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The hemodynamic effects of amyl nitrite and phenylephrine in patients with mitral stenosis and severe pulmonary hypertension
Experimental and laboratory
reports
The hemodynamic effects of amyl nitrite and phenylephrine in patients with mitra,l stenosis and severe pulmonary hypertension W. Beck, M.Sc., M.Med., M.R.C.P. V. Schrire, M.Sc., Ph.D., M.B., F.R.C.P., il.. Vogelpoel, M.D., M.R. C.P. Cape Town, Soulh Africa
S
tudies of the action of amyl nitrite and phenvlephrine in normal subjets1 have’ shown -the predominant effect of these drugs on the systemic circulation. Amy1 nitrite causes a marked drop in systemic pressure, but leaves pulmonary arterial pressure relatively unchanged. On the other hand, phenylephrine markedly raises the systemic pressure and causes a slight rise in the pulmonary arterial pressure, which is due predominantly to an increase in the pulmonary arterial wedge pressure. The striking reduction in the pressure difference between the left and the right ventricles after amyl nitrite, and the increase after phenylephrine, were related to the changes in intensity of murmurs due to ventricular septal defect unassociated with pulmonary hypertension .rm2 In ventricular septal defect with severely elevated pulmonary arterial pressures, the flow through the large defect is mainly dependent upon the relative resistances of the pulmonary and systemic circuits. In this situation the murmurs of ventricular septal defect often failed to soften after the administration of amyl nitrite or to
F.R.C.P.E.
increase after phenylephrine, and even behaved in a paradoxical fashion. Thus, they became loud after amyl nitrite had been inhaled, and they softened after phenylephrine.3 This paradoxical behavior of the murmur was shown to be associated with a greater fall and rise in pulmonary arterial pressure than in systemic pressure after amyl nitrite and phenylephrine, respectively. In the absence of measurements of flow it could only be inferred that responses were brought about by appropriate changes in pulmonary vascular resistance. This study was undertaken to investigate quantitatively the effects of amyl nitrite and phenylephrine in patients with severe pulmonary hypertension. Subjects with severe pulmonary hypertension without intracardiac shunts were selected so that clear separation of pulmonary and systemic pressures could be obtained and estimation of pulmonary blood flow made by dye-dilution studies. Material
and
Eight patients nosis, which was
method with severe subsequently
mitral proved
steby
From the Cardiac Clinic, Groote Schuur Hospital, and C.S.I.R. Cardio-Pulmonary Research Group, Department of Medicine, University of Cape Town, Cape Town, South Africa. Part of the expenses of this work has been defrayed by grants received from the Council for Scientific and Industrial Research and the City Council of Cape Town. Received for publication March 13, 1962.
631
632
Beck,
Schrire,
and
.4m. Heart .I. ,Vowmbcr, 1962
Vogelpoel
operation, and with mean pulmonary arterial pressures between 43 and 93 mm. Hg, were studied during routine cardiac catheterization. &Atria1 fibrillation was present in one (Patient 7). No patient was in frank left or right heart failure at the time of study, but all except one (Patient 8) were severely disabled by low resting cardiac outputs. Catheterization of the right side of the heart was carried out from the right arm; one catheter was wedged in the pulmonaq artery to record the pulmonary arterial via a strain-gauge mawedge pressure, nometer. A second catheter was placed in the main pulmonary artery to record pulmonary arterial pressures, on a capacitance manometer. Systemic arterial pressure was recorded bq- a needle in the brachial or radial artery, on an inductance manometer; and another needle was placed in a second systemic artery, usually the femoral, in order to record systemic dilution curves. All pressure tracings were reN.E.P. photocorded on a six-channel graphic recorder, and the zero level was taken at mid-chest level, with the patient in the recumbent position. The use of three different types of manometer is not ideal for this type of study, but in order to minimize possible errors, each transducer was carefully calibrated to give identical galvanometric deflections for a given pressure obtained from a mercury manometer. Previous experience with these instruments had shown that the calibrations remain accurate for the duration of a catheter study. The notorious tendenc) for base-line drift to occur with the capacitance manometer was minimized by restricting its use to arterial pressure on record pulmonary the sensitivitv setting of 100 mm. Hg, where the drjft is less pronounced. Zero levels were also recorded throughout the procedure before and after each tracmg. [Jsed in this way, no significant base-line drift was detected. Cardiac output was determined from indicator-dilution curves recorded at the femoral artery after the injection of 5 mg. of indocyanine green into the pulmonary artery. The densitometer (Norman N.E.P.) was calibrated by drawing through it known concentrations of dye in the pa-
tient’s blood and constructing a threepoint calibration curve. The cardiac output was estimated b, dividing the dose of dye times 60 by the area under the curve. Recirculation was excluded by replotting the downstroke of the curve on a semilogarithmic basis, as in the standard Hamilton method. Pulmonary arterial, wedge, and systemic pressures and the dye-dilution curves were recorded simultaneously during the first control period. Thereafter the patient was given a crushed vitrella containing 3 minims of amyl nitrite which was to be inhaled for 15 to 20 seconds, and as soon as the fall in systemic pressure occurred, a dilution curve was once more recorded, during the maximal systemic hypotensive phase of the drug; again, all pressures were recorded simultaneously. A second control period was then established, after the effect of the amyl nitrite had worn off, and pressures and flow were recorded simultaneously. Thereafter, phenylephrine in a dose of 0.5 to 1.0 mg. was injected into the main pulmonarv artery or into a peripheral vein, and during the late phase of systemic hypertension and bradycardia a dye curve was recorded. In one subject, phenylephrine was injected into the wedged catheter so that its effects would first be observed on the systemic circuit. Identical studies were performed in 2 additional patients without mitral stenosis. One suffered from pulmonary hypertensive car pulmonale due to a diffusion defect, and the other, from idiopathic pulmonary hypertension. In the latter patient the wedge pressure could not be obtained. All studies were made with the patient in the recumbent posture under mild barbiturate sedation. Results The results in 8 patients who had mitral stenosis are presented. 1. The response to amyl nitrite. The data are presented in Table I and Fig. 1. Measurements were made at two points: the first at 5 seconds after the inhalation of amyl nitrite had started, and the second some 30 seconds later during the inscrip-
Hemodynamic
efects of amyl nitrite and phenylephrine
-...--. _.-.-.--
I C;)NTRoL
633
_./.--’_.-.A ,_.-.-. 1; SECS30SECS
MS. s PlJLM rnPERTENSDN
Fig. f. Hemodynamic effects of inhalation of amyl nitrite. The three columns on the left show the mean systemic, pulmonary arterial, and wedge pressures and flow in 8 patients with mitral stenosis and pulmonary hypertension before, 5 seconds after, and 30 seconds after they had inhaled amyl nitrite. On the right, the results in 2 normal subjects previously studied’ are shown for comparison. In the subjects with mitral stenosis, systemic pressure falls as in normal subjects. Pulmonary arterial pressure falls slightly at the Ssecond period in 5 patients, but in most cases at the 30-second period is not significantly different from the control level. Wedge pressure rises slightly and cardiac output increases.
tion of the primary deflection of the dilution curve and at the time of maximal systemic hypotension. In Patients 1,2,4,5, and 8 there was a slight initial fall in pulmonary arterial pressure at the S-second period before any real effect on systemic pressure became evident (Fig. 2). In the other 3 patients there was no real change. At the 30-second period, Patients 3,5,7, and 8 showed no significant change from the control level. Patients 1 and 4 showed a very slight increase, and Patients 2 and
6 showed a slight fall in mean pulmonary arterial pressure. In all patients, systemic pressures dropped sharply, and in all except one (Patient 2) a tachycardia developed, as occurs in normal subjects beginning some 10 seconds after the inhalation of amyl nitrite has started. All patients except Patient 3 showed a moderate increase in pulmonary arterial wedge pressure during the later phase of maximal effect of the drug on systemic pressure.
634
Beck, Schrire, and Vogelpoel
Table I. Pressures (mm. Hg)
Systemic Patient, ilgv
Sex,
Diagnosis
Stat?
