CURRENT REVIEW

Release of Vasoactive Substances During Cardiopulmonary Bypass Stephen W. Downing, MD, and L. Henry Edmunds, Jr, MD Division of Cardiothoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Cardiopulmonary bypass is associated with bleeding and thrombotic complications, massive fluid shifts, and cellular and hormonal defense reactions that are collectively termed "the whole body inflammatory response." A host of vasoactive substances are produced, released or altered during cardiopulmonary bypass. These hormones, autacoids, and cytokines react with specific receptor proteins distributed throughout the body, and mediate

the vascular smooth muscle and endothelial cell contractions that are responsible for much of the morbidity associated with open heart operations. This essay briefly reviews the actions, sources, and perturbations of the approximately 25 vasoactive substances known or believed to be altered by cardiopulmonary bypass, and provides an introductory reference list. (Ann Thorac Surg 1992;54:123643)

C

Sympathetic Amines

ardiopulmonary bypass (CPB) exposes blood to large areas of synthetic materials and triggers the production and release of numerous vasoactive substances from cellular deposits and whole organs. These vasoactive substances affect local and systemic vascular resistance, vascular permeability, fluid balance, and myocardial contractile force and contribute to the "whole body inflammatory response" associated with CPB [l].Rapid development of new immunochemical assays and heightened interest in the pathophysiology of CPB have accelerated discoveries of vasoactive compounds altered by CPB. Many of these changes are well documented; others await documentation but are likely based on circumstantial evidence. This essay offers a brief but necessarily temporal review of this rapidly unfolding subject. Hormones, autacoids, and cytokines are the mediators of endothelial cell and vascular smooth muscle contraction [2]. As far as we know, CPB does not activate lymphocytes or production of immunoglobulins [3]. Hormones, produced by specialized organs and cells, and plasma autacoids circulate; other autacoids and cytokines normally are local mediators of inflammation. Cytokines, platelet activating factor, and the eicosanoids are nonantibody peptides or phospholipids that are produced in response to specific agonists by cells that circulate (eg, white blood cells) or that are nearly ubiquitous (eg, endothelial cells). Hormones, autacoids, and cytokines all act on specific receptor proteins distributed on different cells throughout the body. Thus when CPB simultaneously and vigorously stimulates the production and release of a host of vasoactive substances, a massive whole body inflammatory response is initiated (Table 1).

Address reprint requests to Dr Edmunds, Department of Surgery, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104.

0 1992 by The Society of Thoracic Surgeons

Epinephrine, norepinephrine, and dopamine are endogenous catecholamines with powerful vasoactive properties [2]. Epinephrine, produced in the adrenal medulla, is primarily a p-agonist and increases heart rate, contractile force, and cardiac output. Epinephrine also increases blood pressure and skeletal muscle blood flow but decreases renal and skin flow. Norepinephrine is primarily an a-agonist and is produced and released from sympathetic nerve terminals. Norepinephrine can increase stroke volume but also increases peripheral vascular resistance and blood pressure so that cardiac output is usually not increased. Dopamine is also produced in the adrenal medulla, and has primarily Padrenergic effects at low concentrations and a-adrenergic effects at high concentrations. Dopamine also stimulates D1 receptors to increase renal and mesenteric blood flow. Cardiopulmonary bypass does not alter plasma concentrations of dopamine [4]. Anesthesia and operation raise epinephrine and norepinephrine concentrations. With CPB, the plasma epinephrine level progressively increases from 150 to 600 pg/mL [3, 41. The norepinephrine level increases from 200 to 700 pg/mL [4-61. With reperfusion of the lungs, epinephrine and norepinephrine concentrations decrease [6] but do not return to normal concentrations for 24 hours. Deep hypothermia with circulatory arrest produces even greater concentrations of sympathetic amines, with the highest levels reached during rewarming (mean epinephrine level, 3,724 pg/mL; norepinephrine, 4,543 pg/mL) [7]. Renin, Angiotensin, a n d Aldosterone Renin is released from the juxtaglomerular cells in the renal cortex in response to changes in renal perfusion pressure, preceptor stimulation, and tubular sodium content. Renin converts angiotensinogen into angiotensin I, which is converted in the lungs to vasoactive angioten0003-4975/92/$5.00

REVIEW DOWNING AND EDMUNDS VASOACTIVE SUBSTANCES DURING BYPASS

Ann Thorac Surg 1992;s:1236-43

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Table 1. Vasoactive Substances Released During Cardiopulmona y Bypass Substance

Primary Source

Epinephrine

Adrenal medulla

Norepinephrine

Sympathetic nerves Adrenal medulla

Dopamine Renin

Vasoactive Effects HR, inotrope, t muscle blood flow, 1 renal and skin blood flow t SV, SVR, BP

t

Dose-dependent a and p effects, t renal and mesenteric blood flow Converts angiotensinogen to angiotensin I

