" N e w " treatment for chronic intractable congestive heart failure G. E. Burch, M.D. J, LeSn-Galindo, M.D. J. A. Cronvich, M.S. New Orleans, La.
Congestive heart failure (CHF) is still one of the most serious illnesses of man and a common cause of death. With severe CHF and the associated myocardial disease, the heart is unable to meet the demands of the tissues of the body for blood, even for the resting state. The classical symptomatic, physical, and hemodynamic manifestations of CHF are too well known to warrant discussion in this report. The pathophysiology and t h e clinical manifestations have been extensively studied for many years throughout the world. But some aspects of the pathophysiology of CHF described almost 30 years ago, 1 especially the changes in the peripheral circulation, venous pressure, and venous tone o f patients with chronic CHF, have been ignored. T h a t all peripheral digital blood vessels are constricted and that venous tone is high in patients with CHF have been clearly demonstrated rheoplethysmographically. 2 Furthermore, peripheral vasodilatation and, most importantly, general systemic vasodilatation in therapy have been shown over 20 years ago to benefit the patient rapidly and dramatically2 In fact, the therapeutic benefits of aminophylline administered intravenously, a common practice for a long time, are apparently due largely to peripheral vasodilatation. This is probably true of nitroglycerin and other periph-
Supported by grant HL-14789 from the National Heart and Lung Institute of the United States Public Health Service, the Rudolph Matas Memorial Fund for the Kate Prewitt Hess Laboratory, the Rowell A. Billups Fund for Research in Heart Disease, and the Feazel Laboratory. From the Department Of Medicine of Tulane University School of Medicine and the Charity Hospital of Louisiana, New Orleans, La. Received for publication Feb. 4, 1976. Reprint requests: G. E. Burch, M.D., 1430 Tulane Ave., New Orleans, La. 70112.
June, 1976, Vol. 91, No. 6, pp. 735-746
eral vasodilator agents as well when used in large doses, This report is concerned with a discussion of the role of the systemic and pulmonary vascular systems in the pathophysiology of congestive heart failure, both acute and chronic, and the demonstration of the dramatic and impressive effect of acute dilatation of the systemic vascular system, especially the venous system, on the clinical and physiologic manifestations of chronic intractable congestive heart failure. Although this report describes the use of an a-adrenergic vasodilating drug in patients with chronic intractable right and left ventricular congestive heart failure, the principles apply to acute left and/or right ventricular congestive heart failure as well. Aspects of the pathophysiology of chronic CHF
It is too frequently not realized that the human cardiovascular system consists of two pumps (and even actually a third one--the venous pumping system4 which is best developed in the skeletal muscles of the extremities). The two pumps (the right and left ventricles) are separated by two vascular systems, 1 the systemic and pulmonic. The systemic vessels contain approximately 4,500 ml. of blood and the pulmonary vessels contain about 500 ml. 1 The largest volume of blood is contained in the venous systems. 5-7 As indicated previously, 1 when the two pumps (right and left ventricles) pump equal amounts of blood, the volume of blood in each vascular bed remains constant. However, if the left ventricle "fails" and pumps less blood per stroke or per minute than the right ventricle, then more blood is pumped into the lungs by t h e right ventricle than is removed from the lungs by the left ventricle.
American Heart Journal
735
Burch, Lebn-Galindo, and Cronvich
Fig. 1A. Rheoplethysmogramsshowing simultaneous time course curves of volumes and rates of digital inflow, outflow, and differencebetween inflowand outflowin a 47-year-oldpatient with severe congestiveheart failure, The curves show all digital vessels to be constricted, including the A-V shunts.
Therefore, the pulmonary vascular bed becomes "congested" with blood, and the clinical and hemodynamic symptoms and signs of left ven~ricular CHF ensue. 1 The blood vessels of the lungs cannot accommodate the entire 4,500 ml. of blood contained in the systemic blood vessels. On the other hand, should the right ventricle fail to pump as much blood as the left ventricle, then all of the blood in the pulmonary vessels could be pumped into the large systemic vessels which could readily accommodate the 500 ml. and still not become tightly congested. 1 However, with right ventricular CHF the systemic veins are "tight," not because a large volume of blood is "stuffed" into the systemic veins but because of high a-adrenergic sympathetic "tone. This high sympathetic tone is manifested by the marked vasoconstriction noted rheoplethysmographically in the digital vessels and the high venous pressure revealed in these studies and described subsequently. T h e reasons or mechanisms responsible for the high a-adrenergic sympathetic tone in CHF are unknown. The concept of the two-pump system of h u m a n circulation is discussed in great detail elsewhere. 1
736
When the smooth muscle tone of the systemic veins is increased because of increased a-adrenergic sympathetic nerve activity, blood is forced into the lungs and into the central systemic venous system and the right side of the heart (the right pump}. This results in distended neck veins, liver distension, pulmonary congestion, and many of the manifestations of CHF, and even the renal dysfunction associated with increased renal venous pressure and venous congestion of CHF. If venous tone is increased in CHF, then an a-adrenergic sympathetic blocking drug should alter this state and should result in improvement of the patient's clinical and physiologic state. This was found to be true, and experimental findings and theoretic considerations of such changes are reported and discussed in this paper.
Theoretic hemodynamic considerations T h e shift of blood in the vascular system between the small vessels and the lungs and vessels of the neck is related to the hemodynamic phenomena associated with the effects of neural and humoral stimuli on the cardiovascular
June, 1976, Vol. 91, No. 6
"New" treatment for chronic intractable C H F
Fig. 1 B. The curves show marked dilatation of all digital blood vessels in response to intravenous administration of 15 mg. of hexamethonium. The drug. was injected in 2.5 mg. amounts over 9 minutes 5 seconds, and this recording was obtained 20 seconds after the final 2.5 mg. dose was given. The total digital volume increased 143 cu. mm. per 5 c.c. part in response to the hexamethonium. The arterial blood pressure decreased from the control value of 142/ 100 to 118/80 mm. Hg.
system. As shown by Eq. (4) of the Appendix, the stress in the wall fibers of an idealized circular cylindrical blood vessel is expressed by S --
pdl 2t, where p is the blood pressure, d~ is the i n t e r n a l d i a m e t e r of the vessel, a n d t is the wall thickness of the vessel, C o n s e q u e n t l y , for a given v o l u m e of wall per unit length of vessel, those vessels with the lower ratios of d~/t h a v e less wall fiber stress and, therefore, h a v e a m e c h a n i c a l a d v a n t a g e over those with larger ratios. T h e small veins in the peripheral v a s c u l a r bed h a v e lower ratios of d~/t t h a n the large veins of the lungs and the large systemic central veins, such as those of the neck. Thus, when n e r v e impulses to increase wall stress arrive with e q u a l i n t e n s i t y a t all vessels, the small veins a n d venules (even capillaries) with their m e c h a n i c a l a d v a n t a g e will c o n t r a c t readily, t h e r e b y displacing the v o l u m e of blood in t h e m ; whereas the larger vessels in the lungs a n d the central systemic vessels of the neck, despite the same and equally intense s y m p a t h e t i c nerve stim-
American Heart J o u r n a l
uli, are forced to dilate to a c c o m m o d a t e the blood forced o u t of the m o r e peripheral, s m a l l venous vessels. I t m a y be n o t e d t h a t , by contracting, the small vessels h a v e a reduction of di/t, t h e r e b y increasing their m e c h a n i c a l a d v a n t a g e even more; b u t the dilated large vessels h a v e an increase of di/t, t h e r e b y increasing f u r t h e r their mechanical disadvantage. I f the stress-inducing impulses are blocked, the resulting r e l a x a t i o n p e r m i t s the s m a l l vessels to return to their n o r m a l dimensions a n d accept the blood which is p u m p e d to t h e m by the left ventricle f r o m the distended larger c e n t r a l veins. In turn, the larger vessels also c a n r e t u r n to n o r m a l size and b e c o m e less congested t h r o u g h out the p u l m o n a r y a n d central systemic venous circulations. T h e s y m p t o m s a n d signs of C H F would be expected, then, to subside.
Physiologic studies: methods and materials Five p a t i e n t s with chronic i n t r a c t a b l e biventricular f u n c t i o n a l Class IV congestive h e a r t failure were studied. T h e p a t i e n t s rested in a
737
Burch, Lebn-Galindo, and Cronvich
Table I. Influence of h e x a m e t h o n i u m chloride (C6) on venous and peripheral circulations of patients with chronic intractable C H F
Patient No.
Age, sex
Total C6 given (mg.)
1 2 3 4 5 Mean
58 F 58 M 30 M 47 F 27 F 44
22.5 22.5 15.0 17.5 12.5 18.0
Arterial pressure (ram. Hg)
Time Heart rate for (beats~rain.) total injection Before [ After (rain.) C~ ] C6 7.8 10.0 3.3 12.3 12.8 9.2
80 70 98 93 110 90
64 70 100 87 110 86
Before C6
After C6
135/85 160/95 115/80 140/110 96/8O 129/90
105/60 115/70 115/80 110/82 84/62 106/71
Systemic venous pressure (ram. H~O)
Basal IR (cu. mm./5 c.c. part/sec.)
Maximal I~ (cu. ram.~5 c.c. part/ sec.)
Before [ After C~ Co
Before [ After C6 " C~
Before [ After C~ C~
293 374 330 375
147 260 270
343
226
3 6 11 5 25 10
25 11 17 26 38 23
22 63 35 23 70 43
35 80 37 49 88 58
*Patient movedtoo much for measurement.
