REVIEW ARTICLE
Does Pharmacotherapy Influence the Inflammatory Responses During Cardiopulmonary Bypass in Children? Berber Kapitein, MD, PhD,* Anne-Wil van Saet, MD,† Hanna D. Golab, PhD,‡ Matthijs de Hoog, MD, PhD,* Saskia de Wildt, MD, PhD,* Dick Tibboel, MD, PhD,* and Ad J. J. C. Bogers, MD, PhD‡
Abstract: Cardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) by factors such as contact of the blood with the foreign surface of the extracorporeal circuit, hypothermia, reduction of pulmonary blood flow during CPB and endotoxemia. SIRS is maintained in the postoperative phase, co-occurring with a counter anti-inflammatory response syndrome. Research on the effects of drugs administered before the surgery, especially in the induction phase of anesthesia, as well as drugs used during extracorporeal circulation, has revealed that they greatly influence these postoperative inflammatory responses. A better understanding of these processes may not only improve postoperative recovery but also enable tailor-made pharmacotherapy, with both health and economic benefits. In this review, we describe the pathophysiology of SIRS and counter antiinflammatory response syndrome in the light of CPB in children and the influence of drugs used on these syndromes. Key Words: cardiopulmonary bypass, systemic inflammatory response syndrome, counter anti-inflammatory response syndrome, drugs (J Cardiovasc Pharmacol Ô 2014;64:191–197)
INFLAMMATORY BALANCE AFTER MAJOR SURGERY The immune system is supposed to protect the body against a variety of pathologic insults.1,2 It does so primarily by maintaining a balance between proinflammatory and antiinflammatory responses. Major surgery with or without cardiopulmonary bypass (CPB) will also evoke a physiologic and self-limiting inflammatory response toward extrinsic factors (anesthesia, hypothermia, or contact of the body with foreign Received for publication October 22, 2013; accepted March 13, 2014. From the *Intensive Care Unit, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; †Department of Anesthesiology, Intensive Care Unit, Erasmus MC, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; and ‡Department of Cardiothoracic Surgery, Erasmus MC, Rotterdam, the Netherlands. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.jcvp.org). Reprints: Berber Kapitein, MD, PhD, Intensive Care Unit, Erasmus MCSophia Children’s Hospital, Dr Molewaterplein, 60, 3015 GJ Rotterdam, the Netherlands (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
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surfaces) and intrinsic factors (the actual tissue damage, ischemia-reperfusion damage, endothelial cell activation).3,4 If the proinflammatory response is exaggerated and/or prolonged, the body may be at risk for end-organ damage.5 This proinflammatory response has been described as the systemic inflammatory response syndrome (SIRS) in the 1992 ACC/SCCM consensus conference. In general, SIRS is diagnosed when 2 or more of the following clinical findings are present: rectal body temperature .388C or ,368C, heart rate .90th percentile for age, respiratory rate .90th percentile for age or hyperventilation to a PaCO2 ,32 mm Hg (4.2 kPa), and white blood cell count of .12,000 cells per microliter or ,4000 cells per microliter.6 Numerous factors of the human immune system contribute to SIRS, from proinflammatory cytokines such as interleukin 1 (IL-1), IL-6, IL-8, and tumor necrosis factor (TNF)-a, to platelet and clotting factors, complement factors and neutrophil degranulation, as seen after surgery.7–10 The crucial mechanism in SIRS seems to be the activation of endothelial cells and endothelial production of cytokines by recruitment of immune cells to the site of damage.11 It has long been thought that the body mounts a counter-response toward this proinflammatory response. Indeed, critically ill patients show several defects in adaptive immunity, varying from decreased T-cell proliferative responses, increased lymphocyte and dendritic cell apoptosis and a shift from a TH1 to a TH2 environment, leading to immune suppression and unresponsiveness of immune cells known as immune anergy.12,13 Bone described this as the counter anti-inflammatory response syndrome (CARS) in 1996.14 We now know that CARS is not a response to SIRS as such but rather coincides with SIRS.15 It seems that both are not particular syndromes but represent an imbalance in physiological mechanisms. Of the extrinsic factors to which the immune system responds, the anesthetic agents given before and during CPB, but possibly also the drugs given in the recovery period seem to influence the inflammatory response. Anesthetic agents, both volatile as well as local and regional agents, may either exert an indirect influence by modulation of the neuroendocrine surgical stress response or a direct influence by affecting the immune cells. Both issues will be addressed in this review. In general, immune cells seem to be the most sensitive to volatile anesthetic agents.16–19 Most research on the immunological effects of anesthetic agents has been performed in vitro because in vivo studies are complicated by confounding factors such as type, duration www.jcvp.org |
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and complexity of surgery and heterogeneity of the patient population itself.20 Furthermore, both in vitro and in vivo studies show conflicting results because of large methodological differences (see Tables, Supplemental Digital Content 1, http://links.lww.com/JCVP/A160; Supplemental Digital Content 2, http://links.lww.com/JCVP/A161; and Supplemental Digital Content 3, http://links.lww.com/JCVP/A162). And, more importantly, data in the pediatric population are scarce. In the following review, we describe the inflammatory processes in the light of CPB with a focus on the pediatric population and elucidate the interactions of perioperative drugs with both syndromes. The pharmacokinetics (PK) and pharmacodynamics of commonly used drugs during CPB have recently been reviewed by our group and are outside the scope of this review.21
IMMUNOLOGICAL BACKGROUND OF INFLAMMATORY RESPONSES IN CPB Postoperative inflammatory responses seem to be evoked by 2 different mechanisms.22 First, surgery will directly activate both the innate and adaptive immune system. Activation of the innate immune cells such as monocytes, macrophages and neutrophils leads to the release of cytokines such as TNF-a, IL-1, IL-6, IL-8, and IL-12.23 This innate immune response is predominantly triggered through Tolllike receptors 2 and 4 (TLR2 and TLR4). Endogenous ligands for these receptors are reactive oxygen species (whose production is triggered by all the intrinsic factors seen in major surgery) and specific danger associated molecular patterns (DAMPs) such as free heme, hyaluronic acid, or heat shock proteins. DAMPs are released after tissue injury and (subsequent) hemorrhage.24–26 Both reactive oxygen species and DAMPs may lead to the production of proinflammatory cytokines by TLR4 signaling.27 Subsequently these cytokines stimulate the adaptive CD4+ T lymphocytes, consisting of T-helper (TH) and T-regulatory (Treg) cells. Historically, 2 subsets of TH cells, TH1 and TH2, have been described, according to the cytokines they produce (see Table, Supplemental Digital Content 1, http://links.lww.com/JCVP/A160). Tregs seem to be mainly responsible for the production of IL-10 and therefore possibly play a major role in immune-regulatory processes. Interestingly, Tregs are capable of selectively expressing TLR2 and TLR4, which could make them susceptible for DAMPs after surgery.28,29 The second mechanism creating a proinflammatory response is the acute stressor state after surgery. The hypothalamic–pituitary–adrenal axis, the adrenergic nervous and renin– angiotensin–aldosteron systems are activated with subsequent release of both cortisol and catecholamines.30 This response is not only thought to induce a proinflammatory state by directly activating the adaptive immune system, but also to induce a shift from a TH1 toward a more regulatory TH2 inflammatory response as seen after surgery and trauma.22 Furthermore, the stressor state leads to a cation dyshomeostasis with cellular influx of calcium, potassium, magnesium, zinc, and selenium. This results in low serum levels and more importantly, in cellular overloading with these cations, leading to activation of
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cells and the induction of oxidative stress by the mitochondria with the production of reactive oxygen species.31 In summary, surgery induces an inflammatory response by direct activation of the innate immune system leading to both proinflammatory and more regulatory anti-inflammatory responses. Furthermore, surgery activates the adaptive immune response, which is mainly a TH2 response with immunoregulatory properties. As will be described, the drugs given perioperatively can influence these different components of the inflammatory responses.
