Coronary Blood Flow Assessed by Transthoracic Echocardiography in Neonates

Coronary flow measurement has provided useful clinical and physiologic information. However, there is little information about values for coronary flow in normal neonates, much less neonates with congenital heart disease. The aim of this study was to assess coronary blood flow in normal neonates and to compare the results with those in infants with ventricular septal defect. The study groups consisted of 12 normal neonates and 9 infants with simple ventricular septal defect associated with pulmonary hypertension. Left ventricular dimension, left ventricular mass, and the diameter of the coronary vessel were measured by standard M-mode and two-dimensional echocardiography. Peak flow velocities, flow velocity integrals, and flow volumes in the left anterior descending and circumflex coronary arteries were measured. The flow signals from the left anterior descending and circumflex coronary arteries were recorded in 84% (10/12) and 17% (2/12), respectively, in the normal neonates and 78% (7/9) and 11% (1/9), respectively, in the patients. The left ventricular end diastolic diameter and mass were significantly lower in normal infants than in the infants with ventricular septal defect (1.56 ± 0.11 vs 1.84 ± 0.09 cm and 5.4 ± 1.6 vs 8.8 ± 0.8 g, respectively, p < 0.01). The mean peak diastolic velocity and the flow velocity time integral in the left anterior descending coronary artery were significantly lower in the normal neonates than in the patients (15 ± 4 vs 28 ± 6 cm/sec and 2.3 ± 0.6 vs 5.9 ± 1.5 cm, respectively, p < 0.01). The coronary flow volume was significantly lower in the normal neonates than in the patients (3.1 ± 1.4 vs 7.9 ± 4.7 ml/min, p < 0.05). However, the flow volume of the left anterior descending coronary artery/left ventricular mass did not show any significant difference between the two groups. Our study demonstrated in neonates that it is feasible to detect noninvasively and to evaluate the flow of the left anterior descending coronary artery under physiologic conditions and abnormal hemodynamic situations. Increased flow volume in the left anterior descending coronary artery in patients with ventricular septal defect may be a compensated mechanism for the increase in oxygen demand of hypertrophic myocardium of the left ventricle.     

Comparison of synchronized and conventional intermittent mandatory ventilation in neonates

Between October 1993 and April 1995, a total of 77 neonates requiring mechanical ventilation were enrolled in this study and were randomly divided into two groups. Group A consisted of 31 premature infants (mean birthweight 1.36 ± 0.29 kg) with respiratory distress syndrome (RDS) and seven neonates (mean birthweight 3.2 ± 0.5 kg) with meconium aspiration syndrome (MAS). Group B consisted of 31 premature infants (mean birthweight 1.31 ± 0.3 kg) with RDS and eight neonates (mean birthweight 3.3 ± 0.5 kg) with MAS. Infants in group A received synchronized intermittent mandatory ventilation (SIMV) and infants in group B received conventional intermittent mandatory ventilation (CIMV) therapy. In premature infants with RDS, our data showed: (i) the duration of ventilation was significantly shorter (P < 0.05) in the synchronized group (156 ± 122 h) compared to the conventional group (242 ± 175 h); (ii) significantly fewer (P <0.05) patients required reintubation in the synchronized group than in the conventional group (three vs 11 patients); (iii) incidence of severe intraventricular hemorrhage (grades 3 and 4) was significantly lower (P < 0.05) in the synchronized group compared to the conventional group (one vs seven patients); (iv) incidence of bronchopulmonary dysplasia was significantly lower (P < 0.05) in the synchronized group than in the control group (one vs seven patients). In neonates with MAS, our data showed no significant difference (P > 0.05) on duration of ventilation, incidence of reintubation, incidence of pneumothorax or mortality rate between synchronized and control groups.     

Pre-operative time course changes in liver function tests in biliary atresia: Its usefulness in the discrimination of biliary atresia in early infancy

