Secondary Logo

Journal Logo

The Relationship Between Inflammatory Activation and Clinical Outcome After Infant Cardiopulmonary Bypass

Allan, Catherine K., MD*,§; Newburger, Jane W., MD, MPH*,§; McGrath, Ellen, RN*; Elder, Jodi, RN*; Psoinos, Charles, BS; Laussen, Peter C., MBBS*,‡; del Nido, Pedro J., MD†,‖; Wypij, David, PhD*,§,#; McGowan, Francis X. Jr., MD‡,¶

doi: 10.1213/ANE.0b013e3181f333aa
Pediatric Anesthesiology: Research Reports
Free
SDC

BACKGROUND: Cardiopulmonary bypass (CPB) induces a systemic inflammatory response. The magnitude and consequences in infants remain unclear. We assessed the relationship between inflammatory state and clinical outcomes in infants undergoing CPB.

METHODS: Plasma concentrations of interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor α, IL-1β, and C-reactive protein (CRP) were measured pre-CPB and immediately post-CPB, and at 6, 12, and 24 hours post-CPB in infants ≤9 months old. Perioperative clinical data were collected prospectively.

RESULTS: Diagnoses of 93 patients included transposition of the great arteries (40), tetralogy of Fallot (28), ventricular septal defect (21), truncus arteriosus (2), and complete atrioventricular canal (2). The median age was 37 days (range = 2 to 264). Pre-CPB IL-6 and CRP were higher in younger infants but were not associated with postoperative inflammatory mediator concentrations or measured clinical outcomes. IL-6 increased post-CPB (median 3.2 pg/mL pre-CPB, 24.2 post-CPB, 95.4 at 6 hours, and 90.3 at 24 hours; all P < 0.001). CRP increased post-CPB, peaking at 24 hours (median 27.5 at 24 hours, 0.3 pre-CPB; P < 0.001). IL-10 and IL-8 increased immediately post-CPB. After adjusting for age and diagnosis, postoperative IL-6 and IL-8 correlated with intensive care unit length of stay and postoperative blood product administration and, for IL-8, 24-hour lactate.

CONCLUSIONS: Greater preoperative cytokine and CRP production in younger infants did not correlate with postoperative outcomes; correlation between postoperative inflammatory mediator production and clinical course was statistically significant but clinically modest. We conclude that in infants undergoing low-to-moderate-complexity cardiac surgery in a single high-volume center, the contribution of inflammatory mediator production to postoperative morbidity is relatively limited.

Published ahead of print September 9, 2010

From the *Department of Cardiology, Department of Cardiac Surgery, and Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital Boston, Massachusetts; the §Department of Pediatrics, Department of Surgery, and Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts; and the #Department of Biostatistics, Harvard School of Public Health7, Boston, Massachusetts.

Supported by grants HL 066186, HL 052589, and RR02172 from the National Institutes of Health, by a fellowship from the Will and Helen Webster Foundation (American Academy of Pediatrics section on Cardiology and Cardiac Surgery), and by the Farb Family Fund.

Address correspondence to Catherine K. Allan, MD, Department of Cardiology, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. Address e-mail to catherine.allan@cardio.chboston.org.

Accepted June 25, 2010

Published ahead of print September 9, 2010

Cardiopulmonary bypass (CPB) is a potent stimulus of the systemic inflammatory response. Mechanisms of inflammatory activation during CPB include blood contact with CPB circuit components, ischemia–reperfusion injury, heparin–protamine interactions, and surgical trauma. Numerous studies have demonstrated activation of the complement cascade, release of endotoxin, and altered production of cytokines during and after CPB.14 These biochemical changes are believed to contribute significantly to the systemic effects of CPB, which range from mild postoperative edema to severe multiorgan system dysfunction.

