Inflammatory response to cardiopulmonary bypass in neonates and young children: endotoxin release, cytokine production, and gastrointestinal permeability

BACKGROUND
The increase in pulmonary vascular resistance (PVR) seen in children after cardiopulmonary bypass has been attributed to transient pulmonary endothelial dysfunction (PED). We therefore examined PED in children with congenital heart disease by assessing the L-arginine-nitric oxide (NO) pathway in terms of substrate supplementation (L-arginine [L-Arg]), stimulation of endogenous NO release (substance P [Sub-P]), and end-product provision (inhaled NO) before and after open heart surgery.


METHODS AND RESULTS
Ten patients (aged 0.62+/-0.27 years) with pulmonary hypertension undergoing cardiac catheterization who had not had surgery and 10 patients (aged 0.65+/-0.73 years) who had recently undergone cardiopulmonary bypass were examined. All were sedated and paralyzed and received positive-pressure ventilation. Blood samples and pressure measurements were taken from catheters in the pulmonary artery and the pulmonary vein or left atrium. Respiratory mass spectrometry was used to measure oxygen uptake, and cardiac output was determined by the direct Fick method. PVR was calculated during steady state at ventilation with room air, during FIO(2) of 0.65, then during additional intravenous infusion of L-Arg (15 mg. kg(-1). min(-1)) and Sub-P (1 pmol. kg(-1). min(-1)), and finally during inhalation of NO (20 ppm). In preoperative patients, the lack of an additional significant change of PVR with L-Arg, Sub-P, and inhaled NO suggests little preexisting PED. Postoperative PVR was higher, with an additional pulmonary endothelial contribution that was restorable with L-Arg and Sub-P.


CONCLUSIONS
Postoperatively, the rise in PVR suggested PED, which was restorable by L-Arg and Sub-P, with no additional effect of inhaled NO. These results may indicate important new treatment strategies for these patients.


4
In vivo leucocyte-endothelial cell interaction induced by extracorporeal circulation: reduction by a coated tube system M Kamler 1 , T Chatterjee 1 , H Jakob 1 , A Stemberger 2 , MM Gebhard and S Hagl 1 1 Department of Cardiac and Exp. Surgery,University of Heidelberg,INF 110,69120 Heidelberg and 2 Department of Exp. Surgery TU Muenchen, Germany O Ob bj je ec ct ti iv ve es s: : The clinical complications of extracorporeal blood circulation (EBC) have been linked to disturbances in the microcirculation. In previous experiments we found in vivo an increased L/E cell interaction following EBC. As a therapeutical approach to prevent these deleterious effects a new agent to coat the tubing system, was used.
M Me et th ho od ds s: : Intravital fluorescence microscopy was used on the dorsal skinfold chamber preparation in syrian golden hamsters. EBC was introduced via a micro-roller pump (1 ml/min) and a 60 cm silicon tube (1 mm inner diameter) shunted between the carotid artery and the jugular vein. Experiments were performed in chronically instrumented, awake animals (age: 10-14 weeks, weight: 65-75 g). Control tubes were uncoated, for the experiment a PEG-Hirudin-Iloprost ® coating was used.
R Re es su ul lt ts s: : Isovolemic EBC for 20 min resulted in an increase in rolling and adherent leukocytes in postcapillary venules. Microand macrohemodynamic parameters and functional capillary density were not affected. The use of the coated tube system resulted in a less pronounced induction of leucocyte/endothelial cell interaction.
C Co on nc cl lu us si io on ns s: : L/E interaction in the microcirculation has been established as an indicator of the systemic activation induced by blood contact to synthetic surfaces during EBC. Coating the extracorporeal circuit reduced the increase in L/E interaction probably as a result of a attenuated activation of the coagulation-fibrinolytic system including a reduced platelet activation. Data are means ± SD; n = 7 in each group; *P < 0.05 BL vs TP; † P < 0.05 Control vs Exp. I In nt tr ro od du uc ct ti io on n: : Modified ultrafiltration (MUF) at the termination of cardiopulmonary bypass (CPB) has been considered to remove accumulated fluid and inflammatory mediators and thereby to improve cerebral metabolic rate in infants after cardiac surgery. The aim of this study was to investigate change in cerebral hemo-dynamics and oxygenation before and after MUF following corrective cardiac surgery of congenital heart defects.

