Vasomotor dysfunction after cardiac surgery

Review

Vasomotor dysfunction after cardiac surgery

Marc Ruela,b,1, Tanveer A. Khana,1, Pierre Voisinea,1, Cesario Bianchia,1, Frank W. Sellkea,*,1

aDivision of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USAbDivision of Cardiac Surgery, University of Ottawa, Ottawa, Ontario, Canada

Received 24 February 2004; received in revised form 28 June 2004; accepted 23 July 2004; Available online 1 September 2004

Summary

Cardiopulmonary bypass and cardioplegic arrest, which allow for support of the circulation and stabilization of the heart during cardiac

procedures, are still used for the vast majority of cardiac operations worldwide. However, in addition to a well-recognized systemic

inflammatory response, cardiopulmonary bypass and cardioplegic arrest elicit complex, multifactorial vasomotor disturbances that vary

according to the affected organ bed, with reduced vascular resistances in the skeletal muscle and peripheral circulation, and increased

propensity to spasm in the cardiac, pulmonary, mesenteric and cerebral vascular beds. This article outlines the nature, mechanistic basis, and

clinical correlates of the vasomotor alterations encountered in patients undergoing cardiac surgery using cardiopulmonary bypass and

cardioplegic arrest.

q 2004 Elsevier B.V. All rights reserved.

Keywords: Cardioplegia; Cardiopulmonary bypass; Endothelial function; Vascular tone

1. Introduction

Continued improvements in cardiopulmonary bypass

(CPB) and myocardial protection techniques over the last

four decades have made cardiac surgical procedures feasible

and safe for the vast majority of patients. Nevertheless,

modern CPB and cardioplegic arrest techniques remain

associated with an acute transcriptional response of

hundreds of genes that primarily affects the largest organ

of the body, the endothelium, as well as other constituents of

blood vessels [1]. The resultant vasomotor disturbances may

clinically manifest as reduced peripheral vascular resist-

ances in the skeletal muscle bed and, conversely, increased

propensity to spasm in the coronary, pulmonary, mesenteric,

and cerebral circulations. Abnormal vascular permeability

and secondary tissue edema may in turn contribute to

malperfusion and dysfunction of the heart, lungs, brain,

kidneys, gastrointestinal tract, and other organs [2–5]. These

phenomena are most striking after cardiac operations for

1010-7940/$ - see front matter q 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.ejcts.2004.07.040

* Corresponding author. Tel.: C1-617-632-8385; fax: C1-617-632-

8287.

E-mail address: [email protected] (F.W. Sellke).1The authors have no relationship to disclose pertaining to this research.

patients in cardiogenic shock [6,7] or in patients for whom

CPB support of more than 80 min is needed [8–10].

Cardioplegia, whether blood or crystalloid, is

also intrinsically associated with functional changes in

the coronary vasculature that add to the effects of CPB. This

may be observed after even routine cardiac cases, with up to

8% of patients having coronary artery spasm manifested by

temporary ST segment elevations on ECG after surgery

[11–13], and an even greater proportion exhibiting myo-

cardial contractile dysfunction that usually peaks 4–6 h

postoperatively [14]. These phenomena may be seen in

virtually any patient regardless of age, and irrespective of

the presence of atherosclerotic coronary artery disease or

other risk factors for endothelial dysfunction [15].

Mechanisms that mediate microvascular alterations after

CPB and cardioplegic arrest include activation of the

complement system, leukocyte-mediated cytokine release,

as well as increases in oxidative stress and disturbances in

calcium homeostasis that result from ischemia-reperfusion

[3] (Fig. 1). These mechanisms lead to an increased local

concentration of nitric oxide from upregulation of inducible

nitric oxide synthase, and to the release of inflammatory

substances such as thromboxane A2 and inducible cycloox-

ygenase from various types of cells, which result in

alterations of vasomotor regulation, endothelial integrity,

European Journal of Cardio-thoracic Surgery 26 (2004) 1002–1014

www.elsevier.com/locate/ejcts

http://www.elsevier.com/locate/ejcts

Fig. 1. Pathophysiology of vasomotor dysfunction after cardiopulmonary bypass and cardioplegic arrest.