In comparison with adults, infants undergoing CPB are believed to have a more pronounced inflammatory response. Multiple studies have demonstrated altered production of specific pro- and anti-inflammatory cytokines,57 and several prior studies have demonstrated a relationship between limited numbers of inflammatory mediators and clinical outcome. However, the ability of these studies to evaluate correlations with a greater number of inflammatory mediators has been somewhat limited, in part because of small sample size and variability in age and diagnosis.810 The purpose of this study was to measure production of pro- and anti-inflammatory cytokines (interleukin [IL]-6, IL-8, IL-10, tumor necrosis factor [TNF]α, and IL-1β) and C-reactive protein (CRP) in a larger group of infants undergoing CPB to test the hypothesis that inflammatory mediator production is related to impaired clinical outcome. This information is necessary for the rational design of clinical studies and potential use of targeted anti-inflammatory therapies.

Back to Top | Article Outline

METHODS

Patients

This was an ancillary study to a National Institutes of Health–supported randomized trial of hematocrit strategy (25% vs. 35% at onset of low-flow bypass) in infant heart surgery; patients were enrolled over 28 consecutive months. The group randomized to 25% hematocrit had a significantly longer length of stay, but all other perioperative variables did not differ between the 25% and 35% groups.11 Eligible patients were ≤9 months old undergoing surgery for biventricular heart disease without aortic arch obstruction. Exclusion criteria included birth weight <2.3 kg, presence of recognizable phenotypic syndromes, significant associated extracardiac anomalies, and previous cardiac surgery. Approval of the Children's Hospital Boston, IRB and parental informed consent were obtained.

Back to Top | Article Outline

Anesthetic and Perfusion Techniques

A standardized high-dose narcotic anesthetic was used, including induction with fentanyl and pancuronium and maintenance with fentanyl and midazolam. The CPB circuit used a roller pump, heparin-bonded tubing, and a membrane oxygenator. The CPB circuit was primed with reconstituted, irradiated whole blood and Plasmalyte A pH 7.4 priming solution. Methylprednisolone (30 mg/kg) was added to the pump prime; other preoperative steroids were not used. Full flow CPB (∼2.5 L/min/m2) was used during cooling and rewarming. Variable periods of reduced flow CPB (approximately 0.75 L/min/m2) were used during deep hypothermia. A pH-stat strategy was used. A uniform regimen of continuous ultrafiltration (but not modified ultrafiltration) was used. Aprotinin was used at the surgeon's discretion in 13 of 93 patients. The dosage of aprotinin was 30,000 kallikrein inhibitor units (KIU) per kilogram in the CPB prime and 30,000 KIU/kg IV before incision followed by 10,000 KIU/kg/h infusion continued through bypass until the end of the surgery.

Back to Top | Article Outline

Postoperative Care

All patients were cared for postoperatively in a dedicated pediatric cardiac intensive care unit (ICU). Regimens of inotropic support, fluid management, and ventilatory support were standardized among cardiac intensivists. Steroid administration postoperatively was not routine, though 6 patients received dexamethasone for stridor, and 1 received hydrocortisone for refractory hypotension for presumed relative adrenal insufficiency. In 3 of these patients, steroids were given in the first 24 hours after surgery. Peritoneal drainage or dialysis catheters were not routinely placed.

Back to Top | Article Outline

Blood Sampling

Whole blood samples were obtained from indwelling arterial or central venous catheters after anesthetic induction but before skin incision, at cessation of CPB, and at 6, 12, and 24 hours post-CPB. Samples were obtained in potassium–EDTA tubes, centrifuged at 3000 rotations per minute (RPM) × 10 minutes at 4°, and stored at −80°C until analysis.

Back to Top | Article Outline

Sample Analysis

Plasma CRP concentrations were determined using high-sensitivity ELISA (Zymutest CRP, Hyphen Biomed, Andresy, France) according to manufacturer's instructions. Plasma concentrations of IL-6, IL-8, IL-10, TNFα, and IL-1β were measured at Harvard Partners Center for Genetics and Genomics with the Zyomyx Protein Microarray Chip (www.zyomyx.com); results were confirmed on random specimens by using ELISAs for individual cytokines (R&D Systems, Minneapolis, Minnesota).

