Search

Secondary hyperparathyroidism (SHPT) is a rare complication of furosemide therapy that can occur in patients treated with the loop diuretic for a long period of time. We report a 6-month-old 28-weeks premature infant treated chronically with furosemide for his bronchopulmonary dysplasia, who developed hypocalcemia and severe SHPT, adversely affecting his bones. Discontinuation of the loop diuretic and the addition of supplemental calcium and calcitriol only partially reversed the SHPT, bringing serum parathyroid hormone level down from 553 to 238 pg/mL. After introduction of the calcimimetic Cinacalcet, we observed a sustained normalization of parathyroid hormone concentration at 27 to 63 pg/mL and, with that correction, of all biochemical abnormalities and healing of the bone disease. No adverse effects were noted. We conclude that in cases of SHPT due to furosemide in which traditional treatment fails, there may be room to consider the addition of a calcimimetic agent.

OBJECTIVES. Inhaled nitric oxide treatment for ventilated premature infants improves survival without bronchopulmonary dysplasia. However, there has been no information regarding possible effects of this therapy on oxidative stress. We hypothesized that inhaled nitric oxide therapy would not influence concentrations of plasma biomarkers of oxidative stress. PATIENTS AND METHODS. As part of the Nitric Oxide Chronic Lung Disease Trial, we collected blood samples at specified intervals from a subpopulation of 100 infants of RESULTS. The demographic characteristics and primary outcome for the infants were representative of the entire group of infants who were in the Nitric Oxide Chronic Lung Disease Trial. For all infants at baseline, before receiving study gas, the concentration of total protein was inversely correlated with the respiratory severity score, and plasma carbonyl was positively correlated with severity score, supporting an association between oxidative stress and severity of lung disease. Infants who survived without bronchopulmonary dysplasia had 30% lower protein carbonylation concentrations at study entry than those who had an adverse outcome. At each of 3 time points (1–10 days) during exposure to study gas, there were no significant differences between control and treated infants for concentrations of plasma protein, 3-nitrotyrosine, and carbonylation. CONCLUSIONS. Inhaled nitric oxide treatment for premature infants who are at risk for bronchopulmonary dysplasia does not alter plasma biomarkers of oxidative stress, which supports the safety of this therapy.

OBJECTIVE. We compared serial measurements of inflammatory mediators and markers in infants treated with inhaled nitric oxide or placebo to assess the effects of inhaled nitric oxide therapy on lung inflammation during bronchopulmonary dysplasia. We investigated relationships between respiratory severity scores and airway concentrations of inflammatory markers/mediators.METHODS. As part of the Nitric Oxide (to Prevent) Chronic Lung Disease trial, a subset of 99 infants (52 placebo-treated infants and 47 inhaled nitric oxide-treated infants; well matched at baseline) had tracheal aspirate fluid collected at baseline, at 2 to 4 days, and then weekly while still intubated during study gas treatment (minimum of 24 days). Fluid was assessed for interleukin-1β, interleukin-8, transforming growth factor-β, N-acetylglucosaminidase, 8-epi-prostaglandin F2α, and hyaluronan. Results were normalized to total protein and secretory component of immunoglobulin A.RESULTS. At baseline, there was substantial variability of each measured substance and no correlation between tracheal aspirate fluid levels of any substance and respiratory severity scores. Inhaled nitric oxide administration did not result in any time-matched significant change for any of the analytes, compared with the placebo-treated group. There was no correlation between any of the measured markers/mediators and respiratory severity scores throughout the 24 days of study gas administration. In the posthoc analysis of data for inhaled nitric oxide-treated infants, there was a difference at baseline in 8-epi-prostaglandin F2α levels for infants who did (n = 21) and did not (n = 26) develop bronchopulmonary dysplasia at postmenstrual age of 36 weeks.CONCLUSIONS. Inhaled nitric oxide, as administered in this study, seemed to be safe. Its use was not associated with any increase in airway inflammatory substances.

