Nitric oxide levels in preterm and term infants and in premature infants with bacteremia

OBJECTIVE: To determine the serum nitric oxide levels in healthy neonates and in infants with bacteremia. METHODS: We performed a prospective study in a tertiary neonatal intensive care unit. The serum nitric oxide levels were measured in all infants at birth (basal) and in the infected neonates also on the first 2 days of bacteremia. RESULTS: Thirty-three neonates (10 term, 23 preterm) were included. Eleven preterm infants (mean gestational age 27 weeks) had bacteremia. The main blood culture isolates included coagulase-negative staphylococci (n=4), Klebsiella pneumoniae (n=3), and Escherichia coli (n=3). The serum nitric oxide levels increased during infection in 10 infants (p <0.008). The mean nitric oxide level before infection was 44 microM and during infection 96 microM (p=0.008). In the healthy babies, the mean nitric oxide level was 26 microM in those with a gestational age <27 weeks, 44 microM in those born between 28 and 36 weeks of gestation, and 63 microM in term infants. CONCLUSIONS: Bacteremic preterm infants produce significantly higher amounts of nitric oxide. The basal nitric oxide levels at birth may be correlated with gestational age.     

Nitric oxide production during the early neonatal period in small-for-gestational-age infants

In a study of endogenous nitric oxide production in growth-retarded, very preterm newborns (<32 wk GA), urinary NOx/creatinine ratio and plasma guanosine 3',5'-cyclic monophosphate levels were determined during the early neonatal period. Newborns were divided into three groups: appropriate-for-gestational-age (AGA, n = 19), moderately small-for-gestational-age (SGA, n = 13) and severely SGA (n = 6) infants. Severely SGA infants showed significant higher values of nitric oxide derivatives during the first 24 h of life compared with the other groups. CONCLUSION: An increased NO production is found in SGA infants during the first 24 h after birth. This may reflect an increased intrauterine nitric oxide production in the feto-placental circulation found in cases with intrauterine growth retardation,     

Exhaled nitric oxide in healthy children: Variability and a lack of correlation with atopy

Nitric oxide (NO) is a free radical produced by several lung cells via the enzyme nitric oxide synthetase (NOS) and can be easily measured in exhaled air by chemiluminescence analysis. As the iso-enzyme iNOS may be induced by cytokines and endotoxin, NO is elevated in several chronic inflammatory airway diseases. Prior to using exhaled nitric oxide (eNO) as a non-invasive marker of airway inflammation in daily routine, the role of possibly influencing factors such as age, time of the day, smoking exposure and intra-individual variability have to be clarified. NO concentrations were measured in 107 healthy children aged 4–18 years at an expiratory flow of 184 ml/s. Spirometry and a skin-prick test were performed and a questionnaire on family history of atopy, personal symptoms of atopic disease and smoke exposure was completed. For intra-individual variability nitric oxide was measured in six children three times daily on 6 consecutive days. Median eNO concentration was 5.7 p.p.b., and increased significantly with age but did not vary with gender. No correlation was found between eNO and smoke exposure, positive skin-prick test, FEV ₁, MEF₂₅ and time of the day. There was no circadian rhythm found in the six children measured on 6 consecutive days, but the eNO showed an intra-individual coefficient of variation of 25.9%. With the help of a two-compartment model of the lung the alveolar NO concentration was estimated to be 4.1 p.p.b and was shown to be constant with age, whereas the airway part of NO steadily increased with age. When comparing eNO values with standardized measurement techniques, the age of the children and the large intra-subject coefficient of variation have to be taken into account, whereas in healthy children subject-specific factors such as atopic history, gender and skin test reactivity did not affect eNO measurement.     