S.D. 1. CF.,
33
Pure
mitral stenosis with severe, pulmonary hypertension
2. E.M.,
41
Mitral
stenosis pulmonary
with severe hypertension
3. B.M.,
25
Mitral
stenosis pulmonary
with severe hypertension
with severe hypertension
4. C.F.,
28
Mitral
stenosis pulmonary
5. B.F.,
18
Mitral
stenosis,
6. E.M.,
26
Severe
pulmonary Mitral stenosis
7. E.F.,
52
Mitral
stenosis pulmonary
with severe hypertension.
stenosis hypertension
with
8. E.F.,
Mitral
26
C.F.-Coloured
female.
E.M.--Ruropean
severe
hypertension.
rkde.
A.F.
pulmonaq
b:.F.---European
Thus, the over-all effect on the pressure differences across the lung in these patients was a slight decline which was due chiefly to the rise in the wedge pressure. This
Control A.N. 5 ser. A.N. 30 sec. Control P.E. early P.E. late Control A4.N. 5 sec. A.N. 30 sec. Control P.E. early P.E. late Control A.N. 5 sec. A.N. 30 sec. Control P.E. earl> P.E. late Control AN. 5 sec. A.N. 30 sec. Control P.E. early P.E. late Control A.N. 5 sec. A.N. 30 ser. Control P.E. early P.E. late Control AN. 5 sec. A.N. 30 sec. Control P.E. early P.E. late Control A.N. 5 sec. :$.N. 30 sec. Control P.E. early P.E. late Control A.N. 5 sec. A.N. 30 ser. Control P.E. early P.E. late female.
B.M:-Bantu
artery
i/
112/72 1 lo/72 80/48 108/72 96/60 140/60 110/70 100/60 90/50 11.5/70 70/50 lZS/SS 170/95 125/95 100/75 165/90 115/75 190/90 115/75 1 lo/72 90/55 115/75 115/75 170/90 13s/75 135/75 95/55 145/85 65/45 190/110 1 lo/60 lOZ/SS 72/40 125/70 G/60 115/95 1 so/90 145/87 125/75 145/87 130/87 190/100 110/70 105/75 65/70 115/75 105/75 190/100 male. B.F.-Bantu
Mean 85 8‘4 59 84 72 113 83 73 53 8.5 57 102 120 105 83 11s 92 123 88 85 68 88 88 117 95 95 78 105 52 137 73 71 SO 88 67 115 110 106 92 106 100 130 83 75 48 88 85 130
female.
decline averaged 31 per cent (range, 6-78). Cardiac output was found to increase in all patients. It increased less in those with a low resting output than in those with
Hemodynamic
Pulvnonnry
artery
CO (L./vvzin.)
Wedge ---
_____ S.D.
efects of away1 nitrite and phenylephrine
635
PVR (L~nits)
TSR ( zhits)
Heart rate
Mean
S.D.
Mean.
(Dye)
87/G ??/40 95/52 SS/SO
59 52 66 61
10.8
34.0
3.1 2 5
6.8 10.8
19.0 33.5
95 95 120 9s
89 75
32 38 45 34 29 44 28 31 34 27 16 28 28 26 28 23 15 38 22 28 35 20 12 18 25 26 38 30 10 42 25 25 29 20 5 15 21 28 32 21 12 24 11 11 16 14 9 13
2.5
162/52 I OS/S?
3?/2? 45/32 so/40 40/32 30/2? 48/42 30/26 38/30 38/30 28/26 18/14 30/26 30/25 32/23 30/25 25/20 18/12 40/35 30/15 30/25 40/30 25/15 lS/lO 2O/lS 32/18 38/20 42/35 32/28 12/8 45/39 28/22 30/20 32/25
1.6 2.2
28.1 21.4
70.6 37.8
10.5 48 108
2.5 2.0
10.4 22.5
21.2 42.5
108 108
1.8 2.5
37.2 20.0
56.7 48.0
108
4 3 2.9
10.9 18.6
19.3 39.7
2.7 2.0
23.0 25.5
45.5 44.0
96 66 90 66 96
2.5 1.8
17.2 27.8
27.2 48.9
1.3 3.0
47.7 6.0
90.0 31.6
4.5 3.0
0.9 5.3
17.3 35.0
2.7 3.5
14.1 10.0
SO.8 20.8
4.3 3.8
5.4 11.0
11.6 23.2
3 4 2.7
15 .3 9.4
33.8
3.9 3.0
4.10 9.7
23.6 35.3
2.0 4.5
19.5 7.6
65.0 18.6
lOO/SS
70
90/G
60 72 92 9.5 78 77
1 lo/60 125/?5 135/?5 115/60 I lo/60 1 OS/60 110/60
2 93
130/?5
150/?5 120/50 1 OS/45 125/55 120/45 180/?0
1 so/so 80/2S 60/25 6?/32
??/30 1 lS/?S 14a/so 100/40 80/35 82/3? 95/45 118/S? 120/40 8?/25 85/29 8?/28 8?/32 10?/45 115/3? 60/38 SO/28 58/3? 62/38 81/50
1 lO/SS
.Z.N.-Amy1
nitrite.
100 73 65 78 70
103 80 43 37 42 46 88 80 60 56 52 62 77 67 46 48 48 so 65 63 45 35 44 46 60 73
P.E.-Phenylephrine.
27/u 3?/20 45/20 26/16 16/8 29/19
PVR-Pulmonary
slightly higher values; the mean increase in cardiac output was 36 per cent (range, 13-72). As a result of the decrease in pressure
vascular
5.9 4.4
4.8 7 3
2.7
resistance.
22.2
TSR-Total
10.7
8.1 20.0 48.1
systemic
5-l
114 96 96 54 60 114 72 102 42 64 84 66 84 54 5-l 60 54 66 36 96 120 96 102 48
resistance.
difference across the lungs and an increase in pulmonary blood flow, the calculated vascular resistance, expressed in simple units obtained by dividing the mean pres-
636
Am. Hart I. A’wrmber, 1963
Beck, Schrire, and Vogelpoel
Fig. 2. The pressure record from Patient 8. From above downward are the electrocardiogram, the pulmonary arterial wedge pressure, the pulmonary arterial pressure, and the systemic pressure. Inhalation of amyl nitrite is indicated by the black line at the bottom. The pulmonary arterial pressure starts to fall before any change occurs in wedge pressure, systemic pressure, or heart rate, which suggests a direct effect on the pulmonary resistance vessels. Later, systemic pressure falls acutely, a tachycardia develops, and the wedge pressure begins to rise. Pulmonary arterial pressure now parallels the increase in wedge pressure, so that after 30 seconds it is back to its control level, although the pressure difference across the lungs is still diminished.
sure gradient by flow, was decreased in all cases. This calculated resistance averaged (range, 31-67).
