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Role of the carotid sinus in response of integrated venous system to pulsatile and nonpulsatile perfusion
Role of the carotid sinus in response of integrated venous system to pulsatile and nonpulsatile perfusion Effects of pulsatile and nonpulsatile perfusion on capacity system were investigated in 33 open-chest mongrel dogs with extracorporeal circulation. In 28 dogs with intact carotid sinus nerves, after changing from nonpulsatile to pulsatile systemic perfusion the mean arterial pressure decreased by 14 ± 1.5 mm Hg, peripheral resistance by 423 ± 15 dyne· cm- 5 . sec, and venous blood volume by 3.3 ± 0.4 ml/kg, After changing from pulsatile perfusion to nonpulsatile systemic perfusion the mean arterial pressure increased by 15 ± 2.2 mm Hg, the peripheral resistance by 431 ± 15 dyne . cm- 5 . sec, and venous volume by 3.9 ± 0.5 ml/kg. The same effects were observed in five dogs with bilateral isolated carotid pulsatile perfusion or nonpulsatile perfusion and systemic nonpulsatile perfusion. These effects were abolished after denervation of pressor receptors and pharmacologic blockade of a and 13 receptors. It is proposed that with nonpulsatile perfusion carotid sinus-mediated vasoconstriction occurs in the downstream part of the capacitive system, where more pronounced wall musculature with increased number of adrenergic receptors is present. The throttle effect caused by this "resistance" part of venous circulation leads to increase of pressure in the upstream section of the capacitive system, compensates for the constrictive effect of the sympathetic tone, and leads finally to an increased volume of the capacity system. We conclude that venous response to different perfusion modalities is critically dependent on intact carotid sinus nerves and adrenergic receptors in the veins. (J THORAC CARDIOVASC SURG 1992;104:1639-46)
Kazutomo Minami, MD," Karel Vyska, PhD,b and Reiner Korfer, MD," Bad Oeynhausen, Germany
~h
regard to the arterial circulation, the coronary perfusion, the microcirculation, and the lymph circulation, extracorporeal circulation (ECC) with pulsatile systemic perfusion was shown to be more favorable for the total organism and for individual organ systems than the ECC with nonpulsatile systemic perfusion.I? Moreover, the pulsatile perfusion was shown to reduce the accumulation of fluid in the lung and brain. Our previous clinical investigations" indicated that pulsatile perfusion when compared with nonpulsatile perfusion result in lower catecholamine release, lower From the Department of Thoracic and Cardiovascular Surgery" and Institute of Molecular Biophysics, Radiopharmacy and Nuclear Medicine," Bad Oeynhausen, Germany. Received for publication Feb. 21,1991. Accepted for publication Dec. 5, 1991. Address for reprints: Kazutomo Minami, MD, Department of Thoracic and Cardiovascular Surgery, Heart Center North Rhine- Westfalia, University of Bochum, Georgstrasse 11,4970 Bad Oeynhausen, Germany.
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mean arterial pressure, and a decreased tendency toward edema formation. On the basis of these data we postulated that the increased tendency toward edema formation by non pulsatile perfusion is due to the carotid sinus-mediated reaction of the venous capacity system to this type of perfusion. Whereas presently it is generally accepted that the control of the resistance vessels is mediated through adrenergic receptors."? the response of the venous system to adrenergic stimulation is still controversial.P'P The aim of this study was therefore to verify in an animal model the involvement of carotid sinus and adrenergic receptors in venous volume regulation during ECC.
Materials and methods The investigations were carried out on a total of 33 mongrel dogs, weighing between 21 and 36 kg (mean 26 ± 5 kg). The animals wereanesthetizedin the supine position with 40 mg/kg chloraloseand 250 rug/kg urethan. After relaxation with pancuronium bromide(Organori/Teknika, Munich, Germany) the dogswere intubated endotracheallyand ventilated with a Starling pump. To prevent counter regulation by the para-aortal pressor receptors bilaterally, the efferents of the vagal nerves
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The Journal of Thoracic and Cardiovascular
1 640 MiMm£ YySKa, /(o!ftl'
Surgery
Automatic clampsx..
Driving unit LPulsatile pump V.cava info Venous I cannula' Oxygenator
00 :0: 0000
~========~o~o
_======:::=J
A. femoralis Fig. 1. Schematic representation of experimental arrangement. (Modified from Miiller-Ruchholtz ER, Losch HM, Grund E, Lochner W. Beeinflussung des kapazitiv-venosen Systems des Kreislaufs durch Stimulation und Blockade der Betarezeptoren: Ein Aspekt des Mechanismus der blutdrucksenkenden Wirkund von Betablockern. Herz Kreislauf 1977;9:790-4.)
were divided below the carotid bifurcation, where they do not join the carotid baroreceptor afferents. Subsequently, splenectomy through an upper midline abdominal incision was performed to prevent splenic reservoir effects. After left lateral positioning of the animal, the heart was exposed by anterolateral thoracotomy through the fifth intercostal space. After anti-
coagulation with 400 Ujkg sodium heparin (Braun AG, Me1-
sungen, Germany), the venae cavae were cannulated through the right atrium and the venous blood was drained by gravity into a bubble oxygenator (Optiflow II Cobe) (Fig. 1). The blood was held normothermic by a heat exchanger (rectal temperature 37.2° to 37.8° C) and was pumped back into the ascending aorta with a roller or a pulsatile pump. The oxygenator was filled with I L of heparinized blood from a donor dog and I L of HAES plasma expander (Kabi AG, Erlangen, Germany). After the azygous vein and the pulmonary hili were ligated bilaterally, the ascending aorta and the pulmonary trunk were clamped. The hili were clamped to exclude the influence of the bronchial circulation. Minimal blood loss from the operation wounds was fed back to the oxygenator.
For systemic nonpulsatile perfusion a roller pump (StockertShiley Munich, Germany) and for systemic pulsatile perfusion a tube pump developed in cooperation with University of Aachen/" were used. With the pulsatile pump a maximal stroke volume of 120 ml and maximal pressure rise of 5000 mm Hg/sec could be achieved. The frequency and the duration of systole in relation to the total cycle duration were regulated to 90 beats/min and 40%,7 respectively. The cardiac output was measured by an electromagnetic flow meter and regulated throughout the whole experiment to a constant value determined with the help of Lochner's formula [Cardiac output (Lyrnin) = 3.5 x 0.112 Xf(kg)2].2s Base excess, pH, oxygen pressure (P02), carbon dioxide pressure, hemoglobin, and hematocrit, were kept constant by adding necessary amounts of sodium bicarbonate, by transfusion or by altering oxygen flow (pH 7.30 to 7.45, P0 2 > 100 mm Hg, carbon dioxide pressure 35 to 47 mm Hg, hemoglobin, 7.8 to 9.0 gm/dl; and hematocrit 30% to 38%). The depths of anesthesia and muscle relaxation in the animals were continually monitored.
