https://doi.org/10.22037/ijpr.2012.1135

Cardiopulmonary Bypass, Inflammation and How to Defy it: Focus on Pharmacological Interventions

authors:

avatar Ali Dabbagh a , avatar Samira Rajaei b , avatar Ayad Bahadori Monfared c , avatar Ali Asghar Keramatinia d , avatar Korosh Omidi d

Anesthesiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Deptartment School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Candidate, Epidemiology Department. School of Public Health, Shahid Beheshti University of Medicine,
Tehran, Iran.
Shahid Beheshti University of Medicine, Tehran, Iran.
Warning: No corresponding author defined!
Iranian Journal of Pharmaceutical Research : IJPR: Vol.11, issue 3; 705-714
article type: Review Article
received: October , 2011
accepted: December , 2011

How To Cite Dabbagh A, Rajaei S, Bahadori Monfared A, Keramatinia A A, Omidi K. Cardiopulmonary Bypass, Inflammation and How to Defy it: Focus on Pharmacological Interventions. Iran J Pharm Res. 2012;11(3):e125833. https://doi.org/10.22037/ijpr.2012.1135.

Abstract

One of the most common health problems are diseases of the cardiovascular system with a great bulk of disease burden; while a considerable number of cardiac patients undergo cardiac surgery; cardiac surgical procedures with cardiopulmonary bypass (CPB) are nowadays among the top list of surgical procedures.
More than half of a century has passed since the introduction of total cardiopulmonary bypass (CPB). One of the main untoward effects of CPB is systemic inflammation; causing an “acute phase reaction” responsible for the production of other unwanted postoperative complications.
The humoral and cellular components of the immune system are among the main parts of these compensatory mechanisms. There are a number of therapeutic agents used to suppress this inflammatory process.
Since CPB is composed of a multitude of items, there are many studies assessing the possible methods and therapeutics for prevention or treatment of inflammation in patients undergoing CPB.
According to a conventional classification, the anti-inflammatory methods are classified as either pharmacologic strategies or technical strategies. The pharmacologic strategies are those with the usage of one or more therapeutic agents; while the technical strategies are those that try to modify the CPB techniques. However, in this manuscript, the main pharmacological strategies are discussed.

Introduction

One of the most common health problems are diseases of the cardiovascular system with a great bulk of disease burden; while a considerable number of cardiac patients undergo cardiac surgery; in such a way that cardiac surgical procedures with cardiopulmonary bypass (CPB) are nowadays among the top of the list of surgical procedures (1).

More than half of a century has passed since the introduction of total cardiopulmonary bypass (CPB) for the first time for cardiac surgery and “is now used successfully thousands of times each day worldwide”. One of the main untoward effects of CPB is systemic inflammation. So, among the unwanted side effects of CPB, systemic inflammation could be mentioned as one of their greatest ones; causing an “acute phase reaction” responsible for the production of other unwanted postoperative complications (2).

Table 1

The total number of papers reviewed and their characteristics

TopicNumber of orticles*Evidence levelYear of publication
1General issues1-13A-B1997-2011
2Aprotinin14-37A-C1966-2010
3Corticosteroids35-44A-B1995-2011
4Antioxidants45-52A-C2001-2010
5Phosphodiesterase Inhibitors53-60B-C1999-2010
6The complement cascade61-65A-B1998-2010
7Miscellaneous Agents66-86A-B1997-2012
8Non-pharmacologic strategies87-111A-C1994-2010

The humoral and cellular components of the immune system are among the main parts of these compensatory mechanisms and at the same time, there are a number of therapeutic agents used to suppress this inflammatory process. Hence, we know that a series of interactions occurs during CPB, finally leading to the “activation of leukocytes and endothelial cells” (2-4).

The CPB is composed of a multitude of items; so, due to the great number of its different parts and also, due to the very great number of resulting interactions between these varying components, there are many studies assessing the possible methods for prevention of inflammation in patients undergoing CPB; In addition, new therapeutic modalities may emerge after studies are performed regarding these many different variables.

According to a conventional classification, the anti-inflammatory methods are classified as either pharmacologic strategies or technical strategies. The pharmacologic strategies are those engaged with the usage of one or more therapeutic agents; while the technical strategies are those that try to modify the CPB techniques.

Objectives

One of the main untoward effects of CPB is systemic inflammation with its cellular and humoral components (5-6).

The CPB is composed of a multitude of elements; so, due to the presence of these elements and their interactions, a wide range of new therapeutic modalities could be used during the CPB procedure as potential locations for defying inflammation (7-10). However, these interventions are classified in one of the two main categories: pharmacologic strategies and technical strategies (11-13).

We studied the current evidence regarding pharmacological strategies used to defy inflammatory response in CPB. Hence, this summarizing review aims to consider different pharmacologic methods used for the treatment of inflammation in patients undergoing CPB for cardiac surgeries.

Methods of the review

For the review process, the Medline search engine was used which was covering articles from 1995 up to now through the following link: http://www.ncbi.nlm.nih.gov/pubmed/.

In Medline, the keywords were searched using Medical Subject Headings (MeSH) which at first, the following subheadings were selected, which resulted in 1010 citations at the time of the study:

“Cardiopulmonary Bypass” and “inflammation”

Then, they were searched separated by AND each time. Then, in each search, the search was completed with the other keywords, for example including “aprotinin”, “glucocorticoids”, “antioxidants”, “Phosphodiesterase Inhibitors” and “Complement System Proteins”.

In the remaining section of the manuscript, the main pharmacological strategies are discussed.

Aprotinin

The Medline search at the time of the study resulted in 77 citations for these phrases:

“Cardiopulmonary Bypass” AND “inflammation” AND “aprotinin”

Aprotinin is a bovine version of the small protein basic pancreatic trypsin inhibitor (known as BPTI), and has a high molecular weight, It is a very potent and nonspecific serine protease inhibitor, which inhibits the important fibrinolytic enzyme trypsin, as well as, its related important proteolytic enzymes. The trade name of aprotitn called “Trasylol”. For many years, aprotinin was administered as an anti-fibrinlytic agent, that decreased the amount of surgical bleeding. In European countries, in the final years of 1950s, aprotinin was used in order to attenuate hyperfibrinolytic conditions; although it had been discovered in 1936 (14).