Back to Top | Article Outline

Clinical Variables

Detailed clinical data were collected prospectively. Preoperative data included diagnosis, demographics, inotrope use, mechanical ventilation, and standard clinical laboratory data. Intraoperative data included CPB, aortic cross-clamp, and circulatory arrest times, blood products administered, lactate concentration, and hematocrit. Postoperative variables included duration of intubation, length of ICU and hospital stay, and lactate concentration. Data were collected on intra- and postoperative blood transfusions, including volumes of individual blood components and total blood products. The total volume of intraoperative blood products included volume of reconstituted whole blood, packed red blood cells (RBCs), fresh frozen plasma (FFP), cryoprecipitate, and platelets. The total volume of postoperative blood products included these same components and 5% albumin. The Pediatric Risk of Mortality III (PRISM III) score, a physiology-based score used to predict risk of mortality, which is frequently used as an index for severity of illness, was calculated for each patient at 24 hours post-CPB.12

Back to Top | Article Outline

Statistical Methods

Because of skewness in their distributions, parametric analyses were performed on concentrations of inflammatory mediators after adding 1 and taking a natural log-transformation. Post-CPB inflammatory mediator concentrations were compared with baseline by using paired t tests. Spearman rank correlation coefficients were used to assess associations between inflammatory mediator concentrations and continuous clinical variables. To account for multiple comparisons, we set statistical significance at P ≤ 0.005 for correlation coefficients. With 93 patients, this study has 80% power to detect correlations of 0.37 or higher using 2-sided 0.005 level tests. Inflammatory mediator concentrations for patients who received aprotinin versus those who did not were compared using the Wilcoxon's ranked sum test. Multivariable linear regression (for lactate concentration and PRISM scores) and proportional hazards regression (for ICU days and blood products) were used to further examine the relationship between log-transformed inflammatory mediator concentrations and clinical outcome variables, adjusting for patient age (≤30 days vs. >30 days) and diagnostic group. Diagnostic groups included d-transposition of the great arteries (dTGA), tetralogy of Fallot (TOF and truncus arteriosus), and ventricular septal defect (ventricular septal defect and complete atrioventricular canal defects). All statistical analyses were performed using SAS/STAT® software, version 9.2 (SAS Institute Inc., Cary, North Carolina).

Back to Top | Article Outline

RESULTS

Ninety-three patients were enrolled. Preoperative inflammatory mediator concentrations were available in 88 (95%) patients. Diagnoses, demographic data, and perioperative variables are reported in Table 1. There were no deaths.

Table 1

Table 1

Back to Top | Article Outline

Plasma CRP, IL-6, IL-10, IL-8, TNF-α, and IL-1β Concentrations – Effects of CPB

Significant changes in the concentration of CRP, IL-6, IL-8, and IL-10 were seen postoperatively in comparison with baseline (Fig. 1). Median IL-6 concentrations increased immediately after CPB (3.2 vs. 24.2 pg/mL) and at 6 (95.4 pg/mL), 12 (98.1 pg/mL), and 24 hours (90.3 pg/mL) post-CPB (all Ps < 0.001). CRP concentration pre-CPB was low and increased at 24 hours (0.3 vs. 27.5 mg/L; P < 0.001). IL-10 concentrations increased immediately after CPB (0.9 vs. 86.4 pg/mL; P < 0.001) and returned to baseline by 24 hours (1.4 pg/mL). Interestingly, significant concentrations of TNF-α and IL-1β were not found at any point (data not shown). IL-8 concentrations were low before CPB (0 pg/mL) and increased immediately after CPB (2.9 pg/mL; P < 0.001) through 24 hours post-CPB. Concentrations of IL-6, IL-8, IL-10, and CRP at all time points were not related to hematocrit at onset of deep hypothermic circulatory arrest, nor did they vary between patients who received aprotinin and those who did not.

Figure 1

Figure 1

Back to Top | Article Outline

Preoperative Inflammatory Status

Preoperative IL-6 and CRP concentrations were highly associated (r = 0.66, P < 0.001). Both correlated with younger age, lower weight, lower preoperative oxygen saturation, and increased postinduction lactate concentrations (Table 2). Preoperative IL-6 and CRP concentrations also correlated with multiple postoperative outcome variables, including lactate concentrations 24 hours post-CPB, 24-hour PRISM III scores, duration of tracheal intubation, and length of ICU and hospital stay (Table 2). There was no significant correlation between preoperative IL-8 or IL-10 concentration and any clinical variable.