M. Ruel et al. / European Journal of Cardio-thoracic Surgery 26 (2004) 1002–1014 1003

and vascular permeability. Since these processes constitute

sine qua non consequences of CPB and cardioplegic arrest

and ultimately impact on the convalescence of cardiac

surgical patients, surgeons and other clinicians caring for

patients undergoing cardiac surgery may benefit from a

better understanding of these alterations, which thereby

constitutes the aim of this article.

2. The central role of nitric oxide

Cardiopulmonary bypass and cardioplegic arrest result in

vasomotor dysfunction through impairments of endothelial

as well as medial vascular responses [16–19], each of which

is separately addressed below. Common to both types of

impairment is an altered concentration of nitric oxide (NO),

a gas produced in healthy endothelial cells by the activation

of constitutive nitric oxide synthase (eNOS), and in a wide

variety of cells such as activated endothelial cells,

inflammatory cells and macrophages, cardiomyocytes,

interstitial cells and vascular smooth muscle cells by the

inducible form of nitric oxide synthase (iNOS).

2.1. eNOS

Physiologic roles of eNOS, which is responsible for the

endothelial production of NO via the conversion of L-

arginine to L-citrulline, include endothelium-dependent

vasorelaxation through the endothelial-mediated activation

of guanylate cyclase, inhibition of leukocyte adhesion, and

M. Ruel et al. / European Journal of Cardio-thoracic Surgery 26 (2004) 1002–10141004

attenuation of platelet activation. In addition to these

endothelial effects, eNOS also regulates tone in the vascular

smooth muscle, to which the endothelium signals, and thus

affects medial vasodilatory responses [20].

eNOS activity is decreased after CPB and cardioplegic

arrest as a result of changes in cell membrane potential

[21–23], substrate and cofactor depletion [5,24], alterations

in the concentration or compartmentalization of

intracellular calcium [25,26], and injury to cell membranes,

associated regulatory enzymes, or ion pumps [19].

Following reperfusion after cardioplegic arrest, increased

breakdown of bioavailable NO occurs from increased

oxidative stress secondary to the generation of oxygen-

derived free-radicals [27], and production is further

impaired by exposure of the endothelium to fragments of

activated complement [28,29], activated neutrophils, and

macrophages [3].

2.2. iNOS

On the other hand the inducible form of NOS, iNOS, is

found in increased quantities in the myocardium after

cardioplegic arrest [30,31], and to a lesser extent in other

organs after CPB [32–36]. In contrast to the low

concentrations of NO produced by eNOS which inhibit

adhesion molecule expression, cytokine synthesis, and

leukocyte adhesion, the large amounts of NO generated by

iNOS under stressed local conditions can be toxic and pro-

inflammatory [37], since the excess NO reacts spon-

taneously with the reactive oxygen radicals released under

inflammatory or postischemic conditions by stressed

endothelial cells and activated leukocytes in order to form

peroxynitrite, which may cause cell apoptosis, cell necrosis,

and circulatory shock [38].

3. Endothelial responses

3.1. Complement activation

Activation of the alternative complement pathway occurs

during CPB as soon as blood gets in contact with

components of the extracorporeal circuit [39]. In addition,

cardioplegic arrest activates the classical complement

pathway, which may cause direct endothelial and cardio-

myocyte injury [40]. The anaphylotoxins C3a, C4a and C5a

are released, which promote neutrophil chemotaxis and

adherence, augment the myocardial inflammatory response,

and cause tissue edema [39,41]. Complement fragments like

C5b-9, known as ‘terminal membrane attack complexes’,

further impair endothelial function by causing direct cell

membrane injury and promoting neutrophil chemotaxis

[28]. Complement activation also causes upregulation of

adhesion molecules and increased generation of oxygen-

derived free radicals [42]. Experimentally, exposure of

isolated myocardial microvessels to zymosan-induced

complement-activated serum reduces NO-mediated endo-

thelium-dependent relaxation [28,29,43], suggesting that

activated complement intrinsically causes endothelial

injury, i.e. in tissues isolated from other blood constituents.

In the clinical setting, complement activation may be

partially inhibited by the administration of heparin [44,45],

by the use of heparin-coated circuits [46,47], by systemic

cooling on CPB [44,48], and by the use of complement

inhibitors such as pexelizumab [49] (Table 1).