ROLE OF THE CELL TYPES OF THE IMMUNE SYSTEM IN SIRS AFTER CPB When investigating the interaction between CPB, inflammation, and pharmacotherapy, one should first recognize the different components of these inflammatory responses because the drugs given influence these cells individually. As said, the innate immune system will be the first to respond to the effects of CPB. Neutrophils, part of the group of polymorphonuclear cells, are the major cellular component of the innate immune system. Neutrophils appear to have a limited capacity of producing cytokines but are pivotal for the capillary leak and tissue damage seen after CPB, caused by endothelial migration.32–34 On activation by proinflammatory cytokines, TNF-a, IL-1b, and IL-8, neutrophils in the circulation express CD62L (L-selectin). CD62L decreases the rolling velocity of neutrophils along endothelial cells and provides the initial attachment to the endothelium. On attachment, CD62L is shed. Simultaneously, the b2-integrin CD18 with the variable alpha units CD11a (leukocyte function associated antigen or LFA), CD11b membrane attack complex (MAC-1), or CD11c enhance attachment of the neutrophils to the endothelium and promote transendothelial migration.8,35,36 Finally, neutrophils migrate through the endothelial barrier and release intracellular enzymes such as elastase and myeloperoxidase.36,37 Several studies reveal that CPB causes increased sequestration of neutrophils into capillaries and raises the amount of human neutrophil elastase in the circulation.38,39 In summary, neutrophils are activated by CPB, and increased expression of both L-selectin and integrins facilitates adherence to endothelial cells with subsequent transmigration leading to tissue damage.
MONOCYTES/MACROPHAGES The innate immune system also includes monocytes and their activated state, macrophages. Like neutrophils, they can extravasate into tissues after activation, also because of upregulation of CD18/CD11a (LFA) and CD18/CD11b (MAC-1) and shedding of CD62L.40–42 Different from neutrophils, monocytes seem to be the main producers of cytokines as seen in post-CPB inflammation.32,43 However, in contradiction with this finding, several studies demonstrate a deactivated state after CPB with lower production of both TNF-a and IL-10. This deactivation seems predictive of increased postoperative morbidity.42,44 Further evidence for a deactivated state in monocytes, 4 hours to several days after CPB, is shown by the decreased expression of the major histocompatibility complex class II (MHC II) molecule HLA-DR after CPB.45,46 This marker is crucial for antigen Ó 2014 Lippincott Williams & Wilkins
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presentation and recognition, and reduction of HLA-DR is associated with increased morbidity and mortality in multiple organ failure and critical illness.44,47–50 Thus, monocytes seem to be heavily involved in both the cytokine burst seen in postCPB SIRS and the hyporesponsiveness of the immune system seen in post-CPB CARS.
COMPLEMENT SYSTEM The complement system is a non-cellular component of the innate immune system and a major trigger in the inflammatory response following contact of blood with a foreign surface.51–53 Depending on its trigger, the classical, lectin, or alternative pathway of the complement cascade is activated. Either pathway leads to activation of C3 and C5 by cleavage of these complement proteins. These final complement products are proinflammatory and optimize opsonization, chemotaxis, and lysis of cells. The cleavage products C3a and C5a are extremely potent anaphylatoxins, and C5b-9 is also known as the MAC, which can directly lyse cells, including cardiomyocytes.54–56 The unique activation of the complement system during CPB is believed to be one of the causative factors of the capillary leak syndrome seen with SIRS.57,58
LYMPHOCYTES Lymphocytes are not only activated by the cytokines and actions of the innate immune response, but also by endogenous (HSP) and exogenous (lipopolysacharide, peptidoglycan) TLR activation,59–61 the sheer stress of CPB62 and the anesthetic agents given.63,64 In CPB, specifically the number of circulating CD4+ T cells starts to decrease immediately after CPB for up to 3 days. This decrease seems to contribute to post-CPB immune suppression. It might be caused by hemodilution, but in view of increasing numbers of natural killer cells and B cells, it is more likely that CD4+ T cells exit the circulation both because of extravasation and apoptosis.65,66 Apoptosis of T cells is thought to be one of the main homeostatic functions in the adaptive immune system to maintain a balance between immune activation and immune suppression.67,68 Several mechanisms may stimulate apoptosis. Increased expression of CD69 seems to suggest enhanced T-cell responsiveness in the early stages of CPB, a state conducive to activation-induced cell death or anergy.69,70 In pediatric CPB, T cells also show increased Fas mediated apoptosis, which was not seen in other surgical procedures.71 Lymphocytes and monocytes are believed to be major compartments of the peripheral blood mononuclear cells, which would account for the cytokine burst seen after CPB despite decreasing circulating numbers of T cells.32 Still, T cells might be responsible for the initial cytokine burst seen in CPB, at least in adults, but this would then trigger restraining mechanisms that ultimately lead to CARS with immune suppression.
INFLUENCE OF THE CPB SYSTEM COMPONENTS ON SIRS IN THE PEDIATRIC POPULATION The inflammatory effects of CPB are more profound in children than in adults. Children are immunologically immature, Ó 2014 Lippincott Williams & Wilkins
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and the organs, the coagulation system and the endocrine system, are still developing. As will be reviewed further, the immune system in the neonatal period consists largely of an innate response as the adaptive response is still developing. But more importantly, neonates’ higher metabolic demands require higher perfusion flow rates per body surface area. In every CPB system, blood-cell components are exposed to shearing forces, which in pediatric CPB are intensified by higher flow rates.72 Finally, in pediatric CPB, the circuit size is disproportionate to the child’s body surface. The resulting dilution of clotting factors, red blood cells, and plasma proteins accelerates the transfusion rate with additional triggering of the inflammatory response.73 In adults, the technique of cell saving was instituted in the early 1990s, and technical advancements have now made salvaged blood available for pediatric surgeries as well.74,75 Miniaturization of the CPB system was undertaken as well. Various studies show that miniaturization of the circuit leads to a lesser amount of transfused red blood cells, platelets, and plasma products, both during CPB and postoperatively; also extubation can be attempted earlier.73,76–78 Other factors such as core temperature, different coatings of the CPB circuit, or the insertion of leukocyte filters did not seem to influence post-CPB inflammation.79–81 In conclusion, technical aspects of CPB have a greater impact on pediatric CPB than on adult CPB. This consideration must be taken into account when studying the effects on inflammation and comparing studies from different centers (see also Tables, Supplemental Digital Content 1, http://links.lww.com/JCVP/A160; and Supplemental Digital Content 2, http://links.lww.com/JCVP/A161).
INFLAMMATORY RESPONSES AFTER CPB IN CHILDREN As said, one of the arguments against extrapolating data from studies in the adult population to the pediatric population is the great contrast between a developed (adult) and a developing (from neonate to adolescent) immune system82. Pediatric cardiothoracic surgery often takes place in the first year of life, when the innate immune response is present, but the adaptive immune response is still developing. Neonates (age up to 4 weeks) have high numbers of circulating TH cells expressing CD4 and CD8, but these cells cannot produce TH specific cytokines such as INFgand IL-10.83–85 These adaptive immune responses increase over the childhood and adolescence life stages toward an adult response. It is very likely that this development interferes with the responses seen with SIRS, especially with the second phase in which cytokine responses, both proinflammatory and anti-inflammatory, are mounted by T lymphocytes. In children, the biphasic cytokine response proved to be less prominent than seen in adults after CPB, but cytokines expression did increase.43,86,87 Both the sparse data and interindividual and interinstitutional differences make it difficult to draw any conclusions, especially when considering the age-specific characteristics of the immune system in pediatric patients. However, it is clear that the latter also respond to CPB with both a proinflammatory and an anti-inflammatory immune responses (see Table, Supplemental Digital Content 3, http://links.lww.com/JCVP/A162). www.jcvp.org |
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When it comes to the influence of medication given during CPB in children, data are even scarcer as will be reviewed in the next section.
