Jesse Davidson

Kinetics of procalcitonin and C-reactive protein and the relationship to postoperative infection in young infants undergoing cardiovascular surgery

Background:The utility of procalcitonin (PCT) and C-reactive protein (CRP) as infectious biomarkers following infant cardiothoracic surgery is not well defined.Methods:We designed a prospective cohort study to evaluate PCT and CRP after infant cardiothoracic surgery. PCT and CRP were drawn preoperatively and 24/72 h postoperation or daily in delayed sternal closure patients. Presence of infection within 10 d of surgery, vasoactive-inotropic scores at 24 and 72 h, and length of intubation, intensive care unit stay, and hospital stay were documented.Results:PCT and CRP were elevated at 24 h. PCT then decreased while CRP increased in patients undergoing delayed sternal closure or cardiopulmonary bypass. In the delayed sternal closure group, PCT was significantly higher on postoperative days 2–5 in patients who ultimately developed infection. Higher PCT was independently associated with increased vasoactive-inotropic score at 72 h. CRP did not correlate with infection or postoperative support.Conclusion:PCT rises after cardiothoracic surgery in infants but decreases by 72 h while CRP remains elevated. Sternal closure may affect CRP but not PCT. PCT is independently associated with circulatory support requirements at 72 h postoperation and with development of infection. PCT may have greater utility as a biomarker in this population.

Alkaline Phosphatase, Soluble Extracellular Adenine Nucleotides, and Adenosine Production after Infant Cardiopulmonary Bypass.

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 (10.4μmol/L vs 12.9μmol/L; p = 0.0004). Inhibition of alkaline phosphatase led to a marked decrease in 13C5-adenosine production (11.9μmol/L vs 2.7μmol/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.

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

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 < .0001) secondary to decreased bone and liver 2 isoforms. Activity declined through 24 hours in 27% of patients. AP activity strongly correlated with serum concentration (r = 0.87‐0.91; P < .0001). Persistent low AP activity at 72 hours was associated independently with occurrence of a major cardiac event (OR 5.6; P < .05). Early AP activity was associated independently with subsequent vasoactive‐inotropic score (P < .001), peak lactate (P < .0001), peak creatinine (P < .0005), N‐terminal pro‐brain natriuretic peptide (P < .05), and intestinal fatty acid binding protein (P < .005). Conclusions AP activity decreases during infant cardiopulmonary bypass and may continue to decrease for 24 hours. Activity loss is secondary to decreased bone and liver 2 isoform concentrations. Early low AP activity is associated independently with subsequent postoperative support and organ injury/dysfunction, and persistence of AP activity ≤80 U/L at 72 hours is associated independently with increased odds of major cardiovascular events.

Procalcitonin (PCT) and Kawasaki Disease: Does PCT Correlate With IVIG-Resistant Disease, Admission to the Intensive Care Unit, or Development of Coronary Artery Lesions?

BACKGROUND Kawasaki disease (KD) remains a clinical diagnosis due to the absence of a sensitive and specific diagnostic test. There are limited published data on the usefulness of procalcitonin (PCT) as a biomarker for the diagnosis or prognosis of children with KD. We hypothesized that PCT might be useful in predicting coronary artery lesions (CALs) and intravenous immunoglobulin (IVIG) resistance. METHODS Eighty-five children with KD who were hospitalized within the first 10 days of illness were retrospectively reviewed. PCT was measured on stored serum or plasma samples obtained at the time of admission (pre-IVIG). Data were analyzed to determine whether there were statistically significant associations with PCT, erythrocyte sedimentation rate, and C-reactive protein levels and the incidence of CALs, pediatric intensive care unit admission, or IVIG-resistant disease in KD patients. RESULTS PCT values in children hospitalized with acute KD ranged from 0.1 ng/mL to 143.9 ng/mL, with a median of 0.49 ng/mL (IQR 0.23-1.29 ng/mL). There was no correlation of PCT with patient age, race, or sex, but it was correlated with day of illness. KD patients with a PCT ≥ 0.5 ng/mL had a significantly higher incidence of IVIG-resistant disease (29% versus 7%, P = .02). There was no association between PCT and development of CALs in our sample. CONCLUSIONS Additional research is needed to establish the sensitivity and specificity of PCT for the diagnosis of KD. PCT may be of value in predicting which children are at increased risk for IVIG-resistant disease.

Myocardial Strain and Strain Rate in Kawasaki Disease: Range, Recovery, and Relationship to Systemic Inflammation/Coronary Artery Dilation.