3.2. Leukocytes and cytokines

3.2.1. Leukocyte activation

Activated leukocytes, through the release of oxygen-

derived free radicals, proteolytic enzymes, and inflamma-

tory cytokines, have been implicated in myocardial and

endothelial damage after ischemia [50], cardioplegia

[31,51], and CPB alone [41]. Focal leukocyte-endothelial

adherence has been identified on electron microscopy

following cardioplegic arrest and reperfusion [17], and

improved myocardial perfusion and recovery of function

have been observed if leukocyte-depleted blood is used to

reperfuse hearts after cardioplegic arrest in animals [51].

Similarly, improved endothelial and vascular smooth

muscle function have been demonstrated when monoclonal

antibodies to adhesion molecules are administered prior to

reperfusion [31,52].

Leukocytes also mediate detrimental myocardial and

systemic effects in response to CPB alone, regardless of the

occurrence of the cardiac-specific ischemia/reperfusion

injury attributed to cardioplegic arrest. For instance, the

expression of selectins is increased after the start of CPB [1,

53], and this process initiates neutrophil rolling, adherence

to the endothelium, and transmigration across the vascular

wall [54]. Granulocyte apoptosis is also decreased after

CPB, effectively prolonging the functional lifespan of

neutrophils [55]. Neutrophil and macrophage infiltration

has been documented in myocardial [56], pulmonary [57],

and mesenteric [41] tissues after CPB, and may clinically

correlate with the degree of post-CPB renal impairment [58].

3.2.2. Cytokine release

Increased circulating levels of tumor necrosis factor-a(TNF-a), interleukin (IL)-6, IL-8, and other cytokines

liberated during CPB have been shown to directly increase

the permeability of blood vessels, mediate inflammation,

and increase the expression of iNOS [30,59–63]. The

expression of vascular endothelial growth factor (VEGF), a

potent vasodilator and inducer of vascular permeability, and

that of its receptor VEGFR-1 are also upregulated after

cardioplegic arrest and reperfusion, resulting in increased

coronary microvascular relaxation responses [64,65]. On

the other hand, responses to another endothelium-dependent

vasodilator, ADP, are unchanged after cardioplegic arrest,

suggesting that the upregulation of VEGF receptors on the

coronary endothelium is selective and may play a role in

Table 1

Overview of vasomotor disturbances due to cardiopulmonary bypass and cardioplegia

Mechanism Site affected Effect Interventions and selected clinical trials

Alternative and

classical complement

activation

Systemic and

myocardial

endothelial cells

Neutrophil chemotaxis

and adherence,

free- radical production

Complement inhibitors. Intravenous Pexelizumab (a C5 complement

inhibitor)!24 h during and after CABG was effective in reducing the

incidence of the composite end-point of death or perioperative

myocardial infarction in 3088 patients [49]

Full systemic heparinization and heparin-coated circuits. Decrease

serum complement complex levels, CK-MB release and systemic

edema in patients after CPB [44–47]

Systemic cooling. Decreases C3a/C5a and elastase release [44,134],

with however no significant difference between 28 and 34 8C [48]

Leukocyte activation

and cytokine release

Systemic and

myocardial endothelial

and medial smooth

muscle cells

Free-radicals,

proteolytic enzymes,

and inflammatory

cytokines production

Leukocyte-depleted cardioplegic solutions. Were effective in

decreasing troponin T release and the incidence of postoperative low

cardiac output in a trial of 160 patients [135]

Antibodies to adhesion molecules. No clinical data. Anti-P-selectin and

anti-CD18 monoclonal antibodies appeared efficacious in reducing lung

and myocardial injury in animals [52,136–138]

Modified ultrafiltration. Decreases systemic cytokine and adhesion

molecules concentrations after CPB, with however no clinically

detectable effect [139]

Free radical formation Myocardial endothelial

cells

Endothelial cell

membrane injury

Blood cardioplegia. Limits superoxide production [140], warm being

potentially better than cold [141]

