Respiratory failure in a term infant with cis and trans mutations in ABCA3.

A full-term female neonate presented with persistent respiratory failure and radiologic studies consistent with surfactant deficiency. Sequencing of the ATP-binding cassette transporter A3 gene (ABCA3) revealed three mutations: R280C, V1399M and Q1589X. The infant underwent bilateral lung transplantation at 9 months of age and is alive at 3 years of age. Parental sequencing demonstrated that two of the mutations (R280C and Q1589X) were oriented on the same allele (cis), whereas V1399M was oriented on the opposite allele (trans). As more than one mutation in ABCA3 can be present on the same allele, parental studies are needed to determine allelic orientation to inform clinical decision making and future reproductive counseling.

Population-based estimates of surfactant protein B deficiency.

OBJECTIVE: Surfactant protein B deficiency is a lethal cause of respiratory distress in infancy that results most commonly from a homozygous frameshift mutation (121ins2). Using independent clinical ascertainment and molecular methods in different populations, we sought to determine allele frequency. STUDY DESIGN: Using clinical characteristics of the phenotype of affected infants, we screened the Missouri linked birth-death database (n = 1 052 544) to ascertain potentially affected infants. We used molecular amplification and restriction enzyme digestion of DNA samples from a metropolitan New York birth cohort (n = 6599) to estimate allele frequency. RESULTS: The point estimate and 95% confidence interval of the 121ins2 allele frequency in the Missouri cohort are 1/1000 individuals (.03-5.6/1000) and in the New York cohort are.15/1000 (. 08-.25/1000). These estimates are not statistically different. CONCLUSIONS: The close approximation of these independent estimates suggests accurate gene frequency (approximately one 121ins2 mutation per 1000-3000 individuals) despite its rare occurrence and that this mutation does not account for the majority of full-term infants with lethal respiratory distress.

The effects of regional pulmonary blood flow on protein flux measurements with PET.

We used PET to evaluate whether changes in regional pulmonary blood flow (PBF) or plasma volume (PV) affect calculations of the pulmonary transcapillary escape rate (PTCER) for 68Ga-labeled transferrin. We reduced PBF in five dogs by inflating a right atrial balloon. Regional PBF decreased 25% to 174 +/- 40 ml/min/100 ml lung without a change in PV or PTCER. In eight other dogs, we decreased PBF and PV via controlled arterial hemorrhage. PBF decreased 45% to 110 +/- 33 ml/min/100 ml lung and PV decreased 22% without a change in PTCER. We also used a series of computer simulations to evaluate the effect of even greater reductions in regional PBF on PTCER calculations. These simulations showed, in support of the experimental data, that if PBF was greater than 40 ml/min/100 ml lung, PTCER could be accurately measured. However, below this level, PV was increasingly under-estimated and PTCER overestimated. The results indicate the sensitivity of the PTCER calculation to errors in the PV measurement, especially in regions of markedly reduced regional PBF.

Lung transplantation in very young infants.

INTRODUCTION: Established successes with adult lung transplantation have laid the foundation for extension of this therapeutic modality to infants and children dying of end-stage pulmonary disease. The purpose of this report is to convey our experience with 19 infants undergoing lung transplantation before the age of 6 months. METHODS: Six patients with predominantly pulmonary vascular disease and 13 patients with primarily pulmonary parenchymal disease have undergone bilateral sequential lung transplantation at our institution since 1990. Mean age at transplant was 104 +/- 44 days, and mean weight was 4.9 +/- 1.6 kg. RESULTS: Although early mortality (32%, 6/19) was higher than that previously reported for older pediatric age groups, long-term survival was similar (44% at a maximum follow-up of 6 years). Although anastomotic complications and infections occurred at a rate approximating that seen in older pediatric age groups, episodes of acute rejection appear to occur with decreased frequency. Similarly, at a mean follow-up of 3 years, only 2 (15%) of 13 long-term survivors have evidence of bronchiolitis obliterans. The functional residual capacity, as measured on infant pulmonary function tests, has gradually increased as the children have grown, suggesting that lung growth is occurring. CONCLUSIONS: Bilateral lung transplantation is a viable alternative in infants dying of end-stage pulmonary disease. Efforts directed toward avoiding the complications that lead to early posttransplant mortality combined with the seemingly lower incidence of early and late rejection may provide long-term results better than those in other age groups.