In order to investigate the possibility of early discrimination of extrahepatic biliary atresia from other cholestatic diseases, a series of results of liver function tests in infants with cholestatic diseases were reviewed. The results of routine liver function tests (LFT) recorded in patients' charts were reviewed within 12 weeks after birth in 47 infants with extrahepatic biliary atresia (BA), 10 infants with neonatal hepatitis (NH) and 130 age-matched control infants (CO) without cholestatic diseases. The mean of each test value for each week after birth was derived from the actual data examined in each infant. No differences were observed between BA and CO in the levels of aminotransferases within 2 weeks after birth. Total bilirubin and direct bilirubin levels were significantly different between BA and CO within 1 week after birth (16.1 ± 3.2 mg/dL vs 11.1 ± 4.5 mg/dL, 4.6 ± 2.6 mg/dL vs 0.7 ± 0.3 mg/dL, respectively) The direct bilirubin-total bilirubin ratio exceeded 25% within the first week in BA. The individual values of direct bilirubin (DB) exceeded 2 mg/dL within the first week in all infants with BA, while none of the individual values exceeded 1.6 mg/dL in CO. Gamma-glutamyl transpeptidase levels were significantly different between BA and CO at 4 weeks (432 ± 272 IU/L vs 79 ± 43 IU/L) and thereafter; and were significantly different between BA and NH at 6 weeks (314 ± 232 IU/l vs 69 ± 58 IU/L) and thereafter. These data suggest that the determination of direct bilirubin within 1 week after birth can detect extrahepatic biliary atresia patients from those with physiologic jaundice, and γ-glutamyl transpeptidase levels may discriminate BA from NH at no later than 6 weeks of age.     

Myocardial Performance in Asphyxiated Full-Term Infants Assessed by Doppler Tissue Imaging

The aim of this study was to assess myocardial performance of full-term infants with perinatal asphyxia using Doppler tissue imaging (DTI) and to correlate it with serum cardiac troponin T (cTnT) concentrations. Twenty-five asphyxiated and 20 nonasphyxiated term infants were investigated. Serum cTnT concentrations were measured between 12 and 24 h of life. Conventional two-dimensional Doppler echocardiography and DTI were done during the first 72 h of life. Right ventricular (RV) and left ventricular (LV) Tei indexes were significantly higher in asphyxiated neonates (mean ± SD: 0.45 ± 0.05 vs. 0.28 ± 0.05, P < 0.001 and 0.51 ± 0.04 vs. 0.38 ± 0.04, P < 0.001, respectively). Mitral and tricuspid systolic (Sm) velocities were significantly lower in asphyxiated neonates (mean ± SD: 5.06 ± 0.89 vs. 6.89 ± 0.94 cm/s, P < 0.001 and 5.78 ± 0.58 vs. 6.69 ± 0.87 cm/s, P < 0.001, respectively). cTnT concentrations were significantly higher in asphyxiated neonates [median (range): 0.17 (0.05–0.23) vs. 0.03 (0–0.07) μg/l, P < 0.001)], and they correlated positively with the LV Tei index (r = 0.67, P < 0.001) and the RV Tei index (r = 0.68, P < 0.001) and negatively with the mitral systolic (Sm) velocity (r = –0.68, P < 0.001) and tricuspid systolic (Sm) velocity (r = –0.41, P = 0.01). A higher cTnT was a significant predictor of mortality, whereas fractional shortening (FS) and DTI measurements did not show any significant predictive value. The DTI technique appears to be more sensitive than conventional echocardiography in the early detection of myocardial dysfunction induced by perinatal asphyxia in full-term infants.     

Intravenous immune globulin in neonatal immune hemolytic disease: does it reduce hemolysis?

We studied the effect of intravenous immune globulin (IVIG) on hemolysis in term, hyperbilirubinemia, Coombs'positive infants utilizing measurement of carboxyhemoglobin fraction corrected for inhaled carbon monoxide (COHbc), a sensitive indicator of hemolysis. COHbc values were determined before and after IVIG infusion. In those babies who responded with a decrease in serum total bilirubin ( n = 19). no exchange transfusions were required and COHbc levels decreased significantly by 24 h post-IVIG from 1.37 ± 0.31 to 1.12 ± 0.26% tHb ( p < 0.0001). There were no corresponding decreases in COHbc levels (1.89 ± 0.54 to 1.82 ± 0.48% tHb; ( p > 0.05) among those whose serum bilirubin levels did not decrease in response to IVIG ( n = 7), and all of these infants required exchange transfusions. Furthermore, the extent of the decrease in COHbc was related to the degree of decrease in serum bilirubin levels, such that the percentage decrease of bilirubin at 24 h was directly correlated with the percentage decrease of COHbc at 24 h ( p = 0.007). We conclude that IVIG, when successful, inhibits hemolysis in these infants.     

