Clinical Use of Complement Inhibitors in Reperfusion Injury

C1 esterase inhibitors have been used with positive outcome in three patients undergoing emergency coronary artery bypass after failed angioplasty. There are additional positive data from a study of 35 patients with attenuated myocardial injury: improved neurological outcome and less blood loss in the human C5 antibody treatment cohort after nonemergent cardiopulmonary bypass. Further, the use of sCR1 in patients undergoing lung transplant requiring bypass has shortened the ventilator-dependent time.

However, in the only randomized controlled clinical trial (Phase IIa) involving a complement antagonist, where sCR1 was administered to 600 patients undergoing adult cardio-pulmonary bypass, there was no demonstrable mitigation of injury to the heart, brain, or other organs. It has been argued that since adult cardiopulmonary bypass has a low mortality and complication rate, averaging only 1 to 2 percent, it would be difficult for any drug to achieve a clinically significant difference. It is noteworthy that among safety trials performed with sCR1, there have been no reported com plications. However, the potential side effects of increased susceptibility to infection might become evident in the future. It is important to keep in mind the beneficial actions of complement and, hence, the possible detrimental effects of its inhibition such as the susceptibility to infectious agents.

Paradoxically complement activation can be protective against reperfusion injury, especially in sublytic quantities. Infusion of 0.5 percent normal human plasma, containing small amounts of activated complement, into rabbits subjected to myocardial ischemia-reperfusion resulted in significantly smaller infarcts. This protective effect of plasma could be reversed by heat inactivation, or by pretreatment with sCR1 or anti-C5a antibody.

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Essentials of Human Physiology

Essentials of Human Physiology

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