Free radical scavengers. N-acetylcysteine added to crystalloid

cardioplegia decreases myeloperoxidase and leukocyte activation, but

with no clinical impact [70]. Similarly, the addition of deferoxamine, an

iron chelator, to cardioplegia reduces release of superoxide and lipid

peroxidation products only [142]. Mannitol was ineffective in a small

study [143]

Prostaglandin

production

Systemic, pulmonary,

and myocardial

endothelial cells

Vasoconstriction,

increased permeability

Aspirin. Preoperative use may protect from protamine-induced

pulmonary vasoconstriction [144]. Data sparse with respect to possible

edema reduction

Steroids. Dextamethasone 1 mg/kg IV at induction may limit

extravascular fluid accumulation, inhibit pulmonary vasoconstriction

[145], and 1.5 g IV methylprednisolone over 24 h improves pulmonary

(controversial [146]) and myocardial function, and decreases CK-MB

release [130]

Intracellular calcium

accumulation

Systemic and


and medial smooth

muscle cells

Increased basal

vascular tone and

propensity to spasm

Low calcium blood cardioplegia. Clinical data sparse. Animal data

suggest optimal calcium concentration of crystalloid solution is between

0.4 and 1.2 mmol/l [89,90]. Optimal concentration in warm blood is

undetermined [91]. In human neonates, the addition of nicardipine, a

calcium-channel blocker, to crystalloid cardioplegia may reduce

myocardial injury [147], although nifedipine was not effective

in adults [148]

Magnesium supplementation. 5-10 mmol/l added to cold blood

cardioplegia may be associated with less ATP depletion [149], less

troponin release and possibly improved performance in humans [150].

Magnesium cardioplegia may also decrease the incidence of atrial

fibrillation by increasing serum magnesium levels [97]

Increased iNOS, ERK,

and MAPK expressions

Systemic and


and medial smooth

muscle cells

Increased permeability,

vasodilatation,

maldistribution

of perfusion

Improvements in CPB circuit biocompatibility. No clinical trial has yet

examined the possible impact of HCC or SMA circuits on iNOS, ERK

and MAPK

Increased peroxynitirite

production, with

resultant cell necrosis

and apoptosis

Peroxynitrite (iNOS degradation product) scavenging. The addition of

glutatione to crystalloid cardioplegia decreased neutrophil adhesion and

improved cardiac function a dog model [151]. Clinical data lacking

Minimization of CPB duration. Animal or observational clinical data

only (clinical RCT setting may be unethical)

Avoidance of alpha-adrenergic agonists. Animal or observational

clinical data only (clinical RCT setting may be unethical)

HSP70 induction with IV glutamine. Small animal data only [103]

CABG, coronary artery bypass grafting; CK-MB, creatine kinase MB isoenzyme; CPB, cardiopulmonary bypass; HCC, heparin-coated circuits; HSP, heat

shock protein; IV, intravenous; RCT, randomized controlled trial; SMA, surface modifying additive.



mediating perioperative increases in myocardial vascular

permeability.

3.3. Ischemia-reperfusion

3.3.1. Free-radicals

Oxidative stresses resulting from ischemia and reperfu-

sion damage not only myocardial endothelial cells after

anoxia and cardioplegia, but also affect systemic, non-

cardiac cells during CPB, largely due to the synthesis of

superoxide anions and hydroxyl radicals, and the interaction

between superoxide anions and NO leading to peroxynitrite

free-radicals [66–68]. In the myocardium, strategies to

decrease oxidative stress associated with cardioplegic arrest

have also been examined; for instance, the addition to

cardioplegic solutions of manganese superoxide dismutase

or deferoxamine, which respectively neutralize superoxide

and hydroxyl free-radicals, has been shown to better

preserve coronary endothelium-dependent relaxation after

cardioplegic arrest in swine [18]. The antioxidant N-

acetylcysteine has been evaluated as a cardioplegia additive

and has resulted in impressive effects in dogs [69] but no

clinically demonstrable benefit a small series of patients

[70]. The well-recognized free-radical scavenging proper-

ties of blood, particularly if warm or tepid, constitute some

of the reasons for its widespread preference over crystalloid

solutions in the composition of cardioplegia, with however

little clinically demonstrable benefit in elective, stable

patients [71–74].