Exhaled and nasal nitric oxide in mechanically ventilated preterm and term newborns

AIM: Nitric oxide (NO) is an important mediator required for neonatal pulmonary circulatory adaptation and for pulmonary defence. Both deficient and excessive NO production have been proposed to play a role in neonatal lung disease. This study aimed to establish a method that allows direct measurement of exhaled and nasal NO concentrations in newborn infants who require intubation and ventilation. METHODS: A rapid-response chemiluminescence NO analyser was used. Gas was sampled from the endotracheal intubation tube, and tidal volumes and flow rates were measured. The nasal NO was sampled from the non-intubated nostril. The accuracy of the method was validated using a lung model. NO levels from six preterm and six term/near-term newborns were studied. Measurements were performed on a daily basis during the first week. RESULTS: An expiration >0.2 s in duration with a flow rate >1.7 ml s(-1) could be accurately analysed for the presence of >1 parts per billion of NO. The very preterm infants with neonatal lung disease had a different postnatal NO output pattern from the lower and upper airways compared with the ventilated term/near-term infants. CONCLUSION: A novel method for measurement of exhaled NO of an intubated newborn is presented. The possible association of exhaled NO concentration with the development of chronic lung disease remains to be studied.     

A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma

This study was conducted to investigate whether a single dose of nebulized budesonide effectively decreased airway inflammation as demonstrated by exhaled nitric oxide (eNO) levels. A single dose of nebulized budesonide, but not nebulized terbutaline, rapidly decreased eNO levels in 6 hours. The decrease in eNO levels induced by nebulized budesonide was correlated to an increase in peak expiratory flow rate.     

从美国胸科学会指南看呼出气一氧化氮测定的临床应用

近年来,随着对呼出气一氧化氮研究的增多,学术界对其临床应用价值的认识逐渐清晰。呼出气一氧化氮的测定已经标准化,但在实际临床工作中,如何在不同情况下选择使用此技术和解读其测定结果,很多医师仍感到困惑。美国胸科学会制定的关于呼出气一氧化氮临床应用的指南对有关问题进行了详细阐述,并给出了具体推荐意见。呼出气一氧化氮测定可用于确定嗜酸粒细胞性气道炎症,协助诊断哮喘,预测吸入皮质激素治疗的有效性,监测气道炎症状况。     

健康儿童呼出气体一氧化氮水平及其与肺功能相关性研究

目的 测定健康儿童呼出气体一氧化氮(eNO)浓度及其与肺功能的相关性.方法 随机测定100名7～8岁健康儿童(男53名;7岁43名)eNO及肺功能,采用SAS(8.2版)软件进行秩相关分析.结果 受试儿童eNO水平[中位数(四分位数间距)为8×10-9[(6～11)×10-9],其中男8×10-9[(6～11)×10-9],女8×10-9[(6～11)×10-9].eNO与肺功能无相关性(复相关系数r=0.22,P=0.32).eNO与身高、体质量有明显的相关性(r=0.22,P=0.03;r=0.23,P=0.02).结论 健康儿童eNO与肺功能无相关性.eNO与肺功能联合检测可全面认识气道炎症和气道高反应性.     

Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome

AIM: To test the hypothesis that inhaled nitric oxide therapy can decrease the incidence of bronchopulmonary dysplasia and death in preterm infants with severe respiratory distress syndrome; to evaluate the possible predictive factors for the response to inhaled nitric oxide therapy. METHODS: Preterm infants (less than 30 weeks' gestation) were randomized to receive during the first week of life inhaled nitric oxide, or nothing, if they presented severe respiratory distress syndrome. Then, the treated infants were classified as non responders and responders. RESULTS: Twenty infants were enrolled in the inhaled nitric oxide therapy group and 20 in the control group. Bronchopulmonary dysplasia and death were less frequent in the inhaled nitric oxide group than in the control group (50 vs. 90%, p=0.016). Moreover, nitric oxide treatment was found to decrease as independent factor the combined incidence of death and BPD (OR=0.111; 95% C.I. 0.02-0.610). A birth weight lower than 750 grams had a significant predictive value for the failure of responding to inhaled nitric oxide therapy (OR 12; 95% C.I. 1.3-13.3). CONCLUSION: Inhaled nitric oxide decreases the incidence of bronchopulmonary dysplasia and death in preterm infants with severe respiratory distress syndrome. Birth weight may influence the effectiveness of inhaled nitric oxide therapy in promoting oxygenation improvement in preterm infants.     

