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Ann Thorac Surg 2008;85:611-617. doi:10.1016/j.athoracsur.2007.10.062
© 2008 The Society of Thoracic Surgeons
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Original Articles: Cardiovascular

Effect of Perfusion Temperature on the Inflammatory Response During Pediatric Cardiac Surgery

Rune Eggum, MDa,e,*, Thor Ueland, PhDb, Tom E. Mollnes, MD, PhDc, Vibeke Videm, MD, PhDf, Pål Aukrust, MD, PhDb,d, Arnt E. Fiane, MD, PhDa, Harald L. Lindberg, MD, PhDa

a Department of Thoracic and Cardiovascular Surgery, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway
b Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway
c Institute of Immunology, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway
d Section of Clinical Immunology and Infectious Diseases, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway
e Department of Vascular Surgery, Buskerud Hospital, Drammen, Norway
f Institute of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, and Department of Immunology and Transfusion Medicine, St. Olav University Hospital, Trondheim, Norway

Accepted for publication October 17, 2007.

* Address correspondence to Dr Eggum, Department of Vascular Surgery, Buskerud Hospital, Drammen, N-3004, Norway (Email: rune.eggum{at}sb-hf.no).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Cardiopulmonary bypass (CPB) triggers the whole body inflammatory response, and it has been suggested that the degree of hypothermia may influence these responses. The aim of this prospective study was to compare the inflammatory response in children undergoing CPB for repair of congenital heart defects, randomized to mild or moderate hypothermia.

Methods: We measured inflammatory markers in blood samples of thirty children with body weight less than 10 kg undergoing open heart surgery randomized to surgery at either mild (32°C) or moderate (25°C) hypothermia. Blood was sampled after induction of anesthesia, at skin closure, 2 hours, 24 hours, and 48 hours postoperatively.

Results: Except for an enhanced interleukin-8 response in the moderate hypothermia group, there were no differences in levels of inflammatory mediators between those with mild and those with moderate hypothermia. In contrast to the modest influence of the degree of hypothermia, long CPB time and long aortic cross-clamp time were accompanied by enhanced inflammation involving raised levels of interleukin-8 and myeloperoxidase, as well as increased leukocyte counts.

Conclusions: Only minor differences in cytokine levels were detected between those with moderate and those with mild hypothermia during CPB. Ischemic aortic cross-clamp time and time on CBP should be as short as possible to avoid an excessive inflammatory response and possibly adverse clinical effects.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Cardiopulmonary bypass (CPB) triggers the whole body inflammatory response. This response is, in many aspects, similar to what is seen in sepsis. Capillary leakage, edema, and organ dysfunction can lead to postoperative morbidity and are correlated to adverse clinical outcomes [1–4]. The CBP-related inflammation involves humoral and cellular immune responses and may be quantified by measuring complement activation factors, cytokines, leukocyte activation, and specific chemo attractant proteins [5, 6].

The inflammatory response during CPB has been shown to be more pronounced in children compared with adults, partially as a result of a relative greater exposure of blood to artificial surfaces in the heart-lung machine. However, preoperative characteristics may also play important roles in young patients [7, 8]. Depending on the complexity of the congenital heart malformation, cytokine baseline values may be elevated in some children, such as those with Down syndrome [9, 10].

In adults it has been shown that normothermia during CPB elicits a stronger inflammatory response than CPB under hypothermia [11, 12], and the degree of complement activation decreases with temperature in vitro [13]. Deep hypothermia may also inhibit less collateral flow. Other studies show no difference in inflammatory response in relation to the peroperative target temperature [14, 15]. The aim of this prospective study was to compare the inflammatory response in children with body weight less than 10 kg undergoing open heart surgery, randomized to mild or moderate hypothermia. We also investigated the inflammatory response in relation to aortic cross-clamp time and the duration of CPB.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Patients
Thirty consecutive patients with body weight less than 10 kg were included. The patients were randomized into two groups by manual drawing of lots at admission to the hospital. Patient characteristics are shown in Table 1. In group A, nine girls and six boys underwent cardiac surgery at mild hypothermia (lowest body temperature 32°C). In group B, eight girls and seven boys underwent cardiac surgery at moderate hypothermia (lowest body temperature 25°C). Surgery was performed with standard techniques by the same surgeons in both groups. Patients with functionally univentricular congenital heart defects, isolated atrial septal defects, immunopathies, coagulopathies, or with an expected CPB time less than 30 minutes were excluded from the study. The diagnoses of the patients included are shown in Table 1. Mean Aristotle Basic Complexity score [16] for group A was 7.2 and 7.6 for group B. The project was approved by the regional ethics committee. Written consent was obtained from the parents before inclusion in the study.