Table 2

Table 2

Back to Top | Article Outline

Inflammation After CPB

Plasma concentrations of IL-6, CRP, and IL-8 at the conclusion of CPB were inversely related to age and lowest preoperative oxygen saturation (Table 3). IL-6 and IL-8 concentrations at the end of CPB correlated positively with CPB duration. IL-8 also correlated positively with aortic cross-clamp time and duration of circulatory arrest and negatively with lowest temperature on CPB. IL-6, IL-8, and CRP immediately after CPB were all positively correlated with peak intraoperative lactate concentration. IL-10 did not correlate with perioperative variables (data not shown).

Table 3

Table 3

Examination of the relationship between immediate post-CPB inflammatory mediators and postoperative variables demonstrated a correlation between IL-8 and clinical outcome variables including 24-hour lactate and PRISM III score and duration of intubation, ICU stay, and hospital stay (Table 3). IL-6 immediately after CPB also correlated with 24-hour lactate and PRISM score, and the correlation with duration of ICU stay approached statistical significance (P = 0.006).

Back to Top | Article Outline

Correlation of Late Postoperative Inflammatory Mediator Concentrations with Clinical Variables

Concentrations of IL-6, IL-8 and CRP at 24 hours post-CPB were not correlated with age or oxygen saturation. However, higher 24-hour IL-6 and IL-8 were associated with worse postoperative outcomes, including longer duration of intubation and ICU stay (Table 4).

Table 4

Table 4

Back to Top | Article Outline

Multivariate Analysis

After adjustment for age and diagnosis, preoperative IL-6, IL-8, and IL-10 were not associated with postoperative variables. Immediately after CPB and at 24 hours, concentrations of IL-6 (P = 0.05 and 0.007) and IL-8 (P = 0.04 and 0.003) remained significantly associated with ICU length of stay, and IL-8 immediately after CPB remained associated with 24-hour lactate (P = 0.004).

Back to Top | Article Outline

Correlation of Inflammatory Mediator Concentrations with Intra- and Postoperative Blood Products

Preoperative CRP (r = 0.32, P = 0.002), but not IL-6, IL-8, or IL-10 (data not shown), correlated with total intraoperative blood products administered per kilogram. No preoperative inflammatory markers correlated with total postoperative blood product administration (data not shown). The relationship between blood product administration and cytokine and CRP production after CPB is summarized in Table 5. There was no correlation with IL-10 production (data not shown). Interestingly, product administration, especially that of non-RBC products (sum of cryoprecipitate, FFP, and platelets), was significantly related to production of IL-6 and IL-8. After adjustment for age and diagnosis, total intraoperative blood products and non-RBC products were associated with 24-hour IL-6 and IL-8 (Table 6). Postoperative non-RBC products were associated with immediate postoperative as well as 24-hour IL-6 and IL-8. Total postoperative blood products were also associated with 24-hour IL-6 and IL-8. In addition, a relationship was seen between postoperative whole blood plus packed RBCs and immediate postoperative IL-8.

Table 5

Table 5

Table 6

Table 6

Back to Top | Article Outline

DISCUSSION

Definitive repair in the neonatal period or early infancy has become the goal for most 2-ventricle congenital cardiac lesions. To our knowledge, our study is the largest to examine the production of multiple cytokines, the acute phase protein CRP, and clinical outcome in such infants. Previous contributions to this field have clearly demonstrated that IL-6, CRP, IL-10, and IL-8 can increase significantly in infants and children after CPB,7,1315 and such increases are widely thought to contribute to postoperative morbidity and mortality. However, the majority of pediatric studies of the inflammatory response to CPB have included small numbers of patients with broad age ranges and diagnostic categories15 or have focused on a limited number of mediators.6,15,16 Other studies that have investigated the breadth of markers evaluated in this study either have not investigated correlation with clinical outcomes6 or have observed older pediatric patients.17 The largest study in neonates undergoing cardiac surgery demonstrated only a link between 4-hour post-CPB IL-6 concentration and possible postoperative myocardial dysfunction, but did not explore the correlation between IL-6 concentrations and outcome variables such as inotrope use, duration of ventilation, or length of ICU stay.5