Volume 104 Number 6 December 1992
The pressure in both venae cavae was regulated to 5 mm Hg with an automatic clamp for the superior vena cava and an automatic control system (modified from Muller-Ruchholz-") for the inferior vena cava (Fig. I). By a tendency of central venous pressure (CYP) to decrease or increase, the automatic clamp opened or closed and the automatic control system moved the oxygenator up or down, respectively. The use of automatic control system provided the possibility to determine the changes of blood volume in the capacitive system under conditions of constant CYP. Because the oxygenator was localized lower than the animal, the blood drained from the venous system by gravity. The downward movement of the oxygenator at the tendency of CYP to increase led to increased drainage and, because of the constant perfusion rate, to reduction of the intracorporeal blood volume and thus to maintenance of CYP at a constant level. At constant output of the pump transporting blood from the bottom of the oxygenator, the drained volume could be recognized as the increase of the blood volume in the oxygenator. The changes in the blood volume in the oxygenator were regarded to be reciprocal of the changes of intracorporeal volume. To estimate the drained venous blood volume, the changes of intracorporeal blood volume were corrected for the changes in the arterial blood volume according to the method of Remington and Hamilton.i" All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals," prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 80-23, revised 1978). To examine the influence of perfusion mode on the systemic circulation and especially on the venous capacity system, the systemic perfusion was alternated in 28 dogs (group A) with intact baroreceptors from pulsatile to nonpulsatile at intervals of 15 to 30 minutes. The pump was switched from one mode to the other after the arterial pressure, the cardiac output, and the oxygenator volume had achieved a steady state. The following parameters were registered continually with a multiple canal monitor device (Gould Brush Recorder, Gould, Inc., Cleveland, Ohio): systolic, diastolic, and mean arterial pressure; pressure in the superior and inferior venae cavae; the weight and the volume of the oxygenator; and cardiac output. Mean arterial pressure was determined automatically by a computer through integration of the pressure pulse and by use of the algorithm described by Yang et al. 27 The arterial blood pressure was measured in the left femoral artery with a Stratham P 23 ID Transducer (Gould, Inc., Cleveland, Ohio), the venous pressure in the superior and inferior caval veins with a Stratham P 23 BB Transducer. The transducer were connected to Cournand catheters inserted through the right femoral vein and the right external jugular vein. The tips of the two catheters were placed by direct palpation approximately 2 ern distal to the ends of the venous cannulas. In four animals in group A the venous pressure was recorded continually after the perfusion pump was turned off and the aorta and the superior and inferior venae cavae cannulas were clamped so that the intracorporeal volume could no longer change. The pressure fell continuously in each vena cava until it stabilized at a new value (usually I minute after circulatory arrest). This value was regarded as the mean filling (static) pressure.
Response to pulsatile and nonpulsatile perfusion
I 64 I
Table I. Changes in mean arterial pressure and total peripheral resistance after switching from nonpulsatile to pulsatile systemic perfusion and vice versa Hemodynamic parameter
Nonpulsatile to pulsatile (n = 40)
Pulsatile to nonpulsatile (n = 37)
91 ± 3 77 ± 2 -14 ± 2
80 ± 3 95 ± 4 15 ±2
<0.005
<0.002
2235 ± 18 1812 ± 20 -423 ± 10 <0.001
1784 ± 14 2215 ± 26 431 ± 10 <0.001
P AF (mm Hg)
Before switch After switch ~PAF (mm
Hg)
p value
TPR (dyne· cm" . sec) Before switch After switch ~TPR (dyne. cm" . sec) p value Note:
Values expressed as mean
±
SEM.
Key: PA F• Mean arterial pressure; ~P Ah change inmean arterial pressure; TPR. total peripheral resistance; ~ TPR. change intotal peripheral resistance.
In eight animals of this group (group A), after the experiments previously described were performed, the carotid sinus nerves were divided bilaterally to inhibit the baroreceptor reflexes of the carotid sinus and aortic arch, and the measurements were repeated. In the other six animals in group A, in the second part of the experiment the effects of nonpulsatile and pulsatile systemic perfusion were studied in animals with intact baroreceptors under the conditions of {3-blockadewith 600 to 1000 f.l.g propranolol (Dociton) and a-blockade with 2500 f.l.g phentolamine (Regitine). In five animals (group B) bilateral common carotid cannulation and proximal ligation was performed. The distal segments of the carotids underwent either pulsatile or non pulsatile perfusion whereas the systemic perfusion was kept nonpulsatile. For both pulsatile and nonpulsatile carotid perfusion a modified roller pump (Stockert-Shiley) was used. By means of an additional flow control system (PFC II 26-10-00, Stockert-Shiley) the rhythmic form of the pulsation with physiologic carotid pressure profiles could be achieved. The device could be triggered either by the animals' own electrocardiogram or by an built-in simulator. In three animals of group B with intact baroreceptors and nonpulsatile systemic perfusion, in the second part of examination the effects of nonpulsatile and pulsatile carotid perfusion were tested under conditions of a-blockade and {3-blockade.
Results The influence of pulsatile and nonpulsatile perfusion on the arterial blood pressure, the peripheral resistance, and the functions ofthe venous capacity system was examined in 28 dogs (group A) with intact pressor receptors. Table I shows that by switching the perfusion from nonpulsatile to pulsatile the mean arterial pressure dropped from 91 ± 3 mm Hg to 77 ± 2 mm Hg (p < 0.005). The peripheral vessel resistance dropped from 2235 ± 18 to 1812 ± 20 dyne· cm- 5 . sec (p < 0.001).
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Table II. Changes in venous blood volume after switching from nonpulsatile to pulsatile systemic perfusion and vice versa
llBV vcn (mljkg) p value
Nonpulsatile to pulsatile (n = 40)
nonpulsatile
Pulsatile to
-3.3 ± 0.4 <0.01
+3.9±0.5 <0.02
(n = 37)
Note: Values expressed as mean ± SEM.
Key: ~BV"n, Change in venous blood volume.
Table III. Estimation of mean filling (static) pressure after pulsatile and nonpulsatile systemic perfusion CVP(mmHg) Perfusion Nonpulsatile sve lye Pulsatile sve rye
Pump on
Pump off
5.0 ± 0.1 5.0 ± 0.1
2.7 ± 0.2 2.5 ± 0.3
5.0 ± 0.1 5.0 ± 0.1
4.0 ± 0.3 4.2 ± 0.2
Table IV. Influence of isolated bilateral carotid perfusion on changes in mean arterial pressure, peripheral resistance, and the venous blood volume after switching from nonpulsatile to pulsatile carotid perfusion (and vice versa) during nonpulsatile systemic perfusion Hemodynamic parameter P A F (rnm Hg) Before switch After switch llP A F (mm Hg) p Value
Nonpulsatile to pulsatile (n
= 5)
Pulsatile to nonpulsatile (n
= 5)
96 ± 9 79 ± 7 -17 ± 2 <0.05
83 ± 9 97 ± 4 14 ± I <0.02
TPR (dyne· cm" . sec) Before switch After switch llTPR (dyne· cm- 5 . sec) p value
2342 ± 24 1864 ± 13 -478 ± 15 <0.05
1804 ± 12 2272 ± 18 468 ± 14 <0.05
llBvvcn (mljkg) p value
-3.7 ± 0.3 <0.05
+4.5 ± 0.5 <0.05
Note: Values expressed as mean ± SEM.
Key: IVC, Inferior vena cava; SVC. superior vena cava.
Key: ~BV"n, Change in venous blood volume; PM, mean arterial pressure: ~P\F. change in mean arterial pressure; TPR. peripheral resistance; ~ TPR, change in peripheral resistance.