Aldosterone

Juxta lomerular celE in renal cortex Lungs (via converting angiotensin I) Adrenal cortex

Vasopressin

Posterior pituitary

t sodium and fluid retention t water and sodium

Atrial natriuretic factor Brad ykinin

Atria

t

Angiotensin I1

Thyroxine

Blood; hi h molecuyaiweight kininogen Thyroid

Triiodothyronine Glucagon

Thyroid Pancreas

Potent vasoconstrictor, aldosterone release

sodium excretion, 1 aldosterone, vasodilator Vasodilator, T capillary permeability Converted to triiodothyronine 1 SVR, t H R a n d C O Inotrope Inotrope

Calcium

Arrythmias

Magnesium C3a

Blood; complement

C4a, C5a

Blood; complement, leukocytes Leukocytes, mesangial cells, endothelium

Platelet activating factor Prostaglandin E, Prostaglandin I, (prostacyclin) Thromboxane A, Leukotrienes LTB4, LTC4, LTD4 Endothelin-1 Nitric oxide Serotonin

Lung Endothelium Platelets WBCs Endothelium Endothelium, leukocytes Platelets

Free 0, radicals, ly sosomal enzymes, proteases Interleukin-1

Leukocytes

Histamine

Mast cells, basophils

During CPB.

Monocytes

t

4-7

t t

t

P 7

++

t

or

c-)

or

4, 8-10

Release decreased by pblockers and hypothermia

or

++

or

11-13

See text

14, 15

Affected by potassium levels

13, 15-18

Vasoconstriction and aradoxical diuresis seen at figher levels Correlation with atrial pressure lost for 24 hours Cleared by pulmonary converting enzymes

-

t

or

or

t 1 t t

-

tr

vascular permeability, hypotension, t HR, coronary vasoconstriction, 4 contractility t vascular permeability, hypo tension

or

t f

15, 19, 20

t

20-23

c-)

or

t 1 t or t t

T

Refers to free fraction only

or

cf

29, 30

Plasma concentration varies during CPB As above

c)

29, 30

As above

31-36

Effects mediated by activation of leukocytes

31-36

As above

37, 38

Also stimulates thromboxane, leukotrienes, platelet factor 4, IL-I, proteases, and superoxide radicals Also metabolized in lung Short half-life in plasma

or

Vasodilation Vasodilation and platelet inhibition Vasoconstriction Vasocontriction, t capillary permeability, corona vasoconstriction, J Vasoconstriction

t t t t t t

t

++

2, 38 2, 38, 39

c,

3740 2, 39-44

Short half-life in plasma Change durin CPB not documentec f

45-47

10-fold more potent than angiotensin I1 Change durin CPB not documentec f Serotonin formed in gut and carried by platelets Significant accumulation in and damage to lungs

t

t t

45, 48, 49

Vasodilation

Inflammatory mediator, 1 SVR, t permeability t capillary permeability, small vessel dilation

24-27 28 29, 30

t t

Vasoconstriction, t BP, HR, contractility t vascular permeability endothelial damage

Refers to free fraction only

c,

L

t,1 or t ! .1 t t t t

c-)

2627

or

Platelet and leukocyte aggregation, vasodilation, t vascular permeability

ZFR

1'

c*

t t t

cf

t

c)

++

1'

c-)

or

t t T

c-)

t

Drops with lung reperfusion, highest levels seen with deep hypothermia

4

c)

c-)

c-)

contractility, arrhythmias

Potassium

t t

t t t t t

resorption

Comments

Early" Lateb References

cf

t

or

t t

2, 45, 5053 2, 5, 34, 35, 5461 48 62, 63

For up to 24 hours after CPB

BP = blood pressure; CO = cardiac output; CPB = cardiopulmonary bypass; GFR = glomerular filtration rate; interleukin-1; SV = stroke volume; SVR = systemic vascular resistance; WBCs = white blood cells; t increased; ++ = no change; 1 = decreased.

=

HR = heart rate; IL-1 = increased; t = slightly

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REVIEW DOWNING AND EDMUNDS VASOACTIVE SUBSTANCES DURING BYPASS

sin I1 by angiotensin converting enzyme [2]. Angiotensin I1 is a potent vasoconstrictor, stimulates aldosterone secretion, and increases sympathetic activity. The renin level remains unchanged [4, 8-10] or increases only slightly during and after CPB [ll, 14, 641. Both @-blockers and hypothermia decrease renin release [ll, 651. Although Taylor and associates [12, 66, 671 have shown an increase in angiotensin I1 from 50 to around 250 pg/mL during CPB, others have shown no increase or a net decrease [ 11, 141 unless significant hypotension is artificially induced [13]. These discrepant observations are probably due to variable renin release, pulmonary blood flow, and angiotensin converting enzyme activity during CPB. Systemic concentrations of angiotensin converting enzyme decrease by one-third during CPB [68]. The level of aldosterone, which technically is not vasoactive, increases from approximately 5 to 18 ng/dL during CPB and returns to normal by 3 hours postoperatively [14, 151. The aldosterone level is also influenced by potassium levels.