Back to Top | Article Outline

Preoperative Inflammation in Infants

Preoperative IL-6 and CRP concentrations in this study were inversely related to patient age. These findings are consistent with a previous study in a small number of children demonstrating that IL-6 concentrations preoperatively were higher in neonates than in older children.9 The notion of a heightened inflammatory state preoperatively is also supported by pediatric studies demonstrating an association between preoperative endotoxemia and increased illness severity postoperatively.18 Additionally, prior studies have documented intramyocardial synthesis of IL-6, TNF-α, and IL-1020as well as myocardial nuclear factor–κB translocation preoperatively in some infants with congenital heart disease, likely indicating myocardial inflammatory activation.19 Although younger infants had higher concentrations of inflammatory mediators preoperatively, we were unable to demonstrate an independent effect of preoperative inflammatory mediator concentrations on postoperative outcomes after adjusting for age and diagnosis. Additionally, while very young age was associated with evidence of preoperative inflammatory activation, exposure to surgery and CPB appeared to trigger inflammation in neonates and older infants to a similar extent, as was demonstrated by lack of correlation between age and 24-hour inflammatory mediator concentrations.

The majority of neonates in the current study underwent repair of dTGA. Interestingly, Appachi et al. demonstrated that neonates with hypoplastic left heart syndrome (HLHS) had higher IL-6 levels pre- and postoperatively than did those with dTGA.21 Thus, preoperative inflammatory mediator concentrations in neonates undergoing higher-complexity operations may have more significance, though the study by Appachi et al. did not investigate the relationship between preoperative IL-6 and postoperative clinical outcome variables in patients with HLHS.

Back to Top | Article Outline

Effects of CPB in Infants

We demonstrated in multivariate analyses that higher postoperative IL-6 and IL-8 concentrations were associated with longer ICU stay and higher 24-hour lactate and, thus, an association with greater postoperative severity of illness. IL-6 is a proinflammatory cytokine whose production is driven by multiple stimuli, including hypoxia, TNF-α, and IL-1β. Its biological activities include stimulation of CRP, which in turn plays a role in complement activation and in mobilization of neutrophils. IL-8 is a cytokine that induces neutrophil chemotaxis along an IL-8 concentration gradient. Neutrophil attraction and activation may be responsible for increased vascular permeability seen after CPB. Although longer duration of ICU stay and lactate are both nonspecific markers of severity of illness, increased vascular permeability could contribute to increased duration of ICU stay by increasing duration or severity of pulmonary capillary leak, pleural effusions, or ascites. Direct myocardial depressant and mitochondrial effects of IL-6 could result in increased lactate concentrations if tissue perfusion and oxidative metabolism, respectively, were impaired as a result.

Despite the important role of TNF-α and IL-1β in inflammatory states, specifically sepsis, and their role in inducing production of other inflammatory mediators, we did not find significant amounts of either cytokine perioperatively. This does not exclude the potential importance of these mediators in CPB-mediated inflammation, because both are produced rapidly in response to inflammatory stimuli and are rapidly cleared. It is possible that significant amounts of one or both were produced in a narrow time window not investigated in this study. Concentrations of TNF-α vary widely in septic patients in part because of its rapid production and clearance. TNF-α and IL-β both stimulate production of IL-6, which is present in the bloodstream for longer periods; therefore, IL-6 is frequently used as the primary measure of inflammatory activation.22 Significant local production of TNF-α or IL-β are also not accounted for in the present study; intramyocardial production of TNF-α and associated myocardial depression occurs in response to ischemia–reperfusion injury and in animal models of CPB.2325