The myocardium can also be protected from ischemia-

reperfusion by inhibiting ‘futile’ cell cycles such as the

poly(ADP-ribose) polymerase nuclear enzyme pathway,

which is overinduced by ischemia and cardioplegic arrest,

consumes ATP, increases the oxygen debt, results in cellular

dysfunction, and yet has little known homeostatic role. In a

recent study in pigs, Khan et al. showed that an intravenous

poly(ADP-ribose) polymerase inhibitor improved myocar-

dial perfusion, reduced the extent of infarction, and

improved cardiac function after regional ischemia and

cardioplegia-CPB [75]. However, no report on the use of

such a strategy in humans is yet available.

Few studies have examined the role of interventions

destined at decreasing systemic oxidative stress during

clinical CPB; in this regard, it is possible that angiotensin-

converting enzyme inhibitors, angiotensin-1 blockers, and

statin drugs could play a role in improving systemic and

myocardial outcomes [76–79], although clinical studies

involving angiotensin-converting enzyme inhibitors have so

far been disappointing [80,81].

3.3.2. Cyclooxygenase

Cardioplegia-reperfusion enhances the myocardial

expression of the inducible isoform of cyclooxygenase

(COX-2), an enzyme involved in prostaglandin synthesis

from the conversion of arachidonic acid. Cyclooxygenase is

implicated in the inflammatory response of diseases such as

rheumatoid arthritis and cancer. In the cardiac and systemic

vasculatures, prostaglandins have either vasodilatory or

vasoconstrictive actions, and their effects on the regulation

of vascular permeability changes are comparable and

synergistic to that of NO. CPB and cardioplegia both result

in the increased expression of COX-2 as well as other

predominantly constrictive prostanglandins, whose overall

effect is vasoconstriction of atrial and ventricular micro-

vessels [82–84]. However, no report is yet available of the

possibly beneficial effects of specific COX-2 inhibitors on

the myocardial and systemic vasculature of patients

operated using cardiopulmonary bypass and cardioplegic

arrest.

3.3.3. Calcium homeostasis

Cardioplegic arrest is associated with cellular depolariz-

ation, calcium (Ca2C) influx through voltage-dependent

Ca2C channels, release of Ca2C from intracellular Ca2C

stores, and increases in intracellular Ca2C concentration, all

of which mediate reperfusion injury. Transsarcolemmal

Ca2C influx via NaC–Ca2C exchange also plays an

important role in ischemia/reperfusion-mediated intracellu-

lar Ca2C accumulation [23,85]. These processes may be

exacerbated by the use of crystalloid over blood cardiople-

gic solutions, as crystalloid-based approaches may increase

myocardial hypoxia during cardioplegic arrest [86,87] and

cause higher accumulations of intracellular Ca2C.

Elevated intracellular Ca2C concentrations also alter the

Ca2C sensitivity of the vascular smooth muscle contractile

apparatus, which is regulated by a myosin light chain kinase

whose activity is in turn governed by Ca2C-calmodulin-

mediated phosphorylation [88]. Consequently, Ca2C over-

loading during cardioplegia constitutes a trigger for the

enhancement of basal vascular tone and agonist-induced

microvascular contraction or spasm after reperfusion,

providing an additional rationale for the use of low Ca2C

concentrations in cardioplegic solutions at a concentration

between 0.4 and 1.2 mmol/l [89,90], with the possible

exception of continuous warm blood cardioplegic tech-

niques [91]. Complete calcium depletion of the cardioplegia

solution should be avoided, as it may paradoxically lead to

increased myocardial injury and necrosis [89,92].