Pt. N o . 4 , 4 7 N F
~
r
150-
~
2
r
125"
Systolic BJP
o; ICO.
x..
x,." X--
~
~X
~
Diostollc B.P
75.
| Venous Pressure
~;
0
2
4
6
8
Io minutes
12
14
16
8
20
Fig. 2. Influence of intravenous hexamethonium on the arterial and systemic venous pressures of the same patient with severe CHF as in Fig. 1. comfortable h o s p i t a l - t y p e bed in the n e u t r a l envir o n m e n t of our climatic observation room. T h e circulation to and from the right index fingertip (2RF) and the right middle fingertip (3RF) was studied rheoplethysmographically, as described previously, s' 9 with the right arm and h a n d resting passively with the digits at heart level. Systemic venous and arterial blood pressures were recorded with suitable pressure transducers a n d recorders while the neck veins were closely observed and p h o t o g r a p h e d and the changes in clinical s y m p toms and signs were carefully noted. In some subjects c o n t i n u o u s direct recordings of systemic venous pressure and arterial blood pressure were
738
obtained. I n other subjects changes in venous pressure were noted merely by observing the neck veins, and the arterial blood pressure was recorded by means of a clinical m e r c u r y type sphygmomanometer. After obtaining baseline m e a s u r e m e n t s and observations, h e x a m e t h o n i u m chloride (25 mg. per milliliter of concentration ) was injected intravenously, 0.1 ml. (2.5 mg.) at a time, into a vein in the left forearm at intervals of 30 to 120 seconds while t h e p a t i e n t was w a t c h e d carefully and observed for changes in arterial blood pressure, systemic venous pressure, neck vein distension, digital blood flow, and clinical manifestations of CHF. T h e m a x i m u m t o t a l a m o u n t of hexamet h o n i u m injected into a n y one subject was intentionally limited to 22.5 mg.
Results Peripheral circulation. T h e r h e o p ] e t h y s m o grams of all of the patients with C H F showed marked digital vasoconstriction prior to the administration of the h e x a m e t h o n i u m {Fig. 1A). Basal digital blood flow was also m a r k e d l y reduced (Fig. 1A). ~' 9 These simultaneous and c o n t i n u o u s recordings of volumes and rates of digital inflow and outflow and o f differences between inflow and outflow revealed constriction of the arterial and venous vessels of the digits. Since the rate of basal flow was also low, the A-V shunts were also constricted in the patients with C H F at rest. As the h e x a m e t h o n i u m was injected intravenously, these simultaneously recorded curves of
June, 1976, Vol. 91, No. 6
"New" treatment for chronic intractable C H F
Total Iv~heart beat Maximal Dv (cu. ram.~5 c.c. part) (cu. mm./5 c.c. part) Before Co
After C6
Before Co
After Co
4.7 6.5 5.5 5.6 10.2 6.5
10.5 10.4 4.8 10.5 10.1 9.3
2.4 4.4 2.0 1.6 2.8 2.6
2.5 5.0 2.1 3.2 5.0 3.6
Increase in total digital volume (cu. mm./5 c.c. part)
8+ * 65 - * 143 95 78 +
blood flow showed t h a t all the digital vessels, including the A-V shunts, dilated and t hat digital inflow and outflow increased markedly (Fig. 1B). T o tal digital volume inCreased considerably throughout the administration of hexamethonium in all patients, indicating the shift of blood from the central systemic vessels to the peripheral vessels. As the peripheral dilatation developed, the patient improved dramatically. T h e data varied quantitatively from patient to patient, but all the digital vessels were tightly constricted in all the patients with CHF prior to a-adrenergic sympathetic nerve blockade. The intravenous administration of hexamethonium dilated all digital vessels in all patients. No effort was made to quantitate the sensitivity of each patient to the drug or to study digital flow On a statistically quantitative basis in any patient or in the group of patients. Systemic venous pressure. Systemic venous pressure measurements obtained with pressure transducers and recorders revealed high pressure in the left forearm vein in all patients in whom it was measured (Table I). T he pressure varied from patient to patient and in accordance with the degree of CHF. As the hexamethonium was injected, systemic venous pressure decreased (Fig. 2) simultaneously with digital vasodilatation. The degree of all vascular dilatation varied directly with the dosage of hexamethonium administered. In fact, the degree o f vascular dilatation attained was arbitrarily decided for each patient by us. T he maximum clinical limit definitely was not reached. As the systemic
A m e r i c a n H e a r t Jo u r n a l
venous tone declined and the veins loosened, the patient improved clinically and the symptoms and signs of CHF reduced dramatically or disappeared. Central
venous
pressure.
The neck veins,
which reflect changes in central and systemic venous pressure, were photographed periodically and watched carefully throughout the investigations. Before hexamethonium was injected, the neck veins of all patients were markedly dilated and congested with blood even with the patient's back rest elevated (Figs. 3 and 4). T he distended neck veins reflected high central venous pressure and high right atrial pressure. Several patients had marked pulsations in the congested external jugular veins because of tricuspid regurgitation. In several patients the veins were turgid to palpation and felt like ropes because their intravenous pressure was so high and their walls so tight. Even the veins of the face and forehead were prominent and turgid in some patients, reflecting the high venous pressure (Fig. 4). As the hexamethonium injected intravenously into a small vein in the left forearm caused the systemic venous pressure to decrease and the digital vascular system to dilate, the neck veins decreased in size and became less and less turgid. Finally, by the time 15 to 17.5 mg. of hexamethonium had been administered, the neck veins and also the forehead veins became visible (Figs. 3 and 4 ). Symptomatically, the patient's neck veins felt soft, and the patient could rotate his head freely without discomfort previously produced by the distended tight veins in the neck. The previous feeling or sensation of intrathoracic fullness, tightness, or congestion subsided and finally disappeared as the neck veins became less distended and the generalized peripheral vasodilatation developed. These symptomatic changes were dramatic and impressive, especially the disappearance of the dyspnea, breathlessness, tightness, and fullness in the chest experienced by the patient. These changes occurred within 5 to 13 minutes of the initial injection of hexamethonium in all patients. Systemic arterial pressure. Before hexamethonium was administered, the arterial blood pressure was not high in any patient, and in a few patients it was impressively low in spite of the peripheral vasoconstriction (Table I). This vascu-
739
Butch, Lebn-Galindo, and Cronvich
AI
Fig. 3. Influence of intravenous hexamethonium on the neck veins of the 47-year-oldpatient with severe CHF hexamethonium (15 mg.) was administered in 2.5 mg. amounts over 12.3 minutes.
Fig. 4. Influence of intravenous hexamethonium on the neck and forehead veins of a 58-year-old patient with severe CHF. The hexamethonium (17.5 mg.) was administered in 2.5 mg. amounts over 10 minutes.
lar state resembled s o m e w h a t the manifestations of impending or mild cardiogenic shock. A l t h o u g h arterial pressure was reduced by the hexamet h o n i u m to relatively low levels, even to 84/62 in one patient, the patients felt m u c h better and were able to s t a n d a n d walk and sit w i t h o u t syncopal s y m p t o m s . T o avoid excessive vasodilatation, the decrease in arterial blood pressure was used as a guideline to discontinue a d m i n i s t r a t i o n of h e x a m e t h o n i u m , T h e blood pressure continued to decrease slightly for 5 to 10 m i n u t e s after administration of the drug was stopped. Because of the effect on blood pressure, the drug was administered in 0.1 ml. (2.5 mg.) a m o u n t s at a
740
time, with 30 to 120 second intervals to allow its full effects to occur before administration of the next 0.1 ml. I t was n o t necessary for the arterial pressure to decrease for the patients to feel better or improve clinically, as in the case of P a t i e n t No, 3 {Table I). I m p r o v e m e n t seems to be definitely more closely related to the reduction in peripheral venous tone {noted r h e o p l e t h y s m o g r a p h i c a l l y ) and to the decline in systemic venous p r e s s u r e (and in p u l m o n a r y venous pressure, n o t observed directly) t h a n to the decrease in arterial blood pressure. Heart rate. H e a r t rate changed very little
June, 1976, Vol. 91, No. 6
"New" treatment for chronic intractable C H F
during the studies (Table I). This is due in part to the fact t h a t small amounts of hexamethonium were used. Respiration. Respiratory rate decreased as the patient's dyspnea became less and his lungs became less congested with blood. Breathing became less labored and the sensation of suffocation or breathlessness disappeared as venous pressure decreased and the neck veins became soft. T h e symptomatic improvement progressively occurred concomitantly with the decrease in venous congestion. In some patients the crepitant r~les in the bases of both lungs decreased in extent and degree and even disappeared. Discussion
The mechanisms and physiologic reasons for the high a-adrenergic sympathetic tone and resultant marked peripheral vascular constriction and the general increase in systemic venous tone in patients with congestive heart failure remain unknown. T h a t such high vascular tone exists in CHF is obvious from these observations and previous publications. 2.3 The theoretic discussions outlined above and in the Appendix indicate the mechanical factors responsible for the shift of blood centrally in CHF, including the shift into the pulmonary vascular system which cannot accommodate more than a small volume of the relatively large amount of blood normally present in the systemic venous reservoir of the body. This shift of blood is responsible for many of the manifestations of CHF. Whether or not the generalized increase in sympathetic tone is responsible, in part at least, directly or indirectly for the altered renal function with the resultant water and salt retention is also not known. T h a t this is so is conceivable, however. Surely, a-adrenergic sympathetic nervous system blocking with hexamethonium does initiate immediate symptomatic improvement of the patient and even marked diuresis associated with the return of renal function to normal in some patients. The precise mechanisms responsible for this diuresis are also not known. The diuresis could be accounted for by the decrease in systemic venous pressure, including pressure in the renal veins. The percentage increase in systemic venous pressure was greater than in arterial pressure in the patients studied. In fact, the arterial blood pressure was only slightly elevated in two patients, whereas systemic venous pressure was
American Heart Journal
increased several-fold in all four patients in whom it was measured {Table I). Furthermore, symptomatic improvement was more directly related to the decrease in venous tone and venous pressure than to the decrease in arterial pressure. One patient improved without any change in systemic arterial pressure. Venous tone in most patients decreased before arterial pressure decreased. All digital vessels were constricted in the patient studied. No measurements were made of the visceral arterial system. The hexamethonium decreased the vascular tone and dilated all blood vessels studied, including systemic veins, all digital vessels, and systemic arteries (except in one patient). With the decrease in tone and the dilatation, as evidenced by the decrease in arterial blood pressure, the decrease in systemic venous pressure and "collapse" of the neck veins, the patient improved symptomatically. One patient had such markedly distended tight neck veins that she was unable to rotate her head without considerable discomfort and fear t h a t she might rupture a neck vein (Fig. 3). With the collapse of the neck veins following administration of hexamethonium, the ability to rotate her head freely and comfortably was most impressive to her. Diuresis developed in the patients, and the crepitant r~les in the bases of both lungs decreased in extent and amount or even disappeared. These changes all suggested t h a t there was preferential increase in venous tone in these patients with CHF in association with an increase in digital vascular tone. The precise reasons for such an increase in venous tone in chronic CHF which was readily interrupted with the a-adrenergic sympathetic blocking agent are unknown, but the increased tone is extremely important in the clinical and physiologic syndrome of CHF. The physiologic and hemodynamic contributions of the high venous tone to the production of the clinical manifestations of CHF need to be studied extensively. The elevated venous tone and venous pressure may be a cause, in large part, for the change in renal function which results in electrolyte and water retention in CHF. The subtle changes in renal function that generalized increase in venous tone and the resultant venous hypertension produce have received little attention. Surely, renal venous pressure must be increased in CHF along with the generalized increase in systemic venous pressure. Hexamethonium decreased systemic venous
741
Burch, Lebn-Galindo, and Cronvich
Fig. 5. The idealized cylindricalvessel used in calculations in the Appendix of wall volume and wall fiber stress.