Objective. The pathogenesis of chronic lung disease (CLD) involves inflammation with proteolytic damage to lung extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that, acting in concert with their tissue inhibitors, tightly orchestrate extracellular matrix morphogenesis and repair after injury. Imbalances in their levels relative to that of their inhibitors have been implicated in diseases characterized by matrix disruption and remodeling. We investigated the possibility that imbalances in MMP-9 and MMP-2 relative to their tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, respectively, in tracheal aspirates of preterm infants may be involved in the development of CLD.Methods. Serial tracheal aspirates collected from birth until extubation in 49 ventilated preterm infants (24-32 weeks’ gestations) were analyzed for MMP-2, MMP-9, TIMP-1, and TIMP-2. Data normalized by TA values of free secretory component of immunoglobulin A were compared for CLD (n = 22) versus no CLD (n = 27). Also, known clinical predictors of CLD (gestational age, birth weight, and sex) were assessed for both groups. Association of predictors with the outcome CLD was assessed by logistic regression.Results. Mean gestational age was lower in CLD infants, but birth weight and gender were comparable for both groups. CLD infants had significantly lower TIMP-1 level with higher MMP-9/TIMP-1 ratio during the first 2 weeks of life and low TIMP-2 and MMP-2 levels during the first 3 days of life compared with no-CLD infants. Logistic regression analysis indicated that the findings are predictive of CLD.Conclusions. We conclude that low tracheal aspirate levels of TIMPs, with a high MMP-9/TIMP-1 ratio early in life, are associated with subsequent development of CLD.

OBJECTIVE: In the previously reported Nitric Oxide for Chronic Lung Disease (NO CLD) trial, ventilated preterm infants who received a course of inhaled nitric oxide (iNO) between 7 and 21 days of life had a significant improvement in survival without bronchopulmonary dysplasia (BPD), as well as a shorter duration of admission and ventilation. However, the price for the drug may be a barrier to widespread use. We sought to estimate the incremental cost-effectiveness of iNO therapy to prevent BPD in infants of METHODS: We used patient-level data from the NO CLD randomized trial. The study took a third-party payer perspective and measured costs and effects through hospital discharge. We applied previously reported hospital per-diem costs stratified according to intensity of ventilatory support, nitric oxide costs from standard market prices, and professional (physician) fees from the Medicare fee schedule. We compared log transformed costs by using multivariable modeling and performed incremental cost-effectiveness analysis with estimation of uncertainty through nonparametric bootstrapping. RESULTS: The mean cost per infant was $193125 in the placebo group and $194702 in the iNO group (adjusted P = .17). The point estimate for the incremental cost per additional survivor without BPD was $21297. For infants in whom iNO was initiated between 7 and 14 days of life, the mean cost per infant was $187407 in the placebo group and $181525 in the iNO group (adjusted P = .46). In this group of early treated infants, there was a 71% probability that iNO actually decreased costs while improving outcomes. CONCLUSIONS: Despite its higher price relative to many other neonatal therapies, iNO in this trial was not associated with higher costs of care, an effect that is likely due to its impact on length of stay and ventilation. Indeed, for infants who receive nitric oxide between 7 and 14 days of life, the therapy seemed to lower costs while improving outcomes.

Bronchopulmonary dysplasia is a chronic, sometimes fatal lung disease, which primarily affects premature infants and often leads to a dependence on mechanical ventilation lasting many months. To identify prognostic factors of mortality at 1 and 2 months of age, the authors reviewed the medical records of the 144 neonates admitted to two neonatal intensive care units in Seattle from January 1, 1986, through December 31, 1988, who required mechanical ventilation throughout the first month of life. Likely predictors of mortality were tested by logistic regression analysis. The calculated mean airway pressure at 30 days of age (MAP30) and the diagnosis of bacterial sepsis at any time during the first month of life (Bact0-30) were statistically significant predictors of mortality (P < .001 and P = .018, respectively) and had the lowest deviance in the regression model. The probability of mortality was estimated by 1/(1 + e-x, where x = -6.510 + 0.4588 (MAP30) + 1.475 (Bact0-30), and where MAP30 is expressed as centimeters of water pressure (1 cm H2O = 0.0978 kPa) and the presence or absence of bacteremia is 1 and 0, respectively. The records of the 57 infants who still required mechanical ventilation at 60 days of age were reanalyzed with clinical data available during the first 2 months of life. Mean airway pressure (MAP60) and the fraction of inspired oxygen (F60) at 60 days of age combined to form the best predictors of mortality, where x = -7.668 + 0.2940 (MAP60) + 5.935 (F60). The occurrence of bacterial sepsis during the first 2 months of life, the degree of hypochloremia, and the duration of chronic sedative use were also significant predictors of survival, even controlling of MAP60 and F60. These regression equations allow more accurate estimation of the likelihood of survival for chronically ventilated infants and may facilitate decisions regarding withdrawal or continuation of life support.