3.3.4. Magnesium

Following crystalloid cardioplegia and reperfusion,

contractile myocardial microvascular responses are

enhanced, whereas intrinsic myogenic contractile responses

are diminished [19]. Supplementation of cardioplegic

solutions with magnesium (Mg2C) at a concentration of

at least 5.0 mM preserves these agonist-induced and

myogenic responses [93]. While the exact causes of this

phenomenon remain unclear, higher local Mg2C concen-

trations may confer protection against endothelial dysfunc-

tion [94], or against alterations of the contractile properties

of vascular smooth muscle by displacing Ca2C from

calcium channels binding sites and hyperpolarizing


sarcolemmal membranes, thus inhibiting Ca2C entry into

cells [95]. Extracellular Mg2C may also act by raising

intracellular Mg2C concentration, thereby reducing the

release of Ca2C from the sarcoplasmic reticulum [12,51], or

by diminishing the depletion of ATP stores and preserving

the intracellular homeostasis of smooth muscle cells. Since

Mg2C supplementation may translate into endothelial

protection and reduce the incidence of coronary vascular

spasm after cardioplegia, its addition to cardioplegic

solutions at a concentration of 5.0 mEq/l or more appears

desirable [90,96]. This was recently shown in a clinical trial

to decrease requirements for internal defibrillation and

temporary epicardial pacing intraoperatively, as well as

decrease the incidence of new postoperative atrial fibrilla-

tion in urgent CABG patients operated using warm blood

cardioplegia [97].

3.4. Apoptosis and heat-shock proteins

Cardioplegic arrest and cardiopulmonary bypass are

intrinsically associated with apoptosis of endothelial and

other vascular cells in the myocardial and systemic vascular

beds of animals and humans [1,98,99]. This is mediated

by a variety of transcriptional genes such as c-FOS and

JUN-b, which are significantly upregulated in peripheral

and myocardial tissues during cardiopulmonary bypass

and cardioplegic arrest [1]. Protection against apoptosis,

necrosis, and detrimental iNOS/peroxynitrite activity may

be afforded by the spontaneously increased production of

cytoplasmic heat shock proteins (HSP) 70, 72, and 73 in

endothelial cells and cardiomyocytes [100–102]. Upregula-

tion of these heat shock proteins could theoretically afford

protection against apoptosis and necrosis. In rats exposed to

CPB, the systemic administration of glutamine, an inducer

of HSP70, resulted in lower plasma concentrations of

interleukin-6 and interleukin-8, preserved eNOS activity,

and attenuated iNOS activity [103]. No such data is yet

available in humans.

Fig. 2. Skeletal muscle expression of activated ERK 1/2 before and after

cardiopulmonary bypass. Immunohistochemistry shows dark staining

localized to peripheral arterioles (black arrows) with decreased expression

after cardiopulmonary bypass (CPB) of activated ERK 1/2, a major

mediator of vascular tone and of the response to alpha-adrenergic agents.

(Adapted from Khan et al. [98]; with permission).

4. Medial responses

Blood flow is regulated in vascular medial smooth

muscle by metabolic, myogenic, and autonomic mechan-

isms, the latter of which is separately discussed below.

Metabolic regulation of vascular medial tone after CPB and

cardioplegic arrest is altered in the peripheral vasculature by

the systemic release of vasoactive substances during CPB,

and in the myocardial circulation by the abnormally

elevated proportion of open potassium channels during

cardioplegia [104]. Myogenic regulation, i.e. the intrinsic

property of medial smooth muscle to regulate vascular

resistance in response to changes in transmural pressure, is

actually preserved in coronary microvessels after CPB and

cardioplegia, but its pressure-diameter relationship is

shifted upward and normalized only in the presence of a

NO antagonist, thus consistent with an increased release of

NO from iNOS [105].

4.1. Autonomic responses

Autonomic medial regulation of peripheral and myocar-

dial arterioles is on the other hand markedly impaired by

CPB. This mechanism, in conjunction with the increased

circulating levels of vasodilator substances and cytokines,

explains much of the decrease in peripheral vascular

resistance frequently observed as patients are being

separated from CPB and thereafter [30,106,107], the

magnitude of which appears to correlate with the duration

of CPB [10]. As previously mentioned, the systemic

induction of iNOS as well as other vasoactive substances

such as bradykinin and VEGF also contributes to this

vasoplegic syndrome [31,64] and to the reductions in

peripheral vascular resistances and increases in vascular

permeability that contribute to the marked generalized

edema frequently observed after cardiac surgery, all with

the potential of culminating in organ malperfusion [85].