This compound can inhibit a number of proteases, including trypsin, kallikrein and plasmin. In the 1960s, for the first time this compound agent was used as a therapeutic agent for the treatment of patients with acute pancreatitis. This was due to its effects in suppressing the proteases (14-17). There are a number of studies, especially during the last decade, demonstrating the role of lower aprotinin doses in decreasing the severity of post CPB systemic anti-inflammatory response syndrome (SIRS). This is probably due to the anti-inflammatory effects of the drug, which resemble the effects of corticosteroids. Also, there are some studies that demonstrate the anti-inflammatory effects of the drug on the release of “tumor necrosis factor-alpha” and “neutrophil integrin CD11b upregulation” (17-19). Besides, aprotinin can inhibit a few inflammatory agents including trypsin, chymotrypsin, plasmin and kallikrein. The related studies have mentioned a range of concentrations from about 125,000 IU/mL to 300,000 IU/mL for this anti-inflammatory action. These substances (i.e. trypsin, chymotrypsin, plasmin and kallikrein) are among the main compounds playing pivotal roles in the inflammation cascade and some are part of the contact system.

Never the less, since 1980s, aprotinin was used experimentally and then clinically to reduce the CPB induced SIRS. In the first series of the cardiac operations, its use demonstrated significantly decreased postoperative bleeding and postoperative transfusion requirements (20- 22).

But, years later, in 2006, the studies published by Karkouti and colleagues (23-25) and also, by Mangano and colleagues (26-28), heavily questioned the safety of the drug worldwide. Those who favored aprotinin claimed that aprotinin treatment could significantly reduce the amount of blood transfusion and put a question mark on the methodology of the two latter studies. However, the critiques claimed that it could not benefit the patients regarding their clinical outcome in reducing morbidity or mortality. It could in best circumstances only be compared with the control groups; while, at the same time, blood transfusion is associated with increased morbidity and mortality (29).

Finally, a high quality study was designed in order to compare the results of aprotinin with the other tow analogs of lysine, namely tranexamic acid and aminocaproic acid. The study was performed in high risk patients who had undergone cardiac surgery. It was entitled the Canadian BART trial (Blood Conservation using Antifibrinolytics: a Randomized Trial in high-risk cardiac surgery patients). In November 2007, after about 2400 patients among the primary total population size of the study (i.e. 2900 patients) entered the study, the Data Safety Monitoring Board of BART trial decided to stop the study before the planned and determined time (30-32), due to the outcome of the patients till the time. Finally, the results demonstrated that aprotinin, when compared with the other tow antifibrinolytic agents (namely tranexamic acid and aminocaproic acid) was the most effective agent regarding its hemostatic effects; Furthermore, it could reduce the patient risk for severe postoperative hemorrhage and the need for postoperative use of blood and its products. Meanwhile the BART trial demonstrated that in patients who had received aprotinin, the one month risk of mortality was increased more than 50% , compared with the other patients (14, 32). After the primary results of the BART trial were gradually revealed, the US Food and Drug Administration (FDA) announced on November 5, 2007, that Trasylol (aprotinin) manufacturer (i.e. Bayer) should halt the marketing of the drug until more comprehensive studies would lead into a decision. This announcement has not been changed yet; though, there are newly emerged studies announcing controversial reports (14, 32-35). So, it seems that the story related to aprotinin uses and hazards will continue.

At the same time, we have to consider that according to the newest available meta-analyses, the use of aprotinin has no major effect on the proteins of acute phase of inflammation or on the cytokines related to inflammation in adult patients undergoing cardiac surgery with CPB.There fore, the present available evidence cannot support the use of aprotinin as anti-inflammatory agent per se (32, 36); though a number of studies still claim its anti-inflammatory effects (37).

Corticosteroids

The Medline search at the time of the study resulted in 39 citations for these phrases:

“Cardiopulmonary Bypass” AND “inflammation” AND “glucocorticoids”

When talking about inflammation, glucocorticoids are among the first drugs that come to the mind. This is however, the same fact for cardiac surgery. These agents have been used for more than 4 decades; while their related studies are not decisive yet.

The basis for using these agents in cardiac surgeries with CPB was the similarity in the clinical condition of the patients undergoing CPB with the patients experiencing infectious SIRS. However, the clinical usefulness of glucocorticoids in CPB is not as definitive yet, though many different clinical benefits of these drug category has been claimed for CPB (1, 35-41) and some have mentioned their possible harms (42-43). Even, some have claimed these drugs to be of no benefit for patients undergoing cardiac surgery with CPB (42-44).

As a general recommendation, the expert guidelines on CABG by the American Heart Association and the American College of Cardiology declared that glucocorticods are inexpensive and may decrease the hazards related to CPB related SIRS (38-41). Although the studies related to the benefits of glucocorticoids in CPB do not have definitive results, these agents are used in the daily practice of cardiac surgery in many centers worldwide (39-44).

Antioxidants

The Medline search at the time of the study resulted in 18 citations for these phrases:

“Cardiopulmonary Bypass” AND “inflammation” AND “antioxidant”

The process of myocardial ischemia and reperfusion, causes myocardial cell death, mainly through cellular apoptosis. Ischemia/reperfusion injury is the result of tissue ischemia beyond the upper tolerable cellular limits. As a rule, the cells tolerate a limited and defined ischemia period. Ischemic events exceeding this defined period, would incur ischemic insults (5). Ischemic times more than the tolerable period would result in a phenomenon named “ischemia/reperfusion injury” (6). The production of reactive oxygen species (ROS; also known as oxygen-free radicals) is the hallmark of ischemia/reperfusion injury (7, 45). Usually, the over-production of the ROS (i.e. ischemia reperfusion injury) happens after restoration of blood flow to the ischemic organ cells (46-47).