Disease-related response to inhaled nitric oxide in newborns with severe hypoxaemic respiratory failure

Inhaled nitric oxide (iNO) has been shown to improve oxygenation in severe persistent pulmonary hypertension of the newborn (PPHN). However, PPHN is often associated with various lung diseases. Thus, response to iNO may depend upon the aetiology of neonatal acute respiratory failure. A total of 150 (29 preterm and 121 term) newborns with PPHN were prospectively enrolled on the basis of oxygenation index (OI) higher than 30 and 40, respectively. NO dosage was stepwise increased (10–80 ppm) during conventional mechanical or high-frequency oscillatory ventilation while monitoring the oxygenation. Effective dosages ranged from 5 to 20 ppm in the responders, whereas iNO levels were unsuccessfully increased up to 80 ppm in the nonresponders. Within 30 min of iNO therapy, OI was significantly reduced in either preterm neonates (51 ± 21 vs 23 ± 17, P < .0001) or term infants with idiopathic or acute respiratory distress syndrome (45 ± 20 vs 20 ± 17, P < .0001), `idiopathic' PPHN (39 ± 14 vs 14 ± 9, P < .0001), and sepsis (55 ± 25 vs 26 ± 20, P < .0001) provided there was no associated refractory shock. Improvement in oxygenation was less significant and sustained (OI = 41 ± 16 vs 28 ± 18, P < .001) in term neonates with meconium aspiration syndrome and much less (OI = 58 ± 25 vs 46 ± 32, P < .01) in those with congenital diaphragmatic hernia. Only 21 of the 129 term newborns (16%) required extracorporeal membrane oxygenation (57% survival). Survival was significantly associated with the magnitude in the reduction in OI at 30 min of iNO therapy, a gestational age ≥34 weeks, and associated diagnosis other than congenital diaphragmatic hernia. Conclusion, iNO improves the oxygenation in most newborns with severe hypoxaemic respiratory failure including preterm neonates. However, response to iNO is disease-specific. Furthermore, iNO when combined with adequate alveolar recruitment and limited barotrauma using exogenous surfactant and HFOV may obviate the need for extracorporeal membrane oxygenation in many term infants. Received: 24 April 1997 / Accepted in revised form 3 January 1998     

Nebulized hypertonic saline/salbutamol solution treatment in hospitalized children with mild to moderate bronchiolitis

Background: The objective of this study was to determine the efficacy and safety of nebulized 3% hypertonic saline solution and salbutamol in the treatment of mild to moderate bronchiolitis. Methods: In a randomized controlled trial, 93 infants with mild to moderate bronchiolitis were divided into two groups. The infants received inhalation of 2.5 mg (0.5 mL) salbutamol dissolved in either 4.0 mL normal (0.9%) saline (control group, n= 43) or 4.0 mL hypertonic (3%) saline (treatment group, n= 50). The therapy was repeated three times daily until discharge. Cough, wheezing, pulmonary physical signs, and the length of hospital stay were recorded. Results: Wheezing remission time was 3.8 ± 1.1 days in the control group and 2.7 ± 0.9 days in the treatment group (P < 0.01). Cough remission time was 6.3 ± 0.9 days in the control group and 5.3 ± 0.8 days in the treatment group (P < 0.01). The moist crackles disappeared at 5.4 ± 0.8 days in the treatment group versus 6.2 ± 0.9 days in the control group (P < 0.01). Furthermore, the average length of hospital stay decreased from 7.4 ± 1.5 days in the control group to 6.0 ± 1.2 days in the treatment group (P < 0.01). No obvious adverse effects were observed. Conclusions: Inhalation of nebulized 3% hypertonic saline solution and salbutamol is a safe and effective therapy for patients with mild to moderate bronchiolitis.     

Neonatal hyperbilirubinemia and its association with thyroid hormone levels and urinary iodine excretion

Objective : To investigate, if, urinary iodine contents as a marker of iodine deficiency and hypothyroidism are associated with the incidence of neonatal hyperbilirubinemia.Methods : One hundred neonates with total serum bilirubin ≥15 mg/dl and with no known cause of jaundice were included in the study as a jaundice group. An equal number (n=100) of non-jaundiced neonates (bilirubin ≤14.9 mg/dl) with matching for age, gestation period and weight were enrolled in the study as a control group.Results : Thirteen neonates (13%) in the study group had urinary iodine levels < 100 mg/dl as against only 2 (2%) in the control group (p<0.05). Thirty-four (34/200-17%) neonates i.e. 17 each in the study and control groups had serum TSH> 5 mU/ml and hence an indirect indicator of iodine deficiency in the study population. The mean serum levels of total T3, T4 and TSH in the study neonates were 1.52 ±1.23 ng/ml, 15.8±12.0 μg/dl & 3.13 ±3.0 mU/ml respectively and did not differ significantly from the mean levels in the control group. Only one neonate in the study group had serum TSH > 20 mU/ml which was suggestive of hypothyroidism, but had normal T3 & T4. Seven neonates in the study group and 8 in the control group had low T4. There was no significant correlation between the maternal and neonatal urine iodine levels, thyroid functions and the bilirubin levels (p>0.01).Conclusion : The jaundiced babies had lower urine oidine levels than the control population. Since, there was no significant difference in the levels of the thyroid hormones, no cause and effect relationship could be inferred between iodine deficiency and jaundice.     