Background Kawasaki Disease (KD), a systemic vasculitis of medium sized vessels, is the most common cause of acquired heart disease among children in the developed world. Some KD patients demonstrate echocardiographic evidence of depressed myocardial mechanics. However, the incidence, etiology, and reversibility of abnormal mechanics in KD patients remain undefined. Methods and results We retrospectively studied 41 KD patients and measured myocardial strain and strain rate by velocity vector imaging from pre-treatment and convalescent echocardiograms. Pre-treatment procalcitonin, C-reactive protein (CRP), and coronary artery z-scores were obtained in all patients and compared between the groups with preserved versus depressed acute phase mechanics. The change in mechanics between the acute and convalescent phases was also assessed. Patients with initially low longitudinal strain improved by the convalescent period (mean difference - 4.0%; p<0.005) with the greatest improvement occurring in patients with the lowest initial strain (−7.3%; p<0.05). Patients with higher initial strain did not change significantly by the convalescent period. Patients with lower longitudinal and circumferential strain demonstrated higher median procalcitonin levels (1.2 vs. 0.3 ng/mL; p<0.05 and 1.8 vs. 0.4 ng/mL; p<0.05 respectively) and a trend towards higher CRP, but no difference in coronary artery z-scores. Strain rate was not associated with inflammatory markers or coronary artery z-scores. Conclusions The range of strain found in our cohort was large. Improvement in mean strain was driven primarily by patients with lower initial strain. Lower strain was associated with increased markers of systemic inflammation, but not proximal coronary artery changes.

Infant cardiopulmonary bypass: CD73 kinetics, association with clinical outcomes, and influence on serum adenosine production capacity

BackgroundExtracellular adenine nucleotides contribute to ischemia–reperfusion injury following infant cardiopulmonary bypass (CPB), whereas conversion to adenosine may be protective. Alkaline phosphatase (AP), a key enzyme responsible for this conversion, decreases after infant CPB. Indirect evidence suggests that soluble CD73 may simultaneously increase and partially offset this loss of AP. We sought to measure CD73 levels in infants undergoing CPB and determine its association with adenosine production capacity and postoperative support requirements.MethodsA prospective cohort study of infants ≤120 days of age undergoing CPB. CD73 was measured before CPB and during rewarming. Multivariable modeling evaluated the contributions of CD73/AP to adenosine production capacity and postoperative support requirements.ResultsSerum samples from 85 subjects were analyzed. The median CD73 concentration increased following CPB (95.2 vs. 179.8 ng/ml; P<0.0001). Rewarming CD73 was independently inversely associated with vasoactive inotropic support (P<0.005) and length of intensive care unit stay (P<0.005). Combined AP activity and CD73 concentration predicted adenosine production capacity (P<0.0001).ConclusionsSerum CD73 increases following infant CPB. Low rewarming CD73 is independently associated with increased postoperative support requirements. CD73 and AP together predict serum adenosine production capacity and may represent potential therapeutic targets to clear extracellular adenine nucleotides and improve outcomes following infant CPB.

Successful Treatment of Myocardial Infarction in an Infant With Kawasaki Disease

Although early treatment with intravenous immunoglobulin reduces the risk of coronary artery aneurysms, in refractory cases of Kawasaki disease, myocardial infarction can result from thrombosis of coronary artery aneurysms. Early recognition of myocardial infarction from Kawasaki disease myocarditis can reduce morbidity and mortality. This report describes successful treatment of myocardial infarction from coronary thrombosis in an infant with Kawasaki disease using intravenous tissue plasminogen activator and abciximab.

Endothelin-1 activation in pediatric patients undergoing surgical coarctation of the aorta repair

AIM To determine endothelin-1 (ET-1) concentration before and after surgical coarctectomy and evaluate its association with left ventricular geometric change. METHODS A prospective, cohort study of 24 patients aged 2 d to 10 years with coarctation of the aorta undergoing surgical repair. A sub-cohort of patients with age < 1 mo was classified as “neonates”. Echocardiograms were performed just prior to surgery and in the immediate post-op period to assess left ventricle mass index and relative wall thickness (RWT). Plasma ET-1 levels were assessed at both time points. Association between ET-1 levels and ventricular remodeling was assessed. RESULTS Patients < 1 year demonstrated higher pre-op ET-1 than post-op (2.8 pg/mL vs 1.9 pg/mL, P = 0.02). Conversely, patients > 1 year had no change in ET-1 concentration before and after surgery (1.1 vs 1.4, NS). Pre-op, patients < 1 year demonstrated significantly higher ET-1 than older children (2.8 vs 1.1, P = 0.001). Post-op there was no difference between the age groups (1.9 vs 1.4, NS). Neither RWT nor left ventricle mass index (LVMI) varied from pre-op to post-op. The subset of neonates showed a strong positive correlation between pre-op ET-1 and RWT (r = 0.92, P = 0.001). Patients with ET-1 > 2 pg/mL pre-op demonstrated higher LVMI (65.7 g/m2.7 vs 38.5 g/m2.7, P = 0.004) and a trend towards higher RWT (45% vs 39%, P = 0.07) prior to repair than those with lower ET-1 concentration. CONCLUSION ET-1 concentration is significantly variable in the peri-operative period surrounding coarctectomy. Older children and infants have different responses to surgical repair suggesting different mechanisms of activation.