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  		Table 1 Patient Characteristics
 
Anesthesia
Anesthesia was the same in the two groups. Midazolam (Alpharma, Oslo, Norway; 0.05 to 0.1 mg/kg) was used as premedication. Induction of anesthesia was achieved by a combination of fentanyl (Alpharma; 15 to 20 µg/kg), thiopentone (Abbott, Abbott Park, IL; 6 to 7 µg/kg) and Pavulon (Organon, Oss, the Netherlands; 0.1 to 0.2 µg/kg). For continuation, fentanyl (15 to 20 µg/kg), isoflurane (Baxter, Deerfield, IL; 0.5 to 1.0% in inspiration gas), and midazolam (0.25 mg/kg) were given. After tracheal intubation, the patients were ventilated with a servo ventilator (Siemens 900 C, Siemens-Elema AB, Solna, Sweden). All patients received a urinary catheter, one or two peripheral venous cannulas, one central venous catheter, and a radial or femoral arterial cannula.

Extracorporeal Circulation
We used a Stöckert roller pump (Sorin Group, Mirandola, Italy) with oxygenator and tubing from Dideco (D-901) with Phisio coating (Sorin Group) [17]. For cannulation, DLP cannulas (Medtronic, Minneapolis, MN) without coating were used. The priming volume of the heart-lung machine was 350 mL. The composition of this volume consisted of heparin (20 mg/L), mannitol (3 mL/kg), sodium bicarbonate (50 mmol/L), and albumin (200 mg/mL) up to 4% of total prime, as well as erythrocytes (saline, adenine, glucose [SAG]) aiming for a target hematocrit of 25% to 30% while on CPB. Heparin (3 mg/kg) was given intravenously to the patient after sternotomy, and CPB was started when the activated clotting time passed 480 seconds. The temperature of the perfusate was set on target before going on CPB to achieve immediate cooling. The alpha-stat strategy was applied during CPB. Hemofiltration was not applied. Pump flow was 2.4 L/m2/minute at mild hypothermia, and 1.5 L/m2/minute during moderate hypothermia, provided a central venous saturation above 60%. Rewarming was started after removal of the aortic clamp. When heating, the gradient between water and venous blood in the heat exchanger was maximum 8°C, and the maximum temperature of the arterial blood was 39°C. The hematocrit before weaning from CPB was above 30%, and the rectal temperature was 36°C or more. Auto transfusion was not used postoperatively, except for the remaining blood in the heart-lung machine. For myocardial protection, St. Thomas’ type II, crystalloid cardioplegic solution was introduced into the aortic root through a Mirafilter IV (Baxter). Initially, 15 mL/kg was given; thereafter, 5 to 10 mL/kg every 20 to 30 minutes.

Blood Sampling Protocol
Blood samples were obtained from the arterial and central venous cannulas at the following times: Pre, preoperatively after the induction of anesthesia; SC, at the time of skin closure; 2 h PO, two hours postoperatively; 24 h PO, 24 hours postoperatively; and 48 h PO, 48 hours postoperatively. The blood samples for the inflammatory markers were drawn into pyrogen-free tubes with ethylenediaminetetraacetic acid as anticoagulant, immediately cooled on melting ice and centrifuged within 20 minutes (2,000g for 10 minutes at 4°C). All samples were stored at –80°C in multiple aliquots and thawed only once.