Vasopressin Vasopressin (antidiuretic hormone) is released from the posterior pituitary primarily in response to changes in serum osmolality [2]. Release is also affected by changes in blood volume, blood pressure, pain, and visceral stimulation. Vasopressin increases water absorption in distal renal collecting tubules, and to a lesser extent alters sodium resorption. Cardiopulmonary bypass increases the concentration of vasopressin from approximately 2 pg/mL to a range of 16 to 80 pg/mL within the first 10 to 30 minutes [13, 15-18]. These concentrations diminish slightly over time, then drop more sharply with cessation of CPB [13, 171. Postoperative measurements conflict; some show a return to baseline vasopressin levels [15], and others show a second substantial increase in the first few hours [13, 171. At the supraphysiologic concentrations (>15 pg/mL) reached during CPB, vasopressin has a paradoxical diuretic effect [65] and also becomes a potent systemic and coronary vasoconstrictor [16]. Elevations in vasopressin levels correlate with decreases in blood pressure during CPB [18].

Atrial Natriuretic Factor This small peptide is released from the atrium in response to distention and stimulates renal excretion of sodium, inhibits aldosterone release, and dilates vascular smooth muscle [2]. Despite atrial manipulations, the level of plasma atrial natriuretic factor decreases with CPB [19] or increases slightly after correction for dilution [15, 201. Secretion of atrial natriuretic factor decreases with hypothermia and increases with rewarming [19]. Postoperatively, atrial natriuretic factor levels increase from a range of 40 to 150 pg/mL to a range of 78 to 350 pg/mL but correlate poorly with atrial pressure for at least 24 hours [15, 19, 201.

Ann Thorac Surg 1992;54:123&43

tivation of the contact system. In vitro the contact system is also activated by cold [21]. Bradykinin is a classic inflammatory mediator; it is a powerful vasodilator, increases capillary permability, and participates in local hyperemia. It has a half-life of 18 to 24 seconds [22] and is degraded by pulmonary converting enzymes [21-231. Angiotensin converting enzyme, which is located on the outer surface of endothelial cells, inactivates bradykinin in peripheral tissues. The bradykinin level is elevated by simple surface cooling of infants from 1.1 to 2.1 ng/mL [21]. During CPB, which activates the contact system and excludes the lungs, the bradykinin level progressively increases to between 5 and 10 ng/mL [2C-221, and the kininogen level drops reciprocally from 7 to 3 pg/mL [23]. Bradykinin levels return to near normal shortly after bypass stops.

Thyroid Hormones The thyroid gland secretes both thyroxine and triiodothyronine (TJ. Both hormones are active, but most plasma thyroxine is converted to T, in peripheral tissues [2]. Triiodothyronine binds to the cell nucleus, mitochondria, certain cytosolic proteins, and probably also cell membrane [24]. The complex reactions of this hormone are not completely understood. Triiodothyronine increases adenosine triphosphate production by mitochondria and increases metabolic rate and heat production. Triiodothyronine reduces systemic vascular resistance and increases heart rate. Cardiac output increases, but it is not clear that T, has a direct inotropic effect on the heart or whether it works indirectly by reducing afterload. There is evidence that T, affects calcium flux at the myocyte cell membrane. The late effects of T, are primarily due to alterations in DNA transcription and increased synthesis of protein and cytosolic messenger RNA. During and after CPB, the total thyroxine level decreases slightly but remains within the normal range [2527]. The free thyroxine level does not change [26] or increases slightly [25]. The total T, level decreases significantly soon after CPB starts [25-271 and falls near [25, 271 or below [26] normal limits. The free T, level decreases at the beginning of bypass [25, 261, and after bypass ends it falls below normal values for at least 24 hours [26]. The level of plasma thyroid stimulating hormone changes during and after bypass, but the changes vary between studies [25-271 and all remain within the normal range.

Glucagon Glucagon, in addition to its role in glucose metabolism, is a stress hormone and cardiac inotrope [69]. The hormone can increase intracellular cyclic 3',5' adenosine monophosphate levels, even in the presence of p-blockade. During CPB, the glucagon level increases from approximately 100 to 200 pg/mL, and it remains elevated for more than 48 hours after operation [28].