In one study, during the early few hours after CABG with CPB, the levels of “neutrophil gelatinase associated lipocalin” in plasma of patients was demonstrated to be an indicator of acute renal injury (48). Also, in another study, it was demonstrated that the release of endothelial nitric oxide and also, the plasma levels of nitrite oxide is strongly dependent on the method used for CPB (49).

In another study, an index called OXY-SCORE was presented. This score is an index which is a collective and brief demonstrator of the components of oxidative stress and its total status. The study demonstrated that this index has a good ability to predict the oxidative status of the patients (50).

Among the many pharmaceuticals mentioned as antioxidants in patients undergoing CPB, Vitamins E and C and also, mannitol, allopurinol, and N-acetyl cysteine (i.e. the endogenous oxygen radical scavengers) are cited more than all the others (49-52). However, most human studies have failed to prove the benefit of routine administration of antioxidants in patients undergoing CPB (50-52).

Phosphodiesterase Inhibitors

The Medline search at the time of the study resulted in 17 citations for these phrases:

“Cardiopulmonary Bypass” AND “inflammation” AND “phosphodiesterase inhibitors”

Phosphodiesterase inhibitors are a group of drugs, which their role as anti-inflammatory agents has been under assessments for more than a decade (1). It has been demonstrated that the administration of phosphodiesterase inhibitors not only could decrease systemic vascular resistance (i.e. decreasing the afterload of the heart), but also, may prevent or alleviate the ensued myocardial dysfunction after CPB (53). Hence, the term “inodilator” has been coined for these agents. The mechanism of action in these agents is an increase in the level of the intracellular cyclic adenosine monophosphate (6).

Pentoxifylline has been shown to “decrease the cellular need for energy” and “the cellular inflammatory reactions” through inhibition of 5›-nucleotidase (54). Morever, the same study showed that pentoxifylline can prevent “myocardial inflammation and I/R injury” in CPB. In another study performed in rats, the 4th type of phosphodiesterase inhibitors could attenuate CPB related SIRS by regulating the pro-inflammatory mediators (55). However, this is not always the case and there are many controversial results in different studies regarding the role of phosphodiesterase inhibitors (56-59). One of the effects of milrinone is to improve the splanchnic circulation in patients undergoing CPB, hence, decreasing the level of systemic inflammatory mediators and preventing “gastric intramucosal acidosis” (59-60).

Finally, it should be said that milrinone is nowadays being used as a drug of choice in many cardiac surgeries using CPB; with a few claimed preventive and therapeutic effects. Suppression of the inflammation due to CPB might be one of them.

The complement cascade

The Medline search at the time of the study resulted in 172 citations for these phrases:

“Cardiopulmonary Bypass” AND “inflammation” AND “complement”

One of the most important players of inflammation, in all of the inflammatory processes (including during CPB) is the complement system. However, there are not a considerable number of therapeutic agents available to treat the effects of this system during CPB (61).

One of the main components of the complement system is a protein called C5. It has a major role in the complement cascade, since it can activate the remaining complement components. A recombinant antibody called pexilizumab can block C5; so, it might have a prominent role in suppressing the acute inflammatory response in CPB (62-64). However, the drug is not currently used as an “everyday medication”.

The components of the “complement cascade” and the “coagulation cascade” are highly inter-related. This relationship causes a number of effects, that is the final result of the sharing between the two cascades. The “direct enhancement of coagulation” due to the effects of the complement cascade in one hand, and the activation of the complement components due to the effects of coagulation enzymes on the other hand, are among the examples of this cross reactions; which would cause a number of inflammatory effects. These inflammatory effects are exactly the “especial position” for anti inflammatory drugs used during CPB (60-61).

Patients undergoing CPB are not the only example. There are a number of other disease states in which, the “complement-coagulation interaction” is the main cause for the creation of untoward lethal effects (60-63).

Although CPB related SIRS is the main cause of the inflammatory response (including the complement cascade), we should undoubtedly consider the role of surgery and anesthetic agents as the minor inevitable etiologies of SIRS. However, we have to consider that the role of anesthesia and surgery in production of inflammation is even more important in the pediatric population group (65).

Miscellaneous agents

Magnesium sulphate infusion is nowadays one of the commonly used anesthetic adjuvants (2-3). Analgesic effects, arrhythmia preventing and anti-arrhythmic properties, vasoconstriction and alleviation of increased pulmonary pressure are among its other applications. There are current studies that have demonstrated its use as an anti-inflammatory agent for patients undergoing cardiac surgery (3). The definite mechanism of action for magnesium sulphate is not yet clear; however, the role of magnesium as an antagonist of N-methyl-D-aspartate receptor (3) and also, a possible anti-apoptotic agent; through antagonizing intracellular calcium has been proposed (67).

Also, some of the anesthetic agents (including some of the volatile gases, a number of the opioids like morphine and, low-dose ketamine), some of the vasoactive agents (including dopexamine, sodium nitroprusside, angiotensin-converting enzyme inhibitors and levosimendane), erythropoietin, heparin and other glycosaminoglycans, statins, and H2 antagonists might suppress the inflammatory response related to CPB (5-6, 68-86).

Non-pharmacologic strategies

Heparin circuits, ultrafiltration and the issues related to ventilator-induced pulmonary inflammation are among the main non pharmacological issues that are not discussed here (87-111).

Conclusion

The current evidence has introduced a wide range of therapeutic agents proposed for suppressing CPB related acute inflammatory status. However, none of these proposed therapeutic modalities are considered yet as the final solution for defying the inflammation in these patients. Hence, inflammation treatment in patients under CPB is still among the hot topics of research in this field. However, there is not enough evidence for most of these available agents as the choice of treatment.

References

  • 1.

    Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update. Eur. J. Cardiothorac. Surg. 2002;21:232-44. [PubMed ID: 11825729].

  • 2.

    Ferasatkish R, Dabbagh A, Alavi M, Mollasadeghi G, Hydarpur E, Moghadam AA, Faritus ZS, Totonchi MZ. Effect of magnesium sulfate on extubation time and acute pain in coronary artery bypass surgery. Acta Anaesthesiol. Scand. 2008;52:1348-52. [PubMed ID: 19025526].

  • 3.

