Relationships Between Systemic Inflammation, Intestinal Damage and Postoperative Organ Dysfunction in Adults Undergoing Low-Risk Cardiac Surgery.

BACKGROUND: Approximately half of patients who undergo cardiac surgery develop systemic inflammatory response syndrome. Extracorporeal circulation and intestinal injury may play a role in this inflammatory response, although their relative contributions remain elusive. Moreover, it is largely unknown to what extent these factors contribute to cardiac surgery-induced postoperative organ dysfunction. METHOD: In this secondary analysis, we measured circulating levels of the intestinal damage marker intestinal fatty acid binding protein (I-FABP) and of the inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, IL-10, IL-1RA, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and MIP-1ß in 180 patients undergoing on-pump cardiac surgery. The average Z-score of levels of the different cytokines was used as an integral measure of the cytokine response. Relationships between duration of extracorporeal circulation, extent of intestinal injury, inflammation, and postoperative organ dysfunction were explored. RESULTS: Plasma I-FABP levels increased during surgery, with peak levels observed at the end of cardiopulmonary bypass (CPB). Except for TNF-α, the levels of all cytokines increased during surgery, with peak levels observed either 2 (MCP-1, MIP-1α, and MIP-1ß), 4 (IL-6, IL-8, and IL-1RA) or 6 (IL-10) hours after the end of CPB. While the duration of CPB significantly correlated with cytokine Z-score (r=0.544, p<0.05), no relationship with I-FABP levels was found. Furthermore, no significant correlations between I-FABP and cytokine levels were observed. The duration of CPB correlated with a deterioration in postoperative kidney function (estimated glomerular filtration rate [eGFR]) and troponin levels. Cytokine Z-score was associated with postoperative troponin levels, fluid administration, inotropic score, pulmonary alveolar-arterial gradient on the first postoperative morning, and deterioration of kidney function (eGFR). I-FABP levels did not correlate with any of the cardiovascular, pulmonary, or renal parameters. CONCLUSIONS: In patients undergoing low-risk cardiac surgery, the duration of CPB represents an important determinant of the systemic cytokine response, whereas both the CPB duration and the systemic inflammatory response contribute to subsequent organ dysfunction. Intestinal damage does not appear to play a relevant role in the postoperative inflammatory response and development of postoperative organ dysfunction in these patients.

Intestinal fatty acid binding protein as a predictor for intra-abdominal pressure-related complications in patients admitted to the intensive care unit; a prospective cohort study (I-Fabulous study).

PURPOSE: Critically ill patients are at risk for intra-abdominal hypertension (IAH) and related complications such as organ failure, abdominal compartment syndrome (ACS), and death. This study aimed to determine the value of urinary and serum intestinal fatty acid binding protein (I-FABP) levels as early marker for IAH-associated complications. METHODS: A prospective observational study was conducted in two academic institutional mixed medical-surgical ICUs in the Netherlands. Adult patients admitted to the ICU with two or more risk factors for IAH (198) were included. Urinary and serum I-FABP and intra-abdominal pressure (IAP) were measured every six hours during 72 h. RESULTS: Fifteen (8%) patients developed ACS and 74 (37%) developed new organ failure. I-FABP and IAP were positively correlated. Patients who developed ACS had higher median baseline levels of urinary I-FABP (235(P25-P75 85-1747)µg/g creat) than patients with IAH who did not develop ACS (87(P25-P75 33-246)µg/g, p = 0.037). With an odds ratio of 1.00, neither urinary nor serum I-FABP indicated increased risk for developing new organ failure or ACS. CONCLUSIONS: A relevant diagnostic value of I-FABP levels for identifying individual patients at risk for intra-abdominal pressure related complications could not be demonstrated.

Norepinephrine Contributes to Enterocyte Damage in Septic Shock Patients: A Prospective Cohort Study.

