Postoperative estradiol levels associate with development of primary graft dysfunction in lung transplantation patients

Abstract

Background: Primary graft dysfunction (PGD) frequently complicates lung transplantation in the immediate postoperative period. Both female gender and estradiol modulate the body's response to injury and can influence the rate of alveolar fluid clearance.

Objective: We hypothesized that female gender and higher estradiol levels would be associated with a lower risk of PGD after lung transplantation.

Methods: We measured plasma estradiol levels preoperatively, 6 hours postoperatively, and 24 hours postoperatively in a cohort of 111 lung transplant recipients at 2 institutions.

Results: Mean age was 57 years (12.5) and 52% were female. Median postoperative estradiol level was 63.9 pg/mL (interquartile range, 28.8-154.3 pg/mL) in male and 65.1 pg/mL (interquartile range, 28.4-217.2 pg/mL) in female patients. Contrary to our hypothesis, higher estradiol levels at 24 hours were associated with an increased risk of PGD at 72 hours in male patients (P = 0.001). This association was preserved when accounting for other factors known to be associated with PGD. However, there was no relationship between gender and risk of PGD or between estradiol levels and PGD in females.

Conclusion: These findings suggest that there might be different biologic effects of estrogens in males and females, and highlight the importance of considering gender differences in future studies of PGD.

Figure 1. Estradiol levels over time

Longitudinal median estradiol level across the pre-transplant, 6-h post-transplant, and 24-h post-transplant time points Panel A, all study subjects; Panel B, female study subjects; Panel C, male study subjects. Dashed line represents subjects with PGD and solid line represents PGD-free subjects. Error bars represent the 95% CI. P-value reported is from GEE modeling.

Figure 2. Estradiol levels in patients with grade 3 PGD

24-hour postoperative estradiol levels were measured in patients with (n=29) and without (n=72) grade 3 PGD at any time in the first 72 hours following transplant. Having grade 3 PGD was associated with higher levels of estradiol on postoperative day 1 (Panel A) p=0.002 by Mann Whitney U test. When analyzed by gender of the recipient, (Panel B) the difference was only seen in males. *p=0.001 by Mann Whitney U test.

Figure 3. Primary graft dysfunction and 24-hour postoperative estradiol quartile

Panel A shows percentage of all patients with grad 3 primary graft dysfunction at any time in the first 72 hours after transplant according to 24-hour postoperative estradiol level. The risk of PGD increases with each quartile of estradiol (p=0.003 for trend by linear-by-linear association). Panel B shows the same data by gender. There is no difference in risk of PGD by estradiol quartiles in females (p=0.299 for trend by linear-by-linear association) but there is an increase risk in males for each quartile (p=0.001 for trend by linear-by-linear association).

Figure 4. Severity of PGD is associated with 24-hour postoperative estradiol level

Panel A shows 24-hour postoperative estradiol level in all patients according to grade of PGD on day 1 (p=NS by Kruskall Wallis test for trend). Panel B shows the same data by gender. Estradiol levels do not vary by PGD grade in females but increasing levels are associated with higher grades of PGD in males (**p=0.014 by Kruskall Wallis test for trend across all grades, p=0.007 by Mann Whitney U test for grade 0 compared to grade 3).

Figure 5. Estradiol levels in patients on cardiopulmonary bypass (CPB)

24-hour postoperative estradiol levels are higher in patients who were placed on cardiopulmonary bypass (CPB) during their transplant (Panel A), (p=0.024 by Mann Whitney U test). There were no differences in estradiol levels between males (N=29) and females (N=29) (Panel B) who were not on CPB (p=0.822) or males (N=18) and females (N=25) that were on CPB (p=0.571).