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Eur J Cardiothorac Surg 2004;26:1002-1014
© 2004 Elsevier Science NL

Review

Vasomotor dysfunction after cardiac surgery

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

a Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
b Division of Cardiac Surgery, University of Ottawa, Ottawa, Ontario, Canada

Received 24 February 2004; received in revised form 28 June 2004; accepted 23 July 2004.

* Corresponding author. Tel.: +1-617-632-8385; fax: +1-617-632-8287. (E-mail: fsellke{at}bidmc.harvard.edu).


   Abstract
Top
 Abstract
1. Introduction
 2. The central role...
 3. Endothelial responses
 4. Medial responses
 5. Clinical implications
 6. Conclusion
 References
 
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.


   1. Introduction
Top
 Abstract
 1. Introduction
2. The central role...
 3. Endothelial responses
 4. Medial responses
 5. Clinical implications
 6. Conclusion
 References
 
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 resistances 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 patients in cardiogenic shock [6,7] or in patients for whom CPB support of more than 80min 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 myocardial contractile dysfunction that usually peaks 4–6h 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 cyclooxygenase from various types of cells, which result in alterations of vasomotor regulation, endothelial integrity, 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.



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

 

   2. The central role of nitric oxide
Top
 Abstract
 1. Introduction
 2. The central role...
3. Endothelial responses
 4. Medial responses
 5. Clinical implications
 6. Conclusion
 References
 
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 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 spontaneously 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
Top
 Abstract
 1. Introduction
 2. The central role...
 3. Endothelial responses
4. Medial responses
 5. Clinical implications
 6. Conclusion
 References
 
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 cardiomyocyte 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 endothelium-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).


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  		Table 1. Overview of vasomotor disturbances due to cardiopulmonary bypass and cardioplegia
 
3.2. Leukocytes and cytokines
3.2.1. Leukocyte activation
Activated leukocytes, through the release of oxygen-derived free radicals, proteolytic enzymes, and inflammatory 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-{alpha} (TNF-{alpha}), 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 mediating perioperative increases in myocardial vascular permeability.

3.3. Ischemia-reperfusion
3.3.1. Free-radicals
Oxidative stresses resulting from ischemia and reperfusion 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 properties 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 myocardial 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 microvessels [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 depolarization, calcium (Ca2+) influx through voltage-dependent Ca2+ channels, release of Ca2+ from intracellular Ca2+ stores, and increases in intracellular Ca2+ concentration, all of which mediate reperfusion injury. Transsarcolemmal Ca2+ influx via Na+–Ca2+ exchange also plays an important role in ischemia/reperfusion-mediated intracellular Ca2+ accumulation [23,85]. These processes may be exacerbated by the use of crystalloid over blood cardioplegic solutions, as crystalloid-based approaches may increase myocardial hypoxia during cardioplegic arrest [86,87] and cause higher accumulations of intracellular Ca2+.

Elevated intracellular Ca2+ concentrations also alter the Ca2+ sensitivity of the vascular smooth muscle contractile apparatus, which is regulated by a myosin light chain kinase whose activity is in turn governed by Ca2+-calmodulin-mediated phosphorylation [88]. Consequently, Ca2+ overloading 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 Ca2+ concentrations in cardioplegic solutions at a concentration between 0.4 and 1.2mmol/l [89,90], with the possible exception of continuous warm blood cardioplegic techniques [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 (Mg2+) at a concentration of at least 5.0mM preserves these agonist-induced and myogenic responses [93]. While the exact causes of this phenomenon remain unclear, higher local Mg2+ concentrations may confer protection against endothelial dysfunction [94], or against alterations of the contractile properties of vascular smooth muscle by displacing Ca2+ from calcium channels binding sites and hyperpolarizing sarcolemmal membranes, thus inhibiting Ca2+ entry into cells [95]. Extracellular Mg2+ may also act by raising intracellular Mg2+ concentration, thereby reducing the release of Ca2+ from the sarcoplasmic reticulum [12,51], or by diminishing the depletion of ATP stores and preserving the intracellular homeostasis of smooth muscle cells. Since Mg2+ 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 5.0mEq/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 fibrillation 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]. Upregulation 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.


   4. Medial responses
Top
 Abstract
 1. Introduction
 2. The central role...
 3. Endothelial responses
 4. Medial responses
5. Clinical implications
 6. Conclusion
 References
 
Blood flow is regulated in vascular medial smooth muscle by metabolic, myogenic, and autonomic mechanisms, 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 myocardial 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-{alpha}, which itself is elevated during CPB and returns to basal levels after 24h [110]. ERK1/2 and MAPK in turn induce interleukin-6 (IL-6) production [111], leading to a cascade of inflammatory events that include leukocytosis, thrombosis 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.



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  		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).

 

   5. Clinical implications
Top
 Abstract
 1. Introduction
 2. The central role...
 3. Endothelial responses
 4. Medial responses
 5. Clinical implications
6. Conclusion
 References
 
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/skeletal 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 perioperative 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 reducing the systemic inflammatory response to CPB [120,121], although the magnitude of this effect remains controversial. Finally, the inhalational administration of low concentrations of NO at 20ppm for 8h 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 demonstrated [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 dysfunction after CPB, is the routine use of alpha-adrenergic agonists for the treatment of hemodynamic instability associated with post-CPB distributive shock. Since peripheral arterioles show decreased alpha-adrenergic responsiveness 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 splanchnic 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 2mg/kg intravenous infusion administered over 20min demonstrated relative safety and potential effectiveness [127]. Other promising approaches in post-CPB vasoplegic syndromes include ‘protecting’ the mesenteric 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 immunologic 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 glucocorticosteroids 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 controlled 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 postoperative blood loss [133]. More research is needed to further examine the clinical impact of these and other mechanistically based interventions on the clinical outcomes of emergency, high-risk, and perhaps even routine cardiac surgical patients operated using CPB and cardioplegic arrest.


   6. Conclusion
Top
 Abstract
 1. Introduction
 2. The central role...
 3. Endothelial responses
 4. Medial responses
 5. Clinical implications
 6. Conclusion
References
 
Cardiopulmonary bypass and cardioplegia are indispensable 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 circumvent 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.


   Footnotes
 
1 The authors have no relationship to disclose pertaining to this research. Back


   References
Top
 Abstract
 1. Introduction
 2. The central role...
 3. Endothelial responses
 4. Medial responses
 5. Clinical implications
 6. Conclusion
 References
 

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