Urinary metabolites of oxidative stress and nitric oxide in preterm and term infants

BACKGROUND: Many neonatal diseases have been associated with oxidative stress and altered nitric oxide status. OBJECTIVE: To determine the effects of clinical interventions on the levels of urinary peroxides, a marker of oxidative stress, and urinary nitrate/nitrites, indices of nitric oxide production and metabolism, in the first 72 h of life in premature infants. METHODS: A single, spot urine sample was collected from 82 premature and 20 healthy term infants within the first 72 h of life. The peroxide levels were quantified using a fluorometric method, and nitrate/nitrite levels were quantified by chemiluminescence. RESULTS: Premature infants had a median peroxide level of 10.0 micromol/mmol creatinine (Cr) (interquartile range 4.8-20.0 micromol/mmol Cr). These values were significantly higher than term infants (median 5.0 micromol/mmol Cr, interquartile range 2.7-10.0 micromol/mmol Cr). Urinary nitrate/nitrite levels were not significantly different between preterm (220.5 micromol/mmol Cr, interquartile range 161-287 micromol/mmol Cr) and healthy term infants (244 micromol/mmol Cr, interquartile range 194-316 micromol/mmol Cr). For urinary peroxides, infants on TPN had significantly higher urinary peroxide levels than infants who were not on TPN at the time of urine collection (p = 0.006). Administration of indomethacin was associated with lower levels of urinary nitrate/nitrites (p = 0.0003). Both effects remained significant after controlling for gestational age, degree of respiratory distress and day of urine collection. CONCLUSION: Monitoring the level of both peroxides and nitrate/nitrite may offer added information about the degree of oxidative stress experienced by a newborn but needs to account for clinical and therapeutic interventions.     

Intestinal permeability in relation to birth weight and gestational and postnatal age

OBJECTIVE: To determine the relation between intestinal permeability and birth weight, gestational age, postnatal age, and perinatal risk factors in neonates. STUDY DESIGN: Intestinal permeability was measured by the sugar absorption test within two days of birth and three to six days later in preterm and healthy term infants. In the sugar absorption test, the urinary lactulose/mannitol ratio is measured after oral ingestion of a solution (375 mosm) of lactulose and mannitol. RESULTS: A first sugar absorption test was performed in 116 preterm (26-36 weeks gestation) and 16 term infants. A second test was performed in 102 preterm and nine term infants. In the preterm infants, the lactulose/mannitol ratio was not related to gestational age (r = -0.09, p = 0.32) or birth weight (r = 0.07, p = 0.43). The median lactulose/mannitol ratio was higher if measured less than two days after birth than when measured three to six days later (0.427 and 0.182 respectively, p<0.001). The lactulose/mannitol ratio was higher in preterm infants than term infants if measured within the first 2 days of life (0.404 and 0.170 respectively, p < 0.001), but not different three to six days later (0.182 and 0.123 respectively, p = 0.08). In multiple regression analysis of perinatal risk factors, only umbilical arterial pH correlated with the lactulose/mannitol ratio in preterm infants less than 2 days of age (T = -1.98, p = 0.05). CONCLUSIONS: In preterm infants (26-36 weeks gestation), intestinal permeability is not related to gestational age or birth weight but is higher during the first 2 days of life than three to six days later. It is higher in preterm infants than in healthy term infants only if measured within two days of birth. This suggests rapid postnatal adaptation of the small intestine in preterm infants.     

Exhaled nitric oxide in chronically ventilated preterm infants

Exhaled nitric oxide (eNO) levels were measured in eight ventilated infants, mean gestational age 25.8 (SD 1.7) weeks and postnatal age 55 (SD 39) days, before and after three days of dexamethasone treatment. The eNO levels fell from a mean of 6.5 (SD 3.4) to 4.2 (SD 2.6) parts per billion (p = 0.031) and the mean supplementary oxygen levels from 62% to 45% (p = 0.0078).     