found to be decrease in 45 per cent
2. The response to phenylephrine. The data are presented in Table I and Fig. 3. Measurements of pressure were made during the initial phase of maximal effect on the pulmonary arterial pressure and during the late phase of systemic hypertension during the inscription of the dilution curve. When phenylephrine was injected into a peripheral vein or main pulmonary artery, a characteristic biphasic pressure response was obtained in all but one (Patient 4). In the initial phase, immediately after the administration of phenylephrine there was a sharp increase in pulmonary arterial pressure, associated with a brief, sharp drop in pulmonary arterial wedge pressure, and a decrease in systemic pressure, associated with a tachycardia. After a few seconds a rise in systemic pressure occurred, associated with a bradycardia; wedge pressure rose to the control level or even higher, and pulmonary arterial pressures remained elevated (Fig. 4). The cardiac output was estimated during the late phase of the response and was
invariably found to be decreased. The average decrease in cardiac output was 22 per cent (range, 7-39). The pressure difference across the lungs as measured at the time when flow was determined was always increased and averaged 52 per cent (range, 18-138). The combination of an increased pressure difference with a reduction in flow resulted in the calculated vascular resistance being increased in all cases by an average of 105 per cent (range, 21-200). In Patient 6, a second close of phenylephrine was injected into the pulmonaqthis injection the artery wedge ; after initial effect was a sharp rise in systemic pressure with bradycardia, which long preceded the increase in pulmonary arterial pressure and the slight drop in wedge pressure (Fig. 5). Discussion I’he reliability of the data. In the presence of severe pulmonary hypertension the pressure differences across the lungs are large, and, therefore, are more easily and accurately measured than in the case of normal pulmonary vascular pressures. The presence of elevated wedge pressures adds to the reliability of the measurement of
Hemodynamic
pressure gradient and makes the differences recorded of greater significance. We therefore, interpret the difference can, between mean pulmonary arterial and mean wedge pressure with a fair degree of confidence. There is good evidence that the pulmo-
ejects of amyl nitrite and phenylephrine
nary arterial wedge pressure accurately reflects the left atria1 pressure in cases of although Murphy7 has mitral stenosis,4-6 come to the opposite conclusion. As has been previously discussed,’ amyl nitrite causes very short-lived transitory effects, which makes accurate calculations of
Fig. 3. The effects of the injection of phenylephrine into the pulmonary artery or systemic vein iu 8 patients with mitral stenosis and pulmonary hypertension (in coluntns on left) are compared with the results obtained in 2 normal subjects previously studied’ (kz colunzns on right). The systemic pressure falls initially, as does the wedge pressure, at a time when the pulmonary arterial pressure is increasing rapidly. This is interpreted as being due to intense pulmonary vasoconstriction which results in diminished venous return to the left side of the heart, In the later phase the systemic and wedge pressures rise because of systemic vasoconstriction, and the pulmonary arterial pressure remains elevated. As in the normal subjects, cardiac output is decreased after the injection of phenylephrine. The biphasic response of the systemic and wedge pressure is not seen in normal subjects, but also occurred in the subjects with pulmonary hypertension without mitral stenosis, which suggests that in the presence of pulmonary hypertension the pulmonary
vasculature
637
is far more reqctivg than in normal subjects.
638
Beck, Schrire, and Vogelpoel
Am. Nozwmber,
Heart
J. 1962
Fig. 4. The pressure record from Patient 6. From above downward are the electrocardiogram, the pulmorrary arterial pressure, the wedge pressure, and the systemic pressure; the injection of phenylephrine is indicated by the heavy line at the bottom of the tracing. Initially, pulmonary arterial pressure rises while wedge pressure falls, and systemic pressure drops acutely, with resultant tachycardia. After about 30 seconds the systemic pressure rises and a bradycardia occurs, wedge pressure also rises slightly, and the pulmonary arterial pressure remains elevated.
Fig. 5. Pressure records from Patient 6 during the injection of phenylephrine into the wedged catheter. Ic’ow the initial effect is a rise in systemic pressure; about 20 seconds later the pulmonary arterial pressure rises and the wedge pressure drops slightly. In this instance the initial effect of phenylephrine has been on the systemic resistance vessels, and the pulmonary effects have occurred later when recirculating phenylephrine reaches the lungs.
flow extremely difficult, since a steady state is not attained. The calculation of cardiac output must, at best, be an approximation under these conditions, even when the dye-dilution technique is used. Nevertheless, from the present data and from data obtained in normal people by us and by other investigators,* there seems to be little doubt that nitrites do significantly increase cardiac output, when they drop the systemic pressure acutely. The data on flow obtained after the
administration of phenylephrine arc niorc likely to be reliable, since the effects of phenylephrine persist for 3 to 4 minutes, which makes the estimation of cardiac output by the dilution methods far more acceptable. As in normal people, phenylephrine has the effect of significantly reducing cardiac output.l~g~10 The inierpretation of changes in calculated vascular resistance. It has been emphasized repeatedly that there is a multiplicity of factors other than tone which can affect
Volume Number
64 5
Hemodynamic
the calculated resistance to flow. Thus, the interpretation of calculated resistance in a situation in which pressure, flow, and heart rate are all changing rapidly is estremely difficult. Nonetheless, some discussion on the possible role of changes in vascular tone is necessary. If it is assumed that the drugs amyl nitrite and phenylephrine have no effect on the viscosity of the blood, on the size of anastomotic vessels, on the opening up of vascular channels previously closed, or on the length of the vascular channels, a significant change in calculated resistance is probably due to a change in the caliber of the vessels. As Burton” has pointed out, there are two factors which influence the caliber of resistance vessels. One is the transmural pressure, which can cause vessels to distend or contract passively because of their inherent elasticity, and the other is muscular tone, which can constrict or dilate vessels in response to reflex activity or vasoactive drugs. It can only be concluded that muscular tone has been affected if the possible effect of a change in transmural pressure is taken into account. The average decrease in pulmonary resistance of 4.5 per cent which was found after rhe inhalation of amyl nitrite may mean a widening of the caliber of the pulmonary vessels, which could be active or passive. Since this decrease in resistance occurred in the face of elevated pulmonary arterial wedge pressures in 7 of the 8 patients, it is possible that the passive distention of the venous segment of the pulmonary vascular bed alone caused the drop in calculated resistance. However, there are two objections to such a conclusion. In 2 subjects (Patients 5 and 8), a brief drop in pulmonary arterial pressure occurred before any change could be detected in the wedge and systemic pressures and the heart rate (Fig. 2). Since a change in blood flow seems unlikely at this early stage after the inhalation of amyl nitrite, a direct effect of amyl nitrite on the pulmonary resistance vessels in these 2 patients appears to fit the facts in the presence of best. Furthermore, moderate to severe pulmonary hypertension, most of the resistance to flow resides at the level of the arteriole, and it is un-
effects of amyl nitrite and phenybephrine
639
likely that relatively small changes in pressure in the venous segment would materially affect the transmural pressure at the level of the arteriole. In the light of the preceding considerations the sequence of events which occurs after the inhalation of amyl nitrite is interpreted in the following manner. Inhaled amyl nitrite initially affects the pulmonary resistance vessels to a variable extent, leading to a sharp initial drop in pressure in some subjects. (The means by which the resistance vessels are apparently affected when the drug is absorbed into the pulmonary capillaries remains ULIexplained.) Thereafter, amyl nitrite reaches the systemic resistance vessels and leads to an acute vasodilatation, with a drop in systemic pressure, tachycardia, and an increased cardiac output. The combined effect of tachycardia and increased venous return elevates the wedge pressure because of the fixed obstruction at the mitral valve. The rise in pulmonary venous pressure lead to a passive rise in may, in turn, pulmonary arterial pressure, which may reach or even exceed the control levels, in spite of some release of pulmonary vasoconstrictor tone. After the administration of phenylephrine into the pulmonary artery or peripheral vein, there is an initial brisk rise in pulmonary arterial pressure, a slight drop in wedge pressure, and a drop in systemic pressure (Fig. 4). This response is quite different from that which occurs in subjects with normal pulmonary arterial pressures, in whom the slight rise in pulmonary arterial pressure is later and, for the most part, secondary to a rise in systemic and wedge pressures.’ Although cardiac output could not be measured during the brief initial phase, it would seern that the above response can only be explained by an illtense vasoconstriction of the pulmonary resistance vessels. This leads to a sharp decrease in venous return to the left side of the heart, with a consequent drop in wedge and systemic pressures. The second phase of the response to phenylephrine consists of a rise in systemic and wedge pressures with bradycardia, and the increase in pulmonary arterial pressure is maintained. The cardiac output during this phase was always decreased by an
640
.4m. Heart .I. ,Voe’cmber, 1962
Beck, Schrire, and Vogelpoel
Table II. Pressures (mm. Hg)
Systemic Patient,
Sex,
Age
Diagnosis
State
S.D.
1. E.M., 48
Hypertensive corpulmonale
Control A.N.
5 sec.
A.N. 30 sec. Control
2.
E.M., 22
Idiopathic pulmonary hypertension
P.E. early P.E. late Control A.N. ‘4.N.
5 sec. 30 sec.