Improving survival of vulnerable infants increases neonatal intensive care unit nosocomial infection rate.

OBJECTIVE: To determine the factors associated with an increasing rate of nosocomial infections in infants with very low birth weights. METHODS: Retrospective review of clinical and nosocomial infection databases for all infants with birth weights of 1500 g or less admitted to an academic neonatal intensive care unit between January 1, 1991, and December 31, 1997 (N = 1184). Two study periods were compared: 1991-1995 and 1996-1997. RESULTS: Among the 1085 infants who survived beyond 48 hours, the proportion who developed nosocomial infections increased from 22% to 31% (P =.001) and the infection rate increased from 0.5 to 0.8 per 100 patient-days (P<.001) during the period from 1996 to 1997. In that same period, the median duration of indwelling vascular access increased from 10 to 16 days (P<.001), and the median duration of mechanical ventilation increased from 7 to 12 days (P<.001). Although the device-specific rate of bloodstream or respiratory infections did not change, the increase in infections was directly attributable to the increasing proportion of infants who required these devices. In both study periods, the peak incidence of initial infection occurred between 10 and 20 days of age. For the entire sample, proportional hazard models identified birth weight, duration of vascular access, and postnatal corticosteroid exposure as significant contributors to the risk of infection. CONCLUSIONS: The increasing number of technology-dependent infants was the primary determinant in the increase of nosocomial infections. Because these infections occur in a small proportion of infants, understanding the host factors that contribute to this vulnerability is necessary to decrease nosocomial infections in neonatal intensive care units.

Bronchial and reverse pulmonary venous blood flow protect the lung from ischemia-reperfusion injury.

We used an intact in vivo canine model of pulmonary ischemia-reperfusion injury to evaluate whether the bronchial circulation or reverse pulmonary venous blood flow would protect the lung from injury during 2 h of unilateral pulmonary arterial (PA) occlusion and lung deflation. Serial measurements of regional extravascular density and transcapillary protein flux were made after reperfusion by using the quantitative imaging technique of positron emission tomography. Twenty-one animals were divided into four experimental groups. In all experimental groups, the left PA was clamped and the left lung was allowed to collapse and remain unventilated for a period of 2 h. In addition, in group I (n = 5) the left bronchial circulation was disrupted and the left pulmonary veins were clamped, in group II (n = 5) the bronchial circulation and the pulmonary veins were left intact, in group III (n = 6) the bronchial circulation was left intact but the pulmonary veins were clamped, and in group IV (n = 5) the bronchial circulation was disrupted but the pulmonary veins remained patent. The rate of protein flux in the left lung was increased only in group I (complete ischemia with lung deflation) [mean 195 x 10(-4) min-1 (range 85-453 x 10(-4) min-1) at 0.25 h and 114 x 10(-4) min-1 (range 22-200 x 10(-4) min-1) at 3 h] after reventilation and PA reperfusion (normal = 49 +/- 31 x 10(-4) min-1). Extravascular density increased significantly from 0.25 to 3 h only in group I.(ABSTRACT TRUNCATED AT 250 WORDS)

Modifying pulmonary ischemia-reperfusion injury by altering ventilatory strategies during ischemia.