Back to Top | Article Outline

Perioperative Blood Product Administration and Inflammation

On multivariate analysis, intraoperative and postoperative total blood product administration were associated with 24-hour IL-6 and IL-8. Analysis of individual blood product components demonstrated that intra- and postoperative non-RBC products were associated with 24-hour IL-6 and IL-8 concentrations. The inflammatory response to CPB has been associated with fibrinolysis and coagulopathy, potentially increasing blood loss and, hence, transfusion requirements.26 Both blood loss and transfusion have also been associated with increased cytokine production in trauma models.27 Transfusion has been increasingly recognized as a risk factor in critically ill patients.28 Although it is not possible to determine causality on the basis of the current study, the association between both intraoperative and postoperative blood product administration and postoperative inflammatory mediator production suggests that perioperative blood product exposure may enhance the inflammatory response and contribute to worse patient outcome.29 It is of interest in this study that non-RBC components in particular were associated with postoperative cytokine concentrations. Although prior clinical studies have investigated the link between transfusion of RBC components and outcomes, recent in vitro data have suggested that both RBC and non-RBC components, including FFP and platelets, may stimulate cytokine production.30

Back to Top | Article Outline

Limitations

Limitations of the present study include the fact that it was from a single center and included only infants undergoing 2 ventricle repairs, excluding potentially sicker infants, such as those with HLHS. Despite its relatively large sample size, the total number and types of patients may have been insufficient to detect small but important effects. Inflammatory pathways not mediated by cytokines (e.g., complement and leukocytes) were not directly examined. Subtle but important effects upon specific organ systems (e.g., brain) were not assessed. The results of this study must also be interpreted in light of the fact that some measures to reduce inflammatory responses to CPB are standard in our institution, including use of steroids in the bypass prime solution. The use of a standard protocol for steroid administration among these patients makes data interpretation easier. Additionally, in a survey, 97% of reporting pediatric centers routinely used steroids in the perioperative period.31 Aprotonin, which has potential anti-inflammatory effects of uncertain clinical importance, was used in 13% of patients studied here. However, there was no significant difference in inflammatory mediator production between patients who received aprotonin and those who did not. There may be other as yet unknown factors that contribute to or ameliorate the inflammatory response that were not adequately controlled for in this study.

Back to Top | Article Outline

Summary

In this study examining the relationship between the inflammatory response to infant CPB and postoperative outcomes, multivariate analyses demonstrated significant correlations between postoperative IL-6 and IL-8 and the length of ICU stay. Postoperative IL-8 production was related to lactate concentrations at 24 hours; postoperative lactate production is widely used as a predictor of morbidity and mortality.32,33 Additionally, there was a correlation between 24-hour IL-6 and IL-8 and total as well as non-RBC blood product administration in the postoperative period. The present study also showed that there was a heightened inflammatory state preoperatively in neonates, but this did not correlate with late postoperative inflammation or outcome. Similarly, we were not able to demonstrate that the peak inflammatory response to CPB was significantly greater in neonates.

This investigation has observed the relationship between inflammatory mediator concentrations and nonspecific outcome variables, such as duration of ICU stay and mechanical ventilation. The inability to define a specific “post-CPB inflammatory phenotype” is a limitation not only to the present study and others like it but also to potential genomic and anti-inflammatory therapeutic investigations. Nonetheless, we believe that one of the most important aspects of this study is that it shows that the relationships between postbypass inflammatory mediators and postoperative clinical variables, though statistically significant, were of modest clinical importance. The correlation coefficients (r values) for associations with important clinical outcomes (duration of ventilation, length of ICU stay, and length of hospital stay) were in the range of 0.2 to 0.3, suggesting that 4% to 9% (r2) of the clinical variability in these outcomes may be related to differences in inflammatory mediator concentrations. Given that median duration of intubation and ICU stay in particular were short (1.2 and 3 days, respectively), we would consider a 4% to 9% change in this variable of only modest clinical significance. We therefore conclude that in infants undergoing reparative surgery of low- to moderate-complexity lesions in a single high-volume center, the pre- and postoperative inflammatory states are associated with negative outcome, but in a clinically limited way. Thus, the potential positive impact of targeted antiinflammatory therapies in this group of patients is likely to be small. The magnitude and importance of the inflammatory response in patients undergoing high complexity surgeries, such as Stage I palliation for HLHS, remains to be determined. Finally, further research is needed to determine if and how variables such as age and cyanosis alter the baseline inflammatory state and subsequent response to CPB in infants and to clarify the relationship between blood product administration and inflammatory response.