tone so th at the large systemic venous vessels relaxed or "loosened" and accommodated a large volume of blood under lower pressure as the left ventricle pumped blood into the peripheral vascular system from the pulmonary vascular system. When the left ventricle pumped more blood out of the lungs t ha n the right ventricle pumped into the lungs, a new state of equilibrium resulted in which there was less blood in the pulmonary venous and entire pulmonary vascular system and in the large central systemic veins but more blood in the smaller peripheral vessels, with all intravenous blood pressure being at lower levels. Th e distribution of blood in the circulation became more normal. T he pressure in the pulmonary vascular system must have been reduced because blood volume in t h a t system was reduced, whereas the pressure in the systemic venous system was reduced, in spite of an increase in its blood volume, because of the decrease in venous tone produced by blocking of the a-adrenergic sympathetic nervous system. In the management of CHF by venesection, the volume of blood is reduced in the systemic veins, which reduces the wall stress on these veins, but the a-adrenergic sympathetic nervous system tone and, in turn, the smooth muscle tone of the venous walls are not reduced, even indirectly. Increase in venous tone is the direct cause for the elevated venous pressure due to high sympathetic nerve stimulation of veins and, in turn, accounts for the venous congestion of CHF. However, hexamethonium interrupts the direct cause for high venous tone by blocking the a-adrenergic sympathetic nervous system tone. Thus, the patient is "bled" into his systemic veins, and blood is redistributed to achieve a more normal distribution of blood volume with a more normal venous and sympathetic nervous tone,
742
vessel wall tone, and intravascular pressure. The pharmacologic and physiologic procedure employed to achieve this state was simple. T h e patients felt better. Respiration was improved. T h e associated decrease in arterial blood pressure unloaded the heart, and its function apparently improved. Hexamethonium, then, really provides, by physiologic readjustments, "intravascular venesection" without blood loss. T h e latter point is especially important if the patient is anemic. This procedure and drug can be used readily clinically in the care of patients with CHF. It should be clearly indicated t hat hexamethonium is most effective when systemic venous pressure is elevated and the lungs are congested with blood. This is evident from previous discussions of the mechanisms of CHF 1 and recent unpublished studies. Thus, this vasoditator would be most effective in patients whose CHF is progressively getting worse or in whom the CHF has reached a stable state as with intractable severe CHF. Hexamethonium is the best vasodilator and a-adrenergic sympathetic blocking agent available today for clinical use for the relief of CHF as described above. It acts rapidly, so t hat the physician can judge when he has administered the proper dose intravenously. T h e full effect is reached in 2 to 3 minutes after injection. Furthermore, its action subsides rapidly. The resultant vasodilatative effects may linger totally or in part for hours or days even though the drug itself has ceased to be present. When hexamethonium is used properly, norepinephrine, its antidote, should never be needed to Correct an overdose of hexamethonium. T he dose of hexamethonium can be carefully and accurately monitored at the bedside for each patient by observing the changes in arterial blood pressure, neck vein distension, and the patient's general state of well-being, as noted above. Thus, the dosage used by us arbitrarily varied according to the patient's response. These studies were not undertaken to quantitate the degree of vascular change produced in CHF by hexamethonium. Although the measurements were quantitative, the objective was to learn the physiologic changes produced and their effects on the physiologic a n d clinical state of CHF and the final clinical well being of the patient. No effort was made to measure cardiac output, end-diastolic pressure in the four cardiac
June, 1976, Vol. 91, No. 6
"New" treatment for chronic intractable C H F
2.0-
.8 .6 .4 4"v r
2
-.\
== ==
.02
0.011 0.1
I
i
.2 Internol
!
,
.4
!
I
.6
Diometer
!
I
i
i
.8 1.0 of Vessel
2 (dil
I
,
,
4
,
6
il
,
8
I0
I 0 x cm.
Fig. 6. Wall thickness (t) vs. internal diameter (di) a s a function of wall volume per centimeter length (V1). With the selection of the exponent x for dimensions of d, t, and V1, these curves apply to a wide range of dimensions. chambers, central v e n o u s pressure, p u l m o n a r y arterial or venous pressure, ejection rate, or o t h e r h e m o d y n a m i c p h e n o m e n a for fear t h a t the m e t h o d s used would c o m p l i c a t e t h e studies. F u r t h e r m o r e , these m e a s u r e m e n t s were n o t necessary. T h e p l a n was to e m p l o y simple m e t h o d s for m o n i t o r i n g the physiologic a n d clinical s t a t e during t h e a d m i n i s t r a t i o n of h e x a m e t h o n i u m since physicians in hospital and emergency r o o m practice should be able to e m p l o y the drug effectively u n d e r practical a n d simple circumstances. T h e role of the decrease in arterial blood pressure in i m p r o v i n g the s t a t e of C H F is not clearly evident f r o m these studies. It m u s t h a v e been a c o n t r i b u t i n g f a c t o r b u t not a necessary one n o r the m o s t i m p o r t a n t one, certainly n o t as i m p o r t a n t as the decrease in systemic v e n o u s a n d peripheral v a s c u l a r tone. T h i s was evident f r o m p a t i e n t s w i t h C H F in w h o m arterial blood pressure was a l r e a d y low a n d the systemic venous pressure e x t r e m e l y high. Also, venous pressure decreased in some p a t i e n t s initially with injection
American Heart Journal
of t h e h e x a m e t h o n i u m with definite s y m p t o m a t i c i m p r o v e m e n t even t h o u g h arterial blood pressure had not changed or h a d decreased minimally. App a r e n t l y , the clinical i m p r o v e m e n t in the s t a t e of C H F was due to the decline in systemic venous pressure and a shift of blood f r o m t h e p u l m o n a r y blood vessels, especially the p u l m o n a r y veins, a n d central veins. F u r t h e r m o r e , merely a decrease in load on the left ventricle w i t h o u t a decrease in a-adrenergic s y m p a t h e t i c nervous s y s t e m t o n e would not p r o d u c e a decrease in systemic venous tone. 1 T h e m e c h a n i c a l d i s a d v a n t a g e u n d e r which the large central veins function as c o m p a r e d to the smaller, m o r e p e r i p h e r a l l y located ones which contain m o s t of t h e blood is readily shown b y the Appendix and Figs. 5, 6, and 7. T h e relative intensity of a-adrenergic s y m p a t h e t i c n e r v e impulse s t i m u l a t i o n for different size veins is y e t to be determined. For example, is t h e intensity of s y m p a t h e t i c n e r v e s t i m u l a t i o n t h e s a m e per u n i t v o l u m e of v e n o u s wall or per s m o o t h muscle cell or per unit cross sectional area of all vessels?
743
Burch, Le6n-Galindo, and Cronvich
IO S 6 z
4
~.
2
r
.~ i.o ~
.8
~
.6
o E Z
.2
OA 0.1
.2 .4 .6 JB 1.0 Internol Oiometer of Vessel
2 (d i ]
4 I0 x cm.
6
8
I0
Fig. 7. Normalizedstress (S~) vs. internal diameter (dJ as a function of wall volumeper centimeter length (Vj. With the selection of the exponent x for the dimensions of dj and V1, these curves apply to a wide range of dimensions.