Changes in the tissue activity and expression of


regulatory enzymes such as MAP kinases (MAPK) are now

also being recognized as major mediators of the complex

autonomic vascular responses observed after CPB. In the

coronary and pulmonary circulations, CPB leads to

enhanced vasoconstriction partly as a result of the rapid

induction of ERK1/2 [16,108,109], a subset of MAPK

involved in a variety of signal transduction mechanisms

triggered by a broad range of effectors including TNF-a,

which itself is elevated during CPB and returns to basal

levels after 24 h [110]. ERK1/2 and MAPK in turn induce

interleukin-6 (IL-6) production [111], leading to a cascade

of inflammatory events that include leukocytosis, thrombo-

sis and lymphocyte activation [112]. On the other hand,

recent evidence indicates that ERK1/2 activity is actually

decreased in the non-cardiac, systemic circulation after

CPB, and that this is associated with reduced contractile

responses of peripheral arterioles (Fig. 2) [113]. These

findings implicate MAPK as a major mediator of the site-

specific vasomotor dysfunction observed after CPB, with a

decreased ERK1/2 activity in the peripheral vasculature

associated with a decreased vascular tone, and an increased

ERK1/2 activity in the myocardial circulation associated

with an increased propensity to coronary spasm.

5. Clinical implications

The most frequent clinical scenario resulting from the

adverse endothelial and medial responses to CPB and

cardioplegic arrest described above can be summarized as

follows: (1) decreased basal tone and decreased alpha-

adrenergic microvascular responses in the peripheral/skele-

tal muscle vascular beds [31,64,113], with propensity

to distributive organ malperfusion, (2) initially decreased

coronary vascular tone during cardioplegia [104] followed

by decreased endothelial-mediated relaxation and

increased propensity to spasm [83,84], modifiable in part

by the composition of the cardioplegic solution [18,90,94],

(3) increased vasocontractile responses in the pulmonary

and mesenteric microcirculations [29,32,41] predisposing to

the development of pulmonary shunt and mesenteric

ischemia, respectively, particularly when vasoactive drugs

are administered to regulate blood pressure after CPB [114],

and (4) impaired but as of this writing still incompletely

characterized endothelium-mediated relaxation responses in

the cerebral microvasculature [115] (Fig. 1).

Several approaches introduced over the years to increase

the safety of CPB may have their clinical benefit explained

at least in part by their propensity to limit vasomotor

disturbances after cardiac surgery. For instance, the

increased expression of COX-2 and enhanced contractile

response of coronary arterioles to serotonin after CPB and

cardioplegia [83,84] suggest that the improvements in

coronary bypass graft patency obtained from the periopera-

tive administration of acetylsalicylic acid may not only

derive from its effects on prevention of platelet aggregation

and thrombus formation [116–118], but also from

the prevention of coronary spasm and preservation of

microvascular flow as a result of COX-2 inhibition.

The advantages of blood over crystalloid cardioplegia in

emergency or high-risk cases may result from the inhibitory

effects of blood on oxygen-derived free radical generation,

improved coronary endothelial oxygenation, enhanced

buffering capacity from histidine and other blood proteins,

and better preservation of the morphology of coronary

endothelial cells [3,82]. Antiproteases such as aprotinin, in

addition to inhibiting fibrinolysis and decreasing blood loss

after cardiopulmonary bypass, are also potent inhibitors of

the bradykinin and kallikrein systems [81,119] and may

confer additional clinical benefit by non-specifically redu-

cing the systemic inflammatory response to CPB [120,121],

although the magnitude of this effect remains controversial.

Finally, the inhalational administration of low concen-

trations of NO at 20 ppm for 8 h was recently associated

with decreased myocardial troponin release [122], but it is

reasonable to speculate that high-dose systemic NO

administration, in parallel with the effects of excessive

local production of NO and peroxynitrite from increased

iNOS activity during CPB, might ultimately prove

detrimental.

Other strategies are also available to help prevent

systemic and coronary vasomotor dysfunction after CPB

and cardioplegic arrest (Table 1). Mild systemic cooling and

the administration of heparin, both of which decrease

complement activation [44,45], the utilization of blood-

based cardioplegic solutions [82,123,124], magnesium

supplementation [93] and moderate calcium depletion [15]

of cardioplegic solutions all have beneficial effects on

endothelium-dependent relaxation, myogenic contraction,

responses to adrenergic agonists, and other indices of

myocardial vascular health after CPB and ischemia-

reperfusion. It should be remembered, however, that several

of these strategies may prove beneficial for emergency or

high-risk patients only, as improved outcomes related to

their use during routine operations has not been demon-

strated [125,126].