We used an intact in vivo canine model of pulmonary ischemia-reperfusion (IR) injury to evaluate the differential effects of alveolar hypoxia and ventilation during 2 h of unilateral warm lung ischemia. Serial measurements of regional pulmonary blood flow, extravascular density (EVD), and transcapillary protein flux were made after reperfusion with the quantitative imaging technique of positron emission tomography. Twenty-seven animals were divided into five experimental groups: VENT O2 (n = 5) in which the left lung was ventilated with 40% O2 during ischemia, STATIC O2 (n = 4) in which the left lung was statically inflated with 40% O2 during ischemia, VENT N2 (n = 5) in which the left lung was ventilated with 100% N2 during ischemia, VENT N2/CO2 (n = 5) in which the left lung was ventilated with 95% N2-5% CO2 during ischemia, and STATIC N2 (n = 8) in which the left lung was statically inflated with 100% N2 during ischemia. These groups were compared with a control group (CONT, = 3) that was studied previously. Protein flux was significantly increased in the previous ischemic lung only for the STATIC N2 group [median 175 x 10(-4) min-1 (range 53-1,217) for the STATIC N2 group vs. 50 x 10(-4) min-1 (range 40-56) for the CONT group] 0.25 h after reperfusion and did not change over 3 h. EVD also increased but not significantly. Protein flux and EVD in the other groups were not different from CONT.(ABSTRACT TRUNCATED AT 250 WORDS)

Injury in nonischemic lung after unilateral pulmonary ischemia with reperfusion.

We developed an in vivo intact canine model to study pulmonary ischemia-reperfusion (IR) injury. The surgical approach simulates that of unilateral lung transplantation but is free of technical difficulties and other factors related to lung preservation. Serial measurements of regional pulmonary blood flow (rPBF), extravascular density (EVD), and transcapillary protein flux were made with the quantitative imaging technique of positron emission tomography. Eleven experimental and six control animals were studied. After 2 h of warm ischemia followed by reperfusion, no significant change occurred in rPBF despite significantly increased EVD, which was greater on the ischemic than on the nonischemic side. Protein flux, measured as a rate constant, was also greater on the ischemic than on the nonischemic side (median 181 x 10(-4)/min, range 104-619, vs. median 90, range 33-132) immediately after reperfusion. Both sides were also significantly different from control values (median 37, range 21-57). On both sides, protein flux decreased over time and at 5 h after reperfusion was not different from that of controls. Data from the control animals showed that these findings in the experimental animals were not due to surgical technique, deterioration in the surgical preparation, or hyperperfusion of the nonischemic lung. Thus IR injury of one lung can lead to similar, but less severe, injury in the contralateral lung. Because injury in the nonischemic lung develops only after reperfusion of the ischemic lung, injury to the nonischemic lung is probably humorally mediated. The model is a useful and relevant method for studying the physiological consequences of pulmonary IR injury.

Inflammation and oxygen free radical formation during pulmonary ischemia-reperfusion injury.

In a companion study, we showed that 2 h of warm unilateral lung ischemia followed by reperfusion resulted in bilateral tissue injury, indicated by increases in extravascular density (EVD) and permeability, measured as the pulmonary transcapillary escape rate (PTCER) for radiolabeled transferrin. EVD and PTCER measurements were obtained with the quantitative imaging technique of positron emission tomography (PET). In the current study, we evaluated this increase in EVD histologically and correlated EVD and PTCER with measurements of oxidant-reactive sulfhydryls (RSH) in plasma as a marker of oxygen free radical (OFR) formation. Histologically edema, leukocyte infiltration, and hemorrhage were all present on the ischemic side, but only after reperfusion, whereas only neutrophil infiltration was observed on the nonischemic side. Histology scores correlated with EVD (r = 0.81) and PTCER (r = 0.75), but permeability was abnormal at times even in the absence of neutrophil infiltration. Plasma RSH concentration from the ischemic lung decreased significantly (P less than 0.05) during pulmonary ischemia (i.e., before reperfusion) and returned to baseline on reperfusion. The degree of RSH oxidation did not correlate with the severity of injury as measured by PET or histology. Thus pulmonary ischemia-reperfusion injury is characterized by inflammation, hemorrhage, edema, and OFR formation. Injury occurred after reperfusion, not after ischemia alone. In addition, injury to the contralateral nonischemic lung suggests a neutrophil-independent circulating mediator of injury.

