The relationship of red blood cell transfusion to intestinal mucosal injury in premature infants.

OBJECTIVE: To determine the incidence of intestinal mucosal injury before and after transfusions in premature infants. STUDY DESIGN: Urine was collected throughout the hospital stay of 62 premature infants and specimens obtained within 24h before and after transfusion were assayed for intestinal fatty acid binding protein (iFABP). A urinary iFABP:creatinine ratio (iFABPu:Cru) of 2.0pg/nmol was considered elevated. RESULT: Forty-nine infants were transfused. iFABPu:Cru was elevated following 71 (75.6%) of 94 transfusions for which urine was available. In 51 (71.8%) of these, iFABPu:Cru was also elevated prior to the transfusion. Among four cases of transfusion-associated NEC, iFABPu was elevated following every sentinel transfusion and prior to three of them. CONCLUSION: Subclinical intestinal mucosal injury is frequent following blood transfusions in premature infants and, when present, usually precedes transfusion. This suggests that transfusion may not be a primary mediator of intestinal injury so much as anemia and its associated conditions. LEVEL OF EVIDENCE: Prognosis study/level 3.

Oral sucrose for heel lance enhances adenosine triphosphate use in preterm neonates with respiratory distress.

OBJECTIVE: To examine the effects of oral sucrose on procedural pain, and on biochemical markers of adenosine triphosphate utilization and oxidative stress in preterm neonates with mild to moderate respiratory distress. STUDY DESIGN: Preterm neonates with a clinically required heel lance that met study criteria (n = 49) were randomized into three groups: (1) control (n = 24), (2) heel lance treated with placebo and non-nutritive sucking (n = 15) and (3) heel lance treated with sucrose and non-nutritive sucking (n = 10). Plasma markers of adenosine triphosphate degradation (hypoxanthine, xanthine and uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured using the Premature Infant Pain Profile. Data were analyzed using repeated measures analysis of variance, chi-square and one-way analysis of variance. RESULTS: We found that in preterm neonates who were intubated and/or were receiving ⩾30% FiO2, a single dose of oral sucrose given before a heel lance significantly increased markers of adenosine triphosphate use. CONCLUSION: We found that oral sucrose enhanced adenosine triphosphate use in neonates who were intubated and/or were receiving ⩾30% FiO2. Although oral sucrose decreased pain scores, our data suggest that it also increased energy use as evidenced by increased plasma markers of adenosine triphosphate utilization. These effects of sucrose, specifically the fructose component, on adenosine triphosphate metabolism warrant further investigation.

Early detection of impending necrotizing enterocolitis with urinary intestinal fatty acid-binding protein.

BACKGROUND: Necrotizing enterocolitis (NEC) is diagnosed after the development of feeding intolerance and characteristic physical and imaging findings. Earlier detection of a subclinical prodrome might allow for the institution of measures that could prevent or attenuate the severity of the disease. OBJECTIVES: We sought to determine whether urinary intestinal fatty acid-binding protein (iFABPu) might be elevated prior to the first clinical manifestations of NEC. METHODS: Urine was collected daily from 62 infants of a gestational age of 24-28 weeks. Based on clinical, imaging and operative findings, subjects were determined to have Bell stage 2 or 3 NEC. In all the subjects with NEC and in 21 age-matched controls, iFABPu was determined using an ELISA, and was expressed in terms of its ratio to urinary creatinine (Cr), i.e. iFABPu/Cru. Receiver operating characteristic (ROC) curves were constructed to define the predictive value of iFABPu/Cru for impending NEC in the days prior to the first clinical manifestations. RESULTS: Five subjects developed NEC (stage 2: n = 3 and stage 3: n = 2). The day before the first clinical manifestation of NEC, a ROC curve showed that an iFABPu/Cru >10.2 pg/nmol predicted impending NEC with a sensitivity of 100% and a specificity of 95.6%. iFABPu/Cru did not predict NEC 2 days prior to the first sign of disease. CONCLUSIONS: An elevated iFABPu was a sensitive and specific predictor of impending NEC 1 day prior to the first clinical manifestations. iFABPu screening might identify infants at a high risk and allow for the institution of measures that could ameliorate or prevent NEC.

Urinary Hypoxanthine as a Measure of Increased ATP Utilization in Late Preterm Infants.

OBJECTIVE: To examine the effect of neonatal morbidity on ATP breakdown in late preterm infants. STUDY DESIGN: Urinary hypoxanthine concentration, a marker of ATP breakdown, was measured from 82 late preterm infants on days of life (DOL) 3 to 6 using high-performance liquid chromatography. Infants were grouped according to the following diagnoses: poor nippling alone (n = 8), poor nippling plus hyperbilirubinemia (n = 21), poor nippling plus early respiratory disease (n = 26), and respiratory disease alone (n = 27). RESULTS: Neonates with respiratory disease alone had significantly higher urinary hypoxanthine over DOL 3 to 6 when compared with neonates with poor nippling (P = .020), poor nippling plus hyperbilirubinemia (P < .001), and poor nippling plus early respiratory disease (P = .017). Neonates with poor nippling who received respiratory support for 2 to 3 days had significantly higher hypoxanthine compared with infants who received respiratory support for 1 day (P = .017) or no days (P = .007). CONCLUSIONS: These findings suggest that respiratory disorders significantly increase ATP degradation in late premature infants.

Oral sucrose for heel lance increases adenosine triphosphate use and oxidative stress in preterm neonates.