Cerebral hemodynamics and oxygenation before and after modified ultrafiltration following corrective cardiac surgery in infants and children
M Me et th ho od ds s: : In 55 neonates and infants below the age of 9 month's (weight 7.5 ± 4 kg) undergoing surgical correction of congenital heart disease by means of full flow CPB (120-150 ml/kg body weight) with moderate hypothermia (24 ± 6°C) and alpha-stat strategy were prospectively studied either to MUF (n = 25) or no MUF (n=20). Continuous determinations of regional cerebral hemoglobin saturation (rSO 2 ) by near infrared spectroscopy (NIRS) and mean flow velocity (MFV) in the middle cerebral artery (MCA) by transcranial Doppler (TCD) provided qualitative on-line information of cerebral perfusion and oxygenation, The pulsatility index (PI) was calculated according to the formula (PI = maximal flow velocity -end-diastolic flow velocity/mean flow velocity). Other hemodynamic parameters such as mean arterial blood pressure (MAP), hemoglobin (Hb) and arterial oxygen saturation (SO 2 ) were simultaneously documented.
R Re es su ul lt ts s: : There was no significant difference in bypass time and minimal rectal temperature in infants with and without MUF. An initially decreased diastolic flow velocity pattern -resulting in higher calculated PI -decreased significantly at the end of operation in infants with more than those without MUF (Table). The change in systemic and regional cerebral hemoglobin saturation was not significantly different in both groups.
C Co on nc cl lu us si io on n: : The magnitude of lowering the cerebrovascular resistance and possible improvements of cerebral perfusion after CPB was more observed in the MUF group. However, the beneficial effect to immediate postoperative hemodynamics and regional oxygenations seem to be not significant. I In nt tr ro od du uc ct ti io on n: : Gastric mucosal acidosis and endotoxemia seems to be responsible for cytokine activation and development of the systemic inflammatory response syndrome (SIRS) in patients with congestive heart failure. In a retrospective study we previously concluded that patients with congestive heart failure (CHF) and a low preoperative cardiac index had a higher incidence of SIRS following cardiopulmonary bypass (CPB) than patients without CHF.
In a prospective study we tried to prove our hypothesis that CHF leads to malperfusion of the gut and subsequently to endotoxin release with cytokine activation.
M Me et th ho od ds s: : We evaluated one group with low risk for developing SIRS (Group1: coronary artery bypass grafting without CHF) and a high risk group (Group 2: mitral valve surgery with CHF) with 10 patients each for clinical and laboratory signs of SIRS as defined by BONE. Intramucosal gastric pH, endotoxin was detected using a tonometric gastric tube (Baxter Inc.), TNFα and interleukin 6 (IL6) were measured with an ELISA at nine different times pre-, intra-and postoperatively.
At the end of CPB gastric pH dropped to 7.33 ± 0.34 in Group 2 whereas the other group remained stable between 7.47 and 7.5 (P < 0.05). Endotoxin levels were significantly elevated and significantly higher in Group 2 (37.2 ± 3.2 pg/ml) than in Group 1 (20.6 ± 3.7 pg/ml; P < 0.05) after aortic cross clamp was opened. In Group 1 only in 1 of 3 patients ( 33% ) with gastric acidosis endotoxin was detected, whereas in Group 2 8/9 patients (88%) endotoxemia occurred.
C Co on nc cl lu us si io on n: : SIRS is more common in patients with CHF undergoing CPB than in others. This seems to be related to a drop of gastric pH as a sign of malperfusion. Consecutively endotoxemia occurs more often and seems to be a trigger of cytokine activation (TNFα, IL6) making higher norepinephrine application necessary. Our study emphasize the role of splanchnic malperfusion and endotoxemia as one mechanism responsible for the development of SIRS.

