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Alkaline Phosphatase in Infant Cardiopulmonary Bypass: Kinetics and Relationship to Organ Injury and Major Cardiovascular Events.

ABSTRACT: OBJECTIVES:To determine the kinetics of alkaline phosphatase (AP) activity and concentration after infant cardiopulmonary bypass, including isoform-specific changes, and to measure the association between postoperative AP activity and major postoperative cardiovascular events, organ injury/dysfunction, and postoperative support requirements STUDY DESIGN: Prospective cohort study of 120 infants ?120 days of age undergoing cardiopulmonary bypass. AP total and isoform-specific activity was assessed at 6 time points (preoperation, rewarming, 6, 24, 48, and 72 hours postoperation). Low AP activity was defined as ?80?U/L. AP concentrations and biomarkers of organ injury/dysfunction were collected through 24 hours postoperation. Major cardiovascular events were defined as cardiac arrest, mechanical circulatory support, or death. RESULTS:AP activity loss occurred primarily during the operation (median decrease 89?U/L; P?

SUBMITTER: Davidson JA

PROVIDER: S-EPMC5726771 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Alkaline Phosphatase in Infant Cardiopulmonary Bypass: Kinetics and Relationship to Organ Injury and Major Cardiovascular Events.

Davidson Jesse A JA Urban Tracy T TT Baird Christine C Tong Suhong S Woodruff Alan A Twite Mark M Jaggers James J Simões Eric A F EAF Wischmeyer Paul P

The Journal of pediatrics 20171101

<h4>Objectives</h4>To determine the kinetics of alkaline phosphatase (AP) activity and concentration after infant cardiopulmonary bypass, including isoform-specific changes, and to measure the association between postoperative AP activity and major postoperative cardiovascular events, organ injury/dysfunction, and postoperative support requirements STUDY DESIGN: Prospective cohort study of 120 infants ≤120 days of age undergoing cardiopulmonary bypass. AP total and isoform-specific activity was ...[more]

PMID: 29144270

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Project description:RATIONALE:Decreased alkaline phosphatase activity after infant cardiac surgery is associated with increased post-operative cardiovascular support requirements. In adults undergoing coronary artery bypass grafting, alkaline phosphatase infusion may reduce inflammation. Mechanisms underlying these effects have not been explored but may include decreased conversion of extracellular adenine nucleotides to adenosine. OBJECTIVES:1) Evaluate the association between alkaline phosphatase activity and serum conversion of adenosine monophosphate to adenosine after infant cardiac surgery; 2) assess if inhibition/supplementation of serum alkaline phosphatase modulates this conversion. METHODS AND RESEARCH:Pre/post-bypass serum samples were obtained from 75 infants <4 months of age. Serum conversion of 13C5-adenosine monophosphate to 13C5-adenosine was assessed with/without selective inhibition of alkaline phosphatase and CD73. Low and high concentration 13C5-adenosine monophosphate (simulating normal/stress concentrations) were used. Effects of alkaline phosphatase supplementation on adenosine monophosphate clearance were also assessed. Changes in serum alkaline phosphatase activity were strongly correlated with changes in 13C5-adenosine production with or without CD73 inhibition (r = 0.83; p<0.0001). Serum with low alkaline phosphatase activity (?80 U/L) generated significantly less 13C5-adenosine, particularly in the presence of high concentration 13C5-adenosine monophosphate (10.4?mol/L vs 12.9?mol/L; p = 0.0004). Inhibition of alkaline phosphatase led to a marked decrease in 13C5-adenosine production (11.9?mol/L vs 2.7?mol/L; p<0.0001). Supplementation with physiologic dose human tissue non-specific alkaline phosphatase or high dose bovine intestinal alkaline phosphatase doubled 13C5-adenosine monophosphate conversion to 13C5-adenosine (p<0.0001). CONCLUSIONS:Alkaline phosphatase represents the primary serum ectonucleotidase after infant cardiac surgery and low post-operative alkaline phosphatase activity leads to impaired capacity to clear adenosine monophosphate. AP supplementation improves serum clearance of adenosine monophosphate to adenosine. These findings represent a potential therapeutic mechanism for alkaline phosphatase infusion during cardiac surgery. NEW AND NOTEWORTHY:We identify alkaline phosphatase (AP) as the primary soluble ectonucleotidase in infants undergoing cardiopulmonary bypass and show decreased capacity to clear AMP when AP activity decreases post-bypass. Supplementation of AP ex vivo improves this capacity and may represent the beneficial therapeutic mechanism of AP infusion seen in phase 2 studies.