IMMUNE SPECIFIC EFFECTS OF DRUGS USED COMMONLY IN CPB It was a long thought that the anti-inflammatory properties of corticosteroids would help to attenuate the proinflammatory response seen after CPB. However, the clinical benefit of corticosteroids given before CPB remains unclear.88 In a prospective study in which 13 infants received methylprednisolone (MP) before CPB for different congenital cardiac defects, blood samples were taken until 48 hours postoperatively. Anesthesia was induced with either halothane or ketamine and maintained with fentanyl (100 mg$kg21$h21) and pancuronium. MP (30 mg/kg), and furosemide (1 mg/kg) were added to the priming solution at initiation of CPB. After cessation, modified ultrafiltration (without leukocyte filtration) was applied as described previously.89 Interestingly, plasma concentrations of the proinflammatory cytokines IL-1b and TNF-a were high at baseline (directly after induction of anesthesia but before surgery) and remained high throughout, without an apparent effect of the surgery itself. Both the concentrations of the anti-inflammatory cytokines IL-1ra and IL-10 increased after the start of CPB with return to baseline levels commencing 6 hours postoperatively. Plasma elastase levels increased after the start of CPB and remained increased throughout the study period (day 3 postoperative).4 Although, in this study, both proinflammatory (IL-6) and anti-inflammatory cytokines as well as elastase levels increased, the actual contribution of MP is hard to single out in view of the study design and as the different agents used to induce anesthesia. The anti-inflammatory effects are exhibited on almost all cell types of the immune system. Dexamethasone is capable of inhibiting CD62L shedding in neutrophils and upregulating CD11 and CD18 integrins.90 In monocytes, MP reduced the HLA-DR expression beyond the depression seen in CPB alone, and this effect also seems to coincide with an induction of the anti-inflammatory cytokine IL-10.91,92 In lymphocytes, a high dose of MP (20 mg/kg before CPB) resulted in immune suppression synergistic with the immune suppression seen after CPB alone.93 For the adaptive immune cells, this synergistic effect resulted in lower numbers of CD3+ T cells, CD4+ T cells, and CD20+ B cells, as well as higher numbers of natural killer cells. However, restoration of these populations took significantly longer, and suppression of T-cell activity was more profound in subjects who had received high-dose MP group compared with controls. In another study, MP decreased complement activation but without improvement in postoperative outcome.94 Thus, corticosteroids seem to enhance the anti-inflammatory response seen after CPB rather than attenuating the proinflammatory response. Opioids are also abundantly used perioperatively. They exhibit a wide variety of immune-regulatory effects through the presence of opioid receptors on almost all cell subsets of the immune system. Murphy et al95 found a greater reduction in integrins (both CD18 as well as CD11a, CD11b and CD11c) on neutrophils after CPB in subjects who had
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received morphine compared with subjects who had received fentanyl. Also, several direct effects on monocyte function have been described.96–100 Lymphocytes also express opioid receptors; their capacity to mount an antibody response was impaired after administration of morphine in vivo, leading to increased susceptibility for infections.98,100,101 Several in vitro studies revealed a biphasic response in cytokine production by T cells in vitro, where an initial increase is followed by a decrease after restimulation of the opioid receptor.102,103 This biphasic response could coincide with increased susceptibility to infections and an anergic immune response after CPB.104 Comparable with the effects of corticosteroids, opioids seem to enhance the anti-inflammatory effects seen after CPB, with a greater effect of fentanyl compared with morphine. Heparin, a mast cell product, is best known for its anticoagulant properties.105 Interestingly, heparin is capable of directly influencing neutrophils. An in vitro study revealed inhibition of neutrophil degranulation and aggregation with the use of heparin.106 Furthermore, in one study, heparin induced apoptosis in neutrophils, which would make them less responsive to activating stimuli.107 Although another study reported similar effects of heparin on lymphoblasts, it could not provide evidence of increased apoptosis in neutrophils.108 As these 2 studies used different concentrations of heparin and different assays, it would seem futile to compare the findings. Interestingly, activation of complement in CPB is thought to be evoked by heparin–protamin complexes rather than by antigen–antibody complexes.109 Thus, the use of heparin in the extracorporeal system would contribute more to the increase in C3a and C5a than contact of the blood with the system solely. Up till now, studies testing different coatings in the CPB system did not demonstrate differences in complement activation.110,111 So while heparin seems to have a more anti-inflammatory effect on neutrophils, its use could also partly explain the proinflammatory activation of complement during CPB. Finally, comparable with MP and opioids, anesthetic agents such as propofol, thiopental, and sufentanil seem to influence lymphocyte function in vitro (see Table, Supplemental Digital Content 3, http://links.lww.com/JCVP/A162).63,64
FUTURE DIRECTIONS This review brings out that many confounding factors may complicate studies in pediatric CPB. We hypothesize that the drugs given during the induction of anesthesia enhance the proinflammatory response in CPB, and that post-CPB agents such as corticosteroids and opioids, which directly affect the different components of the immune system, increase the physiological anti-inflammatory response. Apart from the above-mentioned confounding factors, pharmacokinetic, and pharmacodynamic parameters of drugs must be taken into account. Not only CPB affects several pharmacokinetic parameters, also inflammation influences the metabolism of medication.112,113 If we want to be able to study the influence of drugs on the inflammatory responses in pediatric CPB, we should first study the PK and pharmacodynamics of these drugs in infants and children on CPB, instead of extrapolating findings from studies in adults.21,114 With the obtained information about appropriate dosing Ó 2014 Lippincott Williams & Wilkins
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during pediatric CPB, well-designed randomized controlled trials might alter our notion about drugs traditionally given during CPB, especially MP, opioids, and heparin because these drugs drastically affect the immune system. Ultimately, we should aim for tailor-made pharmacotherapy, combining the inflammatory state of a child with our knowledge of the influence of this inflammatory state on PK, and possibly, on individual specific clearance. Such tailor-made pharmacotherapy could have both health and economic benefits. In conclusion, recognition of the inflammatory response to the drugs used in CPB may be a clue to avoid multiorgan failure because of SIRS, CARS, and nosocomial infections and reduce length of stay in PICU after pediatric cardiovascular surgery. We might even speculate that both SIRS and CARS are iatrogenic induced syndromes originating from functional physiological responses to injury because of the current pharmacotherapeutic regimens. REFERENCES 1. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045. 2. Matzinger P. The evolution of the danger theory. Interview by Lauren Constable, Commissioning Editor. Expert Rev Clin Immunol. 2012;8: 311–317. 3. Tomic V, Russwurm S, Möller E, et al. Transcriptomic and proteomic patterns of systemic inflammation in on-pump and off-pump coronary artery bypass grafting. Circulation. 2005;112:2912–2920. 4. Chew MS, Brandslund I, Brix-Christensen V, et al. Tissue injury and the inflammatory response to pediatric cardiac surgery with cardiopulmonary bypass: a descriptive study. Anesthesiology. 2001;94:745–753. 5. Guirao X, Lowry SF. Biologic control of injury and inflammation: much more than too little or too late. World J Surg. 1996;20:437–446. 6. Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest. 1992;101:1481–1483. 7. Hall RI, Smith MS, Rocker G. The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerations. Anesth Analg. 1997;85:766–782. 8. Hall RI. Cardiopulmonary bypass and the systemic inflammatory response: effects on drug action. J Cardiothorac Vasc Anesth. 2002;16:83–98. 9. Tarnok A, Schneider P. Pediatric cardiac surgery with cardiopulmonary bypass: pathways contributing to transient systemic immune suppression. Shock. 2001;16(suppl 1):24–32. 10. Markewitz A, Lante W, Franke A, et al. Alterations of cell-mediated immunity following cardiac operations: clinical implications and open questions. Shock. 2001;16(suppl 1):10–15. 11. Vallely MP, Bannon PG, Kritharides L. The systemic inflammatory response syndrome and off-pump cardiac surgery. Heart Surg Forum. 2001;4(suppl 1):S7–S13. 12. Abraham E. Physiologic stress and cellular ischemia: relationship to immunosuppression and susceptibility to sepsis. Crit Care Med. 1991;19:613–618. 13. de Waal Malefyt R, Haanen J, Spits H, et al. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991;174:915–924. 14. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med. 1996;24:1125–1128. 15. Osuchowski MF, Welch K, Siddiqui J, et al. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol. 2006;177:1967–1974. 16. Kurosawa S, Kato M. Anesthetics, immune cells, and immune responses. J Anesth. 2008;22:263–277. 17. Schneemilch CE, Schilling T, Bank U. Effects of general anaesthesia on inflammation. Best Pract Res Clin Anaesthesiol. 2004;18:493–507. 18. Homburger JA, Meiler SE. Anesthesia drugs, immunity, and long-term outcome. Curr Opin Anaesthesiol. 2006;19:423–428.