Soluble Intercellular adhesion molecule-1 in newborn infants

The aim of this study was to evaluate the effect of increasing postnatal age on soluble intercellular adhesion molecule-1 (sICAM-1), a very early and sensitive marker of immune activation and response in the serum of newborn infants. Serum sICAM-1 was measured by EIA (T Cell Diagnostics) in 20 healthy adults (controls) and in 43 (24 females/19 males) healthy neonates, of whom 28 were full term, and 15 were born at a gestational age between 35 and 38 weeks of pregnancy, on the 1st, 5th and 30th day of life. Neonatal serum sICAM-1 values showed a very significant increase (P<0.01) from the 1st day (137.3 ± 62.0 ng/ml) to the 5th day (259.3 ± 124.0 ng/ml) and then to the 30th day of life (415.0 ± 114.0 ng/ml), being significantly lower on the 1st day (P<0.01), whereas significantly higher on the 30th day of life (P<0.05), than those in healthy adults (305 ± 195 ng/ml). Serum sICAM-1 values on the 1st day of life depended on both the mode of delivery (significantly higher in neonates born vaginally) and the gestational age at birth (significantly lower in those born at a gestational age over 38 weeks). A significant strong correlation was found in sICAM-1 values between the 1st and the 5th day following delivery (r _P =0.77, P<0.009). Conclusion The results of this study demonstrate a significant rise of serum sICAM-1 during the 1st month of life in healthy neonates suggesting a progressively increased activation of the neonatal immune system. Received: 20 June 1996 and in revised form: 24 March 1997 / Accepted: 24 April 1997     

Ureaplasma urealyticum colonization and bronchopulmonary dysplasia: a comparative prospective multicentre study

To determine the role of tracheal colonization at birth with Ureaplasma urealyticum and other pathogenic bacteria with regard to the development of bronchopulmonary dysplasia (BPD), 97 premature infants with very low birth weight (<1500 g) were followed prospectively over 30 days in a multicentre study. Of those infants, 35 were colonized with Ureaplasma urealyticum (group Ia), 22 with other pathogenic bacteria (group Ib) and 40 infants with sterile tracheal aspirates served as controls (group II). Colonization with Ureaplasma urealyticum or with pathogenic bacteria independently increased the risk of developing BPD as compared to the controls (OR 2.55; 95% CI [1.11, 5.87]). Among Ureaplasma urealyticum and bacterial colonized infants, duration of mechanical ventilation and oxygen requirement were significantly longer than among controls (P < 0.05); during the interval of 11 to 35 days of life, every additional day of ventilation significantly increased the risk of BPD (OR 1.22; CI [1.12, 1.32]). The rate of oxygen supplementation, which was similar in both groups during the first 2 weeks of life, was significantly higher among the colonized infants at day 21 (0.38 ± 0.18 and 0.39 ± 0.16 vs 0.31 ± 0.13, P < 0.05) and at day 28 (0.38 ± 0.21 and 0.34 ± 0.15 vs 0.28 ± 0.12, P < 0.05). For infants still ventilated at age of 28 days, Ureaplasma urealyticum and bacterial colonization were associated with a significant higher risk for BPD than for uncolonized controls (OR 5.53; [1.27, 24.02]. Association of Ureaplasma urealyticum and of bacterial colonization and BPD was not weakened after adjustments were made in a multivariate analysis for other significant risk factors. Conclusion Ureaplasma urealyticum colonization is as an important risk factor in the development of bronchopulmonary dysplasia as bacterial colonization even after treatment with surfactant. Received: 23 January 1997 and in revised form: 30 December 1997 / Accepted: 5 January 1998     

Neonatal gut injury and infection rate: impact of surgical debridement on outcome