By switching from pulsatile to nonpulsatile perfusion the mean arterial pressure increased from 80 ± 3 mm Hg to 95 ± 4 mm Hg (p < 0,002). Thereby the peripheral resistance increased from 1784 ± 14 to 2215 ± 26 dyne. cm- 5 . sec (p < 0.001). Table II reviews of the changes in venous blood volume occurring with different modes of perfusion. By changing from nonpulsatile perfusion to pulsatile perfusion a statistically significant reduction in venous blood volume (3.3 ± 0.5 mljkg) and by changing from pulsatile perfusion to nonpulsatile perfusion a statistically significant increase in venous blood volume (3.9 ± 0.5 mljkg) occurs. After the pulsatile pump is turned off, the mean filling pressure changed only slightly, from 5.0 ± 0.1 to 4.0 ± 0.3 mm Hg in superior vena cava and to 4.2 ± 0.2 mm Hg in inferior vena cava (Table III). After the nonpulsatile pump was turned off, a fall in the mean filling pressure from 5.0 ± 0.1 mm Hg to 2.7 ± 0.2 mm Hg in superior vena cava and to 2.5 ± 0.3 mm Hg in inferior vena cava was observed. In five animals (group B) with intact carotid sinus nerves bilateral pulsatile and nonpulsatile carotid perfusion under nonpulsatile systemic perfusion was carried out. The average hemodynamic parameters observed in this experiment are summarized in Table IV. On changing from nonpulsatile to pulsatile carotid perfusion the
mean arterial pressure fell on average from 96 ± 9 mm Hg by 17 ± 2 mm Hg (p < 0.05). The total peripheral resistance decreased from 2342 ± 24 to 1864 ± 13 dyne. cm ? . sec (p < 0.05). The venous blood volume decreased by 3.7 ± 0.3 mljkg (p < 0.05). By switching from pulsatile to nonpulsatile carotid perfusion the mean arterial pressure increased from 83 ± 9 to 97 ± 4 mm Hg (p < 0.02). The peripheral resistance increased from 1804 ± 12 to 2272 ± 18 dyne. cm- 5 . sec (p < 0.05). The venous blood volume increased by 4.5 ± 0.05 mljkg (p < 0.05). The effects of pulsatile and nonpulsatile perfusion on the mean arterial pressure and the venous capacity system after simultaneous bilateral vagotomy and division of the carotid sinus nerves were investigated in eight animals. As seen in Table V, after division of the carotid sinus and the vagal nerves no significant increase or decrease in mean arterial pressure and venous blood volume could be observed by switching the arterial pump from pulsatile perfusion to nonpulsatile perfusion and vice versa. Also, after a-receptor and ,a-receptor blockade in animals with intact pressor receptors (n = 6), no significant changes in arterial blood pressure or venous blood volume occurred with perfusion mode alteration (Table VI). In the three animals (group B) with intact carotid sinus nerves, with bilateral nonpulsatile perfusion and pulsatile perfusion performed alternately during nonpulsatile sys-
Note: Values expressed as mean ± SEM.
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Response to pulsatile and nonpulsatile perfusion
Table V. The influence of pressor receptor denervation on changes in mean arterial pressure and venous blood volume after switching from nonpulsatile to pulsatile systemic perfusion and vice versa
PAF (rnrn Hg) Beforeswitch After switch £lPAF (rnm Hg) P value £lBV ven (rnl/kg) p value
Nonpulsatile to pulsatile (n = 8)
Pulsatile to nonpulsatile (n = 8)
84 ± 1.5 80 ± 0.2 -4 ± 2.3
81 ± 6.0 84 ± 3.4 +31.6
NS -0.24 ± 0.2
NS
NS
+0.55 ± OJ
NS
Note: Values expressed as mean ± SEM. Key: .1BV,co,Change in venous blood volume; NS, not significant; P A h mean arterial pressure; .1PAh change in mean arterial pressure.
temic perfusion, it was possible to show that the vasomotor reaction in both arterial and venous system can be inhibited by a-receptor and ,6-receptor blockade.
Discussion Experience with ECC in heart surgery to date indicates that in complex and extensive operations with prolonged ECC time the use of nonpulsatile systemic perfusion can lead to pulmonary and cerebral edema, poor diuresis, or heart failure. 28-31 In experimental studies it could be demonstrated that with nonpulsatile perfusion higher release of catecholamines, higher peripheral resistance, arterial pressure, and net fluid accumulation in extravascular space are observed as compared with pulsatile perfusion.32-37 It is generally accepted 2D-23 that the increase of peripheral resistance and arterial pressure with nonpulsatile perfusion reflects a-receptor- and ,6-receptor-mediated response of resistance peripheral vessels to increased circulating levelsof catecholamines and sympathetic tone. 7-9 On the basis of our previous studies.s 3\,38 we postulated that the increased tendency toward edema observed with nonpulsatile perfusion might reflect the response of the capacitive system to nonpulsatile perfusion due to increased circulating levels of catecholamines and sympathetic tone. Because the reaction of capacity vessels to increased sympathetic tone has been controversial'P'P it was the aim of the present study to test this hypothesis in an animal experiment. We focused our effort on analysis of the venous blood volume in response to different modes of systemic perfusion in animals with an intact carotid sinus and in animals with denervated carotid
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Table VI. Influence of a- and ,6-receptor blockade on changes in mean arterial pressure and venous blood volume after switching from nonpulsatile to pulsatile systemic perfusion and vice versa Nonpulsatile to pulsatile (n
= 6)
Pulsatile to nonpulsatile (n
= 6)
PAF (mm Hg) Before switch After switch £lPAF (mm Hg) p value
73 ± 4 67 ± 3 -6 ± 2
64 ± 6 68 ± 2 4 ± I
£lBVven (rnl/kg)
-0.05
+0.45
P value
NS NS
NS NS
Note: Values expressed as mean ± SEM. Key: tiBV von, Change in venous blood volume; NS, not significant; P Ah mean
arterial pressure;
~p AF,
change in mean arterial pressure.
sinuses and in animals being treated with a- and ,6-receptor blockers. In our animal model splenic and cardiopulmonary circulation were eliminated and the perfusion rate and CVP in both venae cavae were held constant. The changes in the intracorporeal blood volume were detected as weight changes of the oxygenator. To obtain the changes of venous blood volume, the changes in total intracorporeal blood volume were corrected for the volume changes in the arterial section of the circulation. Initially we studied the volume changes of the venous system in response to alternating perfusion modes in 28 dogs with intact pressor receptors. The data obtained in this study confirmed the findings of Levine et al.,36 Taylor et al.,37 and Philbin et al., 32 that when compared with pulsatile perfusion, nonpulsatile perfusion leads to a statistically significant rise in arterial mean pressure and total peripheral resistance (Table I) and showed moreover that by switching from pulsatile to nonpulsatile systemic perfusion the venous blood volume significantly increases (Table II) and thus indicated that not only resistance vessels but also the capacitive system are influenced by systemic nonpulsatile perfusion. Because Harrison et al. 39 demonstrated that the absence of a pressure pulse in carotid sinus leads to significant and considerable release of epinephrine at mean arterial pressures of about 80 mm Hg, we decided to test whether the response of the capacitive system to nonpulsatile perfusion observed in this study also has its origin in carotid sinus activity. For this, in fivedogs the common carotid arteries were cannulated and their proximal segments ligated, so that the carotid sinus could be perfused either pulsatile or nonpulsatile, whereas the systemic perfusion was held nonpulsatile. Also, under these conditions
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The Journal of Thoracic and Cardiovascular Surgery
Minami, Vyska, Korfer
~ _...."'"