One standard of practice in need of further research and

foreseeable change, in light of the knowledge gained in

understanding the pathophysiology of vasomotor dysfunc-

tion after CPB, is the routine use of alpha-adrenergic

agonists for the treatment of hemodynamic instability

associated with post-CPB distributive shock. Since periph-

eral arterioles show decreased alpha-adrenergic responsive-

ness after CPB and that these responses are conversely

increased in the mesenteric and coronary circulations, the

widespread use of alpha-adrenergic agonists may constitute

a suboptimal approach for cardiac surgical patients with

vasoplegic syndromes, as these agents can worsen splanch-

nic and cerebral malperfusion, increase pulmonary shunt,

and favor the development of coronary spasm. More

specifically targeted to the underlying cause of vasoplegia

are iNOS/guanylate cyclase inhibitors such as methylene


blue, with which preliminary clinical experience in 54

patients treated a 2 mg/kg intravenous infusion adminis-

tered over 20 min demonstrated relative safety and potential

effectiveness [127]. Other promising approaches in post-

CPB vasoplegic syndromes include ‘protecting’ the mesen-

teric circulation against its exacerbated contractile

responses to alpha-agonists agents with an intravenous

infusion of the eNOS/nitric oxide substrate L-arginine [5].

Several interventions have not delivered on the promises

that experimental data suggested with respect to their

clinical use. This may be related to the falsely exaggerated

effects of CPB in animal models compared to humans (due,

for instance, to less advanced circuits, larger priming to

circulatory volume ratios, lack of a dedicated perfusionist,

non-sterile conditions, larger amounts of embolic material,

etc.), to the rarity and lack of sensitivity of adverse clinical

outcomes, to the large potential for confounding biological

noises such as baseline endothelial function and immuno-

logic response in patients, and to the difficulty in a priori

obtaining a proper treatment effect estimate in order to

perform an adequate sample size calculation prior to

launching these small trials. The clinical use of glucocorti-

costeroids on CPB constitutes one example of disappointing

clinical results, since these agents, despite their theoretical

role in blocking the effects of inflammatory cytokines and

the expression of iNOS and COX-2, have repeatedly not

resulted in appreciable clinical benefit [128,129], with the

possible exception of decreased creatine kinase release and

a reduction in the incidence of postoperative atrial

fibrillation in two recent double-blind randomized con-

trolled trials [130] (Rubens FD et al.; in press). Also

controversial has been the role of inhibiting neutrophil

infiltration with a monoclonal antibody to C5a, which

experimentally results in improved endothelial-dependent

relaxation but no demonstrable benefit on myocardial,

pulmonary, or mesenteric functional recovery [31,131,132],

until one clinical trial demonstrated a dose-dependent

inhibition of the generation of complement byproducts, a

reduction in leukocyte activation, a 40% reduction in

creatine kinase-MB release, a 80% reduction in new

cognitive deficits, and a significant reduction in post-

operative blood loss [133]. More research is needed to

further examine the clinical impact of these and other

mechanistically based interventions on the clinical out-

comes of emergency, high-risk, and perhaps even routine

cardiac surgical patients operated using CPB and cardio-

plegic arrest.

6. Conclusion

Cardiopulmonary bypass and cardioplegia are indispen-

sable tools of the cardiac surgical armamentarium that are

still used for the majority of cardiac operations and will

remain selectively needed for decades to come. However,

these modalities constitute a double-edged sword that lead

to formidable multi-systemic microvascular derangements.

Although most of the pathophysiologic contributors to these

disturbances have been identified and their clinical impact

reasonably well elucidated, therapeutic options to circum-

vent them remain limited. Consequently, the development

and evaluation of new therapeutic modalities oriented at

limiting or eliminating the consequences of vasomotor

dysfunction after cardiac surgery should remain a main

focus of applied cardiac surgical research, as we surgeons

aim at continuously improving the results and safety of the

surgical treatment of heart disease for our patients.

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