OBJECTIVES. We hypothesized that inhaled nitric oxide treatment of premature infants at risk for bronchopulmonary dysplasia would not adversely affect endogenous surfactant function or composition.METHODS. As part of the Nitric Oxide Chronic Lung Disease Trial of inhaled nitric oxide, we examined surfactant in a subpopulation of enrolled infants. Tracheal aspirate fluid was collected at specified intervals from 99 infants with birth weights RESULTS. At baseline, before administration of study gas, surfactant function and composition were comparable in the 2 groups, and there was a positive correlation between minimum surface tension and severity of lung disease for all infants. Over the first 4 days of treatment, minimum surface tension increased in placebo-treated infants and decreased in inhaled nitric oxide–treated infants. There were no significant differences between groups in recovery of large-aggregate surfactant or contents of surfactant protein A, surfactant protein B, surfactant protein C, or total protein, normalized to phospholipid.CONCLUSIONS. We conclude that inhaled nitric oxide treatment for premature infants at risk of bronchopulmonary dysplasia does not alter surfactant recovery or protein composition and may improve surfactant function transiently.

BACKGROUND. Nitric oxide mediates and modulates pulmonary transition from fetal to postnatal life. NO is synthesized by 3 nitric oxide synthase isoforms. One key pathway of nitric oxide metabolism results in nitrotyrosine, a stable, measurable marker of nitric oxide production. OBJECTIVE. The purpose of this study was to assess, by semiquantitative immunohistochemistry, nitric oxide synthase isoforms and nitrotyrosine at different airway and vascular tree levels in the lungs of neonates at different gestational ages and to compare results in control groups to those in infants with chronic lung disease. DESIGN/METHODS. Formalin-fixed, paraffin-embedded, postmortem lung blocks were prepared for immunohistochemistry using antibodies to each nitric oxide synthase isoform and to nitrotyrosine. Blinded observers evaluated the airway and vascular trees for staining intensity (0–3 scale) at 5 levels and 3 levels, respectively. The control population consisted of infants from 22 to 42 weeks' gestation who died in RESULTS. In control and chronic lung disease groups, 22 to 42 weeks' gestation, staining for all 3 of the nitric oxide synthase isoforms was found in the airway epithelium from the bronchus to the alveolus or distal-most airspace. The abundance or distribution of nitric oxide synthase-3 staining in the airways did not show significant correlation with gestational age or severity of chronic lung disease. In the vascular tree, intense nitric oxide synthase-3 and moderate nitric oxide synthase-2 staining was found; nitric oxide synthase-1 was not consistently stained. Nitrotyrosine did stain in the pulmonary tree. Compared with controls where nitrotyrosine staining was minimal, regardless of gestation, in infants with chronic lung disease there was more than fourfold increase between severe chronic lung disease (n = 12) and either mild chronic lung disease or control infants (n = 16). CONCLUSIONS. All 3 of the nitric oxide synthase isoforms and nitrotyrosine are detectable by immunohistochemistry early in lung development. Nitric oxide synthase ontogeny shows no significant changes in abundance or distribution with advancing gestational age nor with chronic lung disease. Nitrotyrosine is significantly increased in severe chronic lung disease.