University Hospital Rotterdam and 2 Blood Interaction Research, Cardiothoracic Surgery, University Hospital Groningen, The Netherlands
O Ob bj je ec ct ti iv ve es s: : Neonates and young children are considered as highrisk patients in developing postoperative complication following open-heart surgery. This usually results from an over-stimulated inflammatory response to cardiopulmonary bypass (CPB), which is thought to be initiated by a number of processes, including blood contact with the artificial surface and reperfusion injury. We performed a study to examine whether there is an increase in gastrointestinal permeability during and after CPB in these young patients, and whether the increase in gastrointestinal permeability will lead to release of endotoxin and further production of tumor necrosis factor α (TNFα).
M Me et th ho od ds s: : Eleven pediatric patients whose body weight was less than 10 kg were prospectively included in this study. Blood samples were taken before, during, and at the end of CPB, and at 1 h, 3 h, 12 h, 24 h and 48 h postoperatively. Endotoxin was measured from platelet rich plasma by the limulus amebocyte lysate assay. TNFα production was measured by enzyme-immunoassay. At postoperative 0 h, 12 h, 24 h, and 48 h, gastrointestinal permeability was determined by the sugar absorption test that measures the ratio of urinary excretion of lactulose/L-rhamnose (non-medi-ated diffusion), D-xylose (passive) and 3-O-methyl-D-glucose (active carrier mediated transport) after oral administration.
R Re es su ul lt ts s: : Endotoxin concentrations were found very low (<3 pg/ml) in most of the samples during and after CPB. Only in one patient high levels of endotoxin were observed at 20 min CPB (16 pg/ml) and 12 h post CPB (17 pg/ml). TNFα increased progressively during the postoperative period (from 1.5 ± 0.5 pg/ml at baseline to 4.2 ± 0.8 pg/ml 48 h postoperatively). An increase in gastrointestinal permeability was found in most of patients (10 of 11) up to 48 h postoperatively, as indicated by increased lactulose/L-rhamnose ratio and decreased D-xylose and 3-O-methyl-D-glucose excretion percentage. No correlation was found between increased gastrointestinal permeability and plasma concentration of endotoxin, nor between endotoxin and TNFα production.
C Co on nc cl lu us si io on ns s: : These results suggest that gastrointestinal permeability increases in neonates and young children undergoing CPB. However, this increase does not lead to clinical significant endotoxemia. TNFα production during and after CPB is likely due to other mechanisms than endotoxin only. M Me et th ho od ds s: : Fresh heparinized human blood was recirculated in in vitro cardiopulmonary bypass circuits (untreated: n = 10; coated n = 10; randomized, blinded for group affiliation). Samples were taken before and 15, 30, 60, 120, and 180 min after commencement of circulation. By means of flow cytometry neutrophil activation (respiratory burst; expression of CD11b), platelet activation (GpIb and GMP140 expression), as well as numbers of monocytes/PMNs binding platelets were assessed.

Regulation of platelet-leukocyte interaction in simulated ECC: attenuation with heparin surface modification
R Re es su ul lt ts s: : Blood cell activation and interaction demonstrated ECCdependent dynamics. SECC produced significant PMN activation and platelet GMP140 expression. Monocytes bound more platelets and at an faster rate than PMNs. In the group with heparin-coated surfaces PMN activation was significantly reduced, GMP140 expression less upregulated and leukocyte-platelet adhesion diminished.
C Co on nc cl lu us si io on ns s: : Heparin coating in SECC reduces neutrophil and platelet activation and attenuates leukocyte-platelet adhesion.
These studies indicate that there are cross-links between hemostatic and inflammatory disorders associated with ECC. Cardiopulmonary bypass (CPB) is associated with a significant inflammatory reaction which has been related to complement activation, and release of various inflammatory mediators and proteolytic enzymes [1]. Aprotinin, a low molecular-weight peptide inhibitor of trypsin, kallikrein and plasmin has been proposed to influence whole body inflammatory response inhibiting kallikrein formation, complement activation and neutrophil activation [2,3]. The present study was designed to determine whether aprotinin is able to reduce the inflammatory reaction to CPB in humans.