- ----
----Arteriovenous anastomosis
True
capillaries
Precapillary
sphincters
CATECHOLAMINE LEVEL LOW
CATECHOLAMINE LEVEL HIGH (measured sympatic tone) non-pulsatile perfusion
,
(lower sympatic tone) non-pulsatile perfusion
~Sympatic ·~reaction
111
• • • •_ __
~ '1} lI"-"{);-"-
AV••n AVo" TPR GVP
Venous wall
~
"Jl--
Blood pressure
I I I I
Fig. 2. Proposed mechanism of carotid sinus-mediatedresponse of venous capacitive systemto nonpulsatile ECC. TPR, Total peripheral resistance; tl Voxy , change in oxygenator volume; tl Vveri- change in venous blood volume.
switching from pulsatile perfusion to nonpulsatile perfusion led to increase of mean arterial pressure and of peripheral resistance and to increase of systemic venous volume (Table IV). These experiments confirmed the involvement of the carotid sinus in regulation of the capacitive system. Further support for this conclusion was obtained in experiments in which either the carotid sinus pressor receptors were denervated or (\'- and {J-receptor blockade was used (Tables V and VI). These experiments indicated that with denervation of the carotid sinus or blockade of adrenergic receptors, by switching pulsatile to non pulsatile systemic perfusion and vice versa no venous volume changes can be observed and so demonstrated that intact carotid baroreceptors and intact venous adrenergic receptors are necessary for the reactive behavior of the venous capacitive system. If venous volume increase observed with nonpulsatile perfusion is analyzed in the light of the findings of Harrison and co-workers.'? Nakano and De Schryver.i? and
Ead and co-workers,"! which demonstrate that nonpulsatile perfusion leads to increase of sympathetic tone, one would expect that the carotid sinus-mediated increase of sympathetic tone would lead to venodilation. The venodilation, however, would be expected to lead to a reduction in the throttle effect in the venous capacitive system and so, at constant CVP, to reduction of the mean capillary pressure. This would lead to reduction of the filtration pressure in capillaries and thus to decreased tendency to edema formation. However, exactly the opposite was observed not only in our clinical studies" but also in animal experiments performed by Korfer and co-workers," who demonstrated in 24 mongrel dogs that the long-term nonpulsatile perfusion ECC leads to increase of myocardial edema (electron microscopic findings) with 40% increase in heart weight. Moreover, Nishigaki and colleagues'? demonstrated in rat experiments that not only in resistance vessels but also in capacitive system the increased sympathetic tone leads to vasoconstriction. To explain this apparent discrepancy, it had to be con-
Volume 104 Number 6 December 1992
sidered that in the venous section of circulation the vessel wall muscularization and the number of adrenergic receptors in the vessel walls increase in the downstream directions 9, 43 (Fig, 2). The more pronounced musculature and higher amount of adrenergic receptors in larger venules (venules of second and first order8, 9, 43) of the capacitive system led to a more pronounced response to increased sympathetic tone, that is, to more pronounced constriction of the downstream vessels and thus to the throttle effect at the end of capacitive segment. Because of this, the pressure in upstream section of venous circulation at constant CVP increases. The raised venous pressure in the upstream section ofvenous circulation not only counteracts the contractile effect of the sympathetic tone in this section but might overcome it and lead finally to an volume increase in the capacity system observed in this study. Because the raised venous pressure is expected to lead to increase of the capillary pressure and thus to a rise in filtration pressure, it becomes evident that this mechanism might also provide a plausible explanation for the tendency to edema formation with non pulsatile perfusion observed both in our previous study and in animal studies of Korfer 38 and thus resolve the apparent discrepancy, In discussing the reaction of the venous capacity system to different forms of perfusion, however, one should consider that, together with the described relationship of venous volume to pressor receptors, other mechanisms could playa role in the organism's response to nonpulsatile perfusion and pulsatile perfusion. For example, the effect of angiotensin is under discussion. German and co-workers' and Taylor and colleagues[' suggested that one cause for the raised peripheral resistance in nonpulsa tile systemic perfusion could lie in the activation of the renin angiotensin mechanism through increased release of angiotensin II by the kidney. How far the angiotensin or other mechanisms are involved in the response of the venous system is still unclear and remains for future studies to elicit. We are indebted to Prof. Dr. G. Arnold of the Institute of ExperimentalSurgery, Universityof Dusseldorf,for his support and valuable suggestions during the animal experiments. We thank Prof. Dr. H. de Marees of the Department of Sports Medicine,Universityof Bochum, for statistical evaluations and Dr. E. Murray for his help in preparing the English-language version of the manuscript. REFERENCES I. Wilkens H, Regelsen W, Hoffmeister FS. The physiologic importance of pulsatile blood flow. N Engl J Med 1962;267:443-6. 2. Mandelbaum I, Burns WHo Pulsatile and nonpulsatile blood flow. JAMA 1965;191:121-3.
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3. Jacobs LA, Klopp EH, Searmore W, Toparz SR, Gott VL. Improved organ function during cardiac bypass with roller pump modified to deliver pulsatile flow. Surgery 1969;58: 703-12. 4. Trinkle JK, Helton NE, Wood RE, Bryant WR. Metabolic comparison of a new pulsatile pump and a roller pump for cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1969;58: 562-9. 5. German JC, Chalmers GS, Hirai J, Mukherjee NO, Wakabayashi A, Connolly JE. Comparison of nonpulsatile and pulsatile extracorporeal circulation on renal tissue perfusion. Chest 1972;61:65-9. 6. Minami K, Korner MM, Vyska K, Kleesiek K, Knobl H, Korfer R. Effects of pulsatile perfusion on plasma catecholamine levels and hemodynamics during and after cardiac surgery using cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1990;99:82-91. 7. Lyons BV, Swaine CR. Effects of adrenergic blocking agents on response of rabbit arterial and venous strips to catecholamines. Proc Soc Exp Bioi Med 1970;133:1422-5. 8. Faber EJ. In situ analysis of o-adrenoceptors on arteriolar and venular smooth muscle in rat skeletal muscle microcirculation. Circ Res 1988;62:37-50. 9. Martin HW, Tolley KT, Saffitz EJ. Autoradiographic delineation of skeletal muscle a-I-adrenergic receptor distribution. Am J Physiol 1990;259: 1402-8. 10. Browse NL, Donald DL, Sheperd JT. Role of the veins in the carotid sinus reflex. Am J PhysioI1966;210:1424-34. II. Freis ED, Rose Jc. Sympathetic nervous system, vascular volume and venous return in relation to cardiovascular integration. Am J Med 1957;22:175-9. 12. Braunwald E, Ross J Jr, Kahler RL, Gaffney TE, Goldblatt A, Mason DT. Reflex control of the systemic venous bed: effects on venous tone of vasoactive drugs, and of baroreceptor and chemoreceptor stimulation. Circ Res 1963;12:539-49. 13. Schlepper M, Witzleb E. Der Einfluss einer veriinderten Pressorezeptorenerregung im Carotissinus auf den Tonus der Gefasse des Menschen. Pflugers Arch 1963;277:623-8. 14. Bartelstone HJ. Role of the veinsin venous return. Circ Res 1960;8: 1059-76. IS. Schmidt RM, Kumada M, Sagawa K. Cardiac output and total peripheral resistance in carotid sinus reflex. Am J PhysioI1971;221:480-5. 16. Muller-Ruchholtz ER, Losch HM, Grund E, Lochner W. Effect of beta adrenergic receptor stimulation on integrated systemic venous bed. Pflugers Arch 1977;370: 247-51. 17. Miiller-Ruchholtz ER, Losch HM, Grund E, Lochner W. Effect of alpha adrenergic receptor stimulation on integrated systemic venous bed. Pflugers Arch 1977;370: 241-6. 18. Alexander RS. The influence of constrictor drugs in the distensibilityof the splanchnic venous system, analyzed on the basis of an aortic model. Circ Res 1954;2:140-7. 19. Zimmerman BG. Sympathetic vasodilatation in the dog's paw. J Pharmacol Exp Ther 1966;152:81-7.