Control P.E. earl> P.E. late
average of 22 per cent. At this time, the pressure gradient across the lungs was increased by an average of 52 per cent. The increase in calculated vascular resistance must reflect a true increase in vascular tone, since the intraluminal pressure at the arteriolar end of the vascular bed is increased, and at the venous end it is either slightly increased or unchanged. In one patient (Patient 6), phenylephrine was injected into the wedged catheter so that its initial effect would be on the systemic circuit (Fig. 5). The initial response then was a rise in systelnic pressure with bradycardia followed by a rise in pulmonary arterial pressure and a drop in wedge pressure. This difference is adequately explained by the fact that phenylephrine has its initial effect on the systemic circuit, and subsequently affects the pulmonary vasculature. Studies3 in patients with ventricular septal defects who had large left-to-right shunts and associated pulmonary hypertension have provided evidence for an unusual responsiveness of the pulmonary resistance vessels to these drugs. It seeined likely that amyl nitrite caused a greater fall in pulmonary than in systetnic resistance, and that phenylephrine had the reverse effect. In our patients who had mitral stenosis and an intact circulatory pathway a marked reactivity of the pulmonary vascular bed to phenylephrine has been demonstrated, but the response to
artery
-___
130/90 100/70
S/50 130/90 110/90 165/90 100/75 100/70 85/65
lOS/SO 105/75
170/115
/
Xean 103 80 62 103 97 115 83 80 72
88 8.5
133
amyl nitrite has been rather disappointing and the evidence for a release of vasomotor tone inconclusive. In order to determine whether the failure of the pulmonary arterial pressure to fall after amyl nitrite was due to the presence of mitral stenosis in these patients, two patients without mitral stenosis were studied (Table II). One had pulmonar) hypertensive car pulmonale, and the other had idiopathic pulmonary hypertension ; and in both the severity of the pulmonary hypertension was comparable to that of the patients with mitral stenosis. A marked pulmonary vasoactive response to phenylephrine was demonstrated in both cases. However, as in most of the cases of mitral stenosis, amyl nitrite had virtually no effect on the pulmonary arterial pressure. It seems, therefore, that amyl nitrite has strikingly different effects on the pulmonary vascular bed in patients with a left-to-right shunt and in those with intact circulatory pathways. It seems unlikely that the lack of effect in the latter group can be ascribed to fixed organic obliterative vascular changes, since other studies have repeatedly demonstrated’* a release of tone in the lung vessels in cases of mitral stenosis, and our results with phenylephrine clearly indicate that the vessels can constrict. Thus, it is suggested that the relative lack of response to amyl nitrite in cases without a left-to-right shunt may be due
P’olrmc A’wabcr
64 5
-___
Pulmonary -__--__-
Hemodynamic
efects of amyl nitrite and phenylephrine
641
co artery
S.D.
Wedge
hfean I
85/40 80/3 7 85/40 84/3 7 105/60 100/40 115/75 115/70 120/70 115/75 130/80 l-12/70
__-
(L./?nin.) ____
S.D.
hfean
(dye)
13/11 10/7 6/3 15/12 10/6 10/B
12 8 4 13 7 9 -
1 55 51 5.5 52 75 60 88 85 87 88 97 94
-
-
to the fact that a much weaker concentration of amyl nitrite reaches the pulmonary resistance vessels. By contrast, when there is a large left-to-right shunt, a large concentration of amyl nitrite absorbed via the pulmonary capillary bed is likely to be rapidly shunted into the lungs, which results in a more potent effect on the pulmonary resistance vessels, as previously postulated.3 Summary
and
conclusions
Ten patients with moderate to severe pulmonary hypertension, 8 of whom had severe mitral stenosis, were studied under the conditions of routine cardiac catheterization, and the effects of the inhalation of amyl nitrite and the injection of phenylephrine were observed. Amy1 nitrite caused a brisk systemic hypotension with tachycardia and an increase in cardiac output, whereas pulmonary arterial pressures remained relatively unchanged and wedge pressures increased in patients with mitral stenosis. Calculated pulmonary vascular resistance declined by an average of 42 per cent, whereas the decline in systemic resistance averaged 46 per cent. The significance of the decline in pulmonary vascular resistance is discussed, and it is suggested, but by no means proved, that it is due to a decrease in pulmonary vascular tone. When phenylephrine was injected into the pulmonary artery or into a systemic
PVR (uds)
TSR (units)
Heart rate
3.1
13.9
33.3
78
4.8 3.3
10.6 11.8
12.9 31.2
2.6 2.8
19.6 --
44.3 29.6
102 78 90 60 114
3.1 2.7
--
23.2 32.6
132 114
66.5
54
2.0
vein, the response was characteristically biphasic. Initially, there was a sharp rise in pulmonary arterial pressure, with a fall in wedge and systemic pressures. Later, a rise in systemic and wedge pressures occurred, and the increase in pulmonary arterial pressure was maintained. These effects also occurred in the 2 patients who had no mitral stenosis. In one patient in whom phenylephrine was injected into the wedged catheter, the pressure responses occurred in the reverse order. Cardiac output which was measured during the later phase was always decreased ; the average reduction was 22 per cent. The increase in calculated pulmonary vascular resistance can only indicate a true increase in pulmonary vasoconstriction. The initial effect of the drug was attributed solely to its pulmonary vasoconstrictive effect, whereas a combined systemic and pulmonary response accounted for the late effect. The abnormal vasoconstrictor response to phenylephrine was similar to that found in cases of ventricular septal defect with pulmonary hypertension. The relative lack of response to amyl nitrite in this group contrasts sharply with the marked pulmonary vasodilator effects found in subjects with ventricular septal defect who have hyperkinetic pulmonary hypertension. Rapid recirculation of amyl nitrite into the pulmonary bed in the latter group may account for the difference
642
Beck, Schrire, and Vogelpoel
in response. This may be related to the concentration of arnyl nitrite which reaches the pulmonary resistance vessels. In the presence of a large left-to-right shunt the concentration is likely to be greater than in cases of no shunt. \Ve wish to thank the Superintendent, Dr. J. Burger, for his permission to publish these findings, and we gratefully acknowledge the assistance of our technicians, Mr. L. W. I’iller and Miss S. Joseph. M:e are particularly grateful to the Council for Scientific and Industrial Research and the City Council of Cape Town for their continued support. REFERENCES 1.
Beck, W., Schrire, V., Vogelpoel, L., Nellen, M.. and Swaneooel. A.: Haemodvnamic effects of amyl nitrite and phenylephrine on the normal human circulation and their relation to changes in cardiac murmurs, Am. J. Cardiol. 8:341, 1961. Vogelpoel, L., Nellen, M., Swanepoel, A., and Schrire. V.: The use of amyl nitrite in the diagnosis of systolic murmurs, Lancet 2:810, 1959. Vogelpoel, L., Schrire, V., Beck, W., Nellen, M., and Swanepoel, A.: Variations in the response of the systolic murmur to vasoactivc drugs in ventricular septal defect, with special reference to the paradoxical response in large defects with pulmonary hypertension, AM. HEART J. 64:169, 1962. .
2.
3.
4.
Hellems, H. K., Haynes, F. NT’., and Dexter, I,. : Pulmonary “capillary” pressure in man, J. -4ppl. Physiol. 2:24, 1940. 5. Connolly, I). C., Kirklin, J. \2’., and Wood, E. H.: Relationship between pulmonary artery wedge pressure and left atria1 pressure in man, Circulation Res. 2:434, 1954. 6. Personal data. 7. Murphy, J. P.: Inaccuracy of wedge pressure as an index of pulmonary capillary pressure, Circulation 17:199. 1958. 8. Honig, C. R., Tenney, S. M., and Gabel, I’. \‘.: The mechanism of cardiovascular action of nitroglycerine. An example of integrated response during the unsteady state, Am. J. Med. 29:910, 1960. 9. Aviado, D. M., and Schmidt, C. F.: Effects of sympathomin~etic drugs on pulmonary circulation, J. Pharmacol. & Exper. Therap. 120:512, 1957. 10. Horvath, S. M., and Knapp, D. W.: Haemodynamic effects of Neo-Synephrine. Am. J. Physiol. 1’78:386, 1954. 11. Burton, A. C.: The relation between pressure and flow in the pulmonary bed, in Ad&, W. R.. and Veith. I.. editors: Pulmonarv circulation, New York, 1959, Grune & Stratton, Inc., p. 26. 12. Wood, I’., Resterman, E. M., Towers, M. I(., and McIllroy, M. B.: The effect of acetylcholinc on pulmonary vascular resistance and left atrial pressure in mitral stenosis, Brit. Heart J. 19:279, 1957.