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45. Quimby KR, Greenidge A, Harris A, et al. Phenotypic commitment of monocytes towards a protective hemoglobin scavenging phenotype (CD14(pos)CD163(high)HLA-DR(low)) following cardiopulmonary bypass. Cytometry B Clin Cytom. 2010;78:357–360. 46. Sbrana S, Parri MS, De Filippis R, et al. Monitoring of monocyte functional state after extracorporeal circulation: a flow cytometry study. Cytometry B Clin Cytom. 2004;58:17–24. 47. Peters M, Petros A, Dixon G, et al. Acquired immunoparalysis in paediatric intensive care: prospective observational study. BMJ. 1999;319:609–610. 48. Asadullah K, Woiciechowsky C, Döcke WD, et al. Immunodepression following neurosurgical procedures. Crit Care Med. 1995;23:1976–1983. 49. Asadullah K, Woiciechowsky C, Döcke WD, et al. Very low monocytic HLA-DR expression indicates high risk of infection–immunomonitoring for patients after neurosurgery and patients during high dose steroid therapy. Eur J Emerg Med. 1995;2:184–190. 50. Allen ML, Peters MJ, Goldman A, et al. Early postoperative monocyte deactivation predicts systemic inflammation and prolonged stay in pediatric cardiac intensive care. Crit Care Med. 2002;30:1140–1145. 51. Moat NE, Shore DF, Evans TW. Organ dysfunction and cardiopulmonary bypass: the role of complement and complement regulatory proteins. Eur J Cardiothorac Surg. 1993;7:563–573. 52. Seghaye MC, Duchateau J, Grabitz RG, et al. Complement activation during cardiopulmonary bypass in infants and children. Relation to postoperative multiple system organ failure. J Thorac Cardiovasc Surg. 1993;106:978–987. 53. Sonntag J, Dahnert I, Stiller B, et al. Complement and contact activation during cardiovascular operations in infants. Ann Thorac Surg. 1998;65: 525–531. 54. Chenoweth DE, Cooper SW, Hugli TE, et al. Complement activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxins. N Engl J Med. 1981;304:497–503. 55. Homeister JW, Satoh P, Lucchesi BR. Effects of complement activation in the isolated heart. Role of the terminal complement components. Circ Res. 1992;71:303–319. 56. Matis LA, Rollins SA. Complement-specific antibodies: designing novel anti-inflammatories. Nat Med. 1995;1:839–842. 57. Stiller B, Sonntag J, Dähnert I, et al. 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. 58. Meri S, Aronen M, Leijala M. Complement activation during cardiopulmonary bypass in children. Complement. 1988;5:46–54. 59. de Jong PR, Schadenberg AW, Jansen NJ, et al. Hsp70 and cardiac surgery: molecular chaperone and inflammatory regulator with compartmentalized effects. Cell Stress Chaperones. 2009;14:117–131. 60. Jansen NJ, van Oeveren W, Gu YJ, et al. Endotoxin release and tumor necrosis factor formation during cardiopulmonary bypass. Ann Thorac Surg. 1992;54:744–747. 61. Schett G, Metzler B, Kleindienst R, et al. Myocardial injury leads to a release of heat shock protein (hsp) 60 and a suppression of the antihsp65 immune response. Cardiovasc Res. 1999;42:685–695. 62. Ijichi S, Mishima M, Matsuda T, et al. Concentration of activated T lymphocytes in extracorporeal blood circulation for plasma separation. J Clin Apher. 1991;6:88–89. 63. Schneemilch CE, Ittenson A, Ansorge S, et al. Effect of 2 anesthetic techniques on the postoperative proinflammatory and anti-inflammatory cytokine response and cellular immune function to minor surgery. J Clin Anesth. 2005;17:517–527. 64. Schneemilch CE, Hachenberg T, Ansorge S, et al. Effects of different anaesthetic agents on immune cell function in vitro. Eur J Anaesthesiol. 2005;22:616–623. 65. Rinder CS, Mathew JP, Rinder HM, et al. Lymphocyte and monocyte subset changes during cardiopulmonary bypass: effects of aging and gender. J Lab Clin Med. 1997;129:592–602. 66. van Kooyk Y, Figdor CG. Activation and inactivation of adhesion molecules. Curr Top Microbiol Immunol. 1993;184:235–256. 67. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27:1230–1251. 68. Le Tulzo Y, Pangault C, Gacouin A, et al. Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. Shock. 2002;18:487–494.
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J Cardiovasc Pharmacol ä Volume 64, Number 2, August 2014 69. Leaes PE, Neumann J, Jung LA, et al. Lymphocyte’s activation and apoptosis after coronary artery bypass graft: a comparative study of two membrane oxygenators–one with and another without a venous-arterial shunt. ASAIO J. 2004;50:611–618. 70. Oka M, Hirazawa K, Yamamoto K, et al. Induction of Fas-mediated apoptosis on circulating lymphocytes by surgical stress. Ann Surg. 1996;223:434–440. 71. Shi SS, Shi CC, Zhao ZY, et al. Effect of open heart surgery with cardiopulmonary bypass on peripheral blood lymphocyte apoptosis in children. Pediatr Cardiol. 2009;30:153–159. 72. Jensen E, Bengtsson A, Berggren H, et al. Clinical variables and proinflammatory activation in paediatric heart surgery. Scand Cardiovasc J. 2001;35:201–206. 73. Hickey E, Karamlou T, You J, et al. Effects of circuit miniaturization in reducing inflammatory response to infant cardiopulmonary bypass by elimination of allogeneic blood products. Ann Thorac Surg. 2006;81: S2367–S2372. 74. Golab HD, Scohy TV, de Jong PL, et al. Intraoperative cell salvage in infants undergoing elective cardiac surgery: a prospective trial. Eur J Cardiothorac Surg. 2008;34:354–359. 75. Cholette JM, Powers KS, Alfieris GM, et al. Transfusion of cell saver salvaged blood in neonates and infants undergoing open heart surgery significantly reduces RBC and coagulant product transfusions and donor exposures: results of a prospective, randomized, clinical trial. Pediatr Crit Care Med. 2013;14:137–147. 76. Golab HD, Bogers JJ. Small, smaller, smallest. Steps towards bloodless neonatal and infant cardiopulmonary bypass. Perfusion. 2009;24:239– 242. 77. Ando M, Takahashi Y, Suzuki N. Open heart surgery for small children without homologous blood transfusion by using remote pump head system. Ann Thorac Surg. 2004;78:1717–1722. 78. Richmond ME, Charette K, Chen JM, et al. The effect of cardiopulmonary bypass prime volume on the need for blood transfusion after pediatric cardiac surgery. J Thorac Cardiovasc Surg. 2013; 145:1058–1064. 