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20. Eckstein JW, Hamilton WK, McCammoud JM. Effect of isoproterenol on peripheral venous tone and transmural right atrial pressure in man. J Clin Invest 1959;38:342-6. 21. Hagemann K, Niehues B, Manoli SH, Arnold G, Lochner W. Ober die Wirkung von Isoprotenerol am Systemkreislauf des Hundes mit cardiopulmonalem Bypass. Z Kardi01 1974;63:542-8. 22. Folkow B, Mellander S. Veins and venous tone. Am Heart J 1964;68:397-408. 23. Sharpey-Schafer EP, Ginsburg J. Humoral agents and venous tone: effects of catecholamines, 5-hydroxytryptamine, histamine, and nitrites. Lancet 1962;2:1337-40. 24. Arnold G, Kosche F, Miessner E, Neitzert A, Lochner W. The importance of the perfusion pressure in the coronary arteries for the contractility and the oxygen consumption of the heart. Pflugers Arch 1968;299:339-43. 25. Miiller-Ruchholtz ER, Losch HM, Grund E, Lochner W. Beeinflussung des kapazitiv-venosen Systems des Kreislaufs durch Stimulation and Blockade der Betarezeptoren: ein Aspekt des Mechanismus der blutdrucksenkenden Wirkung von Betablockern. Herz Kreislauf 1977;9:790-4. 26. Remington JW, Hamilton WF. Quantitative calculation of the time course of cardiac ejection from the pressure pulse. Am J PhysioI1947;148:25-34. 27. Yang SS, BentivoglioLG, Maranhao V, Goldberg H. From cardiac catheterization data to hemodynamic parameters. 3rd ed. Philadelphia: FA Davis, 1988:26-8. 28. Glushien TM, Harris LC Jr. The effect of vasodilatation on metabolic and hemodynamic parameters during and after cardiopulmonary bypass. Anesthesiology 1967;28:985-9. 29. Kirklin JW, McGoon DC, Patrick RT, Theye RA. What is adequate perfusion? In: Allen TG, ed. Extracorporeal circulation. Springfield, Ill: Thomas, 1958;3:125-35. 30. Landymore R W, Murphy DA, Kinley E. Does pulsatile flow improve glucose tolerance during extracorporeal circulation. J Cardiovasc Surg 1981;22:239-44. 31. Korfer R, Steven W, Frenzel H, Arnold G, Bircks W. Pulsatile versus nonpulsatile coronary perfusion in the fibrillating canine heart. ESAO Proc 1980;I:34-8. 32. Philbin DM, Levine FH, Kong K, et al. Attenuation of stress response to cardiopulmonary bypass by the addition of pulsatile flow. Circulation 1981;64:808-12. 33. Minami K, Korner MM, Dramburg W, Miiller KW, Kor-
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
fer R. Pulsatile and nicht-pulsatile extrakorporale Zirkulation: Auswirkungen auf Plasmakatecholaminspiegel and Hamodynamik. J Cardiovasc Surg 1988:36(special issue 1):44. Minami K, Korner MM, Knobl H, Korfer R. Flussigkeitretention and peripherer Widerstand (TPR) bei nicht-pulsatile (NP) and pulsatiler Perfusion (PP). Z Kardiol I988;77(suppl 1):113. Minami K, Thompson T, Notohamiprodjo G, Korner MM, Korfer R. Einfluss der pulsatilen und nichtpulsatilen extrakorporalen Zirkulation auf Fliissigkeitretention nach aortocoronarer Bypassoperation. Z Kardiol 1990;83(suppl I): 131. Levine FH, Philbin DM, Kono K. Plasma vasopressin levels and urinary sodium excretion during cardiopulmonary bypass with and without pulsatile flow. Ann Thorac Surg 1981;32:63-7. Taylor KM, Bain WH, Russell M, Brannan JJ, Morten JJ. Peripheral vascular resistance: angiotensin II-levels during pulsatile and non-pulsatile cardiopulmonary bypass. Thorax 1979;34:594-8. Korfer R. Pulsatile und nicht pulsatile Koronarperfusion am flimmernden Herzen: ein Beitrag zur Myokardprotektion. Habilitationsschrift Universitat Diisseldorf, 1979, Diisseldorf, Germany. Harrison TS, Chawla RC, Seaton JF, Robinson BH. Carotid sinus origin of adrenergic responses compromising the effectiveness of artificial circulatory support. Surgery 1970;68:20-6. Nakano J, De Schryver C. Effect of changes in carotid sinus pulse pressure on catecholamine blood levels.Am J Physiol 1963;204:467-70. Ead HW, Green JH, Neil E. A comparison of the effects of pulsatile and nonpulsatile blood flow through the carotid sinus on the reflexogenic activity of the sinus baroreceptors in the cat. J Physiol (Lond) 1952;118:509-19. Nishigaki K, Faber JE, Ohyanagi M. Interactions between alpha-adrenoceptors and adenosine receptors on microvascular smooth muscle. Am J Physiol 1991;260:HI655H1665. Renkin EM. Control of microcirculation and blood-tissue exchange. In: Handbook of physiology; vol 4. Bethesda, Md: American Physiological Society, 1984:627-87.
Kazutomo Minami, MD," Karel Vyska, PhD,b and Reiner Korfer, MD," Bad Oeynhausen, Germany
~h
regard to the arterial circulation, the coronary perfusion, the microcirculation, and the lymph circulation, extracorporeal circulation (ECC) with pulsatile systemic perfusion was shown to be more favorable for the total organism and for individual organ systems than the ECC with nonpulsatile systemic perfusion.I? Moreover, the pulsatile perfusion was shown to reduce the accumulation of fluid in the lung and brain. Our previous clinical investigations" indicated that pulsatile perfusion when compared with nonpulsatile perfusion result in lower catecholamine release, lower From the Department of Thoracic and Cardiovascular Surgery" and Institute of Molecular Biophysics, Radiopharmacy and Nuclear Medicine," Bad Oeynhausen, Germany. Received for publication Feb. 21,1991. Accepted for publication Dec. 5, 1991. Address for reprints: Kazutomo Minami, MD, Department of Thoracic and Cardiovascular Surgery, Heart Center North Rhine- Westfalia, University of Bochum, Georgstrasse 11,4970 Bad Oeynhausen, Germany.
12/1/36298
mean arterial pressure, and a decreased tendency toward edema formation. On the basis of these data we postulated that the increased tendency toward edema formation by non pulsatile perfusion is due to the carotid sinus-mediated reaction of the venous capacity system to this type of perfusion. Whereas presently it is generally accepted that the control of the resistance vessels is mediated through adrenergic receptors."? the response of the venous system to adrenergic stimulation is still controversial.P'P The aim of this study was therefore to verify in an animal model the involvement of carotid sinus and adrenergic receptors in venous volume regulation during ECC.
Materials and methods The investigations were carried out on a total of 33 mongrel dogs, weighing between 21 and 36 kg (mean 26 ± 5 kg). The animals wereanesthetizedin the supine position with 40 mg/kg chloraloseand 250 rug/kg urethan. After relaxation with pancuronium bromide(Organori/Teknika, Munich, Germany) the dogswere intubated endotracheallyand ventilated with a Starling pump. To prevent counter regulation by the para-aortal pressor receptors bilaterally, the efferents of the vagal nerves
1639
The Journal of Thoracic and Cardiovascular
1 640 MiMm£ YySKa, /(o!ftl'
Surgery
Automatic clampsx..