Infectious burden of gut injury (G-INJ) associated with necrotizing enterocolitis (NEC) or with spontaneous intestinal perforation (SIP) in neonates has not been ascertained. We sought to test the hypotheses that: (1) infants with G-INJ develop higher number of infections including non-concurrent infections than infants without G-INJ in a neonatal intensive care unit (NICU); (2) surgical debridement (DEB) of infants with severe G-INJ is associated with lower infectious morbidity and mortality. All infants admitted to the regional NICU from October 1991 to February 2003 were included in this prospective prevalence investigation of G-INJ and infections. Non-viable (<23 week gestational age) infants, infants with congenital anomalies, and those who developed NEC after SIP were excluded. Standard definitions of National Centers for Disease Control and Prevention were used for different categories of infections. Episodes of infections were classified as concurrent or non-concurrent (post G-INJ) based upon their timing in association with G-INJ. Infants with G-INJ associated with Bell stage II or higher NEC or with SIP were further stratified by DEB into two subgroups. A previously described 7-point clinical score was used to divide G-INJ into mild (0–2), moderate (3–5), and severe (6–7) categories. Surgical outcomes were determined by using χ² and logistic regression analyses. Data are expressed as mean ± SD or as odds ratio (OR) with 95% confidence intervals (CI); P<0.05 was considered significant. Of all 5,481 infants, 954 (17.4%) developed 1,734 episodes of infections. Prevalence of G-INJ was 4% (n=222); of these, 33% (n=73) underwent DEB. Infants with G-INJ had lower mean birth weight (1,414±766 vs. 2,153±104 g; P<0.0001) and lower mean gestational age (29.6±4.2 vs. 32.9±4.8 weeks; P<0.0001) than their peers (n=5,259). Controlling for birth weight and gestational age, odds for non-concurrent blood stream infections (BSIs) in G-INJ infants were higher (OR 13.98, CI 10.289–19.01, P<0.0001) than the remaining population without G-INJ. Forty-four percent of all episodes of fungemia, 32% of all episodes of BSIs occurred in G-INJ infants (P<0.0001). Within the G-INJ group, there were no demographic differences between the DEB and non-DEB infants. Controlling for severity of G-INJ, odds for non-concurrent BSIs (OR 3.45, CI 1.04–11.36, P<0.05) and for mortality (OR 3.35, CI 1–10, P<0.05) among non-DEB infants were higher than in DEB infants. Infants with G-INJ suffered from a disproportionate number of all blood-stream infections in our intensive care nursery. Infants with severe G-INJ whose management includes DEB are more likely to survive and to incur less infectious morbidity.     

Neonatal bilirubin production, reflected by carboxyhaemoglobin concentrations, in Down's syndrome.

AIM: To determine whether increased bilirubin production, reflected by blood carboxyhaemoglobin (COHb) values, is responsible for hyperbilirubinaemia in cases of Down's syndrome with no obvious cause for excessive jaundice. METHODS: Blood was sampled on the third day of life for COHb, total haemoglobin (tHb), and serum total bilirubin, from 19 consecutively born neonates with Down's syndrome (a subset of 34 term babies), who had developed hyperbilirubinaemia (serum bilirubin >/= 256 micromol), and from 32 term controls. COHb, measured by gas chromatography, was corrected for inspired CO (COHbc) and expressed as a percentage of tHb. RESULTS: Significantly more of the Down's syndrome subset developed hyperbilirubinaemia than the controls (10/19 (52%) vs 7/32 (22%), relative risk 2.4, 95% confidence intervals (CI) 1.10 to 5.26). Third day serum bilirubin values (mean (SD)) were higher in the Down's syndrome neonates than in controls (214 +- 63 micromol/l vs 172 +- 54 micromol/l, respectively, p=0.015). Mean (SD) COHbc values were significantly higher in the Down's syndrome neonates than in controls (0.92 +- 0. 24% vs 0.63 +- 0.17%; p<0.0001). However, Down's syndrome neonates who became hyperbilirubinaemic had similar COHbc values to those who did not (0.87 +- 0.26% and 0.95 +- 0.23%, respectively). These values contrast with those of the controls, in whom a significant increase in COHbc was associated with hyperbilirubinaemia (0.74 +- 0. 15% vs 0.60 +- 0.16%, respectively; p<0.05). tHb values were similar in both groups. CONCLUSIONS: Down's syndrome neonates had a greater risk of hyperbilirubinaemia, and higher COHbc values, than controls. However, excessive bilirubin production could not be exclusively responsible for the hyperbilirubinaemia. By inference, decreased bilirubin elimination probably plays a greater part in its pathogenesis than in controls. Down's syndrome neonates may have abnormal erythropoiesis, leading to increased haem turnover.     