79. Stocker CF, Shekerdemian LS, Horton SB, et al. The influence of bypass temperature on the systemic inflammatory response and organ injury after pediatric open surgery: a randomized trial. J Thorac Cardiovasc Surg. 2011;142:174–180. 80. Horton SB, Butt WW, Mullaly RJ, et al. IL-6 and IL-8 levels after cardiopulmonary bypass are not affected by surface coating. Ann Thorac Surg. 1999;68:1751–1755. 81. Warren O, Alexiou C, Massey R, et al. The effects of various leukocyte filtration strategies in cardiac surgery. Eur J Cardiothorac Surg. 2007; 31:665–676. 82. PrabhuDas M, Adkins B, Gans H, et al. Challenges in infant immunity: implications for responses to infection and vaccines. Nat Immunol. 2011;12:189–194. 83. O’Gorman MR, Millard DD, Lowder JN, et al. Lymphocyte subpopulations in healthy 1-3-day-old infants. Cytometry. 1998;34:235–241. 84. Chipeta J, Komada Y, Zhang XL, et al. CD4+ and CD8+ cell cytokine profiles in neonates, older children, and adults: increasing T helper type 1 and T cytotoxic type 1 cell populations with age. Cell Immunol. 1998; 183:149–156. 85. Sack U, Burkhardt U, Borte M, et al. Age-dependent levels of select immunological mediators in sera of healthy children. Clin Diagn Lab Immunol. 1998;5:28–32. 86. Journois D, Israel-Biet D, Pouard P, et al. High-volume, zero-balanced hemofiltration to reduce delayed inflammatory response to cardiopulmonary bypass in children. Anesthesiology. 1996;85:965–976. 87. Wang W, Huang HM, Zhu DM, et al. Modified ultrafiltration in paediatric cardiopulmonary bypass. Perfusion. 1998;13:304–310. 88. Robertson-Malt S, Afrane B, El Barbary M. Prophylactic steroids for pediatric open heart surgery. Cochrane Database Syst Rev. 2007;CD005550. 89. Naik SK, Elliott MJ. Ultrafiltration and paediatric cardiopulmonary bypass. Perfusion. 1993;8:101–112. 90. Filep JG, Delalandre A, Payette Y, et al. Glucocorticoid receptor regulates expression of L-selectin and CD11/CD18 on human neutrophils. Circulation. 1997;96:295–301. 91. Volk T, Schmutzler M, Engelhardt L, et al. Influence of aminosteroid and glucocorticoid treatment on inflammation and immune function during cardiopulmonary bypass. Crit Care Med. 2001;29:2137–2142.
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J Cardiovasc Pharmacol ä Volume 64, Number 2, August 2014 92. McBride WT, Armstrong MA, Crockard AD, et al. Cytokine balance and immunosuppressive changes at cardiac surgery: contrasting response between patients and isolated CPB circuits. Br J Anaesth. 1995;75:724–733. 93. Mayumi H, Zhang QW, Nakashima A, et al. Synergistic immunosuppression caused by high-dose methylprednisolone and cardiopulmonary bypass. Ann Thorac Surg. 1997;63:129–137. 94. Andersen LW, Baek L, Thomsen BS, et al. Effect of methylprednisolone on endotoxemia and complement activation during cardiac surgery. J Cardiothorac Anesth. 1989;3:544–549. 95. Murphy GS, Szokol JW, Marymont JH, et al. 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;104:1334–1342; table. 96. Falke NE, Fischer EG, Martin R. Stereospecific opiate binding in living human polymorphonuclear leucocytes. Cell Biol Int Rep. 1985;9:1041–1047. 97. Lopker A, Abood LG, Hoss W, et al. Stereoselective muscarinic acetylcholine and opiate receptors in human phagocytic leukocytes. Biochem Pharmacol. 1980;29:1361–1365. 98. Mehrishi JN, Mills IH. Opiate receptors on lymphocytes and platelets in man. Clin Immunol Immunopathol. 1983;27:240–249. 99. Ovadia H, Nitsan P, Abramsky O. Characterization of opiate binding sites on membranes of rat lymphocytes. J Neuroimmunol. 1989;21:93–102. 100. McCarthy L, Wetzel M, Sliker JK, et al. Opioids, opioid receptors, and the immune response. Drug Alcohol Depend. 2001;62:111–123. 101. Bussiere JL, Adler MW, Rogers TJ, et al. Differential effects of morphine and naltrexone on the antibody response in various mouse strains. Immunopharmacol Immunotoxicol. 1992;14:657–673. 102. Shahabi NA, Sharp BM. Antiproliferative effects of delta opioids on highly purified CD4+ and CD8+ murine T cells. J Pharmacol Exp Ther. 1995;273:1105–1113. 103. House RV, Thomas PT, Bhargava HN. A comparative study of immunomodulation produced by in vitro exposure to delta opioid receptor agonist peptides. Peptides. 1996;17:75–81.
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Influence of Pharmacotherapy in Children 104. Horan TC, Culver DH, Gaynes RP, et al. Nosocomial infections in surgical patients in the United States, January 1986-June 1992. National nosocomial infections Surveillance (NNIS) system. Infect Control Hosp Epidemiol. 1993;14:73–80. 105. Lam LH, Silbert JE, Rosenberg RD. The separation of active and inactive forms of heparin. Biochem Biophys Res Commun. 1976;69: 570–577. 106. Brown RA, Lever R, Jones NA, et al. Effects of heparin and related molecules upon neutrophil aggregation and elastase release in vitro. Br J Pharmacol. 2003;139:845–853. 107. Manaster J, Chezar J, Shurtz-Swirski R, et al. Heparin induces apoptosis in human peripheral blood neutrophils. Br J Haematol. 1996;94:48–52. 108. Erduran E, Tekelioglu Y, Gedik Y, et al. Apoptotic effects of heparin on lymphoblasts, neutrophils, and mononuclear cells: results of a preliminary in vitro study. Am J Hematol. 1999;61:90–93. 109. Shastri KA, Logue GL, Stern MP, et al. Complement activation by heparin-protamine complexes during cardiopulmonary bypass: effect of C4A null allele. J Thorac Cardiovasc Surg. 1997;114:482–488. 110. Thiara AS, Andersen VY, Videm V, et al. Comparable biocompatibility of Phisio- and Bioline-coated cardiopulmonary bypass circuits indicated by the inflammatory response. Perfusion. 2010;25:9–16. 111. Thiara AS, Mollnes TE, Videm V, et al. Biocompatibility and pathways of initial complement pathway activation with Phisio- and PMEAcoated cardiopulmonary bypass circuits during open-heart surgery. Perfusion. 2011;26:107–114. 112. Vet NJ, de Hoog M, Tibboel D, et al. The effect of inflammation on drug metabolism: a focus on pediatrics. Drug Discov Today. 2011;16: 435–442. 113. Mets B. The pharmacokinetics of anesthetic drugs and adjuvants during cardiopulmonary bypass. Acta Anaesthesiol Scand. 2000;44:261–273. 114. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349:1157–1167.