Aprotinin does not influence the inflammatory reaction to cardiopulmonary bypass in humans
After institutional approval and written informed consent, 60 male patients, scheduled for primary coronary artery bypass grafting, were enrolled in this prospective double-blinded study. The patients were randomized into three groups: Group high dose aprotinin (HD) received 2 × 10 6 KIU followed by 0.5 × 10 6 KIU/h and 2 × 10 6 KIU added to the pump prime; group low dose (LD) received half that dose and the control group (CTRL) received no aprotinin. No corticosteroids were given. Anesthesia consisted of a high dose sufentanil infusion. The CPB circuit was primed with gelatin and the flow rate was maintained at 2.4 l/min/m 2 using a non-pulsatile flow. An anterograde, cold, crystalloid cardioplegic solution was used and mild hypothermia (30°C) was maintained during CPB. We measured tumor necrosis factor (TNF), interleukin 6, 8, 10 (IL6, IL8, IL10), endotoxin, prekallikrein, and prostaglandin D2 (PGD2) at the following time points: 30 min after study drug loading, 10 min after beginning of CPB, before end of CPB, 4 h after CPB, 1st postoperative day (POD1) and 2nd postoperative day (POD2). Data were analyzed using an analysis of variance for repeated measurements after logarithmic transformation to achieve normalization. There was no significant difference between groups in number of anastomosis, duration of CPB and aortic clamping. All three groups showed a significant inflammatory reaction characterized by an increase of TNF up to 46 pg/ml, IL6 up to 600 pg/ml, IL8 up to 27 pg/ml with no difference between the treatment and the placebo groups. This inflammatory reaction started at the beginning of CPB, was maximal 4 h post-CPB and resolved on POD1 and POD2. Endotoxin levels at end of CPB as well as the maximum increase were slightly lower in the treated than in the CTRL group. However, this difference was essentially due to one CTRL patient with very high endotoxin levels. The proinflammatory reaction was accompanied by a significant increase in the anti-inflammatory cytokine IL10. No group has a significant activation of the complement system. Prekallikrein decreased all groups and PGD2 increased in all groups up to 100 pg/ml. Prekallikrein was significantly lower and PGD2 was significantly higher in the CTRL group only 10 min after beginning of CPB.
Our data show that aprotinin has no significant influence on the inflammatory reaction to CPB in men. I In nt tr ro od du uc ct ti io on n: : Measurement of malondialdehyde (MDA) in the serum, as a marker of free radical induced lipid peroxidation may provide possible information on radicals accentuated structural membrane injury. The detection of protein S-100 in serum, which is exclusively specific for cytoplasma of astroglial and Schwann cells in association with extracorporeal perfusion, may quite possibly indicate either an increased cell membrane permeability or cell injury. The aim of this study therefore was to evaluate the serum kinetics of protein S-100 in relationship to possible free radicals mediated cerebral membrane injury in infants undergoing cardiac surgery by means of cardiopulmonary bypass (CPB).
M Me et th ho od ds s: : 56 patients (neonate n = 7, infants n = 16, children n = 23) were enrolled in this study. Cardiac surgery was performed using full-flow CPB (120-150 ml/kg/min), minimal rectal temperature (26 ± 7.5°C), and minimal hemoglobin concentration (7.4 ± 1.1 mg/dl). Total circulatory arrest was not used. Blood samples were collected from the same venous line at the following intervals: before CPB, 10 min. after CPB start, 10 min after aortic cross clamping, during CPB, 5 min following declamping of the aorta. The blood samples were treated separately immediately after collection. The S-100 protein serum concentrations were analyzed using a commercially available LIA kit (Sangtec ® Medical AB, Bromma, Sweden). MDA was measured (MDA-thiobarbituric acid adduct) using HPLC.
R Re es su ul lt ts s: : In comparison to the pre-bypass values, a significant increase in the concentration of protein S-100 was found immediately after the start of CPB (P = 0.01). There was a continuous elevation of the concentration of protein S-100 in the following phases of CPB. However, the main release of protein S-100 was found in the reperfusion phase after the declamping of the aorta and the end of CPB (P = 0.0001). In comparison to the pre-bypass values the serum concentrations of malondialdehyde were decreased 5 minutes after cross clamping of the aorta (P = 0.001).
Parallel to the increase of protein S-100 concomitant elevation of serum MD were also found following the declamping of the aorta and after the end of CPB (P = 0.0003).