OBJECTIVE: To examine the effects of sucrose on pain and biochemical markers of adenosine triphosphate (ATP) degradation and oxidative stress in preterm neonates experiencing a clinically required heel lance. STUDY DESIGN: Preterm neonates that met study criteria (n = 131) were randomized into 3 groups: (1) control; (2) heel lance treated with placebo and non-nutritive sucking; and (3) heel lance treated with sucrose and non-nutritive sucking. Plasma markers of ATP degradation (hypoxanthine, xanthine, and uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured with the Premature Infant Pain Profile. Data were analyzed by the use of repeated-measures ANOVA and Spearman rho. RESULTS: We found significant increases in plasma hypoxanthine and uric acid over time in neonates who received sucrose. We also found a significant negative correlation between pain scores and plasma allantoin concentration in a subgroup of neonates who received sucrose. CONCLUSION: A single dose of oral sucrose, given before heel lance, significantly increased ATP use and oxidative stress in premature neonates. Because neonates are given multiple doses of sucrose per day, randomized trials are needed to examine the effects of repeated sucrose administration on ATP degradation, oxidative stress, and cell injury.

Procedural pain and oxidative stress in premature neonates.

UNLABELLED: Preterm neonates exposed to painful procedures in the neonatal intensive care unit exhibit increased pain scores and alterations in oxygenation and heart rate. It is unclear whether these physiological responses increase the risk of oxidative stress. Using a prospective study design, we examined the relationship between a tissue-damaging procedure (TDP; tape removal during discontinuation of an indwelling central arterial or venous catheter) and oxidative stress in 80 preterm neonates. Oxidative stress was quantified by measuring uric acid (UA) and malondialdehyde (MDA) concentration in plasma before and after neonates (n = 38) experienced a TDP compared to those not experiencing any TDP (control group, n = 42). Pain was measured before and during the TDP using the Premature Infant Pain Profile (PIPP). We found that pain scores were higher in the TDP group compared to the control group (median scores, 11 and 5, respectively; P < .001). UA significantly decreased over time in control neonates but remained stable in TDP neonates (132.76 to 123.23 µM versus 140.50 to 138.9 µM; P = .002). MDA levels decreased over time in control neonates but increased in TDP neonates (2.07 to 1.81 µM versus 2.07 to 2.21 µM, P = .01). We found significant positive correlations between PIPP scores and MDA. Our data suggest a significant relationship between procedural pain and oxidative stress in preterm neonates. PERSPECTIVE: This article presents data describing a significant relationship between physiological markers of neonatal pain and oxidative stress. The method described in this paper can potentially be used to assess the direct cellular effects of procedural pain as well the effectiveness of interventions performed to decrease pain.

An animal model for measuring the effect of common NICU procedures on ATP metabolism.

Neonates exposed to common neonatal intensive care unit (NICU) procedures show alterations in heart rate, blood pressure, and oxygen saturation. However, it is unclear if these physiologic changes increase adenosine triphosphate (ATP) utilization, thus potentially increasing the risk for tissue hypoxia in medically fragile neonates. Plasma uric acid is a commonly used marker of increased ATP utilization because uric acid levels increase when ATP consumption is enhanced. To examine the effect of a common NICU procedure on plasma uric acid concentration, we developed a model that allows for acute monitoring of this biochemical marker in plasma in 7- to 9-day-old rabbits. In our pilot study, we exposed neonatal rabbits to a single heel lance 2.5 hr after catheter placement. We measured uric acid concentration before and 30 min after the heel lance and compared findings to levels in control animals not exposed to the heel lance. Our pilot data shows a significant difference in uric acid concentration over time between the control and heel lance groups (46.2 ± 7.1 µM vs. 54.7 ± 5.8 µM, respectively, p = .027). Calculation of percentage change from baseline showed uric acid concentration increasing in rabbits exposed to heel lance and decreasing in control rabbits (1.5 ± 4.7% vs. -16.1 ± 4.2%, respectively, p = .03). These data suggest that this animal model can be successfully used to examine the biochemical effect of common NICU procedures, such as heel lance, on markers of ATP breakdown and purine metabolism.

Necrotizing enterocolitis is associated with neonatal intestinal injury.

PURPOSE: We hypothesized that a subset of premature newborns has subclinical, intestinal mucosal compromise that predisposes to the development of necrotizing enterocolitis (NEC) days or weeks later. METHODS: Fifty-five newborns of 23 to 36 weeks' gestational age were identified, and urine was collected over the first 90 hours of life. The urinary concentration of intestinal fatty acid binding protein (iFABP(u)), a sensitive marker for intestinal injury, was determined. The diagnosis of NEC was based upon clinical condition, pathology, and/or imaging findings. RESULTS: Neonatal iFABP(u) exceeded 800 pg/mL in 27 subjects, including 9 of 9 who subsequently developed stage 2 or 3 NEC. This degree of iFABP(u) elevation, but not asphyxia, was significantly associated with the development of NEC (P < .01). CONCLUSION: In this population of premature newborns, there was a substantial incidence of intestinal mucosal compromise. All infants who subsequently developed stage 2 or 3 NEC had an elevated iFABP(u). This finding suggests a model for the pathogenesis of some cases of NEC, whereby perinatal mucosal injury predisposes to further damage when feedings are initiated. In addition, neonatal iFABP(u) assessment may represent a tool to identify infants at the highest risk for NEC and allow for the institution of focused, preventive measures.