Driving unit LPulsatile pump V.cava info Venous I cannula' Oxygenator
00 :0: 0000
~========~o~o
_======:::=J
A. femoralis Fig. 1. Schematic representation of experimental arrangement. (Modified from Miiller-Ruchholtz ER, Losch HM, Grund E, Lochner W. Beeinflussung des kapazitiv-venosen Systems des Kreislaufs durch Stimulation und Blockade der Betarezeptoren: Ein Aspekt des Mechanismus der blutdrucksenkenden Wirkund von Betablockern. Herz Kreislauf 1977;9:790-4.)
were divided below the carotid bifurcation, where they do not join the carotid baroreceptor afferents. Subsequently, splenectomy through an upper midline abdominal incision was performed to prevent splenic reservoir effects. After left lateral positioning of the animal, the heart was exposed by anterolateral thoracotomy through the fifth intercostal space. After anti-
coagulation with 400 Ujkg sodium heparin (Braun AG, Me1-
sungen, Germany), the venae cavae were cannulated through the right atrium and the venous blood was drained by gravity into a bubble oxygenator (Optiflow II Cobe) (Fig. 1). The blood was held normothermic by a heat exchanger (rectal temperature 37.2° to 37.8° C) and was pumped back into the ascending aorta with a roller or a pulsatile pump. The oxygenator was filled with I L of heparinized blood from a donor dog and I L of HAES plasma expander (Kabi AG, Erlangen, Germany). After the azygous vein and the pulmonary hili were ligated bilaterally, the ascending aorta and the pulmonary trunk were clamped. The hili were clamped to exclude the influence of the bronchial circulation. Minimal blood loss from the operation wounds was fed back to the oxygenator.
For systemic nonpulsatile perfusion a roller pump (StockertShiley Munich, Germany) and for systemic pulsatile perfusion a tube pump developed in cooperation with University of Aachen/" were used. With the pulsatile pump a maximal stroke volume of 120 ml and maximal pressure rise of 5000 mm Hg/sec could be achieved. The frequency and the duration of systole in relation to the total cycle duration were regulated to 90 beats/min and 40%,7 respectively. The cardiac output was measured by an electromagnetic flow meter and regulated throughout the whole experiment to a constant value determined with the help of Lochner's formula [Cardiac output (Lyrnin) = 3.5 x 0.112 Xf(kg)2].2s Base excess, pH, oxygen pressure (P02), carbon dioxide pressure, hemoglobin, and hematocrit, were kept constant by adding necessary amounts of sodium bicarbonate, by transfusion or by altering oxygen flow (pH 7.30 to 7.45, P0 2 > 100 mm Hg, carbon dioxide pressure 35 to 47 mm Hg, hemoglobin, 7.8 to 9.0 gm/dl; and hematocrit 30% to 38%). The depths of anesthesia and muscle relaxation in the animals were continually monitored.
Volume 104 Number 6 December 1992
The pressure in both venae cavae was regulated to 5 mm Hg with an automatic clamp for the superior vena cava and an automatic control system (modified from Muller-Ruchholz-") for the inferior vena cava (Fig. I). By a tendency of central venous pressure (CYP) to decrease or increase, the automatic clamp opened or closed and the automatic control system moved the oxygenator up or down, respectively. The use of automatic control system provided the possibility to determine the changes of blood volume in the capacitive system under conditions of constant CYP. Because the oxygenator was localized lower than the animal, the blood drained from the venous system by gravity. The downward movement of the oxygenator at the tendency of CYP to increase led to increased drainage and, because of the constant perfusion rate, to reduction of the intracorporeal blood volume and thus to maintenance of CYP at a constant level. At constant output of the pump transporting blood from the bottom of the oxygenator, the drained volume could be recognized as the increase of the blood volume in the oxygenator. The changes in the blood volume in the oxygenator were regarded to be reciprocal of the changes of intracorporeal volume. To estimate the drained venous blood volume, the changes of intracorporeal blood volume were corrected for the changes in the arterial blood volume according to the method of Remington and Hamilton.i" All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals," prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 80-23, revised 1978). To examine the influence of perfusion mode on the systemic circulation and especially on the venous capacity system, the systemic perfusion was alternated in 28 dogs (group A) with intact baroreceptors from pulsatile to nonpulsatile at intervals of 15 to 30 minutes. The pump was switched from one mode to the other after the arterial pressure, the cardiac output, and the oxygenator volume had achieved a steady state. The following parameters were registered continually with a multiple canal monitor device (Gould Brush Recorder, Gould, Inc., Cleveland, Ohio): systolic, diastolic, and mean arterial pressure; pressure in the superior and inferior venae cavae; the weight and the volume of the oxygenator; and cardiac output. Mean arterial pressure was determined automatically by a computer through integration of the pressure pulse and by use of the algorithm described by Yang et al. 27 The arterial blood pressure was measured in the left femoral artery with a Stratham P 23 ID Transducer (Gould, Inc., Cleveland, Ohio), the venous pressure in the superior and inferior caval veins with a Stratham P 23 BB Transducer. The transducer were connected to Cournand catheters inserted through the right femoral vein and the right external jugular vein. The tips of the two catheters were placed by direct palpation approximately 2 ern distal to the ends of the venous cannulas. In four animals in group A the venous pressure was recorded continually after the perfusion pump was turned off and the aorta and the superior and inferior venae cavae cannulas were clamped so that the intracorporeal volume could no longer change. The pressure fell continuously in each vena cava until it stabilized at a new value (usually I minute after circulatory arrest). This value was regarded as the mean filling (static) pressure.
Response to pulsatile and nonpulsatile perfusion
I 64 I
Table I. Changes in mean arterial pressure and total peripheral resistance after switching from nonpulsatile to pulsatile systemic perfusion and vice versa Hemodynamic parameter
Nonpulsatile to pulsatile (n = 40)
Pulsatile to nonpulsatile (n = 37)
91 ± 3 77 ± 2 -14 ± 2
80 ± 3 95 ± 4 15 ±2
<0.005
<0.002
2235 ± 18 1812 ± 20 -423 ± 10 <0.001
1784 ± 14 2215 ± 26 431 ± 10 <0.001
P AF (mm Hg)
Before switch After switch ~PAF (mm
Hg)
p value
TPR (dyne· cm" . sec) Before switch After switch ~TPR (dyne. cm" . sec) p value Note:
Values expressed as mean
±
SEM.
Key: PA F• Mean arterial pressure; ~P Ah change inmean arterial pressure; TPR. total peripheral resistance; ~ TPR. change intotal peripheral resistance.
In eight animals of this group (group A), after the experiments previously described were performed, the carotid sinus nerves were divided bilaterally to inhibit the baroreceptor reflexes of the carotid sinus and aortic arch, and the measurements were repeated. In the other six animals in group A, in the second part of the experiment the effects of nonpulsatile and pulsatile systemic perfusion were studied in animals with intact baroreceptors under the conditions of {3-blockadewith 600 to 1000 f.l.g propranolol (Dociton) and a-blockade with 2500 f.l.g phentolamine (Regitine). In five animals (group B) bilateral common carotid cannulation and proximal ligation was performed. The distal segments of the carotids underwent either pulsatile or non pulsatile perfusion whereas the systemic perfusion was kept nonpulsatile. For both pulsatile and nonpulsatile carotid perfusion a modified roller pump (Stockert-Shiley) was used. By means of an additional flow control system (PFC II 26-10-00, Stockert-Shiley) the rhythmic form of the pulsation with physiologic carotid pressure profiles could be achieved. The device could be triggered either by the animals' own electrocardiogram or by an built-in simulator. In three animals of group B with intact baroreceptors and nonpulsatile systemic perfusion, in the second part of examination the effects of nonpulsatile and pulsatile carotid perfusion were tested under conditions of a-blockade and {3-blockade.