    Dabbagh A, Rajaei S, Shamsolahrar MH. The effect of intravenous magnesium sulfate on acute postoperative bleeding in elective coronary artery bypass surgery. J. Perianesth. Nurs. 2010;25:290-5. [PubMed ID: 20875883].

  • 4.

    Murphy GS, Hessel EA, Groom RC. Optimal perfusion during cardiopulmonary bypass: an evidence-based approach. Anesth. Analg. 2009;108:1394-417. [PubMed ID: 19372313].

  • 5.

    Warren OJ, Smith AJ, Alexiou C, Rogers PL, Jawad N, Vincent C, Darzi AW, Athanasiou T. The inflammatory response to cardiopulmonary bypass: part 1--mechanisms of pathogenesis. J. Cardiothorac. Vasc. Anesth. 2009;23:223-31. [PubMed ID: 18930659].

  • 6.

    Warren OJ, Watret AL, de Wit KL, Alexiou C, Vincent C, Darzi AW, Athanasiou T. The inflammatory response to cardiopulmonary bypass: part 2--anti-inflammatory therapeutic strategies. J. Cardiothorac. Vasc. Anesth. 2009;23:384-93. [PubMed ID: 19054695].

  • 7.

    Patel JA, Ghatak SB. Pexelizumab and its role in the treatment of myocardial infarction and in coronary artery bypass graft surgery: a review. Recent Pat. Cardiovasc. Drug Discov. 2008;3:145-52. [PubMed ID: 18537766].

  • 8.

    Miller BE, Levy JH. The inflammatory response to cardiopulmonary bypass. J. Cardiothorac. Vasc. Anesth. 1997;11:355-66. [PubMed ID: 9161905].

  • 9.

    Lante W, Franke A, Weinhold C, Markewitz A. Immunoglobulin levels and lymphocyte subsets following cardiac operations: further evidence for a T-helper cell shifting. Thorac. Cardiovasc. Surg. 2005;53:16-22. [PubMed ID: 15692913].

  • 10.

    Wan S, LeClerc JL, Vincent JL. Cytokine responses to cardiopulmonary bypass: lessons learned from cardiac transplantation. Ann. Thorac. Surg. 1997;63:269-76. [PubMed ID: 8993291].

  • 11.

    Rimmelé T, Venkataraman R, Madden NJ, Elder MM, Wei LM, Pellegrini RV, Kellum JA. Comparison of inflammatory response during on-pump and off-pump coronary artery bypass surgery. Int. J. Artif. Organs. 2010;33:131-8. [PubMed ID: 20383854].

  • 12.

    Karu I, Tähepõld P, Sulling TA, Alver M, Zilmer M, Starkopf J. Off-pump coronary surgery cause immediate release of myocardial damage markers. Asian Cardiovasc. Thorac. Ann. 2009;17:494-9. [PubMed ID: 19917792].

  • 13.

    Serrano CV Jr, Souza JA, Lopes NH, Fernandes JL, Nicolau JC, Blotta MH, Ramires JA, Hueb WA. Reduced expression of systemic proinflammatory and myocardial biomarkers after off-pump versus on-pump coronary artery bypass surgery: a prospective randomized study. J. Crit. Care. 2010;25:305-12. [PubMed ID: 19781902].

  • 14.

    Dietrich W. Aprotinin: 1 year on. Curr. Opin. Anaesthesiol. 2009;22:121-7. [PubMed ID: 19295302].

  • 15.

    Baden H, Jordal K, Lund F, Zachariae F. A double-blind controlled clinical trial of Trasylol. Preliminary results in acute pancreatitis and in prophylaxis against postoperative pancreatitis. Acta Chir. Scand. Suppl. 1967;378:97-102. [PubMed ID: 4866570].

  • 16.

    Olsen GB, Williams HT. Acute hemorrhagic necrosis of the pancreas of the dog and its suppression with Trasylol. Can. J. Surg. 1966;9:415-9. [PubMed ID: 5296949].

  • 17.

    Hashimoto D, Ohmuraya M, Wang J, Yamamura K, Hirota M, Baba H. Effect of low-molecular weight trypsin inhibitor, nafamostat mesilate, on trypsin activity using the pancreatic acinar cells. Pancreas. 2009;38:595-7. [PubMed ID: 19550278].

  • 18.

    Alonso A, Whitten CW, Hill GE. Pump prime only aprotinin inhibits cardiopulmonary bypass-induced neutrophil CD11b up-regulation. Ann. Thorac. Surg. 1999;67:392-5. [PubMed ID: 10197659].

  • 19.

    Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussières JS, Côté D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R. BART Investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N. Engl. J. Med. 2008;358:2319-31.

  • 20.

    Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J. Thorac. Cardiovasc. Surg. 1989;97:364-72. [PubMed ID: 2465457].

  • 21.

    Bidstrup BP, Royston D, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion in patients with septic endocarditis having open-heart surgery. Lancet. 1988;1:366-7. [PubMed ID: 2448562].

  • 22.

    Fergusson D, Glass KC, Hutton B, Shapiro S. Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding. Clin. Trials. 2005;2:218-29. [PubMed ID: 16279145].

  • 23.

    Beattie WS, Karkouti K. Con: Aprotinin has a good efficacy and safety profile relative to other alternatives for prevention of bleeding in cardiac surgery. Anesth. Analg. 2006;103:1360-4. [PubMed ID: 17122203].

  • 24.

    Karkouti K, Beattie WS. Aprotinin is useful as a hemostatic agent in cardiopulmonary surgery: no. J. Thromb. Haemost. 2006;4:1879-81. [PubMed ID: 16803464].

  • 25.

    Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A, Wijeysundera DN, Fedorko L and Yau TM. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion. 2006;46:327-38. [PubMed ID: 16533273].

  • 26.

    Mangano DT, Tudor IC, Dietzel C. Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N. Engl. J. Med. 2006;354:353-65. [PubMed ID: 16436767].

  • 27.

    Mangano DT, Rieves RD, Weiss KD. Judging the safety of aprotinin. N. Engl. J. Med. 2006;355:2261-2. [PubMed ID: 17124031].