Biochemical Analyses
The following inflammatory markers were analyzed: interleukin (IL)-6, IL-8, IL-10, C3bc, terminal complement complex (TCC), monocyte chemo attractant protein (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), and myeloperoxidase (MPO). The complement activation assays (C3bc and TCC) were designed as double-antibody enzyme immunoassays using neoepitope-specific antibodies as coat. This enables binding of the specific activation product without interference with the native components. Second antibodies against the activation products were added to quantify the amount of activation products bound. The assays were performed principally as described previously [18]. Plasma concentrations of IL-6, IL-8, IL-10, MCP-1, and RANTES were quantified by enzyme immunoassays obtained from R&D System (Minneapolis, MN). The MPO was quantified in immunoassay as previously described [19]. Hematocrit, leukocyte, and platelet counts were determined by using an automated analyzer (CELL-DYN 4000, Abbott Laboratories, Abbott Park, IL). Lactate concentrations and arterial and central venous oxygen saturation were obtained from a blood gas analyzer (Kardiometer, Copenhagen, Denmark).

Statistics
Differences between groups were compared by the Mann-Whitney rank sum test for unpaired data. For paired data, multiple analyses of variance were performed and p values (Tables 2, 3, and 4) Go Go for the effect of time, group, and the interaction between time and group, are reported. Probability values are two-sided with a p value less than 0.05 considered statistically significant. All values were compared statistically with and without correction for hemodilution performed using a hematocrit-based formula [20]. Data are given as mean ± SD.


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  		Table 2 Levels of Inflammatory Mediators According to the Degree of Hypothermia During Cardiopulmonary Bypass
 

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  		Table 3 The Levels of Inflammatory Mediators in Relation to Cardiopulmonary Bypass (CPB) Time
 

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  		Table 4 The Levels of Inflammatory Mediators in Relation to Aortic Cross-Clamp Time
 

   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
The median age was 6 (2 to 14) months and 7 (1 to 18) months, the median weight was 5,950 (4,040 to 9,599) grams and 6,300 (4,720 to 9,900) grams, the median aortic cross-clamp time was 30 (10 to 78) minutes and 23 (14 to 81) minutes, and the CPB time was 49 (33 to 125) minutes and 56 (40 to 123) minutes, in groups A and B, respectively, with no significant differences between the two treatment groups.

Inflammatory Response in Relation to the Degree of Hypothermia
Except for a striking decline in RANTES levels, CPB was accompanied by a marked elevation of the inflammatory markers, and although higher MCP-1, C3bc, and TCC concentrations at time 2 h PO, and higher leukocyte counts at time 48 h PO were observed in the mild hypothermia group, these differences did not reach statistical significance (Table 2). However, IL-8 concentrations were significantly higher (p = 0.012) and IL-10 concentration significantly lower (p < 0.001) in the moderate group compared with the mild hypothermia group as assessed by area under the curve estimations (Table 2). Moreover, the children subjected to mild hypothermia had a significantly higher oxygen extraction according to measured central venous oxygen saturation from time SC to 48 h PO (p = 0.049). A similar pattern was seen for all parameters, whether corrected for hemodilution or not. We did not observe any significant differences in the clinical postoperative outcomes (ie, time on ventilator, urine output, need of inotropic support, length of stay in intensive care unit, operative mortality) between the two groups.

Inflammatory Response in Relation to the Duration of CPB and Aortic Cross-Clamp Time
To further investigate the inflammatory response during CPB in these children, we dichotomized the patients by the median CPB time, long (median 70 minutes) or short (median 43 minutes), and ischemic-aortic cross-clamp time, long (median 40 minutes) or short (median 19 minutes). In the long aortic cross-clamp time group, we found significantly higher plasma concentrations of MCP-1 (p = 0.015) and MPO (p = 0.001). We also observed a trend of higher concentrations of IL-8 (p = 0.094) and leukocyte counts (p = 0.089) and lower concentration of RANTES (p = 0.055) in this group compared with the children with short aortic cross-clamp times (Table 3). In the long CPB group we found significantly higher plasma concentrations of MPO (p = 0.002) and IL-8 (p = 0.003); also leukocyte counts, parameters of complement activation (ie, TCC and C3bc), and lactate concentrations tended to be higher in the long CPB group (Table 4).