Back to Top | Article Outline

ACKNOWLEDGMENTS

We are indebted to the investigators in the Boston hematocrit trials; Ludmila Kyn for database and statistical programming; Donna Donati, Donna Duva, and Lisa-Jean Buckley for data management; and Kathleen Alexander for project coordination.

Back to Top | Article Outline

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
2. Ben-Abraham R, Weinbroum AA, Dekel B, Paret G. Chemokines and the inflammatory response following cardiopulmonary bypass—a new target for therapeutic intervention? A review. Paediatr Anaesth 2003;13:655–61
3. Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993;55:552–9
4. Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 2003;75:S715–20
5. Hovels-Gurich HH, Vazquez-Jimenez JF, Silvestri A, Schumacher K, Minkenberg R, Duchateau J, Messmer BJ, von Bernuth G, Seghaye MC. Production of proinflammatory cytokines and myocardial dysfunction after arterial switch operation in neonates with transposition of the great arteries. J Thorac Cardiovasc Surg 2002;124:811–20
6. Chew MS, Brandslund I, Brix-Christensen V, Ravn HB, Hjortdal VE, Pedersen J, Hjortdal K, Hansen OK, Tonnesen E. Tissue injury and the inflammatory response to pediatric cardiac surgery with cardiopulmonary bypass: a descriptive study. Anesthesiology 2001;94:745–53
7. Hovels-Gurich HH, Schumacher K, Vazquez-Jimenez JF, Qing M, Huffmeier U, Buding B, Messmer BJ, von Bernuth G, Seghaye MC. Cytokine balance in infants undergoing cardiac operation. Ann Thorac Surg 2002;73:601–8
8. Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86:845–57
9. Alcaraz AJ, Manzano L, Sancho L, Vigil MD, Esquivel F, Maroto E, Reyes E, Alvarez-Mon M. Different proinflammatory cytokine serum pattern in neonate patients undergoing open heart surgery. Relevance of IL-8. J Clin Immunol 2005;25:238–45
10. Schumacher K, Korr S, Vazquez-Jimenez JF, von Bernuth G, Duchateau J, Seghaye MC. Does cardiac surgery in newborn infants compromise blood cell reactivity to endotoxin? Crit Care 2005;9:R549–55
11. Newburger JW, Jonas RA, Soul J, Kussman BD, Bellinger DC, Laussen PC, Robertson R, Mayer JE Jr., del Nido PJ, Bacha EA, Forbess JM, Pigula F, Roth SJ, Visconti KJ, du Plessis AJ, Farrell DM, McGrath E, Rappaport LA, Wypij D. Randomized trial of hematocrit 25% versus 35% during hypothermic cardiopulmonary bypass in infant heart surgery. J Thorac Cardiovasc Surg 2008;135:347–54
12. Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated Pediatric Risk of Mortality score. Crit Care Med 1996;24:743–52
13. Arkader R, Troster EJ, Abellan DM, Lopes MR, Junior RR, Carcillo JA, Okay TS. Procalcitonin and C-reactive protein kinetics in postoperative pediatric cardiac surgical patients. J Cardiothorac Vasc Anesth 2004;18:160–5
14. Beghetti M, Rimensberger PC, Kalangos A, Habre W, Gervaix A. Kinetics of procalcitonin, interleukin 6 and C-reactive protein after cardiopulmonary-bypass in children. Cardiol Young 2003;13:161–7
15. Butler J, Pathi VL, Paton RD, Logan RW, MacArthur KJ, Jamieson MP, Pollock JC. Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kilograms. Ann Thorac Surg 1996;62:538–42
16. Seghaye MC, Grabitz RG, Duchateau J, Busse S, Dabritz S, Koch D, Alzen G, Hornchen H, Messmer BJ, Von Bernuth G. Inflammatory reaction and capillary leak syndrome related to cardiopulmonary bypass in neonates undergoing cardiac operations. J Thorac Cardiovasc Surg 1996;112:687–97
