Bioactive Oxylipins in Infants and Children With Congenital Heart Disease Undergoing Pediatric Cardiopulmonary Bypass

Abstract

Objectives: To determine the production of 9-hydroxyoctadecadienoic acid and 13-hydroxyoctadecadienoic acid during cardiopulmonary bypass in infants and children undergoing cardiac surgery, evaluate their relationship with increase in cell-free plasma hemoglobin, provide evidence of bioactivity through markers of inflammation and vasoactivity (WBC count, milrinone use, vasoactive-inotropic score), and examine their association with overall clinical burden (ICU/hospital length of stay and mechanical ventilation duration).

Design: Prospective observational study.

Setting: Twelve-bed cardiac ICU in a university-affiliated children's hospital.

Patients: Children were prospectively enrolled during their preoperative clinic appointments with the following criteria: greater than 1 month to less than 18 years old, procedures requiring cardiopulmonary bypass INTERVENTIONS:: None.

Measurements and main results: Plasma was collected at the start and end of cardiopulmonary bypass in 34 patients. 9-hydroxyoctadecadienoic acid, 13-hydroxyoctadecadienoic acid, plasma hemoglobin, and WBC increased. 9:13-hydroxyoctadecadienoic acid at the start of cardiopulmonary bypass was associated with vasoactive-inotropic score at 2-24 hours postcardiopulmonary bypass (R = 0.25; p < 0.01), milrinone use (R = 0.17; p < 0.05), and WBC (R = 0.12; p < 0.05). 9:13-hydroxyoctadecadienoic acid at the end of cardiopulmonary bypass was associated with vasoactive-inotropic score at 2-24 hours (R = 0.17; p < 0.05), 24-48 hours postcardiopulmonary bypass (R = 0.12; p < 0.05), and milrinone use (R = 0.19; p < 0.05). 9:13-hydroxyoctadecadienoic acid at the start and end of cardiopulmonary bypass were associated with the changes in plasma hemoglobin (R = 0.21 and R = 0.23; p < 0.01). The changes in plasma hemoglobin was associated with milrinone use (R = 0.36; p < 0.001) and vasoactive-inotropic score less than 2 hours (R = 0.22; p < 0.01), 2-24 hours (R = 0.24; p < 0.01), and 24-48 hours (R = 0.48; p < 0.001) postcardiopulmonary bypass. Cardiopulmonary bypass duration, 9:13-hydroxyoctadecadienoic acid at start of cardiopulmonary bypass, and plasma hemoglobin may be risk factors for high vasoactive-inotropic score. Cardiopulmonary bypass duration, changes in plasma hemoglobin, 9:13-hydroxyoctadecadienoic acid, and vasoactive-inotropic score correlate with ICU and hospital length of stay and/mechanical ventilation days.

Conclusions: In low-risk pediatric patients undergoing cardiopulmonary bypass, 9:13-hydroxyoctadecadienoic acid was associated with changes in plasma hemoglobin, vasoactive-inotropic score, and WBC count, and may be a risk factor for high vasoactive-inotropic score, indicating possible inflammatory and vasoactive effects. Further studies are warranted to delineate the role of hydroxyoctadecadienoic acids and plasma hemoglobin in cardiopulmonary bypass-related dysfunction and to explore hydroxyoctadecadienoic acid production as a potential therapeutic target.

Figure 1.

(A) 9-HODE and 13-HODE levels (normalized to LA) increased during cardiopulmonary bypass and the ratio of 9:13-HODE decreased from Start to EndCPB (*p<.01). (B) Single ion GC/MS chromatograms of 9-HODE (Rt=28.77min) and 13-HODE (Rt=29.35 min). Signals from ion fragment with m/z= 339.0 ([M-57–32]+). Y-axis -relative abundance (au); X-axis – time (min.). Chromatograms were normalized on the content of LA in the samples. (C) 9:13-HODE at StartCPB was associated with VIS at 2–24h post-CPB (R²=0.25, p<.01) and milrinone use (R²=0.17, p<.05) (D) 9:13-HODE at EndCPB was associated with VIS at 2–24h (R²=0.17, p<.05) and 24–48h post-CPB (R²=0.12, p<.05) as well as milrinone use (R²=0.19, p<.05).

Figure 2.

(A) The WBC count increased during CPB and remained elevated for 2 days post-CPB (*p<.05, **p<.01). (B) There is an association between the fold change in WBC count and the ratio of 9:13-HODE at StartCPB (R²=0.12, p<.05).

Figure 3.

(A) Cell-free plasma hemoglobin levels increased during cardiopulmonary bypass (*p<.001). (B) The ratio of 9:13-HODE at both StartCPB (R²=0.21, p<.01) and EndCPB (R²=0.23, p<.01) was associated with the change in cell-free plasma hemoglobin. (C) The change in cell-free plasma hemoglobin was associated with milrinone use (R²=0.36, p<.001). (D) The change in cell-free plasma hemoglobin was associated with VIS <2h (R²=0.22, p<.01), 2–24h (R²=0.24, p<.01), and 24–48h (R²=0.48, p<.001) post-CPB.