Objective. Infants with chronic lung disease (CLD) have an arrest of primary and secondary septation. We hypothesized that this may be related to damage or abnormal development of lung collagen secondary to positive pressure ventilation. Our aims were to identify the sites and quantity of collagen in control infants 22 to 72 weeks’ postconceptional age and compare these with infants with various degrees of severity of CLD. Methods. The controls were 22 to 42 weeks’ gestation (n = 30), received minimal ventilator care, and died within 48 hours of birth, plus 5 term infants who died at 43 to 72 weeks’ postconceptional age from nonpulmonary causes. Infants who were 23 to 30 weeks’ gestation, were at risk for CLD, and lived 5 to 94 days (n = 33) were separated into 3 groups on the basis of respiratory score (score group; the integrated area under the curve of the average daily fraction of inspired oxygen × mean airway pressure [cm H2O] over the number of days lived). The score groups, Results. In the controls, the volume density of collagen decreased from a maximum of 9% at 22 weeks to 5% at term and 72 weeks. With Scores ≤69, the fraction of collagen was similar to controls, but in infants with scores 70 to 500, it was increased relative to controls. However, when collagen was expressed as the volume density of interstitial tissue, ie, excluding parenchymal air space, it increased from a low of 5% at 22 weeks to 25% at 72 weeks. In infants with scores 70 to 500, 79% of infants had collagens greater than controls. Saccular and alveolar diameter increased from 40 μm at 23 weeks to 100 μm at 72 weeks. Most infants with severe CLD (scores ≥70) had diameters more than twice that of controls at the same age. The total lung parenchymal collagen had a similar pattern as the volume density of collagen in interstitial tissue, increasing from 0.4 cm3 at 23 weeks to 9.7 cm3 at 72 weeks in the controls. Eighty-five percent of infants with scores 70 to 500 had total parenchymal collagen greater than the 95% confidence interval of the controls. With en face sections, a fine collagen mesh was seen at 23 weeks, which progressively increased in fiber size and quantity until 72 weeks. With severe CLD, the secondary collagen fibers in the saccular wall were thickened, tortuous, and disorganized relative to same-aged controls. Under 30 weeks, in the controls, the interstitium contained a wide, delicate network of interconnected collagen fibers. After positive pressure ventilation, some saccules markedly increased their diameter, which compressed and obliterated the interstitial network. In contrast with severe CLD, the interstitium was wide, with coarse wavy collagen fibers. Conclusions. Parenchymal collagen increases throughout development. Before 30 weeks, there is a delicate complex interstitial collagen network, which may be important for primary septation and subsequent normal development. Positive pressure ventilation, if excessive, and depending on lung maturity and disease state, over a short time can severely compress the interstitium and damage this collagen network and prevent normal primary septation and arrest or distort future lung development. With severe CLD, distal air space diameter increases. There is a failure of primary and secondary septation, arrested lung development and remodeling, with thickened collagenous saccular walls, and a wide interstitium with increased quantity and size of collagen fibers that can affect the mechanics of ventilation. We conclude that normal lung development is dependent on a normal interstitium and, perhaps, collagen architecture and that origins of CLD begin early in the course of positive pressure ventilation.

Background. Infants Methods. The controls were 22 to 42 weeks' gestation (n = 71), received ventilator care, and died within 48 hours of birth, plus 7 term infants who died at 43 to 50 weeks' postconceptional age from nonpulmonary causes. Infants who were 23 to 30 weeks' gestation, at risk for CLD, and who lived 5 to 59 days (n = 44), were separated into groups based on respiratory score (SCORE; The integrated area under the curve of the average daily fraction of inspired oxygen × mean airway pressure (cm H2O) over the number of days lived). The SCORE groups, Results. In the controls, the volume density of parenchymal elastic tissue and absolute quantity of elastic tissue increased progressively from 22 to 50 weeks. In infants with CLD and SCORE ≥20, the volume density and absolute quantity of elastic tissue increased significantly. Mean absolute elastic tissue in the 20 to 69 group was 0.76 ± 0.20 cm3 greater than in the Discussion. Lung elastic tissue maturation is tightly controlled during fetal development. With increasing SCORE, elastic tissue increased >200%, accounting, in part, for the positive end-expiratory pressure needed to maintain end-expiratory lung volume in infants at risk for CLD. Saccule and duct diameters more than doubled, and septa thickened significantly in CLD. We propose the following sequence to be operative in CLD: at birth, the preterm infant (≤30 weeks) has inadequate elastic tissue and elastic recoil, but high surface tension recoil. After surfactant treatment, surface tension recoil markedly decreases, permitting the saccules and ducts, with very low elastic recoil, to be overstretched by volutrauma. The damaged lung responds with elastosis, distorted acinar growth, cellular influx, and upregulation of inflammatory and reparative proteins. This hypothesis can be summarized by the following terms: lung immaturity, inflammation, volutrauma, and elastic tissue alterations.

The modern era of surfactant-replacement therapy (SRT) is almost 30 years old. Capitalizing on the then-new understanding of surfactant composition and function,1 Fujiwara et al2 opened a new decade and a new era in neonatal medicine with their January 12, 1980, report in the Lancet . Their 10-patient phase II open-label single-center study demonstrated physiologic efficacy of exogenous bovine-derived surfactant in infants with respiratory distress syndrome (RDS). On the heels of this report, multiple studies followed. These studies included single-dose safety trials, efficacy trials, dose-ranging trials, and optimal timing trials, all aimed at preventing or treating RDS. Later trials sought to identify term and preterm infants with disorders other than RDS who might benefit from SRT. These later efforts met with more limited success.3–5 More recently, lucinactant, a synthetic surfactant containing a 21 amino acid peptide, sinapultide, has been tested against other surfactants in the management of RDS.6 Against this bright background of remarkable improvement in mortality rates for very low birth weight infants, the shadow of bronchopulmonary dysplasia (BPD) has lengthened. … Address correspondence to William E. Truog, MD, Children's Mercy Hospitals and Clinics, Section of Neonatology, Department of Pediatrics, 2401 Gillham Road, Kansas City, MO 64108. E-mail: wtruog{at}cmh.edu