Role of nitric oxide in neonatology

Nitric oxide has many roles in the body, but one major function is regulation of vascular tone. The discovery of this function in 1987 offered many therapeutic opportunities for mature and premature babies with significant lung disease. However clinical studies have produced different results in these two groups of babies. Term or near-term infants with hypoxic respiratory failure, despite standard intensive care support, should have a trial of inhaled nitric oxide. The situation is less clear with preterm infants. The evidence so far suggests that there is no role for short-term use of inhaled nitric oxide as an effective rescue therapy for very preterm infants with profound respiratory failure. In contrast, less ill preterm infants may benefit from nitric oxide, both in the short and over the long term.     

Exhaled nitric oxide levels in infants with chronic lung disease

Chronic lung disease (CLD) is an inflammatory disorder; in patients with other inflammatory disorders exhaled nitric oxide (NO) levels are elevated. The aim of this study was to test the hypothesis that prematurely born infants with CLD would have elevated exhaled NO levels compared to those without CLD and healthy term-born infants. Ten infants with CLD (median gestational age 26 weeks; CLD group), ten infants without CLD (median gestational age 32 weeks; non-CLD group) and ten term-born infants (term group) were examined at post-conceptional ages between 36 and 45 weeks. NO levels were measured during spontaneous tidal breathing. A facemask was positioned over the infants nose and mouth and a sampling catheter was inserted through a small leak-free valve into the facemask. To measure nasal NO, the tip of the sampling catheter was placed in the nasal space and to measure facemask NO, the catheter tip was positioned inside the facemask at the infants lips. Nasal compared to facemask NO levels were higher in all three groups (CLD; non-CLD; term: P =0.017, P =0.012 and P =0.017, respectively). The CLD group had higher peak nasal and facemask NO levels than the non-CLD ( P =0.011 and P =0.034 respectively) and the term ( P =0.005 and P =0.01 respectively) infants. Regression analysis demonstrated that facemask NO levels were significantly related to CLD, independent of gestational, post-natal and post-conceptional age ( P =0.006). Conclusion:our results suggest that exhaled nitric oxide levels are elevated in chronic lung disease infants. Facemask measurement of nitric oxide levels might be a potentially useful method to monitor infants with chronic lung disease.Abbreviations CLD chronic lung disease - NO nitric oxide     

Assessment of skeletal development in preterm and term infants by quantitative ultrasound

Assessment of skeletal development using a nonionizing method would be desirable in critically ill preterm infants. We investigated the second metacarpus by quantitative ultrasound (QUS). Cross-sectional data were collected in 132 preterm or term infants measured within 24 h from birth and in 142 term infants up to the age of 18 mo. Longitudinal data were collected in 150 preterm infants up to the age of 14 mo. Cross-sectional data were used to devise reference curves for metacarpal speed of sound (mcSOS) and metacarpal bone transmission time (mcBTT). Both parameters increase during the last trimester of gestation. After birth, mcSOS declines up to the 6 mo and then increases up to 18 mo of life. McBTT values remain stable after birth. At birth, QUS values of preterm infants are lower than those observed at birth in term infants. In the longitudinal study, mcSOS showed a trend similar to that observed among term infants, nevertheless, values are lower up to 4-6 mo of life. Among preterm infants, mcBTT increases until it reaches values observed in term infants. Preterm infants in their first months of life have lower QUS values compared with term infants of same weight or length. This study demonstrates that it is possible to follow skeletal development and maturation by QUS in preterm infants. More specifically, the mcBTT values may provide information on bone tissue that is independent of length and weight of the preterm infant. The method here described is safe, repeatable, and reliable.     

Effect of postnatal age and clinical status of newborn infants on bilirubin-binding capacity

Serial determinations of bilirubin-binding capacity were performed in 61 newborn infants during the first 10 days of life. 27 infants were classified as term (gestational age greater than or equal to 36 weeks) and 34 as preterm (gestational age less than or equal to 33 weeks); 34 were classified as 'sick' and 27 as 'well'. Bilirubin-binding capacity was measured by Sephadex gel filtration. In relation to postnatal age, total bilirubin-binding capacity (TBBC) remained stable in well term and preterm infants, decreased slightly in sick preterm infants, and decreased significantly in sick term infants. TBBC, serum albumin, and molr binding ratio (B/A) were significantly higher in well than in sick infants in both term and preterm groups; there were no significant differences between sick term and sick preterm infants. Clinical recovery in 16 infants was associated with a significant rise in TBBC and in B/A. The data suggest that in healthy infants, the serum bilirubin-binding capacity remains relatively unchanged during the first 10 days of life. Clinically ill infants show wide patient-to-patient variability in TBBC. Because of the tendency of TBBC to decrease with postnatal age in sick infants, repeated determinations of TBBC may be indicated for the management of sick jaudiced newborns.     

