Complement activation by in vivo neonatal and in vitro extracorporeal membrane oxygenation

Abstract

Complment activation during extracorporeal membrane oxygenation (ECMO) in newborns can be caused by both the underlying disease processes and by blood contact with the ECMO circuit. We investigated the relative importance of these mechanisms by measuring C3a, C5a and sC5b-9 before, during and after neonatal ECMO in six consecutive newborn patients using enzyme-linked immunoassay. In addition complement activation during in vitro ECMO with repeated flow of the same blood volume was measured using blood from healthy adult donors. C3a increased significantly in vivo after 1 h (from 1035+/-193 to 1865+/-419 microg/l) and in vitro ECMO (from 314+/-75 to 1962+/-1062 microg/l). C5a increased during ECMO without significant differences between in vivo and in vitro activation. In neonatal patients, sC5b-9 rose faster than in vitro, but the rapid increase was also significant for in vitro experiments (in vivo: from 328+/-63 to 1623+/-387 microg/l after 2 h; and in vitro: from 78+/-32 to 453+/-179 microg/l after 8 h). After this initial peak at 1-2 h, complement activation decreased gradually until 2-3 days after the initiation of ECMO. We conclude that in newborns the rapid activation of the complement system after the start of ECMO is predominantly caused by contact with artificial surfaces rather than the patient's underlying disease.

The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology

“…In neonates, Graulich et al detected peaks of C3a at 1 hour and of C5a and TCC at 2 hours. However, contrary to what Vallhonrat et al observed, TCC levels did not return to baseline [20]. …”

“…1). Levels of pro-inflammatory cytokines rise rapidly [13–19], which, in association with activation of the complement and contact systems [20–25], results in leukocyte activation [26–28]. This innate immune response, if severe, persistent or unchecked by a compensatory anti-inflammatory response (CARS) [29], may lead to endothelial injury, disrupted microcirculation, and end-organ dysfunction [30–35].…”

“…In addition, the use of contemporary heparin-bonded circuits has also been shown to reduce complement activation [84]. Studies have examined complement activation in ex-vivo models of ECMO [20, 22, 24], neonatal ECMO [20, 23, 25] and in adult patients [21]. In keeping with CPB, all of these studies revealed rapid elevations in the levels of complement factors during ECMO, with peaks occurring within 1 to 2 hours.…”

The Impact of Venoarterial and Venovenous Extracorporeal Membrane Oxygenation on Cerebral Metabolism in the Newborn Brain

“…While the VV ECMO patients had higher serum creatinine levels (Table 1), post-hoc analyses demonstrated no direct correlation between serum creatinine and either GM or WM creatine (data not shown). On the other hand, systemic inflammation (e.g., elevated c-reactive protein, elevated pro-inflammatory cytokines) has been documented in neonates with ECMO [30, 31], as well as in neonates with clinical sepsis [32] and studies have demonstrated that creatine is often elevated alongside choline in the setting of cerebral inflammation [25, 27]. Taken together, the elevations in creatine and choline suggest that the systemic inflammatory response could extend to the central nervous system, as demonstrated in animal models [33].…”

Measurement of systemic oxygen consumption in patients during extracorporeal membrane oxygenation — description of a new method and the first clinical observations

“…8,9 The elevated VO 2 is an important contributor to the impaired balance of oxygen transport during the early hours after CPB. 8,9 ECMO, like CPB, with its artificial surfaces and interaction with blood, also induces the systemic inflammatory response, [10][11][12] thereby, leading to altered metabolism with an increased metabolic rate. 13 However, ECMO differs from CPB in duration of days to weeks rather than hours.…”