The maximal serum concentrations of protein S-100 correlated significantly to bypass time (r = 0.7, P = 0.0007), cross-clamping time (r = 0.57, P = 0.001) and minimal rectal temperature during CPB (-0.57, P = 0.001). The maximal MDA values correlated significantly to cross-clamping time (r = 0.46, P = 0.004) and minimal rectal temperature (r = 0.40, P = 0.007). O Ob bj je ec ct ti iv ve es s: : Nerve growth factor (NGF) plays a crucial role in the differentiation and survival of sympathetic neurones, including the ones represented in the cardiovascular system. NGF has also been reported to be an intermediary product in various inflammatory reactions. The aim of this study was to investigate whether cardiopulmonary bypass (CPB) has any effects on NGF release and to determine the time course of any changes in its release.
M Me et th ho od ds s: : Twelve consecutive children undergoing elective cardiac surgery were recruited for the purposes of this study. The plasma levels of NGF, interleukin 6 (IL-6) and interleukin-8 (IL-8) were measured by enzyme-linked immunosorbent assay (ELISA). Samples were obtained from the patients at the following time points: induction of anaesthesia, end of CPB, and at 1, 2 and 24 h following CPB.
R Re es su ul lt ts s: : There was a highly significant increase in the release of NGF following CPB, reaching its highest concentration at 2 h following CPB. The pattern of release was very similar to that observed for IL-6 and IL-8. The results are summarised in the Table. C Co on nc cl lu us si io on ns s: : NGF is released following CPB in paediatric patients, with a similar pattern to the one observed for known mediators of the systemic inflammatory response to CPB. Further studies, both in paediatric and adult patients, are needed to elucidate the role of NGF in the pathophysiology of the body response to CPB and to evaluate its clinical impact.

K Khalighi 1 , C Weinstock 2 , R Handgretinger 3 and G Ziemer 1 1 Department of Thoracic & Cardiovascular Surgery, University of Tuebingen, 2 Department of Transfusion Medicine, University of Tuebingen and 3 Pediatric Hematology & Oncology, University of Tuebingen
P Pr ro ob bl le em m: : The extracorporeal circulation (ECC) causes changes in cellular and cytokine pattern in addition to activation of complement system. These alterations result in a temporary depression of immunity and a perioperative susceptibility to infections. T lymphocytes required for both cell-mediated immune response and the production of antibody by B lymphocytes, are composed of two distinct subsets: Th1 and Th2 cells. Th1 cells produce IL-2 and interferon-γ and execute cell-mediated immune response; whereas Th2 cells produce IL-4, IL-5 and IL-10 and assist in antibody production for humoral immunity. While the influence of ECC in production and changes of several interleukins are known, it is still unclear if ECC induces IL-10 production and contribute to depression of immunity.
M Ma at te er ri ia al l a an nd d m me et th ho od ds s: : Twenty patients undergoing open heart operations without evidence of a concomitant malignant or immunologic disease; HIV and HBV seronegative were studied. EDTA-blood samples were drawn on six occasions. WBC was performed and FACS analysis enrolled. IL-10 was measured after cry-opreservation of plasma by quantitative "sandwich" enzyme immunoassay technique (sensitivity 1 pg/ml).
R Re es su ul lt ts s: : The total leukocyte count decreases at the institution of ECC (3521 ± 871) and remains nearly unchanged through the aortic clamping time (3503 ± 1370). After removal of aortic clamp a significant leucocytosis occurs (8085 ± 3571), through 3.POD (10708 ± 3606). The phasic changes of leukocytes is mainly caused by identical course of neutrophils. IL-10 shows a monophasic course with a peak concomitant to removal of aortic clamp (45.5 ± 49.6 pg/ml) and falls to preoperative levels at 3.POD (3.2 ± 4.5 pg/ml).
C Co on nc cl lu us si io on n: : The increased level of IL-10 during the ECC indicates an activation of Th2 cells. IL-10 inhibits the production of IFN-γ, induces the differentiation of Th2 cells from uncommitted T cells. The inhibitory effect of IL-10 on Th1 cell differentiation causes a further depression of cell-mediated immunity during the early postoperative phase.
product provision (inhaled NO) before and after open heart surgery.