The influence of gestation and mechanical ventilation on serum clara cell secretory protein (CC10) concentrations in ventilated and nonventilated newborn infants

Clara cell secretory protein (CC10) is an important anti-inflammatory mediator in the adult lung, but its role in newborn pulmonary protection is uncertain. We examined the early postnatal behavior of CC10 in newborn serum and tracheal fluid and hypothesized that CC10 production is positively influenced by gestation. Blood from 165 infants from the first, third/fourth, and seventh days of life (gestational ages: 23-29 wk, 30-36 wk, >36 wk) and tracheal fluid (TF) from the first day of life from 32 ventilated infants were analyzed for CC10. Surfactant proteins A (SPA) and B (SPB) were also analyzed from the blood of a subgroup of infants. Serum CC10 on day 1 was highest in term infants (69.4 ng/mL), followed by moderately preterm (55.8 ng/mL), and then extremely preterm infants (median 42.1 ng/mL). Term infants also had higher tracheal fluid CC10 than preterm infants. (20.152 ng/mL versus 882 ng/mL). Mechanical ventilation increased serum CC10 only in moderately preterm infants, and only on d 1 [68.4 ng/mL versus 42.1 ng/mL (nonventilated moderately preterm infants)]. Serum CC10 decreased progressively by the end of the first week in all infants, in contrast to SPA and SPB, which increased. Our results show that CC10 is detectable in the blood of newborn infants and that a production surge occurs at birth. This surge is more pronounced in term infants and may confer them with superior extrauterine pulmonary protection compared with preterm infants.     

Plasma homocysteine concentrations of preterm infants.

Mild hyperhomocysteinemia in adults is associated with an increased risk of vascular disease. Although information is available about plasma homocysteine concentrations in childhood, data are entirely lacking for preterm infants despite their known abnormalities of sulfur amino acid metabolism. We measured plasma total homocysteine concentrations of 9 preterm infants (gestational age 23-31 weeks) within 48 h of birth and over the subsequent 14 days of life, and 4 term infants (gestational age 36-39 weeks) on a single occasion within 72 h of birth. As measured within 48 h of birth, average plasma homocysteine and cysteine concentrations of the preterm infants were 3.8 +/- 0.3 and 122 +/- 8 microM, both significantly less than those of the term infants (6.1 +/- 1.3 and 187 +/- 39) and of normal adults (8.2 +/- 0.5 and 232 +/- 6). Plasma homocysteine (but not cysteine) appeared to gradually increase during the first 2 weeks of life (p = 0.053). Our results indicate that hyperhomocysteinemia does not normally occur in preterm infants.     

Intact parathyroid hormone levels during pregnancy, in healthy term neonates and in hypocalcemic preterm infants

We measured parathyroid hormone levels in pregnant and nonpregnant women and at 1, 2 and 5 days of life in healthy term neonates and in hypocalcemic preterm infants using a new immunoradiometric assay which measures only biologically active intact parathyroid hormone and by a mid-molecule parathyroid hormone radioimmunoassay. During pregnancy intact and mid-molecule parathyroid hormone levels did not show any modification and were not different from parathyroid hormone levels of nonpregnant age-matched controls. Serum calcium and phosphorus levels did not vary during each trimester of pregnancy. In cord serum intact and mid-molecule parathyroid hormone values were low in both term and preterm infants. In term neonates intact and mid-molecule parathyroid hormone levels peaked on day 1; in preterm infants intact parathyroid hormone levels peaked on day 1 while mid-molecule parathyroid hormone values peaked on day 2. Intact parathyroid hormone levels showed a more marked increase in preterm (19-fold) than in term neonates (7.5-fold) on day 1. Our data do not confirm the previously reported "physiologic" hyperparathyroidism in pregnancy. Moreover we found a normal parathyroid gland responsiveness to decreasing serum calcium levels in the first days of life in term and preterm infants. Our results suggest that measurement of intact parathyroid hormone 1-84 by immunoradiometric assay in the first days of life is a more sensitive index of parathyroid gland secretory function than the measurement of middle or carboxyl-terminal parathyroid hormone fragments allowing the detection of the dynamic changes of parathyroid hormone which occur in hypocalcemic preterm infants.     