  • 28.

    Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, Hoeft A, Fontes ML, Hillel Z, Ott E, Titov T, Dietzel C, Levin J. Investigators of The Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA. 2007;297:471-9. [PubMed ID: 17284697].

  • 29.

    Koch CG, Li L, Duncan AI, Mihaljevic T, Cosgrove DM, Loop FD, Starr NJ, Blackstone EH. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit. Care Med. 2006;34:1608-16. [PubMed ID: 16607235].

  • 30.

    Takagi H, Manabe H, Kawai N, Goto SN, Umemoto T. Aprotinin increases mortality as compared with tranexamic acid in cardiac surgery: a meta-analysis of randomized head-to-head trials. Interact. Cardiovasc. Thorac. Surg. 2009;9:98-101. [PubMed ID: 19380335].

  • 31.

    Augoustides JG. Perioperative safety of aprotinin in coronary artery bypass graft surgery: is there life after BART. Drug Saf. 2008;31:557-60. [PubMed ID: 18558789].

  • 32.

    Murkin JM. Lessons learned in antifibrinolytic therapy: The BART trial. Semin. Cardiothorac. Vasc. Anesth. 2009;13:127-31. [PubMed ID: 19622534].

  • 33.

    Henry D, Carless P, Fergusson D, Laupacis A. The safety of aprotinin and lysine-derived antifibrinolytic drugs in cardiac surgery: a meta-analysis. CMAJ. 2009;180:183-93. [PubMed ID: 19050037].

  • 34.

    Ide M, Bolliger D, Taketomi T, Tanaka KA. Lessons from the aprotinin saga: current perspective on antifibrinolytic therapy in cardiac surgery. J. Anesth. 2010;24:96-106. [PubMed ID: 20039075].

  • 35.

    Hill GE, Alonso A, Spurzem JR, Stammers AH, Robbins RA. Aprotinin and methylprednisolone equally blunt cardiopulmonary bypass-induced inflammation in humans. J. Thorac. Cardiovasc. Surg. 1995;110:1658-62. [PubMed ID: 8523876].

  • 36.

    Anti-inflammatory effect of aprotinin: a meta-analysis. J. Extra Corpor. Technol. 2009;41:79-86. [PubMed ID: 19681304].

  • 37.

    Landis C. Pharmacologic strategies for combating the inflammatory response. J. Extra Corpor. Technol. 2007;39:291-5. [PubMed ID: 18293823].

  • 38.

    Robertson-Malt S, Afrane B, El Barbary M. Prophylactic steroids for pediatric open heart surgery. Cochrane Database Syst. Rev. 2007;17:CD005550. [PubMed ID: 17943866].

  • 39.

    Chaney MA. Corticosteroids and cardiopulmonary bypass: a review of clinical investigations. Chest. 2002;121:921-31. [PubMed ID: 11888978].

  • 40.

    Baker WL, White CM, Kluger J, Denowitz A, Konecny CP, Coleman CI. Effect of perioperative corticosteroid use on the incidence of postcardiothoracic surgery atrial fibrillation and length of stay. Heart Rhythm. 2007;4:461-8. [PubMed ID: 17399635].

  • 41.

    Marik PE, Fromm R. The efficacy and dosage effect of corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a systematic review. J. Crit. Care. 2009;24:458-63. [PubMed ID: 19327322].

  • 42.

    Raja SG, Dreyfus GD. Modulation of systemic inflammatory response after cardiac surgery. Asian Cardiovasc. Thorac. Ann. 2005;13:382-95. [PubMed ID: 16304234].

  • 43.

    Yasser Mohamed Amr, Elmistekawy E, El-Serogy H. Effects of dexamethasone on pulmonary and renal functions in patients undergoing CABG with cardiopulmonary bypass. Semin. Cardiothorac. Vasc. Anesth. 2009;13:231-7. [PubMed ID: 19948518].

  • 44.

    Cappabianca G, Rotunno C, de Luca Tupputi Schinosa L, Ranieri VM, Paparella D. Protective effects of steroids in cardiac surgery: a meta-analysis of randomized double-blind trials. J. Cardiothorac. Vasc. Anesth. 2011;25:156-65. [PubMed ID: 20537923].

  • 45.

    Bezuhly M, Liwski R, West KA, Morris SF. Activated protein C: an emerging therapeutic agent in the prevention of ischemia-reperfusion injury. J. Reconstr. Microsurg. 2008;24:361-7. [PubMed ID: 18597223].

  • 46.

    Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury-a review. J. Surg. Res. 2008;150:304-30. [PubMed ID: 19040966].

  • 47.

    Sadat U. Signaling pathways of cardioprotective ischemic preconditioning. Int. J. Surg. 2009;7:490-8. [PubMed ID: 19540944].

  • 48.

    Prabhu A, Sujatha DI, Ninan B, Vijayalakshmi MA. Neutrophil gelatinase associated lipocalin as a biomarker for acute kidney injury in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Ann. Vasc. Surg. 2010;24:525-31. [PubMed ID: 20363104].

  • 49.

    Lanzarone E, Gelmini F, Fumero A, Carini M, Costantino ML, Fumero R, Alfieri O. Preservation of endothelium nitric oxide release during beating heart surgery with respect to continuous flow cardiopulmonary bypass. Perfusion. 2010;25:57-64. [PubMed ID: 20194585].

  • 50.

    Veglia F, Werba JP, Tremoli E, Squellerio I, Sisillo E, Parolari A, Minardi F, Cavalca V. Assessment of oxidative stress in coronary artery bypass surgery: comparison between the global index OXY-SCORE and individual biomarkers. Biomarkers. 2009;14:465-72. [PubMed ID: 19863184].

  • 51.

    Collard CD, Gelman S. Pathophysiology, clinical manifestations, and prevention of ischemia-reperfusion injury. Anesthesiology. 2001;94:1133-8. [PubMed ID: 11465607].

  • 52.

    Yeh CH, Chen TP, Wang YC, Lin YM, Fang SW. Cardiomyocytic apoptosis limited by bradykinin via restoration of nitric oxide after cardioplegic arrest. J. Surg. Res. 2010;163:e1-9. [PubMed ID: 20638673].