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Does Pharmacotherapy Influence the Inflammatory Responses During Cardiopulmonary Bypass in Children? Berber Kapitein, MD, PhD,* Anne-Wil van Saet, MD,† Hanna D. Golab, PhD,‡ Matthijs de Hoog, MD, PhD,* Saskia de Wildt, MD, PhD,* Dick Tibboel, MD, PhD,* and Ad J. J. C. Bogers, MD, PhD‡
Abstract: Cardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) by factors such as contact of the blood with the foreign surface of the extracorporeal circuit, hypothermia, reduction of pulmonary blood flow during CPB and endotoxemia. SIRS is maintained in the postoperative phase, co-occurring with a counter anti-inflammatory response syndrome. Research on the effects of drugs administered before the surgery, especially in the induction phase of anesthesia, as well as drugs used during extracorporeal circulation, has revealed that they greatly influence these postoperative inflammatory responses. A better understanding of these processes may not only improve postoperative recovery but also enable tailor-made pharmacotherapy, with both health and economic benefits. In this review, we describe the pathophysiology of SIRS and counter antiinflammatory response syndrome in the light of CPB in children and the influence of drugs used on these syndromes. Key Words: cardiopulmonary bypass, systemic inflammatory response syndrome, counter anti-inflammatory response syndrome, drugs (J Cardiovasc Pharmacol Ô 2014;64:191–197)
INFLAMMATORY BALANCE AFTER MAJOR SURGERY The immune system is supposed to protect the body against a variety of pathologic insults.1,2 It does so primarily by maintaining a balance between proinflammatory and antiinflammatory responses. Major surgery with or without cardiopulmonary bypass (CPB) will also evoke a physiologic and self-limiting inflammatory response toward extrinsic factors (anesthesia, hypothermia, or contact of the body with foreign Received for publication October 22, 2013; accepted March 13, 2014. From the *Intensive Care Unit, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; †Department of Anesthesiology, Intensive Care Unit, Erasmus MC, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; and ‡Department of Cardiothoracic Surgery, Erasmus MC, Rotterdam, the Netherlands. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.jcvp.org). Reprints: Berber Kapitein, MD, PhD, Intensive Care Unit, Erasmus MCSophia Children’s Hospital, Dr Molewaterplein, 60, 3015 GJ Rotterdam, the Netherlands (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
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surfaces) and intrinsic factors (the actual tissue damage, ischemia-reperfusion damage, endothelial cell activation).3,4 If the proinflammatory response is exaggerated and/or prolonged, the body may be at risk for end-organ damage.5 This proinflammatory response has been described as the systemic inflammatory response syndrome (SIRS) in the 1992 ACC/SCCM consensus conference. In general, SIRS is diagnosed when 2 or more of the following clinical findings are present: rectal body temperature .388C or ,368C, heart rate .90th percentile for age, respiratory rate .90th percentile for age or hyperventilation to a PaCO2 ,32 mm Hg (4.2 kPa), and white blood cell count of .12,000 cells per microliter or ,4000 cells per microliter.6 Numerous factors of the human immune system contribute to SIRS, from proinflammatory cytokines such as interleukin 1 (IL-1), IL-6, IL-8, and tumor necrosis factor (TNF)-a, to platelet and clotting factors, complement factors and neutrophil degranulation, as seen after surgery.7–10 The crucial mechanism in SIRS seems to be the activation of endothelial cells and endothelial production of cytokines by recruitment of immune cells to the site of damage.11 It has long been thought that the body mounts a counter-response toward this proinflammatory response. Indeed, critically ill patients show several defects in adaptive immunity, varying from decreased T-cell proliferative responses, increased lymphocyte and dendritic cell apoptosis and a shift from a TH1 to a TH2 environment, leading to immune suppression and unresponsiveness of immune cells known as immune anergy.12,13 Bone described this as the counter anti-inflammatory response syndrome (CARS) in 1996.14 We now know that CARS is not a response to SIRS as such but rather coincides with SIRS.15 It seems that both are not particular syndromes but represent an imbalance in physiological mechanisms. Of the extrinsic factors to which the immune system responds, the anesthetic agents given before and during CPB, but possibly also the drugs given in the recovery period seem to influence the inflammatory response. Anesthetic agents, both volatile as well as local and regional agents, may either exert an indirect influence by modulation of the neuroendocrine surgical stress response or a direct influence by affecting the immune cells. Both issues will be addressed in this review. In general, immune cells seem to be the most sensitive to volatile anesthetic agents.16–19 Most research on the immunological effects of anesthetic agents has been performed in vitro because in vivo studies are complicated by confounding factors such as type, duration www.jcvp.org |
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and complexity of surgery and heterogeneity of the patient population itself.20 Furthermore, both in vitro and in vivo studies show conflicting results because of large methodological differences (see Tables, Supplemental Digital Content 1, http://links.lww.com/JCVP/A160; Supplemental Digital Content 2, http://links.lww.com/JCVP/A161; and Supplemental Digital Content 3, http://links.lww.com/JCVP/A162). And, more importantly, data in the pediatric population are scarce. In the following review, we describe the inflammatory processes in the light of CPB with a focus on the pediatric population and elucidate the interactions of perioperative drugs with both syndromes. The pharmacokinetics (PK) and pharmacodynamics of commonly used drugs during CPB have recently been reviewed by our group and are outside the scope of this review.21
IMMUNOLOGICAL BACKGROUND OF INFLAMMATORY RESPONSES IN CPB Postoperative inflammatory responses seem to be evoked by 2 different mechanisms.22 First, surgery will directly activate both the innate and adaptive immune system. Activation of the innate immune cells such as monocytes, macrophages and neutrophils leads to the release of cytokines such as TNF-a, IL-1, IL-6, IL-8, and IL-12.23 This innate immune response is predominantly triggered through Tolllike receptors 2 and 4 (TLR2 and TLR4). Endogenous ligands for these receptors are reactive oxygen species (whose production is triggered by all the intrinsic factors seen in major surgery) and specific danger associated molecular patterns (DAMPs) such as free heme, hyaluronic acid, or heat shock proteins. DAMPs are released after tissue injury and (subsequent) hemorrhage.24–26 Both reactive oxygen species and DAMPs may lead to the production of proinflammatory cytokines by TLR4 signaling.27 Subsequently these cytokines stimulate the adaptive CD4+ T lymphocytes, consisting of T-helper (TH) and T-regulatory (Treg) cells. Historically, 2 subsets of TH cells, TH1 and TH2, have been described, according to the cytokines they produce (see Table, Supplemental Digital Content 1, http://links.lww.com/JCVP/A160). Tregs seem to be mainly responsible for the production of IL-10 and therefore possibly play a major role in immune-regulatory processes. Interestingly, Tregs are capable of selectively expressing TLR2 and TLR4, which could make them susceptible for DAMPs after surgery.28,29 The second mechanism creating a proinflammatory response is the acute stressor state after surgery. The hypothalamic–pituitary–adrenal axis, the adrenergic nervous and renin– angiotensin–aldosteron systems are activated with subsequent release of both cortisol and catecholamines.30 This response is not only thought to induce a proinflammatory state by directly activating the adaptive immune system, but also to induce a shift from a TH1 toward a more regulatory TH2 inflammatory response as seen after surgery and trauma.22 Furthermore, the stressor state leads to a cation dyshomeostasis with cellular influx of calcium, potassium, magnesium, zinc, and selenium. This results in low serum levels and more importantly, in cellular overloading with these cations, leading to activation of
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cells and the induction of oxidative stress by the mitochondria with the production of reactive oxygen species.31 In summary, surgery induces an inflammatory response by direct activation of the innate immune system leading to both proinflammatory and more regulatory anti-inflammatory responses. Furthermore, surgery activates the adaptive immune response, which is mainly a TH2 response with immunoregulatory properties. As will be described, the drugs given perioperatively can influence these different components of the inflammatory responses.
ROLE OF THE CELL TYPES OF THE IMMUNE SYSTEM IN SIRS AFTER CPB When investigating the interaction between CPB, inflammation, and pharmacotherapy, one should first recognize the different components of these inflammatory responses because the drugs given influence these cells individually. As said, the innate immune system will be the first to respond to the effects of CPB. Neutrophils, part of the group of polymorphonuclear cells, are the major cellular component of the innate immune system. Neutrophils appear to have a limited capacity of producing cytokines but are pivotal for the capillary leak and tissue damage seen after CPB, caused by endothelial migration.32–34 On activation by proinflammatory cytokines, TNF-a, IL-1b, and IL-8, neutrophils in the circulation express CD62L (L-selectin). CD62L decreases the rolling velocity of neutrophils along endothelial cells and provides the initial attachment to the endothelium. On attachment, CD62L is shed. Simultaneously, the b2-integrin CD18 with the variable alpha units CD11a (leukocyte function associated antigen or LFA), CD11b membrane attack complex (MAC-1), or CD11c enhance attachment of the neutrophils to the endothelium and promote transendothelial migration.8,35,36 Finally, neutrophils migrate through the endothelial barrier and release intracellular enzymes such as elastase and myeloperoxidase.36,37 Several studies reveal that CPB causes increased sequestration of neutrophils into capillaries and raises the amount of human neutrophil elastase in the circulation.38,39 In summary, neutrophils are activated by CPB, and increased expression of both L-selectin and integrins facilitates adherence to endothelial cells with subsequent transmigration leading to tissue damage.