Such questions need to be answered for better appreciation of the role or importance of venous tone for the various veins of the body. Regardless, the relative mechanical state of tension and force of the various veins of the body must be related more or less as described above and indicated by Figs. 6 and 7. Surely, in order for the changes noted to occur, the blood is shifted to the more peripherally located systemic veins because hexamethonium blocks the a-adrenergic sympathetic nervous system. Th e value of hexamethonium in the t r e a t m e n t of chronic intractable CHF and acute pul m on ary edema is evident from the clinical response, alone. All patients with CHF improved immediately and impressively following administration of hexamethonium. Several hours after the effects of the drug disappeared some of the patients with chronic and intractable CHF gradually developed dyspnea and central systemic venous and pulmonary congestion again. However, the level of discomfort was less than t ha t prior to administration. One of the patients included in this study was so relieved by the hexamethonium t hat she requested repeat studies in order to receive the hexamethonium injections. An injection can be
744
given daily or even more frequently when the drug is used primarily for clinical care. Some patients developed a good diuresis immediately following the use of the drug. This response certainly indicates t h a t renal functional state was potentially good and was hemodynamically related to the functional state of the cardiovascular system during CHF since hexamethonium is not a diuretic known to act directly as such on the renal parenchyma. We would suggest t h a t t h e renal dysfunction in these patients with chronic CHF was due in large part to the increase in sympathetic nervous system tone and high renal venous pressure. The procedure for administering hexamethonium clinically is simple and c a n be employed at the bedside or in the emergency room with only the use of a sphygmomanometer along with careful clinical observations and understanding. Summary
T he use of hexamethonium injected intravenously in successive 2.5 mg. doses resulted in a-adrenergic sympathetic nerve blocking and associated peripheral vasodilatation with dramatic improvement of the symptoms and signs in
June, 1976, Vol. 91, No. 6
"New" treatment for chronic intractable C H F
patients w i t h marked chronic intractable CHF. The vasodilatating effect of the drug is simple to monitor at the bedside and serves as an effective, simple means to "bleed" the patient intravenously by decreasing systemic venous tone and reducing the wall stress in the vessels. This intravenous "bleeding" results in a shifting of excessive blood from the lungs and central systemic venous areas to the larger volume of the more peripheral systemic venous reservoirs. Rheoplethysmographic recordings of digital blood flow in the fingertips of the patients revealed marked constriction of all vessels of the fingers during CHF. Hexamethonium dilated all these vessels and increased digital blood flow even though arterial blood pressure was reduced b y t h e drug. Theoretic discussions of aspects of the mechanism of congestive heart failure of the two-pump system of the heart of man ~ and the mechanical or hemodynamic advantages of the small veins over the larger centrally located veins tend to explain why the use of hexamethonium benefits the circulation by producing venodilatation. These studies indicate the therapeutic usefulness of hexamethonium in the management of acute and chronic intractable CHF and provides physiologic and theoretic data to explain why the drug is effective.
Appendix
Because of the shift of blood volume in the cardiovascular system in pathologic states, it is of interest to know the relations between the pressure in the vessels of the cardiovascular system and the radial force on and the stress in the wall fibers of the respective vessels. The following analysis is based on an idealized circular cylindrical vessel with walls which are homogeneous radially and which do not elongate axially: Thus, it is assumed t h a t a change in internal diameter (di) is accompanied by an appropriate change in wall thickness (t) to keep constant the volume of wall per unit length (V1) of vessel. In the cylindrical vessel of Fig. 5, the volume of wall v
+
diZ
=~
4
+ d~t +
American Heart Journal
dis ] L 4
-
= tr [ d i t + t2]L
(1)
or, V1 (volume per unit length) = ~r (d~t + t~).
Therefore, ct~ =
V1 qr
t~
V~ = ~r t
t
REFERENCES
1. Butch, G. E.: A primer of congestive heart failure, Springfield, Ill., 1954, Charles C Thomas, Publisher. 2. Burch, G. E.: Evidence for increased venous tone in chronic congestive heart failure, Arch. Intern. Med. 98:750, 1956. 3. Burch, G. E.: A method for measuring venous tone in digital veins of intact man: Evidence for increased digital venous tone in congestive heart failure, Tr. Assoc. Am. Phys. 67:174, 1954. 4. Burch, G. E.: A primer of venous pressure, Springfield, Ill., 1972, Charles C Thomas, Publisher. 5. Gibson, J. G., II, and Evans, W. A., Jr.: Clinical studies of the blood volume. I. Clinical application of a method employing the azo dye "Evans Blue" and the spectrophotometer, J. Clin. invest. 16:301, 1937. 6. Gibson, J. G., II, and Evans, W. A., Jr.: Clinical studies of the blood volume. II. The relation of plasma and total blood volume to venous pressure, blood velocity rate, physical measurements, age and sex in ninety normal humans, J. Clin. Invest. 16:317, 1937. 7. Gibson, J. G., II, and Evans, W. A., Jr.: Clinical studies of the blood volume, iII. Changes in blood volume, venous pressure and blood velocity rate in chronic congestive heart failure, J. Clin. Invest. ] 6:851, 1937. 8. Burch, G. E.: Digital plethysmography, New York, 1954, Grune & Stratton, Inc. 9. Burch, G. E.: The George E. Brown Memorial Lecture: Digital rheoplethysmography, Circulation 13:641, 1956.
t~
// or
t
=
4V1
- d~ + ~ / d i ~ +
(2)
~r
The radial force per unit length on the wall produced by fluid at pressure p is F r = p~rdi, (3) and the stress in the wall fibers is S pdiL pdi 2tL 2t (4) If V~ is constant as d, changes, then
2idi++4vl]1+4v d~
S
=
P
P
--~
2
Normalizing F and S for p = 1 results in F N = ~rdi
745
Burch, Le6n-Galindo, and Cronvich
and
SN = / 1 + /1 V
+
4Vl
7rd~~
I f a c o n s i s t e n t s e t o f u n i t s is u s e d in w h i c h d i = i n t e r n a l d i a m e t e r o f v e s s e l in c e n t i meters t = w a l l t h i c k n e s s in c e n t i m e t e r s L = l e n g t h o f vessel in c e n t i m e t e r s p = p r e s s u r e in d y n e s p e r s q u a r e c e n t i meter t h e n V = v o l u m e in c u b i c c e n t i m e t e r s V~ = v o l u m e in c u b i c c e n t i m e t e r s p e r c e n t i meter length F = r a d i a l f o r c e o n c e n t i m e t e r l e n g t h of w a l l in d y n e s S = s t r e s s in w a l l fibers in d y n e s p e r square centimeter Sx = n o r m a l i z e d w a l l s t r e s s . F o r c o n v e n i e n c e in r e l a t i n g V1, d i , a n d t, t h e c u r v e s in Figs. 6 a n d 7 a r e given. These curves are useful over a wide range of i n t e r n a l d i a m e t e r s (di) a n d w a l l v o l u m e s p e r u n i t l e n g t h (V1) b y a p p r o p r i a t e l y s e l e c t i n g t h e e x p o n -
746
e n t x. F o r e x a m p l e , f r o m Fig. 6, if x = 0, (a) w h e n dl = 2 cm. = 2 x 10 ~ cm. and V~ = 5 c m 2 = 5 • 10 ~ c m 2 , t = 0.61 cm. = 0.61 x 10 ~ cm.; a n d (b) w h e n d~ = 5 cm. a n d V, = 5 c m 2 , t = 0.30 cm. B u t if x = - 5 , t h e n c o r r e s p o n d i n g t o (a) a b o v e , dl = 2 x 10 ~ cm., V~ = 5 x 10 20 cm., a n d t = 0.61 x 10 5 cin. S i m i l a r l y , f r o m Fig. 7, t h e n o r m a l i z e d w a l l s t r e s s (SN) c a n b e d e t e r m i n e d . I n t h i s case, w h e t h e r x = 0 o r - 5 , for d i m e n s i o n s g i v e n f o r (a), S~ = 1.64; a n d for d i m e n s i o n s f o r (b), S~ = 8.33. T h e a c t u a l w a l l s t r e s s is e x p r e s s e d b y S = p x S~. T h e r e f o r e , for t h e d i m e n s i o n s of c a s e (a), a v e n o u s p r e s s u r e o f a p p r o x i m a t e l y 100 m m . of w a t e r (p = 10,000 d y n e s p e r s q u a r e c e n t i m e t e r ) w o u l d r e s u l t in a w a l l s t r e s s S = p x S~ = 10,000 x 1.64 = 16,400 d y n e s p e r s q u a r e c e n t i m e t e r ; w h e r e a s for a v e n o u s p r e s s u r e o f a p p r o x i m a t e l y 400 m m . of w a t e r (p = 40,000 d y n e s p e r s q u a r e c e n t i m e t e r ) , S = 40.000 • 1.64 = 65,600 d y n e s p e r s q u a r e cent i m e t e r . T h e r a p i d i n c r e a s e in S~ as d~ i n c r e a s e s w i t h c o n s t a n t VI is s h o w n b y t h e c u r v e s a n d b y t h e e x a m p l e j u s t c o n s i d e r e d - a n i n c r e a s e o f d~ b y t h e f a c t o r 5 / 2 or 2.5 r e s u l t s in a n i n c r e a s e o f S~ b y t h e f a c t o r 8.33/1.64 o r 5.07.