  • 53.

    Borowski A, Kurt M, Calvo S, Paprotny G, Godehardt E, Fraessdorf J, Ghodsizad A. Metabolic monitoring of postischemic myocardium during intermittent warm-blood cardioplegic administration. Tex. Heart Inst. J. 2010;37:184-8. [PubMed ID: 20401291].

  • 54.

    Schwartz SM, Duffy JY, Pearl JM, Nelson DP. Cellular and molecular aspects of myocardial dysfunction. Crit. Care Med. 2001;29:S214-9. [PubMed ID: 11593064].

  • 55.

    Ustunsoy H, Sivrikoz MC, Tarakcioglu M, Bakir K, Guldur E, Celkan MA. The effects of pentoxifylline on the myocardial inflammation and ischemia-reperfusion injury during cardiopulmonary bypass. J. Card. Surg. 2006;21:57-61. [PubMed ID: 16426349].

  • 56.

    Hamamoto M, Suga M, Takahashi Y, Sato Y, Inamori S, Yagihara T, Nakatani T, Kitamura S. Suppressive effect of phosphodiesterase type 4 inhibitions on systemic inflammatory responses after cardiopulmonary bypass. J. Artif. Organs. 2006;9:144-8. [PubMed ID: 16998698].

  • 57.

    Chanani NK, Cowan DB, Takeuchi K, Poutias DN, Garcia LM, del Nido PJ, McGowan FX Jr. Differential effects of amrinone and milrinone upon myocardial inflammatory signaling. Circulation. 2002;106:I284-9. [PubMed ID: 12354747].

  • 58.

    Yamaura K, Okamoto H, Akiyoshi K, Irita K, Taniyama T, Takahashi S. Effect of low-dose milrinone on gastric intramucosal pH and systemic inflammation after hypothermic cardiopulmonary bypass. J. Cardiothorac. Vasc. Anesth. 2001;15:197-203. [PubMed ID: 11312479].

  • 59.

    Yamaura K, Akiyoshi K, Irita K, Taniyama T, Takahashi S. Effects of olprinone, a new phosphodiesterase inhibitor, on gastric intramucosal acidosis and systemic inflammatory responses following hypothermic cardiopulmonary bypass. Acta Anaesthesiol. Scand. 2001;45:427-34. [PubMed ID: 11300380].

  • 60.

    Möllhoff T, Loick HM, Van Aken H, Schmidt C, Rolf N, Tjan TD, Asfour B, Berendes E. Milrinone modulates endotoxemia, systemic inflammation, and subsequent acute phase response after cardiopulmonary bypass (CPB). Anesthesiology. 1999;90:72-80. [PubMed ID: 9915315].

  • 61.

    Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD. Complement and coagulation: strangers or partners in crime. Trends Immunol. 2007;28:184-92. [PubMed ID: 17336159].

  • 62.

    Huber K, Holmes DR Jr, van’t Hof AW, Montalescot G, Aylward PE, Betriu GA, Widimsky P, Westerhout CM, Granger CB, Armstrong PW. Use of glycoprotein IIb/IIIa inhibitors in primary percutaneous coronary intervention: insights from the APEX-AMI trial. Eur. Heart J. 2010;31:1708-16. [PubMed ID: 20501476].

  • 63.

    Toma M, Fu Y, Ezekowitz JA, McAlister FA, Westerhout CM, Granger CB, Armstrong PW. Does silent myocardial infarction add prognostic value in ST-elevation myocardial infarction patients without a history of prior myocardial infarction? Insights from the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) Trial. Am. Heart J. 2010;160:671-7. [PubMed ID: 20934561].

  • 64.

    Testa L, Van Gaal WJ, Bhindi R, Biondi-Zoccai GG, Abbate A, Agostoni P, Porto I, Andreotti F, Crea F, Banning AP. Pexelizumab in ischemic heart disease: a systematic review and meta-analysis on 15,196 patients. J. Thorac. Cardiovasc. Surg. 2008;136:884-93. [PubMed ID: 18954626].

  • 65.

    Sonntag J, Dähnert I, Stiller B, Hetzer R, Lange PE. Complement and contact activation during cardiovascular operations in infants. Ann. Thorac. Surg. 1998;65:525-31. [PubMed ID: 9485258].

  • 66.

    Göl MK, Nisanoğlu V, Işcan Z, Balci M, Kandemir O, Taşdemir O. Inhibition of systemic inflammatory response with sodium nitroprusside in open heart surgery. J. Cardiovasc. Surg. (Torino). 2002;43:803-9.

  • 67.

    Ghavami S, Mutawe MM, Sharma P, Yeganeh B, McNeill KD, Klonisch T, Unruh H, Kashani HH, Schaafsma D, Los M, Halayko AJ. Mevalonate cascade regulation of airway mesenchymal cell autophagy and apoptosis: a dual role for p53. PLoS One. 2011;6:e16523. [PubMed ID: 21304979].

  • 68.

    Bach F, Grundmann U, Bauer M, Buchinger H, Soltész S, Graeter T, Larsen R, Silomon M. Modulation of the inflammatory response to cardiopulmonary bypass by dopexamine and epidural anesthesia. Acta Anaesthesiol. Scand. 2002;46:1227-35. [PubMed ID: 12421195].

  • 69.

    Berendes E, Möllhoff T, Van Aken H, Schmidt C, Erren M, Deng MC, Weyand M, Loick HM. Effects of dopexamine on creatinine clearance, systemic inflammation, and splanchnic oxygenation in patients undergoing coronary artery bypass grafting. Anesth. Analg. 1997;84:950-7. [PubMed ID: 9141914].

  • 70.

    Murphy GS, Szokol JW, Marymont JH, Avram MJ, Vender JS. The effects of morphine and fentanyl on the inflammatory response to cardiopulmonary bypass in patients undergoing elective coronary artery bypass graft surgery. Anesth. Analg. 2007;104:1334-42. [PubMed ID: 17513621].

  • 71.