M Me et th ho od ds s: : Ten unoperated patients (0.62 ± 0.27 years) with pulmonary hypertension undergoing cardiac catheterisation, and 10 patients (0.64 ± 0.73 years) early after cardiopulmonary bypass were examined. All were sedated, paralysed and received positive pressure ventilation. Blood samples and pressure measurements were taken from catheters in the pulmonary artery and the pulmonary vein or left atrium. Respiratory mass spectrometry was used to measure oxygen uptake, and cardiac output was determined by the direct Fick method. PVR was calculated during steady state at ventilation with room air, during FiO 2 = 0.65, and then during additional intravenous infusion of L-Arg (15 mg/kg/min), Sub-P (1 pmol/kg/min), and finally inhalation of NO (20 parts per million).
R Re es su ul lt ts s: : In both patient groups, oxygen supplementation was the most potent pulmonary vasodilator. In preoperative patients, the lack of a further significant change with L-Arg, Sub-P and inhaled NO suggests little pre-existing PED. Postoperative PVR was higher with an additional endothelial contribution that was restorable with L-Arg and Sub-P.
C Co on nc cl lu us si io on n: : Postoperatively, the rise in PVR suggested pulmonary endothelial dysfunction restorable by L-Arg and Sub-P with no additional effect of inhaled NO. These results may indicate important new treatment strategies for these patients.

15
Is there a capillary leak after cardiopulmonary bypass in pigs? . Left ventricular (LV) power during ejection (= CO × AoP/ejection time) was calculated. Blood samples (before CPB, at 90 min, 120 min CPB and every 30 min until 5 h after CPB) were analyzed for the receptor antagonist IL-1ra, leukocytes, the leukocyte neutral proteinase inhibitor (LNPI to assess leukocyte activation), and plasma protein concentration (PP). Half-life of intravenously injected Evans Blue and intravascular protein content (IVP) were measured before and 3.5 h after CPB. Histologic samples of the LV-wall and septum were assessed for leukocyte infiltration.
R Re es su ul lt ts s: : LV-power was markedly reduced after CPB. Leukocytes, LNPI and IL-1ra were significantly upregulated following CPB and a marked leukocyte infiltration to the subendocardium of the LV was present 5 h after CPB. PP was reduced by the crystalloid primed CPB, it increased after CPB, but did not reach the pre-CPB level. IVP was reduced after CPB. Half-life of intravenously injected Evans Blue was not affected by CPB.
C Co on nc cl lu us si io on n: : In the present model CPB was followed by depression of left ventricular function and a systemic inflammatory response. An increase in microvascular permeability to plasma proteins, however, was absent after 120 min of CPB including 90 min of myocardial ischemia. Fluid shift from the intra-to extravascular compartment occurred due to an increased microvascular effective filtration pressure. This is a result of reduced plasma colloid osmotic pressure due to hemodilution and, in part, to protein loss to the foreign surfaces of the CPB-system. O Ob bj je ec ct ti iv ve es s: : It has been shown that proinflammatory cytokines are suppressed by progesterone (P). cardiopulmonary bypass (CPB) leads to the release of pro-and anti-inflammatory cytokines. Because sex steroids have the ability to adsorb extensively to synthetic surfaces a decrease of P during the contact with the CPB circuit is conceivable. If P concentrations would decrease the inflammatory response to CPB could be effected. The purpose of the study was to look for the course of P in relation to the proinflammatory cytokine interleukin-8 (IL-8) during and after CPB.

Progesterone and interleukin-8 during and after cardiopulmonary bypass in infants and children
M Me et th ho od ds s: : Twelve infants and children (age 2 months to 15 years, median 2.4 years, four females) were operated on CPB for congen-ital heart disease (2 ASD, 5 VSD, 3 Fallot, subaortic stenosis, aortopulmonary window). Blood samples were taken before, during (10 min after onset) and after (disconnection, 6 and 24 h, 3 and 7 days) CPB. Plasma concentrations of P and IL-8 were determined using a RIA-and an ELISA-kit, respectively.
R Re es su ul lt ts s: : P concentrations before CPB were 0,21 ng/ml (median, 0.012-0.72). They increased to a maximum of 5.59 ng/ml (0.13-35.4) at 6 h after CPB. The pre-CPB concentrations were reached on the 7th day post-CPB. This course of P concentrations was similar in female and male infants of every age. The maximum IL-8 concentrations were found at 6 h after CPB. The decline of IL-8 from 6 to 24 h after CPB was correlated to the P concentration at 6 h (r = 0.77).