Results The influence of pulsatile and nonpulsatile perfusion on the arterial blood pressure, the peripheral resistance, and the functions ofthe venous capacity system was examined in 28 dogs (group A) with intact pressor receptors. Table I shows that by switching the perfusion from nonpulsatile to pulsatile the mean arterial pressure dropped from 91 ± 3 mm Hg to 77 ± 2 mm Hg (p < 0.005). The peripheral vessel resistance dropped from 2235 ± 18 to 1812 ± 20 dyne· cm- 5 . sec (p < 0.001).
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Minami, Vyska, Korfer
Table II. Changes in venous blood volume after switching from nonpulsatile to pulsatile systemic perfusion and vice versa
llBV vcn (mljkg) p value
Nonpulsatile to pulsatile (n = 40)
nonpulsatile
Pulsatile to
-3.3 ± 0.4 <0.01
+3.9±0.5 <0.02
(n = 37)
Note: Values expressed as mean ± SEM.
Key: ~BV"n, Change in venous blood volume.
Table III. Estimation of mean filling (static) pressure after pulsatile and nonpulsatile systemic perfusion CVP(mmHg) Perfusion Nonpulsatile sve lye Pulsatile sve rye
Pump on
Pump off
5.0 ± 0.1 5.0 ± 0.1
2.7 ± 0.2 2.5 ± 0.3
5.0 ± 0.1 5.0 ± 0.1
4.0 ± 0.3 4.2 ± 0.2
Table IV. Influence of isolated bilateral carotid perfusion on changes in mean arterial pressure, peripheral resistance, and the venous blood volume after switching from nonpulsatile to pulsatile carotid perfusion (and vice versa) during nonpulsatile systemic perfusion Hemodynamic parameter P A F (rnm Hg) Before switch After switch llP A F (mm Hg) p Value
Nonpulsatile to pulsatile (n
= 5)
Pulsatile to nonpulsatile (n
= 5)
96 ± 9 79 ± 7 -17 ± 2 <0.05
83 ± 9 97 ± 4 14 ± I <0.02
TPR (dyne· cm" . sec) Before switch After switch llTPR (dyne· cm- 5 . sec) p value
2342 ± 24 1864 ± 13 -478 ± 15 <0.05
1804 ± 12 2272 ± 18 468 ± 14 <0.05
llBvvcn (mljkg) p value
-3.7 ± 0.3 <0.05
+4.5 ± 0.5 <0.05
Note: Values expressed as mean ± SEM.
Key: IVC, Inferior vena cava; SVC. superior vena cava.
Key: ~BV"n, Change in venous blood volume; PM, mean arterial pressure: ~P\F. change in mean arterial pressure; TPR. peripheral resistance; ~ TPR, change in peripheral resistance.
By switching from pulsatile to nonpulsatile perfusion the mean arterial pressure increased from 80 ± 3 mm Hg to 95 ± 4 mm Hg (p < 0,002). Thereby the peripheral resistance increased from 1784 ± 14 to 2215 ± 26 dyne. cm- 5 . sec (p < 0.001). Table II reviews of the changes in venous blood volume occurring with different modes of perfusion. By changing from nonpulsatile perfusion to pulsatile perfusion a statistically significant reduction in venous blood volume (3.3 ± 0.5 mljkg) and by changing from pulsatile perfusion to nonpulsatile perfusion a statistically significant increase in venous blood volume (3.9 ± 0.5 mljkg) occurs. After the pulsatile pump is turned off, the mean filling pressure changed only slightly, from 5.0 ± 0.1 to 4.0 ± 0.3 mm Hg in superior vena cava and to 4.2 ± 0.2 mm Hg in inferior vena cava (Table III). After the nonpulsatile pump was turned off, a fall in the mean filling pressure from 5.0 ± 0.1 mm Hg to 2.7 ± 0.2 mm Hg in superior vena cava and to 2.5 ± 0.3 mm Hg in inferior vena cava was observed. In five animals (group B) with intact carotid sinus nerves bilateral pulsatile and nonpulsatile carotid perfusion under nonpulsatile systemic perfusion was carried out. The average hemodynamic parameters observed in this experiment are summarized in Table IV. On changing from nonpulsatile to pulsatile carotid perfusion the
mean arterial pressure fell on average from 96 ± 9 mm Hg by 17 ± 2 mm Hg (p < 0.05). The total peripheral resistance decreased from 2342 ± 24 to 1864 ± 13 dyne. cm ? . sec (p < 0.05). The venous blood volume decreased by 3.7 ± 0.3 mljkg (p < 0.05). By switching from pulsatile to nonpulsatile carotid perfusion the mean arterial pressure increased from 83 ± 9 to 97 ± 4 mm Hg (p < 0.02). The peripheral resistance increased from 1804 ± 12 to 2272 ± 18 dyne. cm- 5 . sec (p < 0.05). The venous blood volume increased by 4.5 ± 0.05 mljkg (p < 0.05). The effects of pulsatile and nonpulsatile perfusion on the mean arterial pressure and the venous capacity system after simultaneous bilateral vagotomy and division of the carotid sinus nerves were investigated in eight animals. As seen in Table V, after division of the carotid sinus and the vagal nerves no significant increase or decrease in mean arterial pressure and venous blood volume could be observed by switching the arterial pump from pulsatile perfusion to nonpulsatile perfusion and vice versa. Also, after a-receptor and ,a-receptor blockade in animals with intact pressor receptors (n = 6), no significant changes in arterial blood pressure or venous blood volume occurred with perfusion mode alteration (Table VI). In the three animals (group B) with intact carotid sinus nerves, with bilateral nonpulsatile perfusion and pulsatile perfusion performed alternately during nonpulsatile sys-
Note: Values expressed as mean ± SEM.
Volume 104 Number 6 December 1992
Response to pulsatile and nonpulsatile perfusion
Table V. The influence of pressor receptor denervation on changes in mean arterial pressure and venous blood volume after switching from nonpulsatile to pulsatile systemic perfusion and vice versa
PAF (rnrn Hg) Beforeswitch After switch £lPAF (rnm Hg) P value £lBV ven (rnl/kg) p value
Nonpulsatile to pulsatile (n = 8)
Pulsatile to nonpulsatile (n = 8)
84 ± 1.5 80 ± 0.2 -4 ± 2.3
81 ± 6.0 84 ± 3.4 +31.6
NS -0.24 ± 0.2
NS
NS
+0.55 ± OJ
NS
Note: Values expressed as mean ± SEM. Key: .1BV,co,Change in venous blood volume; NS, not significant; P A h mean arterial pressure; .1PAh change in mean arterial pressure.
temic perfusion, it was possible to show that the vasomotor reaction in both arterial and venous system can be inhibited by a-receptor and ,6-receptor blockade.
