Jan-Ludvig Svennevig

Evaluation of oxygenators and centrifugal pumps for long-term pediatric extracorporeal membrane oxygenation:

Objective : Two extracorporeal membrane oxygenation (ECMO) circuits for children under 10 kg were evaluated and compared for plasma leakage, hemolysis, blood transfusions, and durability. Methods: Group A (n = 20) was supported by ECMO circuits with the Minimax oxygenator and the Biomedicus centrifugal pump. Group B (n = 10) was supported by ECMO circuits with the Lilliput 2 ECMO oxygenator and the Rotaflow centrifugal pump. Results: ECMO circuit durability, as measured by oxygenator lifespan, was significantly better in Group B than in Group A (p = 0.04). There was significantly lower hemolysis, measured by plasma free hemoglobin, in Group B (p = 0.019), and patients in Group B had significantly less need for antithrombin III transfusion (p = 0.004). No plasma leakage was observed in Group B oxygenators, but plasma leakage was observed in all Group A oxygenators. Conclusion: The combination of a Rotaflow centrifugal pump and Lilliput 2 ECMO oxygenator in pediatric ECMO circuits improved durability and reduced circuit-induced hemolysis. This improvement may be due to the low priming volume, the oxygenators plasma leakage resistance, the suspended rotor of the centrifugal pump, or a combination of these factors. Perfusion (2007) 22, 323—326.

Complement activation in injured patients occurs immediately and is dependent on the severity of the trauma

In order to study the factors related to complement activation, the complement activation products C3bc and TCC were measured in plasma at admittance and during the stay in the intensive care unit in 108 consecutive patients with multiple injuries. These patients were admitted to the surgical department during a 4-month period. Complement activation occurred immediately after the trauma and correlated strongly with the Injury Severity Score and was inversely correlated to the Base Excess. Complement activation also correlated with the number of transfusions. Sepsis caused complement activation later during the stay in hospital. All seven patients developing the adult respiratory distress syndrome (ARDS) had increased complement activation, either on admission or later during the stay in the intensive care unit. Complement activation is known to contribute to organ damage following ischemia and reperfusion. Clinical studies have demonstrated the importance of early restoration of adequate circulation and the present demonstration of a strong negative correlation between complement activation and Base Excess indicates that early restoration of aerobic metabolism may reduce complement activation and the risk for organ dysfunction.

Syndecan-1 plasma levels during coronary artery bypass surgery with and without cardiopulmonary bypass

The glycocalyx covering the endothelium is shed during ischemia and reperfusion. The shedding is accompanied by increased levels of the glycocalyx component syndecan-1 in the circulation. Our aim was to compare plasma levels of syndecan-1 in patients undergoing coronary artery bypass grafting (CABG), with or without the use of cardiopulmonary bypass (CPB). Syndecan-1 plasma concentrations were measured in patients undergoing CABG on-pump (n = 22) or off-pump (n = 22). The syndecan-1 concentration increased significantly from 29.5 ± 4.6 ng/mL at baseline to 98.7 ± 9.8 ng/mL (p < 0.01) after the start of CPB or 30 minutes after the induction of anesthesia in the off-pump group. There were no significant differences in peak syndecan-1 plasma concentrations between on-pump and off-pump patients. Plasma levels of syndecan-1 increased significantly during CABG, with or without the use of CPB. There were no significant differences in syndecan-1 concentrations in the two groups.

Complement activation and bioincompatibility. The terminal complement complex for evaluation and surface modification with heparin for improvement of biomaterials.

The degree of biocompatibility of biomaterials can be evaluated using various assay systems detecting activation of the blood cascade systems, leukocytes or platelets. Activation of complement is one mechanism associated with adverse effects observed when bioincompatible materials are used. We present data showing that the terminal complement compiex, an indicator of terminal pathway activation, is suitable for evaluation of biocompatibility of biomaterials such as cardiopulmonary bypass devices. Furthermore, our results suggest that bioincompatibility is improved when artificial surfaces are modified with end point attached functionally active heparin.

Leucocyte filtration during cardiopulmonary bypass hardly changed leucocyte counts and did not influence myeloperoxidase, complement, cytokines or platelets