reports
The hemodynamic effects of amyl nitrite and phenylephrine in patients with mitra,l stenosis and severe pulmonary hypertension W. Beck, M.Sc., M.Med., M.R.C.P. V. Schrire, M.Sc., Ph.D., M.B., F.R.C.P., il.. Vogelpoel, M.D., M.R. C.P. Cape Town, Soulh Africa
S
tudies of the action of amyl nitrite and phenvlephrine in normal subjets1 have’ shown -the predominant effect of these drugs on the systemic circulation. Amy1 nitrite causes a marked drop in systemic pressure, but leaves pulmonary arterial pressure relatively unchanged. On the other hand, phenylephrine markedly raises the systemic pressure and causes a slight rise in the pulmonary arterial pressure, which is due predominantly to an increase in the pulmonary arterial wedge pressure. The striking reduction in the pressure difference between the left and the right ventricles after amyl nitrite, and the increase after phenylephrine, were related to the changes in intensity of murmurs due to ventricular septal defect unassociated with pulmonary hypertension .rm2 In ventricular septal defect with severely elevated pulmonary arterial pressures, the flow through the large defect is mainly dependent upon the relative resistances of the pulmonary and systemic circuits. In this situation the murmurs of ventricular septal defect often failed to soften after the administration of amyl nitrite or to
F.R.C.P.E.
increase after phenylephrine, and even behaved in a paradoxical fashion. Thus, they became loud after amyl nitrite had been inhaled, and they softened after phenylephrine.3 This paradoxical behavior of the murmur was shown to be associated with a greater fall and rise in pulmonary arterial pressure than in systemic pressure after amyl nitrite and phenylephrine, respectively. In the absence of measurements of flow it could only be inferred that responses were brought about by appropriate changes in pulmonary vascular resistance. This study was undertaken to investigate quantitatively the effects of amyl nitrite and phenylephrine in patients with severe pulmonary hypertension. Subjects with severe pulmonary hypertension without intracardiac shunts were selected so that clear separation of pulmonary and systemic pressures could be obtained and estimation of pulmonary blood flow made by dye-dilution studies. Material
and
Eight patients nosis, which was
method with severe subsequently
mitral proved
steby
From the Cardiac Clinic, Groote Schuur Hospital, and C.S.I.R. Cardio-Pulmonary Research Group, Department of Medicine, University of Cape Town, Cape Town, South Africa. Part of the expenses of this work has been defrayed by grants received from the Council for Scientific and Industrial Research and the City Council of Cape Town. Received for publication March 13, 1962.
631
632
Beck,
Schrire,
and
.4m. Heart .I. ,Vowmbcr, 1962
Vogelpoel
operation, and with mean pulmonary arterial pressures between 43 and 93 mm. Hg, were studied during routine cardiac catheterization. &Atria1 fibrillation was present in one (Patient 7). No patient was in frank left or right heart failure at the time of study, but all except one (Patient 8) were severely disabled by low resting cardiac outputs. Catheterization of the right side of the heart was carried out from the right arm; one catheter was wedged in the pulmonaq artery to record the pulmonary arterial via a strain-gauge mawedge pressure, nometer. A second catheter was placed in the main pulmonary artery to record pulmonary arterial pressures, on a capacitance manometer. Systemic arterial pressure was recorded bq- a needle in the brachial or radial artery, on an inductance manometer; and another needle was placed in a second systemic artery, usually the femoral, in order to record systemic dilution curves. All pressure tracings were reN.E.P. photocorded on a six-channel graphic recorder, and the zero level was taken at mid-chest level, with the patient in the recumbent position. The use of three different types of manometer is not ideal for this type of study, but in order to minimize possible errors, each transducer was carefully calibrated to give identical galvanometric deflections for a given pressure obtained from a mercury manometer. Previous experience with these instruments had shown that the calibrations remain accurate for the duration of a catheter study. The notorious tendenc) for base-line drift to occur with the capacitance manometer was minimized by restricting its use to arterial pressure on record pulmonary the sensitivitv setting of 100 mm. Hg, where the drjft is less pronounced. Zero levels were also recorded throughout the procedure before and after each tracmg. [Jsed in this way, no significant base-line drift was detected. Cardiac output was determined from indicator-dilution curves recorded at the femoral artery after the injection of 5 mg. of indocyanine green into the pulmonary artery. The densitometer (Norman N.E.P.) was calibrated by drawing through it known concentrations of dye in the pa-
tient’s blood and constructing a threepoint calibration curve. The cardiac output was estimated b, dividing the dose of dye times 60 by the area under the curve. Recirculation was excluded by replotting the downstroke of the curve on a semilogarithmic basis, as in the standard Hamilton method. Pulmonary arterial, wedge, and systemic pressures and the dye-dilution curves were recorded simultaneously during the first control period. Thereafter the patient was given a crushed vitrella containing 3 minims of amyl nitrite which was to be inhaled for 15 to 20 seconds, and as soon as the fall in systemic pressure occurred, a dilution curve was once more recorded, during the maximal systemic hypotensive phase of the drug; again, all pressures were recorded simultaneously. A second control period was then established, after the effect of the amyl nitrite had worn off, and pressures and flow were recorded simultaneously. Thereafter, phenylephrine in a dose of 0.5 to 1.0 mg. was injected into the main pulmonarv artery or into a peripheral vein, and during the late phase of systemic hypertension and bradycardia a dye curve was recorded. In one subject, phenylephrine was injected into the wedged catheter so that its effects would first be observed on the systemic circuit. Identical studies were performed in 2 additional patients without mitral stenosis. One suffered from pulmonary hypertensive car pulmonale due to a diffusion defect, and the other, from idiopathic pulmonary hypertension. In the latter patient the wedge pressure could not be obtained. All studies were made with the patient in the recumbent posture under mild barbiturate sedation. Results The results in 8 patients who had mitral stenosis are presented. 1. The response to amyl nitrite. The data are presented in Table I and Fig. 1. Measurements were made at two points: the first at 5 seconds after the inhalation of amyl nitrite had started, and the second some 30 seconds later during the inscrip-
Hemodynamic
efects of amyl nitrite and phenylephrine
-...--. _.-.-.--
I C;)NTRoL
633
_./.--’_.-.A ,_.-.-. 1; SECS30SECS
MS. s PlJLM rnPERTENSDN
Fig. f. Hemodynamic effects of inhalation of amyl nitrite. The three columns on the left show the mean systemic, pulmonary arterial, and wedge pressures and flow in 8 patients with mitral stenosis and pulmonary hypertension before, 5 seconds after, and 30 seconds after they had inhaled amyl nitrite. On the right, the results in 2 normal subjects previously studied’ are shown for comparison. In the subjects with mitral stenosis, systemic pressure falls as in normal subjects. Pulmonary arterial pressure falls slightly at the Ssecond period in 5 patients, but in most cases at the 30-second period is not significantly different from the control level. Wedge pressure rises slightly and cardiac output increases.
tion of the primary deflection of the dilution curve and at the time of maximal systemic hypotension. In Patients 1,2,4,5, and 8 there was a slight initial fall in pulmonary arterial pressure at the S-second period before any real effect on systemic pressure became evident (Fig. 2). In the other 3 patients there was no real change. At the 30-second period, Patients 3,5,7, and 8 showed no significant change from the control level. Patients 1 and 4 showed a very slight increase, and Patients 2 and
6 showed a slight fall in mean pulmonary arterial pressure. In all patients, systemic pressures dropped sharply, and in all except one (Patient 2) a tachycardia developed, as occurs in normal subjects beginning some 10 seconds after the inhalation of amyl nitrite has started. All patients except Patient 3 showed a moderate increase in pulmonary arterial wedge pressure during the later phase of maximal effect of the drug on systemic pressure.
634
Beck, Schrire, and Vogelpoel
Table I. Pressures (mm. Hg)
Systemic Patient, ilgv
Sex,
Diagnosis
Stat?
