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Complement Inhibition Attenuates Human Lung Transplant Reperfusion Injury*: A Multicenter Trial FREE TO VIEW

Martin R. Zamora, MD, FCCP; R. D. Davis, MD, FCCP; S. H. Keshavjee, MD, FCCP; L. Schulman; J. Levin; U. Ryan; G. A. Patterson, MD, FCCP
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*From the University of Colorado, Denver, CO; Duke University, Durham, NC; University of Toronto, Toronto, Ontario, Canada; Columbia-Presbyterian, New York, NY; T Cell Sciences, Needham, MA; and Washington University, St. Louis, MO.

Correspondence to: Martin R. Zamora, MD, FCCP, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262

Chest. 1999;116(suppl_1):46S. doi:10.1378/chest.116.suppl_1.46S
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Lung dysfunction due to ischemia and reperfusion (I/R) injury is a major cause of morbidity, mortality, and increased cost following human lung transplantation (LTx). Since complement (C) activation plays a significant role in I/R injury, we hypothesized that C inhibition would attenuate the degree of I/R injury following LTx. TP10 (soluble C receptor 1 inhibitor) inhibits C activation by inactivating C3 and C5 convertases.

We performed a randomized, double-blinded, placebo-controlled multicenter trial at five North American LTx centers. Fifty-nine patients received either TP10 (10 mg/kg, n = 29) or placebo (P, n = 30) prior to reperfusion of the lung allograft. This dose achieves > 90% C inhibition for 24 to 48 h; activity returns to normal by 72 h. Indications for LTx were emphysema (66%), pulmonary fibrosis (15%), pulmonary hypertension (14%), and other (5%). Patients with cystic fibrosis were excluded from the trial. Outcome variables were Pao2/fraction of inspired oxygen, chest radiograph acute lung injury scores, time receiving mechanical ventilation, ICU and hospital length of stay (LOS), survival, and the incidence of acute rejection and infection.

TP10 led to a significant increase in early extubation of patients. At 24 h, 14 of 29 (48%) TP10-treated patients were extubated vs only 6 of 30 (20%) P-treated patients (p = 0.029). Although more patients in the TP10 group were extubated at 24 h, there was no difference in Pao2/fraction of inspired oxygen between groups (P = 329 ± 24 mm Hg vs TP10 = 305 ± 24, p = not significant). Total time receiving mechanical ventilation (P = 6.8 ± 12.6 d vs TP10 = 4.1 ± 7.5 d) and ICU LOS (P = 9.9 ± 14.9 d vs TP10 = 8.1 ± 9.8 d) both tended to be shorter in the TP10 group but did not achieve statistical significance, likely because of the small sample size and large variability. In patients requiring cardiopulmonary bypass (P = 5, TP10 = 6), the mean duration of mechanical ventilation was reduced by 12 h in the TP10 group (P = 21.5 ± 4.1 h vs TP10 9.5 ± 3.7 h, p = 0.035). Operative deaths (P = 3, TP10 = 2), incidence of infection or rejection, and hospital LOS were not significantly different between groups.

Short-term C inhibition with TP10 led to early extubation in a significantly higher proportion of LTx patients. In patients at risk for I/R and cardiopulmonary bypass injury, the effect of TP10 was greater, with a significant decrease in the number of ventilator-assisted days. Given that prolonged intubation is a significant risk factor for complications in the immunosuppressed host, an agent that decreases the duration of intubation and mechanical ventilation could be of major importance in improving the outcomes of LTx.




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