MONOCYTES/MACROPHAGES The innate immune system also includes monocytes and their activated state, macrophages. Like neutrophils, they can extravasate into tissues after activation, also because of upregulation of CD18/CD11a (LFA) and CD18/CD11b (MAC-1) and shedding of CD62L.40–42 Different from neutrophils, monocytes seem to be the main producers of cytokines as seen in post-CPB inflammation.32,43 However, in contradiction with this finding, several studies demonstrate a deactivated state after CPB with lower production of both TNF-a and IL-10. This deactivation seems predictive of increased postoperative morbidity.42,44 Further evidence for a deactivated state in monocytes, 4 hours to several days after CPB, is shown by the decreased expression of the major histocompatibility complex class II (MHC II) molecule HLA-DR after CPB.45,46 This marker is crucial for antigen Ó 2014 Lippincott Williams & Wilkins
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presentation and recognition, and reduction of HLA-DR is associated with increased morbidity and mortality in multiple organ failure and critical illness.44,47–50 Thus, monocytes seem to be heavily involved in both the cytokine burst seen in postCPB SIRS and the hyporesponsiveness of the immune system seen in post-CPB CARS.
COMPLEMENT SYSTEM The complement system is a non-cellular component of the innate immune system and a major trigger in the inflammatory response following contact of blood with a foreign surface.51–53 Depending on its trigger, the classical, lectin, or alternative pathway of the complement cascade is activated. Either pathway leads to activation of C3 and C5 by cleavage of these complement proteins. These final complement products are proinflammatory and optimize opsonization, chemotaxis, and lysis of cells. The cleavage products C3a and C5a are extremely potent anaphylatoxins, and C5b-9 is also known as the MAC, which can directly lyse cells, including cardiomyocytes.54–56 The unique activation of the complement system during CPB is believed to be one of the causative factors of the capillary leak syndrome seen with SIRS.57,58
LYMPHOCYTES Lymphocytes are not only activated by the cytokines and actions of the innate immune response, but also by endogenous (HSP) and exogenous (lipopolysacharide, peptidoglycan) TLR activation,59–61 the sheer stress of CPB62 and the anesthetic agents given.63,64 In CPB, specifically the number of circulating CD4+ T cells starts to decrease immediately after CPB for up to 3 days. This decrease seems to contribute to post-CPB immune suppression. It might be caused by hemodilution, but in view of increasing numbers of natural killer cells and B cells, it is more likely that CD4+ T cells exit the circulation both because of extravasation and apoptosis.65,66 Apoptosis of T cells is thought to be one of the main homeostatic functions in the adaptive immune system to maintain a balance between immune activation and immune suppression.67,68 Several mechanisms may stimulate apoptosis. Increased expression of CD69 seems to suggest enhanced T-cell responsiveness in the early stages of CPB, a state conducive to activation-induced cell death or anergy.69,70 In pediatric CPB, T cells also show increased Fas mediated apoptosis, which was not seen in other surgical procedures.71 Lymphocytes and monocytes are believed to be major compartments of the peripheral blood mononuclear cells, which would account for the cytokine burst seen after CPB despite decreasing circulating numbers of T cells.32 Still, T cells might be responsible for the initial cytokine burst seen in CPB, at least in adults, but this would then trigger restraining mechanisms that ultimately lead to CARS with immune suppression.
INFLUENCE OF THE CPB SYSTEM COMPONENTS ON SIRS IN THE PEDIATRIC POPULATION The inflammatory effects of CPB are more profound in children than in adults. Children are immunologically immature, Ó 2014 Lippincott Williams & Wilkins
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and the organs, the coagulation system and the endocrine system, are still developing. As will be reviewed further, the immune system in the neonatal period consists largely of an innate response as the adaptive response is still developing. But more importantly, neonates’ higher metabolic demands require higher perfusion flow rates per body surface area. In every CPB system, blood-cell components are exposed to shearing forces, which in pediatric CPB are intensified by higher flow rates.72 Finally, in pediatric CPB, the circuit size is disproportionate to the child’s body surface. The resulting dilution of clotting factors, red blood cells, and plasma proteins accelerates the transfusion rate with additional triggering of the inflammatory response.73 In adults, the technique of cell saving was instituted in the early 1990s, and technical advancements have now made salvaged blood available for pediatric surgeries as well.74,75 Miniaturization of the CPB system was undertaken as well. Various studies show that miniaturization of the circuit leads to a lesser amount of transfused red blood cells, platelets, and plasma products, both during CPB and postoperatively; also extubation can be attempted earlier.73,76–78 Other factors such as core temperature, different coatings of the CPB circuit, or the insertion of leukocyte filters did not seem to influence post-CPB inflammation.79–81 In conclusion, technical aspects of CPB have a greater impact on pediatric CPB than on adult CPB. This consideration must be taken into account when studying the effects on inflammation and comparing studies from different centers (see also Tables, Supplemental Digital Content 1, http://links.lww.com/JCVP/A160; and Supplemental Digital Content 2, http://links.lww.com/JCVP/A161).
INFLAMMATORY RESPONSES AFTER CPB IN CHILDREN As said, one of the arguments against extrapolating data from studies in the adult population to the pediatric population is the great contrast between a developed (adult) and a developing (from neonate to adolescent) immune system82. Pediatric cardiothoracic surgery often takes place in the first year of life, when the innate immune response is present, but the adaptive immune response is still developing. Neonates (age up to 4 weeks) have high numbers of circulating TH cells expressing CD4 and CD8, but these cells cannot produce TH specific cytokines such as INFgand IL-10.83–85 These adaptive immune responses increase over the childhood and adolescence life stages toward an adult response. It is very likely that this development interferes with the responses seen with SIRS, especially with the second phase in which cytokine responses, both proinflammatory and anti-inflammatory, are mounted by T lymphocytes. In children, the biphasic cytokine response proved to be less prominent than seen in adults after CPB, but cytokines expression did increase.43,86,87 Both the sparse data and interindividual and interinstitutional differences make it difficult to draw any conclusions, especially when considering the age-specific characteristics of the immune system in pediatric patients. However, it is clear that the latter also respond to CPB with both a proinflammatory and an anti-inflammatory immune responses (see Table, Supplemental Digital Content 3, http://links.lww.com/JCVP/A162). www.jcvp.org |
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When it comes to the influence of medication given during CPB in children, data are even scarcer as will be reviewed in the next section.