In some patients, coronary artery bypass surgery induces postoperative organ dysfunction despite an apparently adequate revascularization and good haemodynamic performance. This complication may be caused by activation of the body’s inflammatory systems on blood contact with large foreign surfaces in the extracorporeal circuit. Activated leucocytes may play an important role in organ damage, and it is conceivable that leucocyte removal by filtration may decrease the potential side-effects of cardiopulmonary bypass (CPB). The aim of the present study was to investigate possible effects of leucocyte filtration during the whole CPB period in elective coronary artery bypass surgery on biochemical and clinical parameters. Forty patients were randomized to extracorporeal circulation using a leucocyte-depleting filter (group L, n = 20) or to extracorporeal circulation with no leucocyte filter (group C, n = 20). In the leucocyte-depleted group, the mean total white blood cell counts increased from 6.3 (95% confidence interval, 5.5 - 7.0) × 109/l to 7.0 (5.7 - 8.3) × 109/l during extracorporeal circulation and in the control group from 6.3 (5.2 - 7.3) × 109/l to 8.5 (7.2 - 9.8) × 109/l. The intergroup difference was not statistically significant (p = 0.84). A substantial increase in concentrations of interleukin-6, myeloperoxidase and complement activation products were observed in both groups without statistically significant intergroup differences. It is concluded that the leucocyte-depletion filter did not cause a significant reduction of circulating white blood cells during CPB, and there were no significant differences between the groups with respect to the inflammatory markers studied.

Comparison of three oxygenator-coated and one total-circuit-coated extracorporeal devices

The present study was designed to compare the biocompatibility of three cardiopulmonary bypass setups with different surface coatings, and to determine if coating of the whole circuit with one of the coatings was more beneficial than coating of the oxygenator only. Extracorporeal devices entirely coated with synthetic polymers (Avecor, n = 6) were compared to oxygenators coated with synthetic polymers (Avecor, n = 6), end-point, covalently attached heparin (CBAS, n = 6) or absorbed heparin (Duraflo 2, n = 6) in an in vitro model of a heart-lung machine. The circuits were primed with fresh human whole blood and Ringer’s acetate and recirculated at 4 l/min at 30°C for 2 h. Test samples were obtained at regular intervals and analysed for myeloperoxidase (MPO), platelet counts, β-thromboglobulin, heparin, prothrombin fragment 1+2, plasmin-anti-plasmin complexes, and complement activation products. The mean MPO concentrations increased in the Avecor-coated oxygenator group (AV) from 247 at the start to 671 μg/l at the termination of the experiments, in the Avecor-coated total circuit group (AV-T) from 116 to 288 μg/l, in the Duraflo 2 coated oxygenator group (DU) from 160 to 332 μg/l, and in the CBAS-coated oxygenator (CA) group from 172 to 311 μg/l. The MPO concentrations increased significantly in all groups (p < 0.03). The increase in group A was significantly higher than in the other three groups (p = 0.007). The mean platelet counts decreased in the Avecor-coated total circuit group from 117 at start to 99 × 109/l at termination of the experiments, in the Avecor-coated oxygenator group from 119 to 103 × 109/l, in the Duraflo 2 group from 96 to 86 × 109/l, and in the CBAS group from 132 to 123 × 109/l. The platelet counts decreased significantly in all groups (p < 0.01), but the intergroup differences were not significant (p = 0.15). The mean β-thromboglobulin concentrations increased in the Avecor-coated total circuit group from 193 at the start to 754 ng/ml at the termination of the experiments, in the Avecor-coated oxygenator group from 474 to 1654 ng/l, in the Duraflo 2 group from 496 to 1280 ng/l, and in the CBAS group from 418 to 747 ng/l. The β-thromboglobulin increase was significant in each group (p < 0.01), but not between the groups (p = 0.49). The mean heparin concentrations in the Duraflo 2 group increased from 2460 at the start to 2897 IU/l at termination of the experiments, in the CBAS group from 2468 to 2518 IU/l. In the Avecor-coated oxygenator group heparin concentrations decreased from 2010 to 1968 IU/l, and in the Avecor-coated total circuit group from 2002 to 1927 IU/l. The differences in heparin concentrations were significant between the Duraflo 2 group and the other groups (p < 0.05). The mean prothrombin fragment 1+2 concentrations increased in the CBAS group from 0.4 at the start to 2.1 nmol/l at the end of the experiments, in the Avecor-coated oxygenator group from 0.4 to 0.6 nmol/l, in the Avecor-coated total circuit group from 0.3 to 0.4 nmol/l, and in the Duraflo 2 group from 1.2 to 1.3 nmol/l. The prothrombin fragment 1+2 increase was significant in all groups (p < 0.05), but there were no significant intergroup differences (p = 0.54). There were no significant differences at the termination of the experiments among the four groups regarding complement activation as measured by C3 activation products and the terminal complement complex. In the present in vitro model of a heart-lung machine, none of the three specific setups with different coatings was superior with regard to all test parameters. The CBAS group generated the highest levels of prothrombin fragment 1+2 formation, but least complement activation. The increasing plasma heparin concentrations in the Duraflo 2 group indicated more unstable heparin bonding. The Avecor-coated total circuit group were superior to the Avecor-coated oxygenator group regarding plasma concentrations of MPO, but not compared to the CBAS and Duraflo 2-coated oxygenator groups.

Interleukin-6 may predict survival in extracorporeal membrane oxygenation treatment.