S.D. 1. CF.,
33
Pure
mitral stenosis with severe, pulmonary hypertension
2. E.M.,
41
Mitral
stenosis pulmonary
with severe hypertension
3. B.M.,
25
Mitral
stenosis pulmonary
with severe hypertension
with severe hypertension
4. C.F.,
28
Mitral
stenosis pulmonary
5. B.F.,
18
Mitral
stenosis,
6. E.M.,
26
Severe
pulmonary Mitral stenosis
7. E.F.,
52
Mitral
stenosis pulmonary
with severe hypertension.
stenosis hypertension
with
8. E.F.,
Mitral
26
C.F.-Coloured
female.
E.M.--Ruropean
severe
hypertension.
rkde.
A.F.
pulmonaq
b:.F.---European
Thus, the over-all effect on the pressure differences across the lung in these patients was a slight decline which was due chiefly to the rise in the wedge pressure. This
Control A.N. 5 ser. A.N. 30 sec. Control P.E. early P.E. late Control A4.N. 5 sec. A.N. 30 sec. Control P.E. early P.E. late Control A.N. 5 sec. A.N. 30 sec. Control P.E. earl> P.E. late Control AN. 5 sec. A.N. 30 sec. Control P.E. early P.E. late Control A.N. 5 sec. A.N. 30 ser. Control P.E. early P.E. late Control AN. 5 sec. A.N. 30 sec. Control P.E. early P.E. late Control A.N. 5 sec. :$.N. 30 sec. Control P.E. early P.E. late Control A.N. 5 sec. A.N. 30 ser. Control P.E. early P.E. late female.
B.M:-Bantu
artery
i/
112/72 1 lo/72 80/48 108/72 96/60 140/60 110/70 100/60 90/50 11.5/70 70/50 lZS/SS 170/95 125/95 100/75 165/90 115/75 190/90 115/75 1 lo/72 90/55 115/75 115/75 170/90 13s/75 135/75 95/55 145/85 65/45 190/110 1 lo/60 lOZ/SS 72/40 125/70 G/60 115/95 1 so/90 145/87 125/75 145/87 130/87 190/100 110/70 105/75 65/70 115/75 105/75 190/100 male. B.F.-Bantu
Mean 85 8‘4 59 84 72 113 83 73 53 8.5 57 102 120 105 83 11s 92 123 88 85 68 88 88 117 95 95 78 105 52 137 73 71 SO 88 67 115 110 106 92 106 100 130 83 75 48 88 85 130
female.
decline averaged 31 per cent (range, 6-78). Cardiac output was found to increase in all patients. It increased less in those with a low resting output than in those with
Hemodynamic
Pulvnonnry
artery
CO (L./vvzin.)
Wedge ---
_____ S.D.
efects of away1 nitrite and phenylephrine
635
PVR (L~nits)
TSR ( zhits)
Heart rate
Mean
S.D.
Mean.
(Dye)
87/G ??/40 95/52 SS/SO
59 52 66 61
10.8
34.0
3.1 2 5
6.8 10.8
19.0 33.5
95 95 120 9s
89 75
32 38 45 34 29 44 28 31 34 27 16 28 28 26 28 23 15 38 22 28 35 20 12 18 25 26 38 30 10 42 25 25 29 20 5 15 21 28 32 21 12 24 11 11 16 14 9 13
2.5
162/52 I OS/S?
3?/2? 45/32 so/40 40/32 30/2? 48/42 30/26 38/30 38/30 28/26 18/14 30/26 30/25 32/23 30/25 25/20 18/12 40/35 30/15 30/25 40/30 25/15 lS/lO 2O/lS 32/18 38/20 42/35 32/28 12/8 45/39 28/22 30/20 32/25
1.6 2.2
28.1 21.4
70.6 37.8
10.5 48 108
2.5 2.0
10.4 22.5
21.2 42.5
108 108
1.8 2.5
37.2 20.0
56.7 48.0
108
4 3 2.9
10.9 18.6
19.3 39.7
2.7 2.0
23.0 25.5
45.5 44.0
96 66 90 66 96
2.5 1.8
17.2 27.8
27.2 48.9
1.3 3.0
47.7 6.0
90.0 31.6
4.5 3.0
0.9 5.3
17.3 35.0
2.7 3.5
14.1 10.0
SO.8 20.8
4.3 3.8
5.4 11.0
11.6 23.2
3 4 2.7
15 .3 9.4
33.8
3.9 3.0
4.10 9.7
23.6 35.3
2.0 4.5
19.5 7.6
65.0 18.6
lOO/SS
70
90/G
60 72 92 9.5 78 77
1 lo/60 125/?5 135/?5 115/60 I lo/60 1 OS/60 110/60
2 93
130/?5
150/?5 120/50 1 OS/45 125/55 120/45 180/?0
1 so/so 80/2S 60/25 6?/32
??/30 1 lS/?S 14a/so 100/40 80/35 82/3? 95/45 118/S? 120/40 8?/25 85/29 8?/28 8?/32 10?/45 115/3? 60/38 SO/28 58/3? 62/38 81/50
1 lO/SS
.Z.N.-Amy1
nitrite.
100 73 65 78 70
103 80 43 37 42 46 88 80 60 56 52 62 77 67 46 48 48 so 65 63 45 35 44 46 60 73
P.E.-Phenylephrine.
27/u 3?/20 45/20 26/16 16/8 29/19
PVR-Pulmonary
slightly higher values; the mean increase in cardiac output was 36 per cent (range, 13-72). As a result of the decrease in pressure
vascular
5.9 4.4
4.8 7 3
2.7
resistance.
22.2
TSR-Total
10.7
8.1 20.0 48.1
systemic
5-l
114 96 96 54 60 114 72 102 42 64 84 66 84 54 5-l 60 54 66 36 96 120 96 102 48
resistance.
difference across the lungs and an increase in pulmonary blood flow, the calculated vascular resistance, expressed in simple units obtained by dividing the mean pres-
636
Am. Hart I. A’wrmber, 1963
Beck, Schrire, and Vogelpoel
Fig. 2. The pressure record from Patient 8. From above downward are the electrocardiogram, the pulmonary arterial wedge pressure, the pulmonary arterial pressure, and the systemic pressure. Inhalation of amyl nitrite is indicated by the black line at the bottom. The pulmonary arterial pressure starts to fall before any change occurs in wedge pressure, systemic pressure, or heart rate, which suggests a direct effect on the pulmonary resistance vessels. Later, systemic pressure falls acutely, a tachycardia develops, and the wedge pressure begins to rise. Pulmonary arterial pressure now parallels the increase in wedge pressure, so that after 30 seconds it is back to its control level, although the pressure difference across the lungs is still diminished.
sure gradient by flow, was decreased in all cases. This calculated resistance averaged (range, 31-67).
