Alkaline Phosphatase Activity and Endotoxemia After Infant Cardiothoracic Surgery

Davidson, Jesse; Urban, Tracy T; Tong, Suhong; Maddux, Aline B; Hill, G. F.; Frank, Benjamin S.; Watson, John D.; Jaggers, James; Simões, Eric A F; Wischmeyer, Paul E.

doi:10.1097/shk.0000000000001162

Cited by 15 publications

(10 citation statements)

References 38 publications

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“…Finally, duration of mechanical ventilation would indicate worsening disease severity and also lead to increased central pressures, venous congestion, and subsequent intestinal edema and injury. Alternatively, the intestinal injury and subsequent endotoxin leak could cause direct lung injury and cause longer duration of mechanical ventilation (52,53). Our data confirm the previous finding in Typpo et al (26) that CPB time and vasopressor use are associated with higher postoperative IFABP, but the remainder of the associations are novel in a pediatric population.…”

Section: Clinical Factors Associated With Higher Post-operative Ifabpsupporting

confidence: 87%

Immediate Post-operative Enterocyte Injury, as Determined by Increased Circulating Intestinal Fatty Acid Binding Protein, Is Associated With Subsequent Development of Necrotizing Enterocolitis After Infant Cardiothoracic Surgery

et al. 2020

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Objectives: 1 Measure serial serum intestinal fatty acid binding protein levels in infants undergoing cardiac surgery with cardiopulmonary bypass to evaluate for evidence of early post-operative enterocyte injury. 2 Determine the association between immediate post-operative circulating intestinal fatty acid binding protein levels and subsequent development of necrotizing enterocolitis. Design: Observational cohort study. Intestinal fatty acid binding protein was measured pre-operatively, at rewarming, and at 6 and 24 h post-operatively. Percent of goal enteral kilocalories on post-operative day 5 and episodes of necrotizing enterocolitis were determined. Multivariable analysis assessed for factors independently associated with clinical feeding outcomes and suspected/definite necrotizing enterocolitis. Setting: Quaternary free-standing children's hospital pediatric cardiac intensive care unit. Patients: 103 infants <120 days of age undergoing cardiothoracic surgery with cardiopulmonary bypass. Interventions: None. Results: Median pre-operative intestinal fatty acid binding protein level was 3.93 ng/ml (range 0.24-51.32). Intestinal fatty acid binding protein levels rose significantly at rewarming (6.35 ng/ml; range 0.54-56.97; p = 0.008), continued to rise slightly by 6 h (6.57 ng/ml; range 0.75-112.04; p = 0.016), then decreased by 24 h (2.79 ng/ml; range 0.03-81.74; p < 0.0001). Sixteen subjects (15.7%) developed modified Bell criteria Stage 1 necrotizing enterocolitis and 9 subjects (8.8%) developed Stage 2 necrotizing Conclusions: Intestinal fatty acid binding protein levels rise following infant cardiopulmonary bypass, indicating early post-operative enterocyte injury. Intestinal fatty acid binding protein was not associated with percent of goal enteral nutrition achieved on post-operative day 5, likely due to protocolized feeding advancement based on clinically observable factors. Higher intestinal fatty acid binding protein at 6 h post-operatively was independently associated with subsequent development of necrotizing enterocolitis and may help identify patients at risk for this important complication.

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Section: Clinical Factors Associated With Higher Post-operative Ifabpsupporting

confidence: 87%

Immediate Post-operative Enterocyte Injury, as Determined by Increased Circulating Intestinal Fatty Acid Binding Protein, Is Associated With Subsequent Development of Necrotizing Enterocolitis After Infant Cardiothoracic Surgery

et al. 2020

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“…These enzymes are well established as biomarkers of liver and bone disease, but their physiologic roles remain incompletely understood. Recent evidence points towards a potential protective effect of AP in the mitigation of AKI through dephosphorylation of nephrotoxic molecules including extracellular adenine nucleotides 24–26 and endotoxin 27–29 . Phase 2 human studies have demonstrated efficacy of AP in the treatment of sepsis-induced AKI 30–32 .…”

Section: Introductionmentioning

confidence: 99%

Alkaline Phosphatase Treatment of Acute Kidney Injury in an Infant Piglet Model of Cardiopulmonary Bypass with Deep Hypothermic Circulatory Arrest