The cytokine network and its association with complement activation during cardiac surgery with cardiopulmonary bypass (CPB) is complex. Extracorporeal membrane oxygenation (ECMO) differs from CPB in duration of days to weeks rather than hours. However, few studies have analyzed the levels of inflammatory mediators during ECMO treatment. Plasma samples from 22 patients [nine neonates, one infant, four children and eight adults (14 males and eight female)] who underwent ECMO treatment were collected prior to, during and after treatment, and analyzed for concentrations of inflammatory and anti-inflammatory cytokines and parameters of complement activation. Seven children were treated for cardiac and seven for pulmonary failure and, in the adult group, four were treated for cardiac and four for pulmonary failure. ECMO was performed with veno-arterial (VA) bypass in all children and five adults, and with veno-venous (VV) bypass in three adults. Fourteen patients survived (64%) and eight (36%) patients died during follow-up. A marked (~99%) and rapid (i.e., within two days) decrease in IL-6 was seen in survivors. The non-survivors were characterized by persistently high IL-6 levels throughout the observation period (i.e., until death). C-reactive protein (CRP) levels showed a similar pattern as the IL-6, with higher levels in non-survivors throughout the observation period. However, in contrast to IL-6, the differences between survivors and non-survivors reached statistical significance, but only at the end of the observation period. It is possible that early measurements of IL-6 in ECMO patients could give prognostic information beyond that of CRP.

Assessment of probability of survival in penetrating injuries using the TRISS methodology

By the TRISS methodology, probability of survival in injury can be estimated. It is based on a statistical analysis of outcome which is influenced by the severity of the injuries as expressed in the Injury Severity Score (ISS), the physiological function as expressed in the Trauma Score (TS) and the patients age. We have used the TRISS formula in 206 patients with penetrating injury. Of these patients, 149 sustained stab wounds, 32 gunshot wounds and 25 others. ISS ranged from 2 to 38, the mean ISS being 9. The function was good (TS greater than 14) in 85 per cent. Estimated probability of survival ranged from 1.00 to 0.42. Three patients (1.5 per cent) died. The probability of their survival was 0.92, 0.96 and 0.98, respectively. All the fatal cases had serious predisposing conditions: chronic pulmonary disease, alcoholism, and psychiatric illness. In penetrating injury, the patients functional status at the start of treatment is of greater importance for the outcome than the anatomical severity. The concept of the methodology of TRISS for assessment of probability of survival seems useful for review and comparison in injury care.

Granulocytes in bronchial lavage fluid after major vascular surgery

Increased numbers of polymorphonuclear granulocytes (PMN) in the airways, as measured by PMN content in bronchial lavage fluid (P<0.01), were found 3 h postoperatively in ten patients undergoing surgery for lumbar aortic aneurysms. An increase in plasma levels of the complement split product C3dg from 6 (0–19) AU/ml preoperatively to 20 (13–50) AU/ml 3 h after surgery (P<0.01), indicates an activation of the complement cascade. These changes were not accompanied by increased elastase activity in the bronchial lavage fluid or by major changes in pulmonary blood gas exchange or vascular resistance, indicating that massive PMN activation, analogous lo that proposed in adult respiratory distress syndrome (ARDS) had not taken place. In conclusion, complement system activation and migration of PMN into the airways, as seen in connection with major vascular surgery, does not seem to contribute to ARDS‐type pulmonary dysfunction.

An ex vivo Perfusion Model to Evaluate Hyperacute Rejection in a Discordant Pig-to-Human Combination

Inadequate supplies of human organs for transplantation have evoked an escalating interest in human xenotransplantation. Hyperacute rejection precludes use of discordant organs. We have developed an ex vivo perfusion model in order to evaluate hyperacute rejection in a pig-to-human combination. Pig kidneys (n = 6) perfused with human blood deteriorated rapidly and rejection was seen after 70 (60–87) min (median, 95% confidence interval). Kidneys perfused with pig blood survived 300 (216–360) min, corresponding to the upper time limit of the model. Increases in prostaglandin E2 and 6-keto-prostaglandin F1α indicated endothelial activation. Sequential blood samples revealed a strong progressive inflammatory response with reduced leukocyte and platelet counts, granulocyte activation indicated by increased myeloperoxidase, and complement activation, shown by an increase in C3 activation products and the terminal SC5b-9 complement complex. A significant role for classical pathway activation was indicated by formation of C1rs-C1 inhibitor complexes and activation of C4, whereas factor B was not significantly activated. Biopsies at rejection demonstrated hyperacute rejection with inflammatory changes involving the vessels as well as the nephrons. Where the inflammatory markers could be studied in pig blood, activation was less than in human blood. The present discordant xenotransplant model is a valuable adjunct for evaluation of changes occurring in the human blood perfusate as well as in the pig kidney during hyperacute rejection.