found to be decrease in 45 per cent
2. The response to phenylephrine. The data are presented in Table I and Fig. 3. Measurements of pressure were made during the initial phase of maximal effect on the pulmonary arterial pressure and during the late phase of systemic hypertension during the inscription of the dilution curve. When phenylephrine was injected into a peripheral vein or main pulmonary artery, a characteristic biphasic pressure response was obtained in all but one (Patient 4). In the initial phase, immediately after the administration of phenylephrine there was a sharp increase in pulmonary arterial pressure, associated with a brief, sharp drop in pulmonary arterial wedge pressure, and a decrease in systemic pressure, associated with a tachycardia. After a few seconds a rise in systemic pressure occurred, associated with a bradycardia; wedge pressure rose to the control level or even higher, and pulmonary arterial pressures remained elevated (Fig. 4). The cardiac output was estimated during the late phase of the response and was
invariably found to be decreased. The average decrease in cardiac output was 22 per cent (range, 7-39). The pressure difference across the lungs as measured at the time when flow was determined was always increased and averaged 52 per cent (range, 18-138). The combination of an increased pressure difference with a reduction in flow resulted in the calculated vascular resistance being increased in all cases by an average of 105 per cent (range, 21-200). In Patient 6, a second close of phenylephrine was injected into the pulmonaqthis injection the artery wedge ; after initial effect was a sharp rise in systemic pressure with bradycardia, which long preceded the increase in pulmonary arterial pressure and the slight drop in wedge pressure (Fig. 5). Discussion I’he reliability of the data. In the presence of severe pulmonary hypertension the pressure differences across the lungs are large, and, therefore, are more easily and accurately measured than in the case of normal pulmonary vascular pressures. The presence of elevated wedge pressures adds to the reliability of the measurement of
Hemodynamic
pressure gradient and makes the differences recorded of greater significance. We therefore, interpret the difference can, between mean pulmonary arterial and mean wedge pressure with a fair degree of confidence. There is good evidence that the pulmo-
ejects of amyl nitrite and phenylephrine
nary arterial wedge pressure accurately reflects the left atria1 pressure in cases of although Murphy7 has mitral stenosis,4-6 come to the opposite conclusion. As has been previously discussed,’ amyl nitrite causes very short-lived transitory effects, which makes accurate calculations of
Fig. 3. The effects of the injection of phenylephrine into the pulmonary artery or systemic vein iu 8 patients with mitral stenosis and pulmonary hypertension (in coluntns on left) are compared with the results obtained in 2 normal subjects previously studied’ (kz colunzns on right). The systemic pressure falls initially, as does the wedge pressure, at a time when the pulmonary arterial pressure is increasing rapidly. This is interpreted as being due to intense pulmonary vasoconstriction which results in diminished venous return to the left side of the heart, In the later phase the systemic and wedge pressures rise because of systemic vasoconstriction, and the pulmonary arterial pressure remains elevated. As in the normal subjects, cardiac output is decreased after the injection of phenylephrine. The biphasic response of the systemic and wedge pressure is not seen in normal subjects, but also occurred in the subjects with pulmonary hypertension without mitral stenosis, which suggests that in the presence of pulmonary hypertension the pulmonary
vasculature
637
is far more reqctivg than in normal subjects.
638
Beck, Schrire, and Vogelpoel
Am. Nozwmber,
Heart
J. 1962
Fig. 4. The pressure record from Patient 6. From above downward are the electrocardiogram, the pulmorrary arterial pressure, the wedge pressure, and the systemic pressure; the injection of phenylephrine is indicated by the heavy line at the bottom of the tracing. Initially, pulmonary arterial pressure rises while wedge pressure falls, and systemic pressure drops acutely, with resultant tachycardia. After about 30 seconds the systemic pressure rises and a bradycardia occurs, wedge pressure also rises slightly, and the pulmonary arterial pressure remains elevated.
Fig. 5. Pressure records from Patient 6 during the injection of phenylephrine into the wedged catheter. Ic’ow the initial effect is a rise in systemic pressure; about 20 seconds later the pulmonary arterial pressure rises and the wedge pressure drops slightly. In this instance the initial effect of phenylephrine has been on the systemic resistance vessels, and the pulmonary effects have occurred later when recirculating phenylephrine reaches the lungs.
flow extremely difficult, since a steady state is not attained. The calculation of cardiac output must, at best, be an approximation under these conditions, even when the dye-dilution technique is used. Nevertheless, from the present data and from data obtained in normal people by us and by other investigators,* there seems to be little doubt that nitrites do significantly increase cardiac output, when they drop the systemic pressure acutely. The data on flow obtained after the
administration of phenylephrine arc niorc likely to be reliable, since the effects of phenylephrine persist for 3 to 4 minutes, which makes the estimation of cardiac output by the dilution methods far more acceptable. As in normal people, phenylephrine has the effect of significantly reducing cardiac output.l~g~10 The inierpretation of changes in calculated vascular resistance. It has been emphasized repeatedly that there is a multiplicity of factors other than tone which can affect
Volume Number
64 5
Hemodynamic
the calculated resistance to flow. Thus, the interpretation of calculated resistance in a situation in which pressure, flow, and heart rate are all changing rapidly is estremely difficult. Nonetheless, some discussion on the possible role of changes in vascular tone is necessary. If it is assumed that the drugs amyl nitrite and phenylephrine have no effect on the viscosity of the blood, on the size of anastomotic vessels, on the opening up of vascular channels previously closed, or on the length of the vascular channels, a significant change in calculated resistance is probably due to a change in the caliber of the vessels. As Burton” has pointed out, there are two factors which influence the caliber of resistance vessels. One is the transmural pressure, which can cause vessels to distend or contract passively because of their inherent elasticity, and the other is muscular tone, which can constrict or dilate vessels in response to reflex activity or vasoactive drugs. It can only be concluded that muscular tone has been affected if the possible effect of a change in transmural pressure is taken into account. The average decrease in pulmonary resistance of 4.5 per cent which was found after rhe inhalation of amyl nitrite may mean a widening of the caliber of the pulmonary vessels, which could be active or passive. Since this decrease in resistance occurred in the face of elevated pulmonary arterial wedge pressures in 7 of the 8 patients, it is possible that the passive distention of the venous segment of the pulmonary vascular bed alone caused the drop in calculated resistance. However, there are two objections to such a conclusion. In 2 subjects (Patients 5 and 8), a brief drop in pulmonary arterial pressure occurred before any change could be detected in the wedge and systemic pressures and the heart rate (Fig. 2). Since a change in blood flow seems unlikely at this early stage after the inhalation of amyl nitrite, a direct effect of amyl nitrite on the pulmonary resistance vessels in these 2 patients appears to fit the facts in the presence of best. Furthermore, moderate to severe pulmonary hypertension, most of the resistance to flow resides at the level of the arteriole, and it is un-
effects of amyl nitrite and phenybephrine
639
likely that relatively small changes in pressure in the venous segment would materially affect the transmural pressure at the level of the arteriole. In the light of the preceding considerations the sequence of events which occurs after the inhalation of amyl nitrite is interpreted in the following manner. Inhaled amyl nitrite initially affects the pulmonary resistance vessels to a variable extent, leading to a sharp initial drop in pressure in some subjects. (The means by which the resistance vessels are apparently affected when the drug is absorbed into the pulmonary capillaries remains ULIexplained.) Thereafter, amyl nitrite reaches the systemic resistance vessels and leads to an acute vasodilatation, with a drop in systemic pressure, tachycardia, and an increased cardiac output. The combined effect of tachycardia and increased venous return elevates the wedge pressure because of the fixed obstruction at the mitral valve. The rise in pulmonary venous pressure lead to a passive rise in may, in turn, pulmonary arterial pressure, which may reach or even exceed the control levels, in spite of some release of pulmonary vasoconstrictor tone. After the administration of phenylephrine into the pulmonary artery or peripheral vein, there is an initial brisk rise in pulmonary arterial pressure, a slight drop in wedge pressure, and a drop in systemic pressure (Fig. 4). This response is quite different from that which occurs in subjects with normal pulmonary arterial pressures, in whom the slight rise in pulmonary arterial pressure is later and, for the most part, secondary to a rise in systemic and wedge pressures.’ Although cardiac output could not be measured during the brief initial phase, it would seern that the above response can only be explained by an illtense vasoconstriction of the pulmonary resistance vessels. This leads to a sharp decrease in venous return to the left side of the heart, with a consequent drop in wedge and systemic pressures. The second phase of the response to phenylephrine consists of a rise in systemic and wedge pressures with bradycardia, and the increase in pulmonary arterial pressure is maintained. The cardiac output during this phase was always decreased by an
640
.4m. Heart .I. ,Voe’cmber, 1962
Beck, Schrire, and Vogelpoel
Table II. Pressures (mm. Hg)
Systemic Patient,
Sex,
Age
Diagnosis
State
S.D.
1. E.M., 48
Hypertensive corpulmonale
Control A.N.
5 sec.
A.N. 30 sec. Control
2.
E.M., 22
Idiopathic pulmonary hypertension
P.E. early P.E. late Control A.N. ‘4.N.
5 sec. 30 sec.