Intact Parathyroid Hormone Levels during Pregnancy, in Healthy Term Neonates and in Hypocalcemic Preterm Infants

ABSTRACT. We measured parathyroid hormone levels in pregnant and nonpregnant women and at 1, 2 and 5 days of life in healthy term neonates and in hypocalcemic preterm infants using a new immunoradiometric assay which measures only biologically active intact parathyroid hormone and by a mid-molecule parathyroid hormone radioimmunoassay. During pregnancy intact and mid-molecule parathyroid hormone levels did not show any modification and were not different from parathyroid hormone levels of nonpregnant age-matched controls. Serum calcium and phosphorus levels did not vary during each trimester of pregnancy. In cord serum intact and mid-molecule parathyroid hormone values were low in both term and preterm infants. In term neonates intact and mid-molecule parathyroid hormone levels peaked on day 1; in preterm infants intact parathyroid hormone levels peaked on day 1 while mid-molecule parathyroid hormone values peaked on day 2. Intact parathyroid hormone levels showed a more marked increase in preterm (19-fold) than in term neonates (7.5-fold) on day 1. Our data do not confirm the previously reported "physiologic" hyperparathyroidism in pregnancy. Moreover we found a normal parathyroid gland responsiveness to decreasing serum calcium levels in the first days of life in term and preterm infants. Our results suggest that measurement of intact parathyroid hormone 1-84 by immunoradiometric assay in the first days of life is a more sensitive index of parathyroid gland secretory function than the measurement of middle or carboxyl-terminal parathyroid hormone fragments allowing the detection of the dynamic changes of parathyroid hormone which occur in hypocalcemic preterm infants.     

Growth and body composition in preterm infants with bronchopulmonary dysplasia

OBJECTIVE: To compare growth and body composition in preterm infants with bronchopulmonary dysplasia (BPD) with normal healthy term infants during the first year of life. DESIGN: Twenty nine preterm infants with BPD (mean (SD) gestational age 27.1 (1.6) weeks; birth weight 852 (173) g) were followed prospectively. Anthropometry and body composition determined by total body electrical conductivity were measured and compared with those of healthy term infants at the same post-term age. RESULTS: In infants with BPD, the mean weight standard deviation scores (SD scores) 6 weeks after term were significantly lower (-1.44 and -2.68, boys and girls respectively) than in healthy term infants of the same age and did not improve during the first year. The mean length SD score was significantly lower in infants with BPD 6 weeks after term than in healthy term infants of the same age, and, although it improved significantly during the first year, the mean length SD score in girls with BPD was significantly below 0 12 months after term. In infants with BPD, the mean free fat mass (FFM) SD score and the mean total body fat (TBF) SD score at 6 weeks post-term age were significantly below 0. The mean FFM SD scores (-1.01 and -2.56, boys and girls respectively) and the mean TBF SD scores (-1.14 and -2.40, boys and girls respectively) 12 months after term were significantly lower than in healthy term infants of the same age. CONCLUSIONS: Preterm infants with BPD have impaired growth, with a deficit in TBF and FFM already 6 weeks after term; FFM and TBF remain low compared with healthy term infants during the first year of life. Nutritional intervention studies in infants with BPD are needed to evaluate if nutrition is the major determinant of growth and body composition or if this pattern of growth in preterm infants with BPD is the result of disturbed endocrine control.