow, G. N., and Felig, P.: Diazepam-Induced Amnesia for Cardioversion, J. A. M. A. 200: 997, 1967. 3 Hendrix, G. H.: Intravenous Use of Diazepam in Cardioversion, Southern Med. J. 62: 483, 1969. 4 Dalen, J. E., Evans, G. L., Banas, J. S., Jr., Brooks, H. L., Paraskos, J. A., and Dexter, L.: The Hemodynamic and Respiratory Effects of
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Diazepam (Valium), Anesthesiology 30: 259, 1969. Bianco, J. A., Freedberg, L. E., Powell, W. J., Jr., and Daggett, W. M.: Influence of Vagal Stimulation on Ventricular Compliance, Amer. J. Physiol. 218: 264, 1970. Powell, W. J., Jr., Daggett, W. M., Magro, A. E., Bianco, J. A., Buckley, M. J., Sanders, C. A., Kantrowitz, A. R., and Austen, W. G.: Effects of Intra-Aortic Balloon Counterpulsation on Cardiac Performance, Oxygen Con sumption, and Coronary Blood Flow, Circ. Res. 26: 753, 1970. Wildenthal, K., Mierzwiak, D. S., and Mitchell, J. H.: Acute Effects of Increased Serum Osmolality on Left Ventricular Performance, Amer. J. Physiol. 216: 898, 1969. Abel, R. M., Staroscik, R. N., and Reis, R. L.: The Effects of Diazepam on Left Ventricular Contractility and Coronary Blood Flow, Circula tion 39-40: 33, 1969 (Suppl. 3). Sullivan, J. M., and Gorlin, R.: Effect of 1-Epinephrine on the Coronary Circulation in Human Subjects With and Without Coronary Artery Disease, Circ. Res. 21: 919, 1967.