C Co on nc cl lu us si io on n: : The results were in contrast to our expectation because P increased with CPB. However, the significant increase with a maximum at 6 h after CPB needs further explanation. The maximal P concentrations coincided with the peak of the IL-8 response and correlated to the following decrease of IL-8. We speculate that the release of P during and after CPB could be of benefit in terminating the associated proinflammatory response. Further studies are needed to clarify the physiology and role of the P increase in the setting of CPB.

Department of Physiology, University Hospital, University of Technology Aachen, Germany
It is well known that blood contact to foreign surfaces is leading to an inflammatory response including stimulation of complement system and leukocytes.
Investigating the influence of modified biomaterials on leukocyte activation we used a dynamic model approaching flow conditions of extracorporeal circulation. Four different surface modifications (three heparin and one non-heparin coatings) were compared to each other and native control material, which is routinely used in cardiopulmonary bypass and extracorporeal circulation. Fresh human donor blood was heparinized and recirculated for 180 min in a tubing circuit with an integrated blood filter and a roller pump.
Leukocyte number, differential blood analyses, elastase and anaphylatoxin C5a were determined to investigate the effects of blood/surface contact on leukocytes.
Leukocyte stimulation was reduced in different amount compared to the control depending on the coating method. Heparin coatings showed a slight drop of monocyte and granulocyte percentage after 180 min of perfusion, whereas the control and the nonheparin modification induced a larger decrease. Elastase and C5a concentrations detected differences between the modifications themselves. C5a and elastase increased in each case in the course of the perfusion time.
We conclude that heparin coatings induce less leukocyte activation than the native control material. M Me et th ho od ds s: : In a prospective, randomized, controlled study, 73 patients were enrolled. In Group UF patients (n = 21), zero-balanced ultrafiltration was performed during re-warming and modified ultrafiltration immediately after CPB. In Group MP patients (n = 26), 1 g methylprednisolone was given 30 min before CPB. The Group C patients (n = 26), received placebo instead.
R Re es su ul lt ts s: : After CPB the concentration of interleukin(IL)-6 was significantly lower in Group UF and in Group MP compared with Group C (105 ± 20 and 124 ± 29 vs 203 ± 46 pg/ml, respectively; P < 0.05, mean ± SEM). Anti-inflammatory IL-10 showed a significant (P < 0.01) peak after CPB in Group MP as compared to Group UF and also to Group C. In Group UF, intrapulmonary shunt fraction decreased during modified ultrafiltration from 31 ± 1.2 to 25 ± 1.3% while PaO 2 and mean arterial pressure increased (P < 0.01). After CPB the PaO 2 and also oxygen distribution in Group MP were higher (P < 0.05) as compared with Group C patients. Extubation-time was shorter in the UF-group compared to the Group C patients (6.1 ± 0.5 vs 8.6 ± 0.7 h, respectively; P < 0.05).
C Co on nc cl lu us si io on ns s: : The combination of zero-balanced and modified ultrafiltration reduces SIRS immediately after CPB, resulting in higher arterial pressure, improved pulmonary gas exchange, and shorter need of respiratory support. Methylprednisolone led to a marked reduction of the pro-inflammatory and an increase of antiinflammatory response. Both strategies to reduce SIRS had positive influence on clinical parameters.
both groups during hypothermic TCA. However marked divergent change in the mitochondrial cyt.aa3 signal was noted between the neonates and the infants particularly during TCA. These discordant divergent patterns in the intracellular and intravascular NIRS signal continued also during reperfusion after TCA.
C Co on nc cl lu us si io on n: : The main preliminary finding in this study was the paradoxical increased signal of mitochondrial cyt.aa3 during TCA in the neonates with HLHS in comparison to the infants despite the simultaneous relative decline in intravascular concentration of HbO 2 in both groups. The observed age dependent change in the cyt.aa3 patterns may indicate an alteration of oxygen metabolism at mitochondrial level and possible disturbance of electron transport of the oxidative pathway in deep hypothermic TCA.