Influence of plasma glucagon levels on glycemic control in children with type 1 diabetes

Objective: The aim of this study was to investigate the association between plasma glucose (PG), HbA1c and plasma glucagons levels in children with type 1 diabetes to determine the influence of plasma glucagon on their glycemic control. Methods: The study was conducted in 60 Japanese children, aged 13.3 ± 4.6 years, with type 1 diabetes for at least 3 years of diabetes. Most of the subjects had absent pancreatic β‐cell function. We compared the glucagon levels among patient groups stratified according to the 2‐hour postprandial levels (<50, 50–99, 100–199, 200–299, and ≥300 mg/dL), and the HbA1c levels (<7.0, 7.0–7.9, 8.0–8.9, and ≥9%). Results: The mean 2‐hour postprandial PG, HbA1c and plasma glucagon levels were 174 ± 97 mg/dL, 7.7 ± 1.3% and 84.0 ± 32.6 pg/mL, respectively. The glucagon levels were highly correlated with the PG levels (r = 0.553, P < 0.0001) and mildly correlated with the HbA1c levels (r = 0.301, P = 0.0192). Patients with high PG levels had significantly higher levels of glucagon as compared with those with lower PG levels (139.4 ± 47.2, 78.4 ± 17.3, 82.4 ± 21.0, 98.3 ± 29.2 and 93.8 ± 18.3 pg/mL, P = 0.0009). On the other hand, there were no significant differences in plasma glucagon levels among patient groups stratified according to HbA1c levels (P = 0.1566), however, patients with HbA1c levels ≥ 9% had significantly higher levels of glucagon than those with HbA1c levels < 7% (113.3 ± 53.4 vs 80.8 ± 18.4 pg/mL, P = 0.0291). Conclusion: These results suggest that patients with high PG are likely to have high concentrations of plasma glucagon, which may aggravate glycemic control progressively, leading to elevation of HbA1c levels.     

新生儿高胆红素血症再入院的现状和危险因素分析

目的 探讨新生儿高胆红素血症再入院情况及相关危险因素。方法 选择2017年1月至2019年12月新生儿高胆红素血症再入院患儿85例作为研究组,按1：2比例在同期新生儿高胆红素血症未再入院病例中配对随机选取170例作为对照组,分析比较两组患儿的临床资料及再入院的危险因素。结果 研究期间新生儿高胆红素血症再入院率为2.30%,中位再入院间隔天数为5 d。研究组首次出院时总胆红素和间接胆红素水平明显高于对照组（P < 0.05）;首次住院期间蓝光治疗时间长于对照组（P < 0.05）。研究组出生体重、胎龄、首次入院时年龄均低于对照组（P < 0.05）,研究组合并葡萄糖-6-磷酸脱氢酶（G-6-PD）缺乏症比例和合并溶血病比例高于对照组（P < 0.05）。多因素logsitic分析显示,胎龄小、首次入院时年龄小、合并G-6-PD缺乏症是新生儿高胆红素血症再入院的危险因素（分别OR=1.792、1.415、2.829,P < 0.05）。结论 对存在胎龄小、首次入院时年龄小、合并G-6-PD缺乏症等高危因素的高胆红素血症新生儿,应加强住院及出院后管理,防止该病再入院的发生。     

Intensified chemotherapy without SCT in infant ALL: Results from COG P9407 (Cohort 3)

Background

Infants with acute lymphoblastic leukemia (ALL) present with aggressive disease and a poor prognosis. Early relapse within 6–9 months of diagnosis is common. Approximately 75% of infants have MLL‐rearranged (MLL‐R) ALL with event free survival (EFS) ranging from 20% to 30%. Children's Oncology Group (COG) P9407 used shortened (46 weeks), intensified therapy to address early relapse and poor EFS.

Procedure

P9407 therapy was modified three times for induction toxicity resulting in three cohorts of therapy. One hundred forty‐seven infants were enrolled in the third cohort.

Results

We report an overall 5‐year EFS and OS of 42.3 ± 6% and 52.9 ± 6.5% respectively. Poor prognostic factors included age ≤90 days at diagnosis, MLL‐R ALL and white cell count ≥50,000/μl. For infants ≤90 days of age, the 5‐year EFS was 15.5 ± 10.1% and 48.5 ± 6.7% for those >90 days (P < 0.0001). Among infants >90 days of age, 5‐year EFS rates were 43.8 ± 8% for MLL‐R versus 69.1 ± 13.6% for MLL‐germline ALL (P < 0.0001).

Conclusions

Age ≤90 days at diagnosis was the most important prognostic factor. Despite shortened therapy with early intensification, EFS remained less than 50% overall in MLL‐R ALL. Pediatr Blood Cancer 2015;62:419–426. © 2014 Wiley Periodicals, Inc.     