June, 1976, Vol, 91, No. 6
Congestive heart failure (CHF) is still one of the most serious illnesses of man and a common cause of death. With severe CHF and the associated myocardial disease, the heart is unable to meet the demands of the tissues of the body for blood, even for the resting state. The classical symptomatic, physical, and hemodynamic manifestations of CHF are too well known to warrant discussion in this report. The pathophysiology and t h e clinical manifestations have been extensively studied for many years throughout the world. But some aspects of the pathophysiology of CHF described almost 30 years ago, 1 especially the changes in the peripheral circulation, venous pressure, and venous tone o f patients with chronic CHF, have been ignored. T h a t all peripheral digital blood vessels are constricted and that venous tone is high in patients with CHF have been clearly demonstrated rheoplethysmographically. 2 Furthermore, peripheral vasodilatation and, most importantly, general systemic vasodilatation in therapy have been shown over 20 years ago to benefit the patient rapidly and dramatically2 In fact, the therapeutic benefits of aminophylline administered intravenously, a common practice for a long time, are apparently due largely to peripheral vasodilatation. This is probably true of nitroglycerin and other periph-
Supported by grant HL-14789 from the National Heart and Lung Institute of the United States Public Health Service, the Rudolph Matas Memorial Fund for the Kate Prewitt Hess Laboratory, the Rowell A. Billups Fund for Research in Heart Disease, and the Feazel Laboratory. From the Department Of Medicine of Tulane University School of Medicine and the Charity Hospital of Louisiana, New Orleans, La. Received for publication Feb. 4, 1976. Reprint requests: G. E. Burch, M.D., 1430 Tulane Ave., New Orleans, La. 70112.
June, 1976, Vol. 91, No. 6, pp. 735-746
eral vasodilator agents as well when used in large doses, This report is concerned with a discussion of the role of the systemic and pulmonary vascular systems in the pathophysiology of congestive heart failure, both acute and chronic, and the demonstration of the dramatic and impressive effect of acute dilatation of the systemic vascular system, especially the venous system, on the clinical and physiologic manifestations of chronic intractable congestive heart failure. Although this report describes the use of an a-adrenergic vasodilating drug in patients with chronic intractable right and left ventricular congestive heart failure, the principles apply to acute left and/or right ventricular congestive heart failure as well. Aspects of the pathophysiology of chronic CHF
It is too frequently not realized that the human cardiovascular system consists of two pumps (and even actually a third one--the venous pumping system4 which is best developed in the skeletal muscles of the extremities). The two pumps (the right and left ventricles) are separated by two vascular systems, 1 the systemic and pulmonic. The systemic vessels contain approximately 4,500 ml. of blood and the pulmonary vessels contain about 500 ml. 1 The largest volume of blood is contained in the venous systems. 5-7 As indicated previously, 1 when the two pumps (right and left ventricles) pump equal amounts of blood, the volume of blood in each vascular bed remains constant. However, if the left ventricle "fails" and pumps less blood per stroke or per minute than the right ventricle, then more blood is pumped into the lungs by t h e right ventricle than is removed from the lungs by the left ventricle.
American Heart Journal
735
Burch, Lebn-Galindo, and Cronvich
Fig. 1A. Rheoplethysmogramsshowing simultaneous time course curves of volumes and rates of digital inflow, outflow, and differencebetween inflowand outflowin a 47-year-oldpatient with severe congestiveheart failure, The curves show all digital vessels to be constricted, including the A-V shunts.
Therefore, the pulmonary vascular bed becomes "congested" with blood, and the clinical and hemodynamic symptoms and signs of left ven~ricular CHF ensue. 1 The blood vessels of the lungs cannot accommodate the entire 4,500 ml. of blood contained in the systemic blood vessels. On the other hand, should the right ventricle fail to pump as much blood as the left ventricle, then all of the blood in the pulmonary vessels could be pumped into the large systemic vessels which could readily accommodate the 500 ml. and still not become tightly congested. 1 However, with right ventricular CHF the systemic veins are "tight," not because a large volume of blood is "stuffed" into the systemic veins but because of high a-adrenergic sympathetic "tone. This high sympathetic tone is manifested by the marked vasoconstriction noted rheoplethysmographically in the digital vessels and the high venous pressure revealed in these studies and described subsequently. T h e reasons or mechanisms responsible for the high a-adrenergic sympathetic tone in CHF are unknown. The concept of the two-pump system of h u m a n circulation is discussed in great detail elsewhere. 1
736
When the smooth muscle tone of the systemic veins is increased because of increased a-adrenergic sympathetic nerve activity, blood is forced into the lungs and into the central systemic venous system and the right side of the heart (the right pump}. This results in distended neck veins, liver distension, pulmonary congestion, and many of the manifestations of CHF, and even the renal dysfunction associated with increased renal venous pressure and venous congestion of CHF. If venous tone is increased in CHF, then an a-adrenergic sympathetic blocking drug should alter this state and should result in improvement of the patient's clinical and physiologic state. This was found to be true, and experimental findings and theoretic considerations of such changes are reported and discussed in this paper.
Theoretic hemodynamic considerations T h e shift of blood in the vascular system between the small vessels and the lungs and vessels of the neck is related to the hemodynamic phenomena associated with the effects of neural and humoral stimuli on the cardiovascular
June, 1976, Vol. 91, No. 6
"New" treatment for chronic intractable C H F
Fig. 1 B. The curves show marked dilatation of all digital blood vessels in response to intravenous administration of 15 mg. of hexamethonium. The drug. was injected in 2.5 mg. amounts over 9 minutes 5 seconds, and this recording was obtained 20 seconds after the final 2.5 mg. dose was given. The total digital volume increased 143 cu. mm. per 5 c.c. part in response to the hexamethonium. The arterial blood pressure decreased from the control value of 142/ 100 to 118/80 mm. Hg.
system. As shown by Eq. (4) of the Appendix, the stress in the wall fibers of an idealized circular cylindrical blood vessel is expressed by S --
pdl 2t, where p is the blood pressure, d~ is the i n t e r n a l d i a m e t e r of the vessel, a n d t is the wall thickness of the vessel, C o n s e q u e n t l y , for a given v o l u m e of wall per unit length of vessel, those vessels with the lower ratios of d~/t h a v e less wall fiber stress and, therefore, h a v e a m e c h a n i c a l a d v a n t a g e over those with larger ratios. T h e small veins in the peripheral v a s c u l a r bed h a v e lower ratios of d~/t t h a n the large veins of the lungs and the large systemic central veins, such as those of the neck. Thus, when n e r v e impulses to increase wall stress arrive with e q u a l i n t e n s i t y a t all vessels, the small veins a n d venules (even capillaries) with their m e c h a n i c a l a d v a n t a g e will c o n t r a c t readily, t h e r e b y displacing the v o l u m e of blood in t h e m ; whereas the larger vessels in the lungs a n d the central systemic vessels of the neck, despite the same and equally intense s y m p a t h e t i c nerve stim-
American Heart J o u r n a l
uli, are forced to dilate to a c c o m m o d a t e the blood forced o u t of the m o r e peripheral, s m a l l venous vessels. I t m a y be n o t e d t h a t , by contracting, the small vessels h a v e a reduction of di/t, t h e r e b y increasing their m e c h a n i c a l a d v a n t a g e even more; b u t the dilated large vessels h a v e an increase of di/t, t h e r e b y increasing f u r t h e r their mechanical disadvantage. I f the stress-inducing impulses are blocked, the resulting r e l a x a t i o n p e r m i t s the s m a l l vessels to return to their n o r m a l dimensions a n d accept the blood which is p u m p e d to t h e m by the left ventricle f r o m the distended larger c e n t r a l veins. In turn, the larger vessels also c a n r e t u r n to n o r m a l size and b e c o m e less congested t h r o u g h out the p u l m o n a r y a n d central systemic venous circulations. T h e s y m p t o m s a n d signs of C H F would be expected, then, to subside.
Physiologic studies: methods and materials Five p a t i e n t s with chronic i n t r a c t a b l e biventricular f u n c t i o n a l Class IV congestive h e a r t failure were studied. T h e p a t i e n t s rested in a
737
Burch, Lebn-Galindo, and Cronvich
Table I. Influence of h e x a m e t h o n i u m chloride (C6) on venous and peripheral circulations of patients with chronic intractable C H F
Patient No.
Age, sex
Total C6 given (mg.)
1 2 3 4 5 Mean
58 F 58 M 30 M 47 F 27 F 44
22.5 22.5 15.0 17.5 12.5 18.0
Arterial pressure (ram. Hg)
Time Heart rate for (beats~rain.) total injection Before [ After (rain.) C~ ] C6 7.8 10.0 3.3 12.3 12.8 9.2
80 70 98 93 110 90
64 70 100 87 110 86
Before C6
After C6
135/85 160/95 115/80 140/110 96/8O 129/90
105/60 115/70 115/80 110/82 84/62 106/71
Systemic venous pressure (ram. H~O)
Basal IR (cu. mm./5 c.c. part/sec.)
Maximal I~ (cu. ram.~5 c.c. part/ sec.)
Before [ After C~ Co
Before [ After C6 " C~
Before [ After C~ C~
293 374 330 375
147 260 270
343
226
3 6 11 5 25 10
25 11 17 26 38 23
22 63 35 23 70 43
35 80 37 49 88 58
*Patient movedtoo much for measurement.