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Acute phase response following cardiopulmonary bypass: impact of corticoid therapy Cardiac surgery with cardiopulmonary bypass (CPB) leads to an acute phase response characterized by the synthesis of proinflammatory cytokines and activation of the complement system. The following study was performed to analyse the influence of corticoid-premedication on acute phase response and clinical course of the patients.
Twenty-one male patients with three-vessel disease and normal or moderately impaired left ventricular function undergoing elective or urgent CABG-surgery were included. 10 patients received 125 mg of dexamethasone in addition to the standard premedication regimen, while 11 patients served as controls. Blood samples were drawn preoperatively, 10 min after termination of CPB and 4 h after CPB to determine the levels of inter-leukin-6 (IL-6), interleukin-8, tumor-necrosis-factor (TNF) and the anaphylatoxin C3a.
There was a marked increase of cytokines and activation of the complement system in all patients following the surgical intervention. Corticoid treatment resulted in a significant reduction of IL-6, IL-8 and TNF 10 min and 4 h following CPB. The activation of complement did not differ in both patients groups.
Pretreatment with corticosteroids results in a significant suppression of the cytokine response following CPB, which, however, does not have a major impact on the clinical course. Further studies have to analyse, whether inhibition of the acute phase response may lead to clinical improvements in selected high-risk patients. Troponin I values in SC-blood rose from 2 ± 1.1 ng/ml (mean ± SEM) before aortic cross-clamping (AoX) to 9.1 ± 3.2 ng/ml at the end of CPB and peaked 2 hours post CBP at 28.1 ± 10.9 ng/ml (P < 0.03). Troponin I concentration in cardiac lymph rose from 352 ± 64 ng/ml before AoX and became significantly higher in the following hours with a maximum value at 6 hours post CPB (12 638 ± 5321 ng/ml; P < 0.01). A significant correlation between the lymphatic and SC-blood concentrations was noted.
C Co on nc cl lu us si io on n: : (1) a significant release of TNFα was not observed in our study. (2)  The prognostic value of elevated serum levels of procalcitonin (PCT) in patients early after cardiac operation on cardiopulmonary bypass (CPB) remains unclear and was therefore investigated in a prospective study.
Using a modified APACHE-II-score 39 patients (group I) at high risk and 20 patients (group II) at low risk were identified on the first postoperative day after cardiac surgery on CPB and hypother-mic (26°C) cardioplegic (HTK-solution, 4°C, 15 ml/kg body weight) cardiac arrest. There were no differences regarding length of operation, CPB and aortic clamping time. While preoperative mortality reached 23%, infection rate 41% and complication rate 59% in group I, the postoperative course was uneventful in all but 2 patients (10%) in group II suffering from infections. PCT serum levels were measured (LUMItest ® , Fa. Brahms) preoperatively (PCT0), at the 1. (PCT1), 2. (PCT2) and 5. (PCT5) postoperative day in all patients and analyzed with respect to infections, complications and perioperative mortality.
The mean PCT levels were significantly elevated in both groups early after surgery, however, they reached significant higher values in group I compared to group II (see table): In group I PCT1/2/5 were significantly increased in patients suffering from a complication, PCT2/5 in patients with an infection and PCT5 in patients who died perioperatively (see table): PCT serum levels are significantly elevated in patients early after cardiac surgery on CPB. Very high serum levels of PCT at the first postoperative day are predictors for the occurrence of complications, at the second postoperative day for a high incidence of infections and at the fifth postoperative day for a significantly worsened outcome.

27
Corticosteroids reduce early troponin-T release after cardiac surgery with cardiopulmonary bypass in men.
Y Tabardel 1 , D Schmartz 2 , JL Leclerc 2 , AA D'Hollander 2 , JL Vincent 2 and J Duchateau 3 1 A de Rothschild Foundation, Paris, France; Free University of Brussels, 2 Erasme Hospital and 3 Brugmann Hospital, Brussels, Belgium O Ob bj je ec ct ti iv ve es s: : To study whether administration of corticosteroids (CS) prior to cardiac surgery for coronary artery bypass grafting (CABG), can influence early troponin-T release after cardiac surgery with cardiopulmonary bypass (CPB).