Discussion Experience with ECC in heart surgery to date indicates that in complex and extensive operations with prolonged ECC time the use of nonpulsatile systemic perfusion can lead to pulmonary and cerebral edema, poor diuresis, or heart failure. 28-31 In experimental studies it could be demonstrated that with nonpulsatile perfusion higher release of catecholamines, higher peripheral resistance, arterial pressure, and net fluid accumulation in extravascular space are observed as compared with pulsatile perfusion.32-37 It is generally accepted 2D-23 that the increase of peripheral resistance and arterial pressure with nonpulsatile perfusion reflects a-receptor- and ,6-receptor-mediated response of resistance peripheral vessels to increased circulating levelsof catecholamines and sympathetic tone. 7-9 On the basis of our previous studies.s 3\,38 we postulated that the increased tendency toward edema observed with nonpulsatile perfusion might reflect the response of the capacitive system to nonpulsatile perfusion due to increased circulating levels of catecholamines and sympathetic tone. Because the reaction of capacity vessels to increased sympathetic tone has been controversial'P'P it was the aim of the present study to test this hypothesis in an animal experiment. We focused our effort on analysis of the venous blood volume in response to different modes of systemic perfusion in animals with an intact carotid sinus and in animals with denervated carotid
I 643
Table VI. Influence of a- and ,6-receptor blockade on changes in mean arterial pressure and venous blood volume after switching from nonpulsatile to pulsatile systemic perfusion and vice versa Nonpulsatile to pulsatile (n
= 6)
Pulsatile to nonpulsatile (n
= 6)
PAF (mm Hg) Before switch After switch £lPAF (mm Hg) p value
73 ± 4 67 ± 3 -6 ± 2
64 ± 6 68 ± 2 4 ± I
£lBVven (rnl/kg)
-0.05
+0.45
P value
NS NS
NS NS
Note: Values expressed as mean ± SEM. Key: tiBV von, Change in venous blood volume; NS, not significant; P Ah mean
arterial pressure;
~p AF,
change in mean arterial pressure.
sinuses and in animals being treated with a- and ,6-receptor blockers. In our animal model splenic and cardiopulmonary circulation were eliminated and the perfusion rate and CVP in both venae cavae were held constant. The changes in the intracorporeal blood volume were detected as weight changes of the oxygenator. To obtain the changes of venous blood volume, the changes in total intracorporeal blood volume were corrected for the volume changes in the arterial section of the circulation. Initially we studied the volume changes of the venous system in response to alternating perfusion modes in 28 dogs with intact pressor receptors. The data obtained in this study confirmed the findings of Levine et al.,36 Taylor et al.,37 and Philbin et al., 32 that when compared with pulsatile perfusion, nonpulsatile perfusion leads to a statistically significant rise in arterial mean pressure and total peripheral resistance (Table I) and showed moreover that by switching from pulsatile to nonpulsatile systemic perfusion the venous blood volume significantly increases (Table II) and thus indicated that not only resistance vessels but also the capacitive system are influenced by systemic nonpulsatile perfusion. Because Harrison et al. 39 demonstrated that the absence of a pressure pulse in carotid sinus leads to significant and considerable release of epinephrine at mean arterial pressures of about 80 mm Hg, we decided to test whether the response of the capacitive system to nonpulsatile perfusion observed in this study also has its origin in carotid sinus activity. For this, in fivedogs the common carotid arteries were cannulated and their proximal segments ligated, so that the carotid sinus could be perfused either pulsatile or nonpulsatile, whereas the systemic perfusion was held nonpulsatile. Also, under these conditions
I 644
The Journal of Thoracic and Cardiovascular Surgery
Minami, Vyska, Korfer
~ _...."'"
- ----
----Arteriovenous anastomosis
True
capillaries
Precapillary
sphincters
CATECHOLAMINE LEVEL LOW
CATECHOLAMINE LEVEL HIGH (measured sympatic tone) non-pulsatile perfusion
,
(lower sympatic tone) non-pulsatile perfusion
~Sympatic ·~reaction
111
• • • •_ __
~ '1} lI"-"{);-"-
AV••n AVo" TPR GVP
Venous wall
~
"Jl--
Blood pressure
I I I I
Fig. 2. Proposed mechanism of carotid sinus-mediatedresponse of venous capacitive systemto nonpulsatile ECC. TPR, Total peripheral resistance; tl Voxy , change in oxygenator volume; tl Vveri- change in venous blood volume.
switching from pulsatile perfusion to nonpulsatile perfusion led to increase of mean arterial pressure and of peripheral resistance and to increase of systemic venous volume (Table IV). These experiments confirmed the involvement of the carotid sinus in regulation of the capacitive system. Further support for this conclusion was obtained in experiments in which either the carotid sinus pressor receptors were denervated or (\'- and {J-receptor blockade was used (Tables V and VI). These experiments indicated that with denervation of the carotid sinus or blockade of adrenergic receptors, by switching pulsatile to non pulsatile systemic perfusion and vice versa no venous volume changes can be observed and so demonstrated that intact carotid baroreceptors and intact venous adrenergic receptors are necessary for the reactive behavior of the venous capacitive system. If venous volume increase observed with nonpulsatile perfusion is analyzed in the light of the findings of Harrison and co-workers.'? Nakano and De Schryver.i? and
Ead and co-workers,"! which demonstrate that nonpulsatile perfusion leads to increase of sympathetic tone, one would expect that the carotid sinus-mediated increase of sympathetic tone would lead to venodilation. The venodilation, however, would be expected to lead to a reduction in the throttle effect in the venous capacitive system and so, at constant CVP, to reduction of the mean capillary pressure. This would lead to reduction of the filtration pressure in capillaries and thus to decreased tendency to edema formation. However, exactly the opposite was observed not only in our clinical studies" but also in animal experiments performed by Korfer and co-workers," who demonstrated in 24 mongrel dogs that the long-term nonpulsatile perfusion ECC leads to increase of myocardial edema (electron microscopic findings) with 40% increase in heart weight. Moreover, Nishigaki and colleagues'? demonstrated in rat experiments that not only in resistance vessels but also in capacitive system the increased sympathetic tone leads to vasoconstriction. To explain this apparent discrepancy, it had to be con-
Volume 104 Number 6 December 1992
sidered that in the venous section of circulation the vessel wall muscularization and the number of adrenergic receptors in the vessel walls increase in the downstream directions 9, 43 (Fig, 2). The more pronounced musculature and higher amount of adrenergic receptors in larger venules (venules of second and first order8, 9, 43) of the capacitive system led to a more pronounced response to increased sympathetic tone, that is, to more pronounced constriction of the downstream vessels and thus to the throttle effect at the end of capacitive segment. Because of this, the pressure in upstream section of venous circulation at constant CVP increases. The raised venous pressure in the upstream section ofvenous circulation not only counteracts the contractile effect of the sympathetic tone in this section but might overcome it and lead finally to an volume increase in the capacity system observed in this study. Because the raised venous pressure is expected to lead to increase of the capillary pressure and thus to a rise in filtration pressure, it becomes evident that this mechanism might also provide a plausible explanation for the tendency to edema formation with non pulsatile perfusion observed both in our previous study and in animal studies of Korfer 38 and thus resolve the apparent discrepancy, In discussing the reaction of the venous capacity system to different forms of perfusion, however, one should consider that, together with the described relationship of venous volume to pressor receptors, other mechanisms could playa role in the organism's response to nonpulsatile perfusion and pulsatile perfusion. For example, the effect of angiotensin is under discussion. German and co-workers' and Taylor and colleagues[' suggested that one cause for the raised peripheral resistance in nonpulsa tile systemic perfusion could lie in the activation of the renin angiotensin mechanism through increased release of angiotensin II by the kidney. How far the angiotensin or other mechanisms are involved in the response of the venous system is still unclear and remains for future studies to elicit. We are indebted to Prof. Dr. G. Arnold of the Institute of ExperimentalSurgery, Universityof Dusseldorf,for his support and valuable suggestions during the animal experiments. We thank Prof. Dr. H. de Marees of the Department of Sports Medicine,Universityof Bochum, for statistical evaluations and Dr. E. Murray for his help in preparing the English-language version of the manuscript. REFERENCES I. Wilkens H, Regelsen W, Hoffmeister FS. The physiologic importance of pulsatile blood flow. N Engl J Med 1962;267:443-6. 2. Mandelbaum I, Burns WHo Pulsatile and nonpulsatile blood flow. JAMA 1965;191:121-3.
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