OBJECTIVES: In septic patients, both systemic inflammation and splanchnic hypoperfusion may cause enterocyte damage. Catecholamines may exert additional detrimental effects on mesenteric blood flow in these patients, and thereby contribute to this damage. Enterocyte damage itself results in impairment of gut barrier function and consequent translocation of bacteria/toxins. This may contribute to multiple organ failure and death by sustaining or amplifying the systemic inflammatory response. The aim of the study was 2-fold: to investigate which factors contribute to enterocyte damage in septic patients, and to assess whether enterocyte damage is associated with a sustained or amplified systemic inflammatory response. METHODS: In this prospective observational cohort study in 129 patients with septic shock admitted to the ICU, we serially measured plasma levels of Intestinal Fatty Acid-Binding Protein (I-FABP, a marker for enterocyte damage) and of cytokines Tumor Necrosis Factor (TNF)-α, Interferon (IFN)-y, Interleukin (IL)-1ß, IL-6, IL-8, IL-1 Receptor Antagonist (RA), and IL-10. Clinical data were collected from electronic patient files. RESULTS: A total of 129 patients were included in the study. The median age of the patients was 67 years [56-74]. The median norepinephrine infusion rate was 0.2 µg/kg/min [0.1-0.5]. Overall, 28-day mortality was 31 (24%). Similar to previous work, I-FABP levels at admission were independently associated with mortality (odds ratio 3.101 [1.138-8.448]). Acute Physiology and Chronic Health Evaluation II score and an increase in norepinephrine infusion rate between days 1 and 3 were independently associated with area under curve I-FABP levels, whereas mean arterial pressure and creatinine levels were not. No correlations were found between any of the measured cytokines and plasma I-FABP levels. Furthermore, high I-FABP levels were not related with the subsequent course of cytokine levels. CONCLUSIONS: In patients with septic shock, norepinephrine use is associated with more enterocyte damage. Although enterocyte damage is associated with increased 28-day mortality, it is not associated with a sustained or amplified systemic inflammatory response.

Markers of Intestinal Damage and their Relation to Cytokine Levels in Cardiac Surgery Patients.

OBJECTIVES: In patients undergoing cardiac surgery, both extracorporeal circulation (ECC) and intraoperative mesenterial hypoperfusion may account for increased cytokine levels and lead to postoperative gastrointestinal (GI) symptoms. METHODS: We investigated levels of the intestinal damage markers intestinal fatty acid binding protein (I-FABP in plasma [n = 72] and urine [n = 37]), citrulline (in plasma [n = 35]), and claudin-3 (in urine [n = 37]) in patients undergoing aortic or mitral valve surgery with or without coronary artery bypass grafting. Furthermore, the relationship between these markers and the surgery-induced cytokine response was explored by measuring serial plasma levels of tumor necrosis factor-α, interleukin (IL)-6, IL-8, and IL-10 (n = 35). Finally, the relationship between markers of intestinal damage and GI-symptoms (abdominal pain, ileus, vomiting, diarrhea, time to first defecation) was assessed. RESULTS: Plasma and urinary I-FABP levels, and urinary claudin-3 levels peaked at the end of surgery, while citrulline levels were not influenced by surgery. ECC duration correlated with plasma I-FABP levels (r = 0.31, P = 0.007). Plasma levels of all measured cytokines increased during surgery, with peak levels observed either at the end of surgery or on the first postoperative day. While ECC duration correlated with IL-6 and IL-8 release (r = 0.43, P = 0.01 and r = 0.36, P = 0.04 respectively), there was no direct relationship between I-FABP and claudin-3 levels and cytokine concentrations. No patients developed significant GI or non-GI complications, and I-FABP and claudin-3 release appeared not to be related to postoperative GI symptoms, although the incidence of these symptoms may have limited a reliable assessment. CONCLUSIONS: Longer duration of ECC is associated with a more pronounced release of intestinal injury markers and inflammatory cytokines, but intestinal injury markers are not directly related to the observed increase in cytokine levels or GI-symptoms. These findings indicate that ECC duration contributes to the cytokine response observed in cardiac surgery patients and that intestinal injury itself is not a causative factor for this response.