Davidson

Khailová

Treece

et al. 2019

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Acute kidney injury (AKI) is associated with prolonged hospitalization and mortality following infant cardiac surgery, but therapeutic options are limited. Alkaline phosphatase (AP) infusion reduced AKI in phase 2 sepsis trials but has not been evaluated for cardiac surgery-induced AKI. We developed a porcine model of infant cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA) to investigate post-CPB/DHCA AKI, measure serum/renal tissue AP activity with escalating doses of AP infusion, and provide preliminary assessment of AP infusion for prevention of AKI. Infant pigs underwent CPB with DHCA followed by survival for 4 h. Groups were treated with escalating doses of bovine intestinal AP (1, 5, or 25U/kg/hr). Anesthesia controls were mechanically ventilated for 7 h without CPB. CPB/DHCA animals demonstrated histologic and biomarker evidence of AKI as well as decreased serum and renal tissue AP compared to anesthesia controls. Only high dose AP infusion significantly increased serum or renal tissue AP activity. Preliminary efficacy evaluation demonstrated a trend towards decreased AKI in the high dose AP group. The results of this dose-finding study indicate that AP infusion at the dose of 25U/kg/hr corrects serum and tissue AP deficiency and may prevent AKI in this piglet model of infant CPB/DHCA.

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“…TNAP is the dominant circulating isoenzyme and has been successfully used as a biomarker of liver and bone disease [17]; however, its physiological role is not fully understood. Recently, APs have been shown to dephosphorylate and detoxify two key pathologic molecules thought to contribute to inflammation and organ injury after both cardiac surgery and sepsis: bacterial-derived lipopolysaccharide (LPS-endotoxin) [10,[18][19][20][21][22][23][24][25] and extracellular adenine nucleotides (ATP, ADP, and AMP) released during cellular necrosis or apoptosis [26][27][28][29][30]. AP removes one phosphate group from the conserved lipid A moiety of LPS resulting in a monophosphoryl product with reduced toxicity [21,31].…”

Section: Introductionmentioning

confidence: 99%

Tissue alkaline phosphatase activity and expression in an experimental infant swine model of cardiopulmonary bypass with deep hypothermic circulatory arrest

Khailová

Robison

Jaggers³

et al. 2020

J Inflamm

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Background: Infant cardiac surgery with cardiopulmonary bypass results in decreased circulating alkaline phosphatase that is associated with poor postoperative outcomes. Bovine intestinal alkaline phosphatase infusion represents a novel therapy for post-cardiac surgery organ injury. However, the effects of cardiopulmonary bypass and bovine-intestinal alkaline phosphatase infusion on tissue-level alkaline phosphatase activity/expression are unknown. Methods: Infant pigs (n = 20) underwent cardiopulmonary bypass with deep hypothermic circulatory arrest followed by four hours of intensive care. Seven control animals underwent mechanical ventilation only. Cardiopulmonary bypass/deep hypothermic circulatory arrest animals were given escalating doses of bovine intestinal alkaline phosphatase infusion (0-25 U/kg/hr.; n = 5/dose). Kidney, liver, ileum, jejunum, colon, heart and lung were collected for measurement of tissue alkaline phosphatase activity and mRNA. Results: Tissue alkaline phosphatase activity varied significantly across organs with the highest levels found in the kidney and small intestine. Cardiopulmonary bypass with deep hypothermic circulatory arrest resulted in decreased kidney alkaline phosphatase activity and increased lung alkaline phosphatase activity, with no significant changes in the other organs. Alkaline phosphatase mRNA expression was increased in both the lung and the ileum. The highest dose of bovine intestinal alkaline phosphatase resulted in increased kidney and liver tissue alkaline phosphatase activity. Conclusions: Changes in alkaline phosphatase activity after cardiopulmonary bypass with deep hypothermic circulatory arrest and bovine intestinal alkaline phosphatase delivery are tissue specific. Kidneys, lung, and ileal alkaline phosphatase appear most affected by cardiopulmonary bypass with deep hypothermic circulatory arrest and further research is warranted to determine the mechanism and biologic importance of these changes.

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Alkaline Phosphatase Activity and Endotoxemia After Infant Cardiothoracic Surgery

Abstract: Endotoxemia is common in infants undergoing CPB. Native AP activity and endotoxemia are inversely related and ex vivo addition of exogenous AP reduces whole blood EAA. Future research should evaluate AP as a therapy to reduce the harmful effects of endotoxemia following infant CPB.

Cited by 15 publications

References 38 publications

Immediate Post-operative Enterocyte Injury, as Determined by Increased Circulating Intestinal Fatty Acid Binding Protein, Is Associated With Subsequent Development of Necrotizing Enterocolitis After Infant Cardiothoracic Surgery

Immediate Post-operative Enterocyte Injury, as Determined by Increased Circulating Intestinal Fatty Acid Binding Protein, Is Associated With Subsequent Development of Necrotizing Enterocolitis After Infant Cardiothoracic Surgery

Alkaline Phosphatase Treatment of Acute Kidney Injury in an Infant Piglet Model of Cardiopulmonary Bypass with Deep Hypothermic Circulatory Arrest

Tissue alkaline phosphatase activity and expression in an experimental infant swine model of cardiopulmonary bypass with deep hypothermic circulatory arrest

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