Bradykinin

Electrolytes

This small vasoactive peptide is produced by cleavage of high-molecular-weight kininogen by kallikrein during ac-

Bypass also alters plasma electrolytes, and potassium, calcium, and magnesium have cardiovascular effects. Po-

Ann Thorac Surg 1992;54:123643

tassium is a negative inotrope and has an indirect effect on intracellular calcium [2]. Calcium is a positive inotrope and a weak vasoconstrictor. Magnesium antagonizes some actions of calcium [29]. Many variables alter plasma electrolyte levels during CPB. Levels of potassium and to a lesser extent calcium are monitored carefully during and after CPB and both are maintained within the normal range. Hyperkalemia is aggressively treated by diuretics, bicarbonate, insulin, and glucose and occasionally dialysis during CPB. Magnesium is sometimes added to cardioplegic solutions to minimize deleterious effects of intracellular calcium. The plasma magnesium level generally decreases during and after bypass [30], and deficiency may contribute to difficult ventricular arrhythmias.

Complement The interaction of blood and the synthetic surfaces of the perfusion circuit activates factor XI1 (Hageman factor) and the contact activation system. This system contains four primary proteins: factor XII, factor XI, prekallikrein, and high-molecular-weight kininogen. Activation of factor XI initiates the coagulation cascade; cleavage of highmolecular-weight kininogen by kallikrein produces bradykinin. Cleavage of plasminogen by kallikrein (weakly) and tissue plasminogen activator, which is produced by endothelial cells, produces the fibrinolytic enzyme plasmin. Activation of the contact system also activates the first component of complement, C1, by formation of activated factor XI1 fragments, XIIa and XIIf. Activation of the complement cascade via either the classic or alternative pathways (there is evidence that both pathways are activated during cardiopulmonary bypass) leads to formation of C3a, C4a, and C5a. These complement fragments are anaphylatoxins that increase vascular permeability, release histamine from mast cells, and cause hypotension and contraction of airway smooth muscle [31, 321. C3a also causes cardiac dysfunction manifested by tachycardia, coronary vasoconstriction, and reduced contractility [33]. These actions occur at physiologic concentrations of C3a and are probably mediated by release of leukotrienes, histamine, and platelet activating factor [33]. C5a rapidly binds to white blood cells [34], and measurements vary during cardiopulmonary bypass [34-361. Plasma C3a concentrations increase progressively during bypass [34] and remain elevated more than 3 hours after bypass before decreasing to normal levels within 10 to 12 hours [36]. Plasma C4a concentrations do not increase during CPB but increase significantly immediately afterward [35].

Platelet Activating Factor Platelet activating factor is a phospholipid autacoid produced by neutrophils, monocytes, eosinophils, mast cells, glomerular mesangial cells, and endothelial cells [2, 701 but not platelets in response to various stimuli including thrombin, complement, vasopressin, angiotensin 11, bradykinin, leukotrienes, adenosine triphosphate, and cardiopulmonary bypass [36, 701. The primary action of platelet activating factor appears to be amplification of

REVIEW DOWNING AND EDMUNDS VASOACTIVE SUBSTANCES DURING BYPASS

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platelet and leukocyte responses during thrombosis, shock, anaphylaxis, and local inflammation. Platelet activating factor stimulates platelet and leukocyte aggregation and release, is a potent vasodilator, and increases vascular permeability [2, 701. Platelet activating factor stimulates thromboxane, leukotriene and interleukin-1 production and release of platelet factor 4, superoxide radicals, and various proteases and cytokines [70]. Platelet activating factor binds to specific cellular receptors and is metabolized by cellular membrane and cytosolic enzymes more slowly than most other autacoids [70]. In 7 patients, CPB increased platelet activating factor threefold to fourfold 24 hours after operation [37].

Eicosanoids The eicosanoids are autacoids that can be produced by nearly every mammalian cell in response to stimulation but are not stored [2]. Normally, these compounds do not circulate, but act locally at or near their sites of production. This family of vasoactive phospholipids is derived from arachidonic acid, which is metabolized by either cyclooxygenase, which produces the prostanoids and is irreversibly inhibited by aspirin, or lipooxygenase, which produces the leukotrienes (LTs) [2]. The most important prostanoids are prostaglandin E, (PGE,), PGI, (prostacyclin), and thromboxane A,. The most important leukotrienes are LTB,, LTC,, and LTD,. Prostaglandin E, is primarily produced and metabolized in the lung [2] and is a powerful vasodilator that acts on arterioles and precapillary and postcapillary sphincters. The level of prostaglandin E, increases abruptly when CPB starts and decreases quickly when bypass ends [381. Prostacyclin is primarily produced by endothelial cells and is not normally produced by platelets [2]. Prostacyclin is also a vasodilator and is approximately 5 times more potent than PGE,. Prostacyclin is also a potent inhibitor of platelet aggregation. This autacoid has a short half-life in plasma (

Release of vasoactive substances during cardiopulmonary bypass.

Cardiopulmonary bypass is associated with bleeding and thrombotic complications, massive fluid shifts, and cellular and hormonal defense reactions tha...
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