Pt. N o . 4 , 4 7 N F
~
r
150-
~
2
r
125"
Systolic BJP
o; ICO.
x..
x,." X--
~
~X
~
Diostollc B.P
75.
| Venous Pressure
~;
0
2
4
6
8
Io minutes
12
14
16
8
20
Fig. 2. Influence of intravenous hexamethonium on the arterial and systemic venous pressures of the same patient with severe CHF as in Fig. 1. comfortable h o s p i t a l - t y p e bed in the n e u t r a l envir o n m e n t of our climatic observation room. T h e circulation to and from the right index fingertip (2RF) and the right middle fingertip (3RF) was studied rheoplethysmographically, as described previously, s' 9 with the right arm and h a n d resting passively with the digits at heart level. Systemic venous and arterial blood pressures were recorded with suitable pressure transducers a n d recorders while the neck veins were closely observed and p h o t o g r a p h e d and the changes in clinical s y m p toms and signs were carefully noted. In some subjects c o n t i n u o u s direct recordings of systemic venous pressure and arterial blood pressure were
738
obtained. I n other subjects changes in venous pressure were noted merely by observing the neck veins, and the arterial blood pressure was recorded by means of a clinical m e r c u r y type sphygmomanometer. After obtaining baseline m e a s u r e m e n t s and observations, h e x a m e t h o n i u m chloride (25 mg. per milliliter of concentration ) was injected intravenously, 0.1 ml. (2.5 mg.) at a time, into a vein in the left forearm at intervals of 30 to 120 seconds while t h e p a t i e n t was w a t c h e d carefully and observed for changes in arterial blood pressure, systemic venous pressure, neck vein distension, digital blood flow, and clinical manifestations of CHF. T h e m a x i m u m t o t a l a m o u n t of hexamet h o n i u m injected into a n y one subject was intentionally limited to 22.5 mg.
Results Peripheral circulation. T h e r h e o p ] e t h y s m o grams of all of the patients with C H F showed marked digital vasoconstriction prior to the administration of the h e x a m e t h o n i u m {Fig. 1A). Basal digital blood flow was also m a r k e d l y reduced (Fig. 1A). ~' 9 These simultaneous and c o n t i n u o u s recordings of volumes and rates of digital inflow and outflow and o f differences between inflow and outflow revealed constriction of the arterial and venous vessels of the digits. Since the rate of basal flow was also low, the A-V shunts were also constricted in the patients with C H F at rest. As the h e x a m e t h o n i u m was injected intravenously, these simultaneously recorded curves of
June, 1976, Vol. 91, No. 6
"New" treatment for chronic intractable C H F
Total Iv~heart beat Maximal Dv (cu. ram.~5 c.c. part) (cu. mm./5 c.c. part) Before Co
After C6
Before Co
After Co
4.7 6.5 5.5 5.6 10.2 6.5
10.5 10.4 4.8 10.5 10.1 9.3
2.4 4.4 2.0 1.6 2.8 2.6
2.5 5.0 2.1 3.2 5.0 3.6
Increase in total digital volume (cu. mm./5 c.c. part)
8+ * 65 - * 143 95 78 +
blood flow showed t h a t all the digital vessels, including the A-V shunts, dilated and t hat digital inflow and outflow increased markedly (Fig. 1B). T o tal digital volume inCreased considerably throughout the administration of hexamethonium in all patients, indicating the shift of blood from the central systemic vessels to the peripheral vessels. As the peripheral dilatation developed, the patient improved dramatically. T h e data varied quantitatively from patient to patient, but all the digital vessels were tightly constricted in all the patients with CHF prior to a-adrenergic sympathetic nerve blockade. The intravenous administration of hexamethonium dilated all digital vessels in all patients. No effort was made to quantitate the sensitivity of each patient to the drug or to study digital flow On a statistically quantitative basis in any patient or in the group of patients. Systemic venous pressure. Systemic venous pressure measurements obtained with pressure transducers and recorders revealed high pressure in the left forearm vein in all patients in whom it was measured (Table I). T he pressure varied from patient to patient and in accordance with the degree of CHF. As the hexamethonium was injected, systemic venous pressure decreased (Fig. 2) simultaneously with digital vasodilatation. The degree of all vascular dilatation varied directly with the dosage of hexamethonium administered. In fact, the degree o f vascular dilatation attained was arbitrarily decided for each patient by us. T he maximum clinical limit definitely was not reached. As the systemic
A m e r i c a n H e a r t Jo u r n a l
venous tone declined and the veins loosened, the patient improved clinically and the symptoms and signs of CHF reduced dramatically or disappeared. Central
venous
pressure.
The neck veins,
which reflect changes in central and systemic venous pressure, were photographed periodically and watched carefully throughout the investigations. Before hexamethonium was injected, the neck veins of all patients were markedly dilated and congested with blood even with the patient's back rest elevated (Figs. 3 and 4). T he distended neck veins reflected high central venous pressure and high right atrial pressure. Several patients had marked pulsations in the congested external jugular veins because of tricuspid regurgitation. In several patients the veins were turgid to palpation and felt like ropes because their intravenous pressure was so high and their walls so tight. Even the veins of the face and forehead were prominent and turgid in some patients, reflecting the high venous pressure (Fig. 4). As the hexamethonium injected intravenously into a small vein in the left forearm caused the systemic venous pressure to decrease and the digital vascular system to dilate, the neck veins decreased in size and became less and less turgid. Finally, by the time 15 to 17.5 mg. of hexamethonium had been administered, the neck veins and also the forehead veins became visible (Figs. 3 and 4 ). Symptomatically, the patient's neck veins felt soft, and the patient could rotate his head freely without discomfort previously produced by the distended tight veins in the neck. The previous feeling or sensation of intrathoracic fullness, tightness, or congestion subsided and finally disappeared as the neck veins became less distended and the generalized peripheral vasodilatation developed. These symptomatic changes were dramatic and impressive, especially the disappearance of the dyspnea, breathlessness, tightness, and fullness in the chest experienced by the patient. These changes occurred within 5 to 13 minutes of the initial injection of hexamethonium in all patients. Systemic arterial pressure. Before hexamethonium was administered, the arterial blood pressure was not high in any patient, and in a few patients it was impressively low in spite of the peripheral vasoconstriction (Table I). This vascu-
739
Butch, Lebn-Galindo, and Cronvich
AI
Fig. 3. Influence of intravenous hexamethonium on the neck veins of the 47-year-oldpatient with severe CHF hexamethonium (15 mg.) was administered in 2.5 mg. amounts over 12.3 minutes.
Fig. 4. Influence of intravenous hexamethonium on the neck and forehead veins of a 58-year-old patient with severe CHF. The hexamethonium (17.5 mg.) was administered in 2.5 mg. amounts over 10 minutes.
lar state resembled s o m e w h a t the manifestations of impending or mild cardiogenic shock. A l t h o u g h arterial pressure was reduced by the hexamet h o n i u m to relatively low levels, even to 84/62 in one patient, the patients felt m u c h better and were able to s t a n d a n d walk and sit w i t h o u t syncopal s y m p t o m s . T o avoid excessive vasodilatation, the decrease in arterial blood pressure was used as a guideline to discontinue a d m i n i s t r a t i o n of h e x a m e t h o n i u m , T h e blood pressure continued to decrease slightly for 5 to 10 m i n u t e s after administration of the drug was stopped. Because of the effect on blood pressure, the drug was administered in 0.1 ml. (2.5 mg.) a m o u n t s at a
740
time, with 30 to 120 second intervals to allow its full effects to occur before administration of the next 0.1 ml. I t was n o t necessary for the arterial pressure to decrease for the patients to feel better or improve clinically, as in the case of P a t i e n t No, 3 {Table I). I m p r o v e m e n t seems to be definitely more closely related to the reduction in peripheral venous tone {noted r h e o p l e t h y s m o g r a p h i c a l l y ) and to the decline in systemic venous p r e s s u r e (and in p u l m o n a r y venous pressure, n o t observed directly) t h a n to the decrease in arterial blood pressure. Heart rate. H e a r t rate changed very little
June, 1976, Vol. 91, No. 6
"New" treatment for chronic intractable C H F
during the studies (Table I). This is due in part to the fact t h a t small amounts of hexamethonium were used. Respiration. Respiratory rate decreased as the patient's dyspnea became less and his lungs became less congested with blood. Breathing became less labored and the sensation of suffocation or breathlessness disappeared as venous pressure decreased and the neck veins became soft. T h e symptomatic improvement progressively occurred concomitantly with the decrease in venous congestion. In some patients the crepitant r~les in the bases of both lungs decreased in extent and degree and even disappeared. Discussion
The mechanisms and physiologic reasons for the high a-adrenergic sympathetic tone and resultant marked peripheral vascular constriction and the general increase in systemic venous tone in patients with congestive heart failure remain unknown. T h a t such high vascular tone exists in CHF is obvious from these observations and previous publications. 2.3 The theoretic discussions outlined above and in the Appendix indicate the mechanical factors responsible for the shift of blood centrally in CHF, including the shift into the pulmonary vascular system which cannot accommodate more than a small volume of the relatively large amount of blood normally present in the systemic venous reservoir of the body. This shift of blood is responsible for many of the manifestations of CHF. Whether or not the generalized increase in sympathetic tone is responsible, in part at least, directly or indirectly for the altered renal function with the resultant water and salt retention is also not known. T h a t this is so is conceivable, however. Surely, a-adrenergic sympathetic nervous system blocking with hexamethonium does initiate immediate symptomatic improvement of the patient and even marked diuresis associated with the return of renal function to normal in some patients. The precise mechanisms responsible for this diuresis are also not known. The diuresis could be accounted for by the decrease in systemic venous pressure, including pressure in the renal veins. The percentage increase in systemic venous pressure was greater than in arterial pressure in the patients studied. In fact, the arterial blood pressure was only slightly elevated in two patients, whereas systemic venous pressure was
American Heart Journal
increased several-fold in all four patients in whom it was measured {Table I). Furthermore, symptomatic improvement was more directly related to the decrease in venous tone and venous pressure than to the decrease in arterial pressure. One patient improved without any change in systemic arterial pressure. Venous tone in most patients decreased before arterial pressure decreased. All digital vessels were constricted in the patient studied. No measurements were made of the visceral arterial system. The hexamethonium decreased the vascular tone and dilated all blood vessels studied, including systemic veins, all digital vessels, and systemic arteries (except in one patient). With the decrease in tone and the dilatation, as evidenced by the decrease in arterial blood pressure, the decrease in systemic venous pressure and "collapse" of the neck veins, the patient improved symptomatically. One patient had such markedly distended tight neck veins that she was unable to rotate her head without considerable discomfort and fear t h a t she might rupture a neck vein (Fig. 3). With the collapse of the neck veins following administration of hexamethonium, the ability to rotate her head freely and comfortably was most impressive to her. Diuresis developed in the patients, and the crepitant r~les in the bases of both lungs decreased in extent and amount or even disappeared. These changes all suggested t h a t there was preferential increase in venous tone in these patients with CHF in association with an increase in digital vascular tone. The precise reasons for such an increase in venous tone in chronic CHF which was readily interrupted with the a-adrenergic sympathetic blocking agent are unknown, but the increased tone is extremely important in the clinical and physiologic syndrome of CHF. The physiologic and hemodynamic contributions of the high venous tone to the production of the clinical manifestations of CHF need to be studied extensively. The elevated venous tone and venous pressure may be a cause, in large part, for the change in renal function which results in electrolyte and water retention in CHF. The subtle changes in renal function that generalized increase in venous tone and the resultant venous hypertension produce have received little attention. Surely, renal venous pressure must be increased in CHF along with the generalized increase in systemic venous pressure. Hexamethonium decreased systemic venous
741
Burch, Lebn-Galindo, and Cronvich
Fig. 5. The idealized cylindricalvessel used in calculations in the Appendix of wall volume and wall fiber stress.