Project description:BackgroundIn a rabbit model of cardiopulmonary bypass (CPB) and cardioplegic arrest, we previously showed that hyperoxic myocardial reperfusion was associated with increased left ventricular (LV) systolic dysfunction and myocardial injury compared with normoxic reperfusion. The aim of this study was to evaluate in our experimental model the impact of post-CPB reperfusion conditions on other organs potentially vulnerable to ischemic injury such as the brain and kidney.MethodsAfter 60?min of CPB, aortic cross-clamp, and cold cardioplegic arrest, rabbits were reperfused under hyperoxic or normoxic conditions for 120?min. Left ventricular systolic contractility (LV?+?dP/dt) and diastolic relaxation (LV -dP/dt) were continuously recorded, and end-organ injury was assessed by measuring circulating biomarkers specific for kidney (cystatin C and creatinine) and brain injury [S100B and neuron specific enolase (NSE)]. At completion of the protocol, kidney and brain tissues were harvested for measuring oxidant stress (OS), inflammation and apoptosis.ResultsFollowing aortic cross-clamp removal, rabbits exposed to normoxic reperfusion demonstrated preserved LV systolic and diastolic function compared with hyperoxic reperfusion (LV?+?dP/dt: 70?±?14% of pre-CPB vs. 36?±?21%, p?=?0.018; LV -dP/dt: 72?±?36% of pre-CPB vs. 33?±?20%, p?=?0.023). Similarly, CPB increased plasma creatinine, S100B and NSE that were significantly attenuated by normoxic reperfusion compared with hyperoxic reperfusion (creatinine: 4.0?±?0.5 vs. 7.1?±?0.8?mg/dL, p?=?0.004; S100B: 4.0?±?0.8 vs. 6.7?±?1.0?ng/mL, p?=?0.047; NSE: 57.7?±?6.8 vs. 101.3?±?16.1?pg/mL, p?=?0.040). Furthermore, both kidney and brain tissues showed increased mRNA expression and activation of pathways for OS, inflammation, and apoptosis, that were reduced under normoxic compared with hyperoxic conditions.ConclusionsNormoxic reperfusion ameliorates cardiac, renal and neural injury compared with hyperoxic reperfusion in an in vivo animal model of CPB and cardioplegic arrest. This protective effect of normoxic reperfusion may be due to a reduction in signaling pathways for OS, inflammation, and apoptosis.

Project description:BACKGROUND:Necrotizing enterocolitis (NEC) is a devastating disease of intestinal inflammation that primarily affects premature infants. A potential risk factor for necrotizing enterocolitis is exposure of the premature neonatal intestine to environmental bacteria and their proinflammatory products such as lipopolysaccharide. The metalloenzyme alkaline phosphatase (ALP) has been shown to reduce lipopolysaccharide-mediated inflammation. Additionally, premature rat pups have reduced alkaline phosphatase activity and expression as compared to full term pups. To explore the possibility that the human premature neonatal intestine has a paucity of alkaline phosphatase activity, we measured endogenously produced intestinal alkaline phosphatase activity in meconium as a function of gestational age. To test whether breast milk could serve as a source of exogenous alkaline phosphatase to the neonatal intestine through ingestion, we measured alkaline phosphatase activity in breast milk across a range of time points post-birth. METHODS:Alkaline phosphatase activity was quantified in 122 meconium samples from infants of gestational ages ranging from 24 to 40?weeks and in 289 breast milk samples collected from 78 individual mothers between days 2-49 post-birth. RESULTS:We observed a strong positive correlation between the meconium alkaline phosphatase activity and gestational age, with preterm infants having lower meconium alkaline phosphatase activities than early term or term infants. Breast milk alkaline phosphatase activity was highest in the first week post-birth, with peak alkaline phosphatase activity at day 2 post-birth, followed by relatively low alkaline phosphatase activity in weeks 2-7. CONCLUSIONS:Our results are consistent with the two major risk factors for necrotizing enterocolitis development, preterm birth and lack of breast milk feeding, both contributing to a paucity of alkaline phosphatase activity and impaired capacity to detoxify proinflammatory bacterial products such as lipopolysaccharide.

Dataset Information

Alkaline Phosphatase in Infant Cardiopulmonary Bypass: Kinetics and Relationship to Organ Injury and Major Cardiovascular Events.

Publications

Alkaline Phosphatase in Infant Cardiopulmonary Bypass: Kinetics and Relationship to Organ Injury and Major Cardiovascular Events.

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