    Bartoc C, Frumento RJ, Jalbout M, Bennett-Guerrero E, Du E, Nishanian E. A randomized, double-blind, placebo-controlled study assessing the anti-inflammatory effects of ketamine in cardiac surgical patients. J. Cardiothorac. Vasc. Anesth. 2006;20:217-22. [PubMed ID: 16616662].

  • 72.

    Zilberstein G, Levy R, Rachinsky M, Fisher A, Greemberg L, Shapira Y, Appelbaum A, Roytblat L. Ketamine attenuates neutrophil activation after cardiopulmonary bypass. Anesth. Analg. 2002;95:531-6. [PubMed ID: 12198030].

  • 73.

    Roytblat L, Talmor D, Rachinsky M, Greemberg L, Pekar A, Appelbaum A, Gurman GM, Shapira Y, Duvdenani A. Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth. Analg. 1998;87:266-71. [PubMed ID: 9706914].

  • 74.

    Stammberger U, Hamacher J, Pache JC, Schmid RA. sCR1sLe(X) reduces lung allograft ischemia-reperfusion injury but does not ameliorate acute rejection. Eur. J. Cardiothorac. Surg. 2002;22:368-72. [PubMed ID: 12204725].

  • 75.

    Kyriakides C, Wang Y, Austen WG Jr, Favuzza J, Kobzik L, Moore FD Jr, Hechtman HB. Sialyl Lewis(x) hybridized complement receptor type 1 moderates acid aspiration injury. Am. J. Physiol. Lung Cell Mol. Physiol. 2001;281:L1494-9. [PubMed ID: 11704546].

  • 76.

    Zacharowski K, Otto M, Hafner G, Marsh HC Jr, Thiemermann C. Reduction of myocardial infarct size with sCR1sLe(x), an alternatively glycosylated form of human soluble complement receptor type 1 (sCR1), possessing sialyl Lewis x. Br. J. Pharmacol. 1999;128:945-52. [PubMed ID: 10556930].

  • 77.

    Billings FT, Pretorius M, Siew ED, Yu C, Brown NJ. Early postoperative statin therapy is associated with a lower incidence of acute kidney injury after cardiac surgery. J. Cardiothorac. Vasc. Anesth. 2010;24:913-20. [PubMed ID: 20599398].

  • 78.

    Hudetz JA, Pagel PS. Neuroprotection by ketamine: a review of the experimental and clinical evidence. J. Cardiothorac. Vasc. Anesth. 2010;24:131-42. [PubMed ID: 19640746].

  • 79.

    Hudetz JA, Patterson KM, Iqbal Z, Gandhi SD, Byrne AJ, Hudetz AG, Warltier DC, Pagel PS. Ketamine attenuates delirium after cardiac surgery with cardiopulmonary bypass. J. Cardiothorac. Vasc. Anesth. 2009;23:651-7. [PubMed ID: 19231245].

  • 80.

    Liu T, Li G, Xu G. Levosimendan may prevent postoperative atrial fibrillation through anti-inflammatory and antioxidant modulation. J. Cardiothorac. Vasc. Anesth. 2009;23:757-8. [PubMed ID: 19101169].

  • 81.

    Cho EJ, Yoon JH, Hong SJ, Lee SH, Sim SB. The effects of sevoflurane on systemic and pulmonary inflammatory responses after cardiopulmonary bypass. J. Cardiothorac. Vasc. Anesth. 2009;23:639-45. [PubMed ID: 19362013].

  • 82.

    Krzych LJ, Szurlej D, Bochenek A. Rationale for propofol use in cardiac surgery. J. Cardiothorac. Vasc. Anesth. 2009;23:878-85. [PubMed ID: 19577484].

  • 83.

    Ozturk T, Gok S, Nese N. Levosimendan attenuate reperfusion injury in an isolated perfused rat heart model. J. Cardiothorac. Vasc. Anesth. 2010;24:624-8. [PubMed ID: 19875306].

  • 84.

    Krzych L, Szurlej D, Bochenek A. Response: Is it reasonable to discourage propofol use in cardiac surgery patients until strong evidence is provided? J. Cardiothorac. Vasc. Anesth. 2011;25:202.

  • 85.

    Poulsen TD, Andersen LW, Steinbrüchel D, Gøtze JP, Jørgensen OS, Olsen NV. Two large preoperative doses of erythropoietin do not reduce the systemic inflammatory response to cardiac surgery. J. Cardiothorac. Vasc. Anesth. 2009;23:316-23. [PubMed ID: 18948032].

  • 86.

    Foroughi M, Rahimian H, Dabbagh A, Majidi M, Hekmat M, Beheshti M, Shahzamani M. Postoperative n-terminal pro-brain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment. J. Cardiothorac. Vasc. Anesth. 2012. Article in Press.

  • 87.

    Gunaydin S, Ucar HI, Serter T, McCusker K, Ozcelik G, Salman N, Yorgancioglu AC. Hyaluronan based heparin free coated open and closed extracorporeal circuits for high risk coronary revascularization. J. Extra Corpor. Technol. 2010;42:286-92. [PubMed ID: 21313926].

  • 88.

    Thiara AS, Andersen VY, Videm V, Mollnes TE, Svennevig K, Hoel TN, Fiane AE. Comparable biocompatibility of Phisio- and Bioline-coated cardiopulmonary bypass circuits indicated by the inflammatory response. Perfusion. 2010;25:9-16. [PubMed ID: 20172900].

  • 89.

    Wagner WR, Johnson PC, Thompson KA, Marrone GC. Heparin-coated cardiopulmonary bypass circuits: hemostatic alterations and postoperative blood loss. Ann. Thorac. Surg. 1994;58:734-40. [PubMed ID: 7944696].

  • 90.

    Gunaydin S, McCusker K, Sari T, Onur MA, Zorlutuna Y. Clinical performance and biocompatibility of hyaluronan-based heparin-bonded extracorporeal circuits in different risk cohorts. Interact. Cardiovasc. Thorac. Surg. 2010;10:371-6. [PubMed ID: 20026488].

  • 91.