tone so th at the large systemic venous vessels relaxed or "loosened" and accommodated a large volume of blood under lower pressure as the left ventricle pumped blood into the peripheral vascular system from the pulmonary vascular system. When the left ventricle pumped more blood out of the lungs t ha n the right ventricle pumped into the lungs, a new state of equilibrium resulted in which there was less blood in the pulmonary venous and entire pulmonary vascular system and in the large central systemic veins but more blood in the smaller peripheral vessels, with all intravenous blood pressure being at lower levels. Th e distribution of blood in the circulation became more normal. T he pressure in the pulmonary vascular system must have been reduced because blood volume in t h a t system was reduced, whereas the pressure in the systemic venous system was reduced, in spite of an increase in its blood volume, because of the decrease in venous tone produced by blocking of the a-adrenergic sympathetic nervous system. In the management of CHF by venesection, the volume of blood is reduced in the systemic veins, which reduces the wall stress on these veins, but the a-adrenergic sympathetic nervous system tone and, in turn, the smooth muscle tone of the venous walls are not reduced, even indirectly. Increase in venous tone is the direct cause for the elevated venous pressure due to high sympathetic nerve stimulation of veins and, in turn, accounts for the venous congestion of CHF. However, hexamethonium interrupts the direct cause for high venous tone by blocking the a-adrenergic sympathetic nervous system tone. Thus, the patient is "bled" into his systemic veins, and blood is redistributed to achieve a more normal distribution of blood volume with a more normal venous and sympathetic nervous tone,
742
vessel wall tone, and intravascular pressure. The pharmacologic and physiologic procedure employed to achieve this state was simple. T h e patients felt better. Respiration was improved. T h e associated decrease in arterial blood pressure unloaded the heart, and its function apparently improved. Hexamethonium, then, really provides, by physiologic readjustments, "intravascular venesection" without blood loss. T h e latter point is especially important if the patient is anemic. This procedure and drug can be used readily clinically in the care of patients with CHF. It should be clearly indicated t hat hexamethonium is most effective when systemic venous pressure is elevated and the lungs are congested with blood. This is evident from previous discussions of the mechanisms of CHF 1 and recent unpublished studies. Thus, this vasoditator would be most effective in patients whose CHF is progressively getting worse or in whom the CHF has reached a stable state as with intractable severe CHF. Hexamethonium is the best vasodilator and a-adrenergic sympathetic blocking agent available today for clinical use for the relief of CHF as described above. It acts rapidly, so t hat the physician can judge when he has administered the proper dose intravenously. T h e full effect is reached in 2 to 3 minutes after injection. Furthermore, its action subsides rapidly. The resultant vasodilatative effects may linger totally or in part for hours or days even though the drug itself has ceased to be present. When hexamethonium is used properly, norepinephrine, its antidote, should never be needed to Correct an overdose of hexamethonium. T he dose of hexamethonium can be carefully and accurately monitored at the bedside for each patient by observing the changes in arterial blood pressure, neck vein distension, and the patient's general state of well-being, as noted above. Thus, the dosage used by us arbitrarily varied according to the patient's response. These studies were not undertaken to quantitate the degree of vascular change produced in CHF by hexamethonium. Although the measurements were quantitative, the objective was to learn the physiologic changes produced and their effects on the physiologic a n d clinical state of CHF and the final clinical well being of the patient. No effort was made to measure cardiac output, end-diastolic pressure in the four cardiac
June, 1976, Vol. 91, No. 6
"New" treatment for chronic intractable C H F
2.0-
.8 .6 .4 4"v r
2
-.\
== ==
.02
0.011 0.1
I
i
.2 Internol
!
,
.4
!
I
.6
Diometer
!
I
i
i
.8 1.0 of Vessel
2 (dil
I
,
,
4
,
6
il
,
8
I0
I 0 x cm.
Fig. 6. Wall thickness (t) vs. internal diameter (di) a s a function of wall volume per centimeter length (V1). With the selection of the exponent x for dimensions of d, t, and V1, these curves apply to a wide range of dimensions. chambers, central v e n o u s pressure, p u l m o n a r y arterial or venous pressure, ejection rate, or o t h e r h e m o d y n a m i c p h e n o m e n a for fear t h a t the m e t h o d s used would c o m p l i c a t e t h e studies. F u r t h e r m o r e , these m e a s u r e m e n t s were n o t necessary. T h e p l a n was to e m p l o y simple m e t h o d s for m o n i t o r i n g the physiologic a n d clinical s t a t e during t h e a d m i n i s t r a t i o n of h e x a m e t h o n i u m since physicians in hospital and emergency r o o m practice should be able to e m p l o y the drug effectively u n d e r practical a n d simple circumstances. T h e role of the decrease in arterial blood pressure in i m p r o v i n g the s t a t e of C H F is not clearly evident f r o m these studies. It m u s t h a v e been a c o n t r i b u t i n g f a c t o r b u t not a necessary one n o r the m o s t i m p o r t a n t one, certainly n o t as i m p o r t a n t as the decrease in systemic v e n o u s a n d peripheral v a s c u l a r tone. T h i s was evident f r o m p a t i e n t s w i t h C H F in w h o m arterial blood pressure was a l r e a d y low a n d the systemic venous pressure e x t r e m e l y high. Also, venous pressure decreased in some p a t i e n t s initially with injection
American Heart Journal
of t h e h e x a m e t h o n i u m with definite s y m p t o m a t i c i m p r o v e m e n t even t h o u g h arterial blood pressure had not changed or h a d decreased minimally. App a r e n t l y , the clinical i m p r o v e m e n t in the s t a t e of C H F was due to the decline in systemic venous pressure and a shift of blood f r o m t h e p u l m o n a r y blood vessels, especially the p u l m o n a r y veins, a n d central veins. F u r t h e r m o r e , merely a decrease in load on the left ventricle w i t h o u t a decrease in a-adrenergic s y m p a t h e t i c nervous s y s t e m t o n e would not p r o d u c e a decrease in systemic venous tone. 1 T h e m e c h a n i c a l d i s a d v a n t a g e u n d e r which the large central veins function as c o m p a r e d to the smaller, m o r e p e r i p h e r a l l y located ones which contain m o s t of t h e blood is readily shown b y the Appendix and Figs. 5, 6, and 7. T h e relative intensity of a-adrenergic s y m p a t h e t i c n e r v e impulse s t i m u l a t i o n for different size veins is y e t to be determined. For example, is t h e intensity of s y m p a t h e t i c n e r v e s t i m u l a t i o n t h e s a m e per u n i t v o l u m e of v e n o u s wall or per s m o o t h muscle cell or per unit cross sectional area of all vessels?
743
Burch, Le6n-Galindo, and Cronvich
IO S 6 z
4
~.
2
r
.~ i.o ~
.8
~
.6
o E Z
.2
OA 0.1
.2 .4 .6 JB 1.0 Internol Oiometer of Vessel
2 (d i ]
4 I0 x cm.
6
8
I0
Fig. 7. Normalizedstress (S~) vs. internal diameter (dJ as a function of wall volumeper centimeter length (Vj. With the selection of the exponent x for the dimensions of dj and V1, these curves apply to a wide range of dimensions.