17. Khabar KS, elBarbary MA, Khouqeer F, Devol E, al-Gain S, al-Halees Z. Circulating endotoxin and cytokines after cardiopulmonary bypass: differential correlation with duration of bypass and systemic inflammatory response/multiple organ dysfunction syndromes. Clin Immunol Immunopathol 1997;85:97–103
18. Lequier LL, Nikaidoh H, Leonard SR, Bokovoy JL, White ML, Scannon PJ, Giroir BP. Preoperative and postoperative endotoxemia in children with congenital heart disease. Chest 2000;117:1706–12
19. Qing M, Schumacher K, Heise R, Woltje M, Vazquez-Jimenez JF, Richter T, Arranda-Carrero M, Hess J, von Bernuth G, Seghaye MC. Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects. J Am Coll Cardiol 2003;41:2266–74
20. Mou SS, Haudek SB, Lequier L, Pena O, Leonard S, Nikaidoh H, Giroir BP, Stromberg D. Myocardial inflammatory activation in children with congenital heart disease. Crit Care Med 2002;30:827–32
21. Appachi E, Mossad E, Mee RB, Bokesch P. Perioperative serum interleukins in neonates with hypoplastic left-heart syndrome and transposition of the great arteries. J Cardiothorac Vasc Anesth 2007;21:184–90
22. Song M, Kellum JA. Interleukin-6. Crit Care Med 2005;33:S463–5
23. Meldrum DR, Meng X, Dinarello CA, Ayala A, Cain BS, Shames BD, Ao L, Banerjee A, Harken AH. Human myocardial tissue TNFalpha expression following acute global ischemia in vivo. J Mol Cell Cardiol 1998;30:1683–9
24. Stein B, Frank P, Schmitz W, Scholz H, Thoenes M. Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase. J Mol Cell Cardiol 1996;28:1631–9
25. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987;330:662–4
26. Jaggers J, Lawson JH. Coagulopathy and inflammation in neonatal heart surgery: mechanisms and strategies. Ann Thorac Surg 2006;81:S2360–6
27. Escobar GA, Cheng AM, Moore EE, Johnson JL, Tannahill C, Baker HV, Moldawer LL, Banerjee A. Stored packed red blood cell transfusion up-regulates inflammatory gene expression in circulating leukocytes. Ann Surg 2007;246:129–34
28. Markhorst DG, Kneyber MC. Should critically ill patients be routinely transfused to a normal haemoglobin level? Arch Dis Child 2007;92:1038–9
29. Fransen E, Maessen J, Dentener M, Senden N, Buurman W. Impact of blood transfusions on inflammatory mediator release in patients undergoing cardiac surgery. Chest 1999;116:1233–9
30. Schneider SO, Rensing H, Graber S, Kreuer S, Kleinschmidt S, Kreimeier S, Muller P, Mathes AM, Biedler AE. Impact of platelets and fresh frozen plasma in contrast to red cell concentrate on unstimulated and stimulated cytokine release in an in vitro model of transfusion. Scand J Immunol 2009;70:101–5
31. Checchia PA, Bronicki RA, Costello JM, Nelson DP. Steroid use before pediatric cardiac operations using cardiopulmonary bypass: an international survey of 36 centers. Pediatr Crit Care Med 2005;6:441–4
32. Charpie JR, Dekeon MK, Goldberg CS, Mosca RS, Bove EL, Kulik TJ. Serial blood lactate measurements predict early outcome after neonatal repair or palliation for complex congenital heart disease. J Thorac Cardiovasc Surg 2000;120:73–80
33. Munoz R, Laussen PC, Palacio G, Zienko L, Piercey G, Wessel DL. Changes in whole blood lactate levels during cardiopulmonary bypass for surgery for congenital cardiac disease: an early indicator of morbidity and mortality. J Thorac Cardiovasc Surg 2000;119:155–62
© 2010 International Anesthesia Research Society