Clinical characteristics associated with postoperative intestinal epithelial barrier dysfunction in children with congenital heart disease

Abstract

Objective: Children with congenital heart disease have loss of intestinal epithelial barrier function, which increases their risk for postoperative sepsis and organ dysfunction. We do not understand how postoperative cardiopulmonary support or the inflammatory response to cardiopulmonary bypass might alter intestinal epithelial barrier function. We examined variation in a panel of plasma biomarkers to reflect intestinal epithelial barrier function (cellular and paracellular) after cardiopulmonary bypass and in response to routine ICU care.

Design: Prospective cohort.

Setting: University medical center cardiac ICU.

Patients: Twenty children aged between newborn and 18 years undergoing repair or palliation of congenital heart disease with cardiopulmonary bypass.

Interventions: We measured baseline and repeated plasma intestinal fatty acid-binding protein, citrulline, claudin 3, and dual sugar permeability testing to reflect intestinal epithelial integrity, epithelial function, paracellular integrity, and paracellular function, respectively. We measured baseline and repeated plasma proinflammatory (interleukin-6, tumor necrosis factor-α, and interferon-γ) and anti-inflammatory (interleukin-4 and interleukin-10) cytokines, known to modulate intestinal epithelial barrier function in murine models of cardiopulmonary bypass.

Measurements and main results: All patients had abnormal baseline intestinal fatty acid-binding protein concentrations (mean, 3,815.5 pg/mL; normal, 41-336 pg/mL). Cytokine response to cardiopulmonary bypass was associated with early, but not late, changes in plasma concentrations of intestinal fatty acid-binding protein 2 and citrulline. Variation in biomarker concentrations over time was associated with aspects of ICU care indicating greater severity of illness: claudin 3, intestinal fatty acid-binding protein 2, and dual sugar permeability test ratio were associated with symptoms of feeding intolerance (p < 0.05), whereas intestinal fatty acid-binding protein was positively associated with vasoactive-inotrope score (p = 0.04). Citrulline was associated with larger arteriovenous oxygen saturation difference (p = 0.04) and had a complex relationship with vasoactive-inotrope score.

Conclusions: Children undergoing cardiopulmonary bypass for repair or palliation of congenital heart disease are at risk for intestinal injury and often present with evidence for loss of intestinal epithelial integrity preoperatively. Greater severity of illness requiring increased cardiopulmonary support rather than the inflammatory response to cardiopulmonary bypass seems to mediate late postoperative intestinal epithelial barrier function.

Figure 1

Change in Minimally Invasive Plasma Intestinal Epithelial Barrier Function Biomarkers and Regulatory Cytokines after Cardiopulmonary Bypass. FABP2, Intestinal Fatty Acid Binding Protein; IL-10, Interleukin 10; IL-4, Interleukin 4; IL-6, Interleukin 6; TNF-α, Tumor Necrosis Factor α; INF-γ, Interferon γ. a. Baseline and post-CPB pro-inflammatory response over time; b. Baseline and post-CPB anti-inflammatory response over time; c–f. Change over time of plasma FABP2, claudin 3, citrulline, and dual sugar permeability test (DSPT- Urinary Lactulose/Mannitol Ratio), respectively. Early (<48 hours) but not late changes in plasma biomarkers of enterocyte integrity (FABP2) were associated with post-bypass inflammatory cascade. Plasma FABP2 levels rise in response to CPB (p=0.01). Mean citrulline levels are normal pre-operatively and fall post-operatively, but remained within the age-appropriate normal range (14–39µmol/L). Repeated claudin 3 and Lactulose/Mannitol ratios were significantly associated (p<0.01) and rise remote from cardiopulmonary bypass (CPB). *Claudin 3, FABP2, Citrulline, and Lactulose/Mannitol ratios had statistically significant change over time, p<0.05, mixed effects linear regression with time zero as the referent group.

Figure 2

Plasma FABP2 and Citrulline Change with Vasoactive-Inotrope Score. FABP2, Intestinal Fatty Acid Binding Protein; VIS, vasoactive infusion score. FABP2, Intestinal Fatty Acid Binding Protein *p<0.05 In mixed effects linear regression model with the lowest VIS as the referent group, we evaluate repeated measures of plasma FABP2 and citrulline over time. All patients with vasoactive infusion score (VIS) > 10 were on epinephrine infusions. All patients with VIS > 20 were also receiving vasopressin infusions.

Figure 3

Plasma Claudin 3 and FABP2 are Associated with Symptoms of Post-Operative Feeding Intolerance FABP2, Intestinal Fatty Acid Binding Protein *p<0.05 Feeding Intolerance Score is a count variable of the number of feeding intolerance symptoms experienced by a patient in the preceeding 24 hours. Claudin 3 (p=0.02) concentrations and FABP2 (p=0.02) were significantly associated with symptoms of feeding intolerance, mixed effects linear regression.

Figure 4

Plasma Citrulline Concentration Correlates with AVDO2 AVDO2, Arteriovenous oxygen saturation difference Higher citrulline concentration correlated with larger AVDO2 which may suggest adaptive responses to hypoxia and poor cardiac output in children with CHD (r=0.51, p=0.02).