    Gunaydin S, Farsak B, McCusker K, Vijay V, Sari T, Onur MA, Gurpinar A, Zorlutuna Y. Clinical and biomaterial evaluation of hyaluronan-based heparin-bonded extracorporeal circuits with reduced versus full systemic anticoagulation in reoperation for coronary revascularization. J. Cardiovasc. Med. (Hagerstown). 2009;10:135-42. [PubMed ID: 19377380].

  • 92.

    Andersson J, Larsson R, Richter R, Ekdahl KN, Nilsson B. Binding of a model regulator of complement activation (RCA) to a biomaterial surface: surface-bound factor H inhibits complement activation. Biomaterials. 2001;22:2435-43. [PubMed ID: 11511041].

  • 93.

    Draaisma AM, Hazekamp MG, Anes N, Schoof PH, Hack CE, Sturk A, Dion RA. Phosphorylcholine coating of bypass systems used for young infants does not attenuate the inflammatory response. Ann. Thorac. Surg. 2006;81:1455-9. [PubMed ID: 16564292].

  • 94.

    Kiliç D, Gunaydin S, Kisa U, Sari T, Deveci O, Zorlutuna Y. Clinical efficacy of leukofiltration on cardiopulmonary bypass related inflammatory response: Fact or Foe? Inflamm. Res. 2009;58:292-7.

  • 95.

    Welsby IJ, Jones WL, Arepally G, De Lange F, Yoshitani K, Phillips-Bute B, Grocott HP, Becker R, Mackensen GB. Effect of combined anticoagulation using heparin and bivalirudin on the hemostatic and inflammatory responses to cardiopulmonary bypass in the rat. Anesthesiology. 2007;106:295-301. [PubMed ID: 17264724].

  • 96.

    Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD. The role of complement in biomaterial-induced inflammation. Mol. Immunol. 2007;44:82-94. [PubMed ID: 16905192].

  • 97.

    Stiller B, Sonntag J, Dähnert I, Alexi-Meskishvili V, Hetzer R, Fischer T, Lange PE. Capillary leak syndrome in children who undergo cardiopulmonary bypass: clinical outcome in comparison with complement activation and C1 inhibitor. Intensive Care Med. 2001;27:193-200. [PubMed ID: 11280634].

  • 98.

    Gunaydin S, Mccusker K, Vijay V. Clinical performance and biocompatibility of novel hyaluronan-based heparin-bonded extracorporeal circuits. J. Extra Corpor. Technol. 2005;37:290-5. [PubMed ID: 16350383].

  • 99.

    Valle-Giner I, Martí-Bonmatí E, Alegría-Torán A, Montero A, Morcillo EJ. Changes in alpha-tocopherol and retinol levels during cardiopulmonary bypass correlate with maximal arterial partial pressure of oxygen. Free Radic. Res. 2007;41:1061-7. [PubMed ID: 17729125].

  • 100.

    Apostolakis EE, Koletsis EN, Baikoussis NG, Siminelakis SN, Papadopoulos GS. Strategies to prevent intraoperative lung injury during cardiopulmonary bypass. J. Cardiothorac. Surg. 2010;5:1.

  • 101.

    Li S, Price R, Phiroz D, Swan K, Crane TA. Systemic inflammatory response during cardiopulmonary bypass and strategies. J. Extra Corpor. Technol. 2005;37:180.

  • 102.

    Lappegård KT, Fung M, Bergseth G, Riesenfeld J, Mollnes TE. Artificial surface-induced cytokine synthesis: effect of heparin coating and complement inhibition. Ann. Thorac. Surg. 2004;78:38-44. [PubMed ID: 15223398].

  • 103.

    Day JR, Taylor KM. The systemic inflammatory response syndrome and cardiopulmonary bypass. Int. J. Surg. 2005;3:129-40. [PubMed ID: 17462274].

  • 104.

    Miranda DR, Gommers D, Papadakos PJ, Lachmann B. Mechanical ventilation affects pulmonary inflammation in cardiac surgery patients: the role of the open-lung concept. J. Cardiothorac. Vasc. Anesth. 2007;21:279-84. [PubMed ID: 17418750].

  • 105.

    Eichenbaum KD, Neustein SM. Acute lung injury after thoracic surgery. J. Cardiothorac. Vasc. Anesth. 2010;24:681-90. [PubMed ID: 20060320].

  • 106.

    Raja SG, Berg GA. Impact of off-pump coronary artery bypass surgery on systemic inflammation: current best available evidence. J. Card. Surg. 2007;22:445-55. [PubMed ID: 17803591].

  • 107.

    Kunes P, Mandak J, Harrer J, Kolackova M, Andrys C, Holicka M, Krejsek J. Up-regulation of the Apo/Fas (CD95) complex on neutrophils harvested during cardiac surgery: distinct findings in patients operated on with or without the use of cardiopulmonary bypass. Perfusion. 2010;25:41-6. [PubMed ID: 20164160].

  • 108.

    Elahi MM, Yii M, Matata BM. Significance of oxidants and inflammatory mediators in blood of patients undergoing cardiac surgery. J. Cardiothorac. Vasc. Anesth. 2008;22:455-67. [PubMed ID: 18503942].

  • 109.

    McFarlane HJ, MacDonald J, Collins TC, Molyneaux PJ, Carman WF. Severe pneumonia after cardiac surgery as a result of infection with parainfluenza virus type 4. J. Cardiothorac. Vasc. Anesth. 2009;23:84-6. [PubMed ID: 18834791].

  • 110.

    Schober P, Kalmanowicz M, Schwarte LA, Loer SA. Cardiopulmonary bypass increases endogenous carbon monoxide production. J. Cardiothorac. Vasc. Anesth. 2009;23:802-6. [PubMed ID: 19394869].

  • 111.

    Zangrillo A, Garozzo FA, Biondi-Zoccai G, Pappalardo F, Monaco F, Crivellari M, Bignami E, Nuzzi M, Landoni G. Miniaturized cardiopulmonary bypass improves short-term outcome in cardiac surgery: a meta-analysis of randomized controlled studies. J. Thorac. Cardiovasc. Surg. 2010;139:1162-9. [PubMed ID: 19775708].