Phototherapy for neonatal hyperbilirubinemia affects cytokine production by peripheral blood mononuclear cells

The capacity of peripheral blood mononuclear cells (PBMC) to produce interleukin (IL) IL-1β, IL-2, IL-3, IL-6, IL-10 and tumor necrosis factor-α (TNFα) was examined in term newborns with hyperbilirubinemia after 24 hours' exposure to phototherapy (wave length 425–475 nm). The results were compared with those from untreated neonates. Fifty newborns spontaneously delivered at term were included in the study. Blood samples were collected from 20 newborns before and 24 h after phototherapy. The control group consisted of 30 neonates examined on two consecutive days. PBMC isolated from blood samples were incubated in vitro for cytokine production. The concentration of cytokines in the supernatants was tested using ELISA kits (for IL-1β, IL-6, IL-10 and TNFα), or by bioassays (for IL-2 and IL-3). Phototherapy caused a 70% increase in IL-2 secretion (123 ± 27 vs 208 ± 30 units/ml, P < 0.01) and 56% in IL-10 production (1.07 ± 0.19 vs 1.67 ± 0.33 ng/ml, P < 0.03), whereas the spontaneous secretion of IL-1β was reduced by 43% (13.7 ± 2.3 vs 7.3 ± 1.7 ng/ml, P < 0.02). In the control group the secretion of these cytokines was similar on the two consecutive days and did not differ significantly from secretion in the other group before phototherapy. On the other hand, lipopolysaccharide induced TNFα production was higher on the second day in the two groups of newborns irrespective of phototherapy (388 ± 58 vs 683 ± 88 pg/ml, P < 0.001, in the control group and 384 ± 75 vs 588 ± 91, P < 0.05, before and after phototherapy). The synthesis of IL-3 and IL-6 did not change significantly between the two days of the study. The results demonstrate that in addition to the well-known positive effect of phototherapy on the neonate serum bilirubin level, this treatment affects the function of the immune system in newborns via alterations in cytokine production. Received: 4 September 1997 / Accepted: 14 February 1998     

Neonatal bilirubin production-conjugation imbalance: effect of glucose-6-phosphate dehydrogenase deficiency and borderline prematurity

OBJECTIVE: To evaluate relations between production and conjugation of bilirubin in the pathophysiology of jaundice in glucose-6-phosophate dehydrogenase (G6PD) deficient neonates. METHODS: Term and borderline premature (35-37 weeks gestational age), healthy, male, G6PD deficient neonates were studied close to the beginning of the 3rd day. Blood carboxyhaemogobin corrected for inspired CO (COHbc; an index of bilirubin production) and serum total conjugated bilirubin (TCB; a reflection of bilirubin conjugation) were measured in simultaneously drawn blood samples by gas chromatography and reverse phase high performance liquid chromatography respectively. A bilirubin production-conjugation index comprising COHbc/TCB was determined; a high index reflects imbalance between the bilirubin production and conjugation processes. COHbc and TCB individually and the production-conjugation index were studied in relation to serum total bilirubin (STB) concentration. RESULTS: Fifty one G6PD deficient neonates were sampled at 51 (8) hours. COHbc values did not correlate with STB (r=0.22, p=0.15). TCB did correlate inversely with STB (r=-0.42, p=0.004), and there was a positive correlation between the production-conjugation index and STB (r=0.45, p=0.002). The production-conjugation index (median (interquartile range)) was higher in the premature (n=8) than term neonates (2.31 (2.12-3.08) v 1.05 (0.53-1.81), p=0.003). This difference was the result of changes in TCB. CONCLUSIONS: The data show that jaundice in G6PD deficient neonates is the result of an imbalance between production and conjugation of bilirubin with a tendency for inefficient bilirubin conjugation over increased haemolysis in its pathogenesis. Borderline premature infants are at special risk of bilirubin production-conjugation imbalance.     

Follow-up study of auditory brainstem responses in hyperbilirubinemic newborns treated with exchange transfusion