Control P.E. earl> P.E. late
average of 22 per cent. At this time, the pressure gradient across the lungs was increased by an average of 52 per cent. The increase in calculated vascular resistance must reflect a true increase in vascular tone, since the intraluminal pressure at the arteriolar end of the vascular bed is increased, and at the venous end it is either slightly increased or unchanged. In one patient (Patient 6), phenylephrine was injected into the wedged catheter so that its initial effect would be on the systemic circuit (Fig. 5). The initial response then was a rise in systelnic pressure with bradycardia followed by a rise in pulmonary arterial pressure and a drop in wedge pressure. This difference is adequately explained by the fact that phenylephrine has its initial effect on the systemic circuit, and subsequently affects the pulmonary vasculature. Studies3 in patients with ventricular septal defects who had large left-to-right shunts and associated pulmonary hypertension have provided evidence for an unusual responsiveness of the pulmonary resistance vessels to these drugs. It seeined likely that amyl nitrite caused a greater fall in pulmonary than in systetnic resistance, and that phenylephrine had the reverse effect. In our patients who had mitral stenosis and an intact circulatory pathway a marked reactivity of the pulmonary vascular bed to phenylephrine has been demonstrated, but the response to
artery
-___
130/90 100/70
S/50 130/90 110/90 165/90 100/75 100/70 85/65
lOS/SO 105/75
170/115
/
Xean 103 80 62 103 97 115 83 80 72
88 8.5
133
amyl nitrite has been rather disappointing and the evidence for a release of vasomotor tone inconclusive. In order to determine whether the failure of the pulmonary arterial pressure to fall after amyl nitrite was due to the presence of mitral stenosis in these patients, two patients without mitral stenosis were studied (Table II). One had pulmonar) hypertensive car pulmonale, and the other had idiopathic pulmonary hypertension ; and in both the severity of the pulmonary hypertension was comparable to that of the patients with mitral stenosis. A marked pulmonary vasoactive response to phenylephrine was demonstrated in both cases. However, as in most of the cases of mitral stenosis, amyl nitrite had virtually no effect on the pulmonary arterial pressure. It seems, therefore, that amyl nitrite has strikingly different effects on the pulmonary vascular bed in patients with a left-to-right shunt and in those with intact circulatory pathways. It seems unlikely that the lack of effect in the latter group can be ascribed to fixed organic obliterative vascular changes, since other studies have repeatedly demonstrated’* a release of tone in the lung vessels in cases of mitral stenosis, and our results with phenylephrine clearly indicate that the vessels can constrict. Thus, it is suggested that the relative lack of response to amyl nitrite in cases without a left-to-right shunt may be due
P’olrmc A’wabcr
64 5
-___
Pulmonary -__--__-
Hemodynamic
efects of amyl nitrite and phenylephrine
641
co artery
S.D.
Wedge
hfean I
85/40 80/3 7 85/40 84/3 7 105/60 100/40 115/75 115/70 120/70 115/75 130/80 l-12/70
__-
(L./?nin.) ____
S.D.
hfean
(dye)
13/11 10/7 6/3 15/12 10/6 10/B
12 8 4 13 7 9 -
1 55 51 5.5 52 75 60 88 85 87 88 97 94
-
-
to the fact that a much weaker concentration of amyl nitrite reaches the pulmonary resistance vessels. By contrast, when there is a large left-to-right shunt, a large concentration of amyl nitrite absorbed via the pulmonary capillary bed is likely to be rapidly shunted into the lungs, which results in a more potent effect on the pulmonary resistance vessels, as previously postulated.3 Summary
and
conclusions
Ten patients with moderate to severe pulmonary hypertension, 8 of whom had severe mitral stenosis, were studied under the conditions of routine cardiac catheterization, and the effects of the inhalation of amyl nitrite and the injection of phenylephrine were observed. Amy1 nitrite caused a brisk systemic hypotension with tachycardia and an increase in cardiac output, whereas pulmonary arterial pressures remained relatively unchanged and wedge pressures increased in patients with mitral stenosis. Calculated pulmonary vascular resistance declined by an average of 42 per cent, whereas the decline in systemic resistance averaged 46 per cent. The significance of the decline in pulmonary vascular resistance is discussed, and it is suggested, but by no means proved, that it is due to a decrease in pulmonary vascular tone. When phenylephrine was injected into the pulmonary artery or into a systemic
PVR (uds)
TSR (units)
Heart rate
3.1
13.9
33.3
78
4.8 3.3
10.6 11.8
12.9 31.2
2.6 2.8
19.6 --
44.3 29.6
102 78 90 60 114
3.1 2.7
--
23.2 32.6
132 114
66.5
54
2.0
vein, the response was characteristically biphasic. Initially, there was a sharp rise in pulmonary arterial pressure, with a fall in wedge and systemic pressures. Later, a rise in systemic and wedge pressures occurred, and the increase in pulmonary arterial pressure was maintained. These effects also occurred in the 2 patients who had no mitral stenosis. In one patient in whom phenylephrine was injected into the wedged catheter, the pressure responses occurred in the reverse order. Cardiac output which was measured during the later phase was always decreased ; the average reduction was 22 per cent. The increase in calculated pulmonary vascular resistance can only indicate a true increase in pulmonary vasoconstriction. The initial effect of the drug was attributed solely to its pulmonary vasoconstrictive effect, whereas a combined systemic and pulmonary response accounted for the late effect. The abnormal vasoconstrictor response to phenylephrine was similar to that found in cases of ventricular septal defect with pulmonary hypertension. The relative lack of response to amyl nitrite in this group contrasts sharply with the marked pulmonary vasodilator effects found in subjects with ventricular septal defect who have hyperkinetic pulmonary hypertension. Rapid recirculation of amyl nitrite into the pulmonary bed in the latter group may account for the difference
642
Beck, Schrire, and Vogelpoel
in response. This may be related to the concentration of arnyl nitrite which reaches the pulmonary resistance vessels. In the presence of a large left-to-right shunt the concentration is likely to be greater than in cases of no shunt. \Ve wish to thank the Superintendent, Dr. J. Burger, for his permission to publish these findings, and we gratefully acknowledge the assistance of our technicians, Mr. L. W. I’iller and Miss S. Joseph. M:e are particularly grateful to the Council for Scientific and Industrial Research and the City Council of Cape Town for their continued support. REFERENCES 1.
Beck, W., Schrire, V., Vogelpoel, L., Nellen, M.. and Swaneooel. A.: Haemodvnamic effects of amyl nitrite and phenylephrine on the normal human circulation and their relation to changes in cardiac murmurs, Am. J. Cardiol. 8:341, 1961. Vogelpoel, L., Nellen, M., Swanepoel, A., and Schrire. V.: The use of amyl nitrite in the diagnosis of systolic murmurs, Lancet 2:810, 1959. Vogelpoel, L., Schrire, V., Beck, W., Nellen, M., and Swanepoel, A.: Variations in the response of the systolic murmur to vasoactivc drugs in ventricular septal defect, with special reference to the paradoxical response in large defects with pulmonary hypertension, AM. HEART J. 64:169, 1962. .
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Hellems, H. K., Haynes, F. NT’., and Dexter, I,. : Pulmonary “capillary” pressure in man, J. -4ppl. Physiol. 2:24, 1940. 5. Connolly, I). C., Kirklin, J. \2’., and Wood, E. H.: Relationship between pulmonary artery wedge pressure and left atria1 pressure in man, Circulation Res. 2:434, 1954. 6. Personal data. 7. Murphy, J. P.: Inaccuracy of wedge pressure as an index of pulmonary capillary pressure, Circulation 17:199. 1958. 8. Honig, C. R., Tenney, S. M., and Gabel, I’. \‘.: The mechanism of cardiovascular action of nitroglycerine. An example of integrated response during the unsteady state, Am. J. Med. 29:910, 1960. 9. Aviado, D. M., and Schmidt, C. F.: Effects of sympathomin~etic drugs on pulmonary circulation, J. Pharmacol. & Exper. Therap. 120:512, 1957. 10. Horvath, S. M., and Knapp, D. W.: Haemodynamic effects of Neo-Synephrine. Am. J. Physiol. 1’78:386, 1954. 11. Burton, A. C.: The relation between pressure and flow in the pulmonary bed, in Ad&, W. R.. and Veith. I.. editors: Pulmonarv circulation, New York, 1959, Grune & Stratton, Inc., p. 26. 12. Wood, I’., Resterman, E. M., Towers, M. I(., and McIllroy, M. B.: The effect of acetylcholinc on pulmonary vascular resistance and left atrial pressure in mitral stenosis, Brit. Heart J. 19:279, 1957.