The complexity of the congenital heart malformation as well as the occurrence of Down syndrome could influence the inflammatory response during CPB [9, 10]. However, there were no differences in cytokine or complement levels either at baseline or during the study period between those with simple congenital cardiac malfunction and those with complicated malfunction with cyanosis (data not shown). Moreover, similar results were obtained even when the patients with Down syndrome were excluded from the data analyses (data not shown).


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
The inflammatory response that accompanies open heart surgery is multifactorial, both in adults and children [21]. The mismatches between the foreign surfaces in the heart-lung machine and blood vessel surfaces are extreme in children. Therefore, specially designed heart-lung machines with small priming volumes and surfaces are developed [22, 23]. The surgical trauma, anesthesia, and deviation from normal organ perfusion are other important factors causing inflammatory activation [24, 25]. It has also been suggested that the degree of hypothermia may influence the inflammatory response during CPB. Deep hypothermia and circulatory arrest have been shown to trigger less-pronounced inflammatory response than low-flow CPB in newborns, as assessed by measurements of IL-6, IL-8, and C3a [26, 27]. This phenomenon may be a result of a shorter CPB time, but a protective effect of hypothermia per se may also be part of the explanation [6, 13]. However, in the present randomized study, designed to further elucidate this issue, we did not find any significantly attenuated inflammatory response in the moderate hypothermia group. In fact, this group showed an enhanced IL-8 response and an attenuated IL-10 response during CPB potentially suggesting an inflammatory net effect. Our findings are in accordance with the study of Caputo and colleagues [28], who conclude that normothermic CPB is associated with reduced oxidative stress compared with hypothermic CPB, and these authors also showed a decreased level of the antiinflammatory cytokine IL-10 in the hypothermia group.

Chemokines like IL-8 and MCP-1 are, respectively, potent activators of neutrophils and monocytes [29]. Activation of neutrophils results in degranulation with increased release of MPO that together with increased production of reactive oxygen species may lead to tissue damage, and are important contributors to inflammation. A long CPB time has previously been associated with increased levels of IL-8 and MPO, potentially reflecting enhanced activation of neutrophils [10]. Our results in the present study further support such a notion by showing raised IL-8 and MPO levels accompanied by increased leukocyte counts in patients with long CPB times. A similar pattern was also seen in patients with long aortic cross-clamp times. Both long CPB time and long aortic cross-clamp time may induce enhanced oxidative stress, possibly contributing to the enhanced IL-8 and MCP-1 levels through nuclear factor {kappa}B activation [30]. In contrast to the increased levels of MCP-1 and IL-8, patients with long aortic cross-clamp time showed decreased plasma levels of RANTES. As platelets are the major cellular contributor to circulating RANTES levels [31], this phenomenon most probably reflects excessive platelet activation with degranulation of platelets in vivo in the long aortic cross-clamp time group.

The present study has some limitations such as a relatively low number of patients. We also lack data on cytokine levels prior to anesthesia. Moreover, the different variables such as CPB time and the degree of hypothermia are clearly not independent variables. Thus, duration of CPB will be longer in those with moderate as compared with those with mild hypothermia in that it takes longer to cool and rewarm from 25°C, rendering it difficult to evaluate the relative importance of each factor. Nevertheless, although those with moderate hypothermia showed some trends for a higher degree of inflammation than those with mild hypothermia during CPB, the differences were rather modest. In contrast, the aortic cross-clamp time and time on CBP were associated with increased chemokine levels and leukocyte activation, underscoring that these procedures should be as short as possible to avoid an excessive inflammatory response and possible adverse clinical effects.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
We thank Torill Anita Weisethaunet for skillful technical assistance, and the pediatric team in our department for their cooperation. This study was supported by grants from the Norwegian Foundation for Health and Rehabilitation, the Professor Hall and Stockback funds, the Research Council of Rikshospitalet, the Family Blix Foundation, and the Odd Fellow Foundation.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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  17. Draaisma AM, Hazekamp MG, Anes N, et al. Phosphorylcholine coating of bypass systems used for young infants does not attenuate the inflammatory response Ann Thorac Surg 2006;81:1455-1459.[Abstract/Free Full Text]
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