Changes in auditory brainstem responses (ABR) were studied and followed in hyperbilirubinemic newborns before and after exchange transfusion (ET), in order to check their usefulness in the early detection of acute and chronic bilirubin encephalopathy. ABR were measured in 10 newborns with marked hyperbilirubinemia (total bilirubin concentration [TBC] ≧ 20 mg/dL, direct bilirubin concentration < 2 mg/dL) before and after ET. The means of birthweight, gestational age, and day of life on admission were 3267 g, 38.2 weeks and 3.4 days, respectively. The ABR measurements were performed before ET and 6.0 days (the mean) after the ET. The follow-up of ABR was performed at 3 months of life. In comparison with the control values, the mean latencies of ABR were significantly prolonged (I, I-III, and I-V: P < 0.05) and the mean amplitudes were significantly decreased (I, III and V: P < 0.001) before ET. Significant improvement of ABR was noticed after the ET, especially in the shortening of the latency of wave I (P < 0.02) and in increasing the amplitudes of wave III and V (P < 0.02 and (P < 0.01, respectively), though the recovery of the latency of I-V (P < 0.02) and the amplitudes of I, III and V wave (P < 0.001, P < 0.001 and P < 0.01, respectively) were delayed in comparison to the control. The follow-up data of ABR showed that, in two of nine infants (one was lost from the follow-up), there were still abnormal findings at 3 months of age. Only one of these, who prolonged the recovery of ABR until 5 years of age, developed a border intelligence. Though ET is effective for improvement of acute bilirubin encephalopathy with impaired ABR, a complete recovery of the ABR might be delayed in marked hyperbilirubinemia. The delay in improvement of ABR abnormalities might be possibly used as an early predictor for following chronic bilirubin encephalopathy.     

Serum 25 hydroxyvitamin D status in 6‐month‐old infants in Guangzhou,China: A paired longitudinal follow up study

To assess the vitamin D status in healthy 6‐month‐old infants, as well as vitamin D supplementation and feeding patterns in Guangzhou, China, serum 25‐hydroxyvitamin D (25OHD) concentrations of 202 infants were measured at birth (cord blood) and at 6 months of age in Guangzhou, China. Questionnaires acquiring demographic characteristics, maternal and infantile vitamin D supplementation during pregnancy and first 6 months after birth, and feeding patterns during the first 6 months were completed by participating mothers. Physical examinations and blood sampling were carried out among infants at 6 months of age. The majority of infants (93.6%) were supplemented with vitamin D during the first 6 months of life on a voluntary basis. The M ± SD of cord serum 25OHD concentration was 46.2 ± 16.4 nmol/L, whereas the M ± SD of 25OHD concentration at 6 months was 82.9 ± 24.9 nmol/L. Serum 25OHD concentrations <30 nmol/L were seen in 34 (16.8%) infants at birth but only one (0.5%) at 6 months. Only 11 (5.4%) infants had concentrations >75 nmol/L at birth, whereas the majority of infants (n = 131, 64.9%) had concentrations >75 nmol/L at 6 months. The main predictors of 25OHD levels at 6 months included season, vitamin D supplementation, parental education level, and feeding patterns. To conclude, serum 25OHD concentrations were low at birth in a southern Chinese population, and infantile supplementation is an effective way to improve 25OHD status. Exclusively breastfed infants might need greater vitamin D supplementation, and individualized vitamin D supplementation plans might be needed.     

Effect of patent ductus arteriosus and indomethacin treatment on serum cardiac troponin T levels in preterm infants with respiratory distress syndrome

Cardiac troponin T (cTnT) represents a sensitive and specific marker of ischemic myocardial damage in adult and neonatal populations. The aim of this study was to detect the potential ischemic effect of persistent patent ductus arteriosus (PDA) and indomethacin treatment on the coronary vascular bed by measuring cTnT concentrations. cTnT levels were measured in 23 preterm infants (<32 weeks of gestational age) with respiratory distress syndrome (RDS), 11 with PDA and 12 without, at 2, 4, and 7 days after birth. cTnT concentrations (mean ± SEM) significantly decreased (P < 0.05) from the 2nd (0.63 ± 0.09 μg/l) and the 4th (0.77 ± 0.13 μg/l) to the 7th postnatal day (0.28 ± 0.04 μg/l). At day 2 after birth, cTnT levels in preterm infants with RDS were significantly higher (P < 0.05) than our reference values for healthy preterm neonates (0.63 ± 0.09 μg/l vs 0.18 ± 0.04 μg/l). No differences were found between RDS infants with and without PDA at 2 (0.65 ± 0.13 vs 0.61 ± 0.14 μg/l), 4 (0.71 ± 0.21 vs 0.87 ± 0.16 μg/l), and 7 (0.26 ± 0.05 vs 0.29 ± 0.07 μg/l) days of life. In infants with PDA, cTnT levels did not differ before the first dose of indomethacin was given (0.65 ± 0.14 μg/l) or 2 h (0.65 ± 0.15 μg/l) and 48 h (0.71 ± 0.21 μg/l) afterwards. Conclusion In preterm infants with RDS the occurrence of PDA and indomethacin treatment are not associated with ischemic cardiac damage as detected by cTnT measurements. Received: 23 December 1998 and in revised form: 4 May 1999 / Accepted: 11 October 1999