To the Editor. — In their recent review article in Pediatrics , “Inhaled Nitric Oxide for Preterm Infants: A Systematic Review,”1 Barrington and Finer report on meta-analyses of nitric-oxide (NO) studies in premature infants. They include our NO CLD study2 as 1 of 2 studies testing the effect of inhaled NO (iNO) started beyond the first 3 days of life with the primary outcome of improving survival without bronchopulmonary dysplasia (BPD) measured at 36 weeks' postmenstrual age. In their article, Barrington and Finer stated that “[t]he study by Ballard et al reported a significant benefit of iNO in improving rates of survival without BPD. However, the figures given in the article (165 of 294 vs 182 of 288 patients) were not significant when RevMan software was used to calculate the [relative risk] and its CIs [confidence intervals] … or when SPSS software was used to perform a simple χ2 test … or unadjusted, logistic regression analysis. The reason for this discrepancy is not clear.” On the basis of this analysis, they stated in their abstract that “[l]ater use of inhaled nitric oxide to prevent …

* Abbreviations: NINOS = : Neonatal Inhaled Nitric Oxide Study Group • ECMO = : extracorporeal membrane oxygenation It is a rare event indeed in pediatrics when three important and well-designed reports, each describing a test of the same potentially life-saving new therapy for an important clinical syndrome, arrive in a single 7-month period. Such an exciting time frame has now been defined by the recent publication of Wessel et al,1 which follows closely the reports of Roberts et al2 and the Neonatal Inhaled Nitric Oxide Study Group (NINOS).3 These three studies jointly describe the role of inhaled nitric oxide in the treatment of neonatal respiratory disorders characterized by pulmonary hypertension. Because of the marked similarities in patient populations, in study design, and, not least, in outcomes, these three studies deserve close inspection and at least an attempt at integration of their results. Treatment of neonatal pulmonary hypertensive disorders, occurring either in association with pulmonary parenchymal disease or as isolated idiopathic disorders, has proven frustrating. From the original description of the syndrome of “persistent fetal circulation” (now persistent pulmonary hypertension of the newborn) in 19694to its more recent and complete characterization,5investigators have sought the Holy Grail of an agent capable of immediate, sustained, and selective reduction of elevated pulmonary vascular resistance. Many supportive approaches, including induction of an elevated arterial pH, administration of systemic vasopressor agents, and administration of nonspecific vasodilator agents (eg, prostacyclin or tolazoline) have been used. Results have been … Address correspondence to: William E. Truog, MD, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO 64108-9898.

Adult respiratory distress syndrome, commonly seen in adults, is not well recognized in children. A retrospective chart review was carried out to determine the relative incidence, predisposing conditions, clinical course, and outcome of children with adult respiratory distress syndrome. Fifteen patients were identified. The most common predisposing conditions were near-drowning and near-strangulation with a noticeable absence of major trauma. Mortality was 60%. Death was most often secondary to central nervous system complications. Air leak was the most common complication of treatment. Two of six survivors suffered major neurologic handicaps. Long-term pulmonary sequelae were minimal.

Chronic lung disease in prematurely born infants, defined as the need for increased inspired oxygen at 28 days of age, was thought to be more common in some institutions than in others. To test this hypothesis, we surveyed the experience in the intensive care nurseries at Columbia and Vanderbilt Universities, the Universities of Texas at Dallas, Washington at Seattle, and California at San Francisco, the Brigham and Women's Hospital in Boston, Texas Children's Hospital in Houston, and Mt Sinai Hospital in Toronto. The survey included 1,625 infants with birth weights of 700 to 1,500 g. We confirmed the relationship of risk to low birth weight, white race, and male sex. Significant differences in the incidence of chronic lung disease were found between institutions even when birth weight, race, and sex were taken into consideration through a multivariate logistic regression analysis. Columbia had one of the best outcomes for low birth weight infants and the lowest incidence of chronic lung disease.