Such questions need to be answered for better appreciation of the role or importance of venous tone for the various veins of the body. Regardless, the relative mechanical state of tension and force of the various veins of the body must be related more or less as described above and indicated by Figs. 6 and 7. Surely, in order for the changes noted to occur, the blood is shifted to the more peripherally located systemic veins because hexamethonium blocks the a-adrenergic sympathetic nervous system. Th e value of hexamethonium in the t r e a t m e n t of chronic intractable CHF and acute pul m on ary edema is evident from the clinical response, alone. All patients with CHF improved immediately and impressively following administration of hexamethonium. Several hours after the effects of the drug disappeared some of the patients with chronic and intractable CHF gradually developed dyspnea and central systemic venous and pulmonary congestion again. However, the level of discomfort was less than t ha t prior to administration. One of the patients included in this study was so relieved by the hexamethonium t hat she requested repeat studies in order to receive the hexamethonium injections. An injection can be
744
given daily or even more frequently when the drug is used primarily for clinical care. Some patients developed a good diuresis immediately following the use of the drug. This response certainly indicates t h a t renal functional state was potentially good and was hemodynamically related to the functional state of the cardiovascular system during CHF since hexamethonium is not a diuretic known to act directly as such on the renal parenchyma. We would suggest t h a t t h e renal dysfunction in these patients with chronic CHF was due in large part to the increase in sympathetic nervous system tone and high renal venous pressure. The procedure for administering hexamethonium clinically is simple and c a n be employed at the bedside or in the emergency room with only the use of a sphygmomanometer along with careful clinical observations and understanding. Summary
T he use of hexamethonium injected intravenously in successive 2.5 mg. doses resulted in a-adrenergic sympathetic nerve blocking and associated peripheral vasodilatation with dramatic improvement of the symptoms and signs in
June, 1976, Vol. 91, No. 6
"New" treatment for chronic intractable C H F
patients w i t h marked chronic intractable CHF. The vasodilatating effect of the drug is simple to monitor at the bedside and serves as an effective, simple means to "bleed" the patient intravenously by decreasing systemic venous tone and reducing the wall stress in the vessels. This intravenous "bleeding" results in a shifting of excessive blood from the lungs and central systemic venous areas to the larger volume of the more peripheral systemic venous reservoirs. Rheoplethysmographic recordings of digital blood flow in the fingertips of the patients revealed marked constriction of all vessels of the fingers during CHF. Hexamethonium dilated all these vessels and increased digital blood flow even though arterial blood pressure was reduced b y t h e drug. Theoretic discussions of aspects of the mechanism of congestive heart failure of the two-pump system of the heart of man ~ and the mechanical or hemodynamic advantages of the small veins over the larger centrally located veins tend to explain why the use of hexamethonium benefits the circulation by producing venodilatation. These studies indicate the therapeutic usefulness of hexamethonium in the management of acute and chronic intractable CHF and provides physiologic and theoretic data to explain why the drug is effective.
Appendix
Because of the shift of blood volume in the cardiovascular system in pathologic states, it is of interest to know the relations between the pressure in the vessels of the cardiovascular system and the radial force on and the stress in the wall fibers of the respective vessels. The following analysis is based on an idealized circular cylindrical vessel with walls which are homogeneous radially and which do not elongate axially: Thus, it is assumed t h a t a change in internal diameter (di) is accompanied by an appropriate change in wall thickness (t) to keep constant the volume of wall per unit length (V1) of vessel. In the cylindrical vessel of Fig. 5, the volume of wall v
+
diZ
=~
4
+ d~t +
American Heart Journal
dis ] L 4
-
= tr [ d i t + t2]L
(1)
or, V1 (volume per unit length) = ~r (d~t + t~).
Therefore, ct~ =
V1 qr
t~
V~ = ~r t
t
REFERENCES
1. Butch, G. E.: A primer of congestive heart failure, Springfield, Ill., 1954, Charles C Thomas, Publisher. 2. Burch, G. E.: Evidence for increased venous tone in chronic congestive heart failure, Arch. Intern. Med. 98:750, 1956. 3. Burch, G. E.: A method for measuring venous tone in digital veins of intact man: Evidence for increased digital venous tone in congestive heart failure, Tr. Assoc. Am. Phys. 67:174, 1954. 4. Burch, G. E.: A primer of venous pressure, Springfield, Ill., 1972, Charles C Thomas, Publisher. 5. Gibson, J. G., II, and Evans, W. A., Jr.: Clinical studies of the blood volume. I. Clinical application of a method employing the azo dye "Evans Blue" and the spectrophotometer, J. Clin. invest. 16:301, 1937. 6. Gibson, J. G., II, and Evans, W. A., Jr.: Clinical studies of the blood volume. II. The relation of plasma and total blood volume to venous pressure, blood velocity rate, physical measurements, age and sex in ninety normal humans, J. Clin. Invest. 16:317, 1937. 7. Gibson, J. G., II, and Evans, W. A., Jr.: Clinical studies of the blood volume, iII. Changes in blood volume, venous pressure and blood velocity rate in chronic congestive heart failure, J. Clin. Invest. ] 6:851, 1937. 8. Burch, G. E.: Digital plethysmography, New York, 1954, Grune & Stratton, Inc. 9. Burch, G. E.: The George E. Brown Memorial Lecture: Digital rheoplethysmography, Circulation 13:641, 1956.
t~
// or
t
=
4V1
- d~ + ~ / d i ~ +
(2)
~r
The radial force per unit length on the wall produced by fluid at pressure p is F r = p~rdi, (3) and the stress in the wall fibers is S pdiL pdi 2tL 2t (4) If V~ is constant as d, changes, then
2idi++4vl]1+4v d~
S
=
P
P
--~
2
Normalizing F and S for p = 1 results in F N = ~rdi
745
Burch, Le6n-Galindo, and Cronvich
and
SN = / 1 + /1 V
+
4Vl
7rd~~
I f a c o n s i s t e n t s e t o f u n i t s is u s e d in w h i c h d i = i n t e r n a l d i a m e t e r o f v e s s e l in c e n t i meters t = w a l l t h i c k n e s s in c e n t i m e t e r s L = l e n g t h o f vessel in c e n t i m e t e r s p = p r e s s u r e in d y n e s p e r s q u a r e c e n t i meter t h e n V = v o l u m e in c u b i c c e n t i m e t e r s V~ = v o l u m e in c u b i c c e n t i m e t e r s p e r c e n t i meter length F = r a d i a l f o r c e o n c e n t i m e t e r l e n g t h of w a l l in d y n e s S = s t r e s s in w a l l fibers in d y n e s p e r square centimeter Sx = n o r m a l i z e d w a l l s t r e s s . F o r c o n v e n i e n c e in r e l a t i n g V1, d i , a n d t, t h e c u r v e s in Figs. 6 a n d 7 a r e given. These curves are useful over a wide range of i n t e r n a l d i a m e t e r s (di) a n d w a l l v o l u m e s p e r u n i t l e n g t h (V1) b y a p p r o p r i a t e l y s e l e c t i n g t h e e x p o n -
746
e n t x. F o r e x a m p l e , f r o m Fig. 6, if x = 0, (a) w h e n dl = 2 cm. = 2 x 10 ~ cm. and V~ = 5 c m 2 = 5 • 10 ~ c m 2 , t = 0.61 cm. = 0.61 x 10 ~ cm.; a n d (b) w h e n d~ = 5 cm. a n d V, = 5 c m 2 , t = 0.30 cm. B u t if x = - 5 , t h e n c o r r e s p o n d i n g t o (a) a b o v e , dl = 2 x 10 ~ cm., V~ = 5 x 10 20 cm., a n d t = 0.61 x 10 5 cin. S i m i l a r l y , f r o m Fig. 7, t h e n o r m a l i z e d w a l l s t r e s s (SN) c a n b e d e t e r m i n e d . I n t h i s case, w h e t h e r x = 0 o r - 5 , for d i m e n s i o n s g i v e n f o r (a), S~ = 1.64; a n d for d i m e n s i o n s f o r (b), S~ = 8.33. T h e a c t u a l w a l l s t r e s s is e x p r e s s e d b y S = p x S~. T h e r e f o r e , for t h e d i m e n s i o n s of c a s e (a), a v e n o u s p r e s s u r e o f a p p r o x i m a t e l y 100 m m . of w a t e r (p = 10,000 d y n e s p e r s q u a r e c e n t i m e t e r ) w o u l d r e s u l t in a w a l l s t r e s s S = p x S~ = 10,000 x 1.64 = 16,400 d y n e s p e r s q u a r e c e n t i m e t e r ; w h e r e a s for a v e n o u s p r e s s u r e o f a p p r o x i m a t e l y 400 m m . of w a t e r (p = 40,000 d y n e s p e r s q u a r e c e n t i m e t e r ) , S = 40.000 • 1.64 = 65,600 d y n e s p e r s q u a r e cent i m e t e r . T h e r a p i d i n c r e a s e in S~ as d~ i n c r e a s e s w i t h c o n s t a n t VI is s h o w n b y t h e c u r v e s a n d b y t h e e x a m p l e j u s t c o n s i d e r e d - a n i n c r e a s e o f d~ b y t h e f a c t o r 5 / 2 or 2.5 r e s u l t s in a n i n c r e a s e o f S~ b y t h e f a c t o r 8.33/1.64 o r 5.07.
June, 1976, Vol, 91, No. 6