IMMUNE SPECIFIC EFFECTS OF DRUGS USED COMMONLY IN CPB It was a long thought that the anti-inflammatory properties of corticosteroids would help to attenuate the proinflammatory response seen after CPB. However, the clinical benefit of corticosteroids given before CPB remains unclear.88 In a prospective study in which 13 infants received methylprednisolone (MP) before CPB for different congenital cardiac defects, blood samples were taken until 48 hours postoperatively. Anesthesia was induced with either halothane or ketamine and maintained with fentanyl (100 mg$kg21$h21) and pancuronium. MP (30 mg/kg), and furosemide (1 mg/kg) were added to the priming solution at initiation of CPB. After cessation, modified ultrafiltration (without leukocyte filtration) was applied as described previously.89 Interestingly, plasma concentrations of the proinflammatory cytokines IL-1b and TNF-a were high at baseline (directly after induction of anesthesia but before surgery) and remained high throughout, without an apparent effect of the surgery itself. Both the concentrations of the anti-inflammatory cytokines IL-1ra and IL-10 increased after the start of CPB with return to baseline levels commencing 6 hours postoperatively. Plasma elastase levels increased after the start of CPB and remained increased throughout the study period (day 3 postoperative).4 Although, in this study, both proinflammatory (IL-6) and anti-inflammatory cytokines as well as elastase levels increased, the actual contribution of MP is hard to single out in view of the study design and as the different agents used to induce anesthesia. The anti-inflammatory effects are exhibited on almost all cell types of the immune system. Dexamethasone is capable of inhibiting CD62L shedding in neutrophils and upregulating CD11 and CD18 integrins.90 In monocytes, MP reduced the HLA-DR expression beyond the depression seen in CPB alone, and this effect also seems to coincide with an induction of the anti-inflammatory cytokine IL-10.91,92 In lymphocytes, a high dose of MP (20 mg/kg before CPB) resulted in immune suppression synergistic with the immune suppression seen after CPB alone.93 For the adaptive immune cells, this synergistic effect resulted in lower numbers of CD3+ T cells, CD4+ T cells, and CD20+ B cells, as well as higher numbers of natural killer cells. However, restoration of these populations took significantly longer, and suppression of T-cell activity was more profound in subjects who had received high-dose MP group compared with controls. In another study, MP decreased complement activation but without improvement in postoperative outcome.94 Thus, corticosteroids seem to enhance the anti-inflammatory response seen after CPB rather than attenuating the proinflammatory response. Opioids are also abundantly used perioperatively. They exhibit a wide variety of immune-regulatory effects through the presence of opioid receptors on almost all cell subsets of the immune system. Murphy et al95 found a greater reduction in integrins (both CD18 as well as CD11a, CD11b and CD11c) on neutrophils after CPB in subjects who had
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received morphine compared with subjects who had received fentanyl. Also, several direct effects on monocyte function have been described.96–100 Lymphocytes also express opioid receptors; their capacity to mount an antibody response was impaired after administration of morphine in vivo, leading to increased susceptibility for infections.98,100,101 Several in vitro studies revealed a biphasic response in cytokine production by T cells in vitro, where an initial increase is followed by a decrease after restimulation of the opioid receptor.102,103 This biphasic response could coincide with increased susceptibility to infections and an anergic immune response after CPB.104 Comparable with the effects of corticosteroids, opioids seem to enhance the anti-inflammatory effects seen after CPB, with a greater effect of fentanyl compared with morphine. Heparin, a mast cell product, is best known for its anticoagulant properties.105 Interestingly, heparin is capable of directly influencing neutrophils. An in vitro study revealed inhibition of neutrophil degranulation and aggregation with the use of heparin.106 Furthermore, in one study, heparin induced apoptosis in neutrophils, which would make them less responsive to activating stimuli.107 Although another study reported similar effects of heparin on lymphoblasts, it could not provide evidence of increased apoptosis in neutrophils.108 As these 2 studies used different concentrations of heparin and different assays, it would seem futile to compare the findings. Interestingly, activation of complement in CPB is thought to be evoked by heparin–protamin complexes rather than by antigen–antibody complexes.109 Thus, the use of heparin in the extracorporeal system would contribute more to the increase in C3a and C5a than contact of the blood with the system solely. Up till now, studies testing different coatings in the CPB system did not demonstrate differences in complement activation.110,111 So while heparin seems to have a more anti-inflammatory effect on neutrophils, its use could also partly explain the proinflammatory activation of complement during CPB. Finally, comparable with MP and opioids, anesthetic agents such as propofol, thiopental, and sufentanil seem to influence lymphocyte function in vitro (see Table, Supplemental Digital Content 3, http://links.lww.com/JCVP/A162).63,64
FUTURE DIRECTIONS This review brings out that many confounding factors may complicate studies in pediatric CPB. We hypothesize that the drugs given during the induction of anesthesia enhance the proinflammatory response in CPB, and that post-CPB agents such as corticosteroids and opioids, which directly affect the different components of the immune system, increase the physiological anti-inflammatory response. Apart from the above-mentioned confounding factors, pharmacokinetic, and pharmacodynamic parameters of drugs must be taken into account. Not only CPB affects several pharmacokinetic parameters, also inflammation influences the metabolism of medication.112,113 If we want to be able to study the influence of drugs on the inflammatory responses in pediatric CPB, we should first study the PK and pharmacodynamics of these drugs in infants and children on CPB, instead of extrapolating findings from studies in adults.21,114 With the obtained information about appropriate dosing Ó 2014 Lippincott Williams & Wilkins
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during pediatric CPB, well-designed randomized controlled trials might alter our notion about drugs traditionally given during CPB, especially MP, opioids, and heparin because these drugs drastically affect the immune system. Ultimately, we should aim for tailor-made pharmacotherapy, combining the inflammatory state of a child with our knowledge of the influence of this inflammatory state on PK, and possibly, on individual specific clearance. Such tailor-made pharmacotherapy could have both health and economic benefits. In conclusion, recognition of the inflammatory response to the drugs used in CPB may be a clue to avoid multiorgan failure because of SIRS, CARS, and nosocomial infections and reduce length of stay in PICU after pediatric cardiovascular surgery. We might even speculate that both SIRS and CARS are iatrogenic induced syndromes originating from functional physiological responses to injury because of the current pharmacotherapeutic regimens. REFERENCES 1. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045. 2. Matzinger P. The evolution of the danger theory. Interview by Lauren Constable, Commissioning Editor. Expert Rev Clin Immunol. 2012;8: 311–317. 3. Tomic V, Russwurm S, Möller E, et al. Transcriptomic and proteomic patterns of systemic inflammation in on-pump and off-pump coronary artery bypass grafting. Circulation. 2005;112:2912–2920. 4. Chew MS, Brandslund I, Brix-Christensen V, et al. Tissue injury and the inflammatory response to pediatric cardiac surgery with cardiopulmonary bypass: a descriptive study. Anesthesiology. 2001;94:745–753. 5. Guirao X, Lowry SF. Biologic control of injury and inflammation: much more than too little or too late. World J Surg. 1996;20:437–446. 6. Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest. 1992;101:1481–1483. 7. Hall RI, Smith MS, Rocker G. The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerations. Anesth Analg. 1997;85:766–782. 8. Hall RI. Cardiopulmonary bypass and the systemic inflammatory response: effects on drug action. J Cardiothorac Vasc Anesth. 2002;16:83–98. 9. Tarnok A, Schneider P. Pediatric cardiac surgery with cardiopulmonary bypass: pathways contributing to transient systemic immune suppression. Shock. 2001;16(suppl 1):24–32. 10. Markewitz A, Lante W, Franke A, et al. Alterations of cell-mediated immunity following cardiac operations: clinical implications and open questions. Shock. 2001;16(suppl 1):10–15. 11. Vallely MP, Bannon PG, Kritharides L. The systemic inflammatory response syndrome and off-pump cardiac surgery. Heart Surg Forum. 2001;4(suppl 1):S7–S13. 12. Abraham E. Physiologic stress and cellular ischemia: relationship to immunosuppression and susceptibility to sepsis. Crit Care Med. 1991;19:613–618. 13. de Waal Malefyt R, Haanen J, Spits H, et al. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991;174:915–924. 14. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med. 1996;24:1125–1128. 15. Osuchowski MF, Welch K, Siddiqui J, et al. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol. 2006;177:1967–1974. 16. Kurosawa S, Kato M. Anesthetics, immune cells, and immune responses. J Anesth. 2008;22:263–277. 17. Schneemilch CE, Schilling T, Bank U. Effects of general anaesthesia on inflammation. Best Pract Res Clin Anaesthesiol. 2004;18:493–507. 18. Homburger JA, Meiler SE. Anesthesia drugs, immunity, and long-term outcome. Curr Opin Anaesthesiol. 2006;19:423–428.
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