Use of stable isotope labeling technique and mass isotopomer distribution analysis of [(13)C]palmitate isolated from surfactant disaturated phospholipids to study surfactant in vivo kinetics in a premature infant.

Pulmonary surfactant is a complex mixture of phospholipids and proteins which lowers surface tension and maintains alveolar expansion at end expiration. Developmental and genetic disruption of pulmonary surfactant metabolism leads to respiratory distress in newborns. Stable isotope labeling of metabolic precursors of disaturated phospholipids, the most abundant and specific component of pulmonary surfactant, permits the measurement of the kinetics of surfactant metabolism in vivo. We measured [U-(13)C(6)]glucose incorporation into palmitic acid derived from disaturated surfactant phospholipids. A 24 h infusion of [U-(13)C(6)]glucose (140 mg kg(-1)) was administered to a premature infant who required mechanical ventilation for respiratory distress syndrome; tracheal aspirate samples were obtained at the start of the infusion and at regular intervals for the next 70 h. Each tracheal aspirate sample was incubated with osmium tetroxide to isolate disaturated surfactant phospholipids. Methyl esters of the fatty acids in the disaturated phospholipids were prepared and the enrichment of [(13)C]methyl palmitate was measured by gas chromatography/mass spectrometry (GC/MS) and gas chromatography/combination/isotope ratio mass spectrometry (GC/C/IRMS). Mass isotopomer distribution analysis (MIDA) was used to calculate the fractional synthetic rate (FSR) of palmitate synthesized from acetate. With both GC/MS and GC/C/IRMS, palmitate (13)C enrichment was first detected 12.3 h after the start of the tracer infusion. The enrichment increased in a linear fashion, reached a peak at 47 h and remained constant in the remainder of the samples. The FSR of palmitate from acetate was 5.2% per day. Stable isotope techniques and MIDA will provide insights into the kinetics of surfactant metabolism in newborns with respiratory dysfunction.

Measurement of protein flux with positron emission tomography in neonates.

AIM: To determine whether abnormal transvascular protein flux can be measured with positron emission tomography (PET) in neonates with respiratory distress syndrome (RDS). METHODS: Fourteen infants with normal gas exchange (non-RDS group) underwent one PET measurement and 12 infants with RDS (the RDS group) underwent two measurements of protein flux, as determined by the pulmonary transcapillary escape rate for 68Gallium labelled transferrin (PTCER). RESULTS: The mean PTCER for the RDS infants (132 +/- 39 10(-4)/min) was significantly greater than that for infants without RDS (75 +/- 27 10(-4)/min). PTCER did not change between measurements in the infants with RDS, including five who received and responded to surfactant replacement between the two scans. CONCLUSIONS: Increased transvascular flux of large molecular weight proteins complicates RDS in preterm infants. PET provides a tool with which to evaluate the processes that contribute to pulmonary dysfunction in neonates.

Brain death secondary to arteriovenous hemangioma of the forearm.

We describe the association of brain death in an infant with a large cutaneous hemangioma of the forearm. The irreversible cerebral injury is presumed to be secondary to cerebral hypoperfusion as a result of a combination of systemic hypotension and a systemic vascular "steal" phenomenon caused by the cutaneous hemangioma.

High-frequency oscillation and paralysis stabilize surfactant protein-B--deficient infants.

OBJECTIVE: To determine if high-frequency oscillatory ventilation and neuromuscular blockade improve oxygenation and chest radiographic appearance more effectively than high-frequency oscillation alone for surfactant protein-B (SP-B)--deficient infants. STUDY DESIGN: We reviewed medical records and chest radiographs of five SP-B--deficient infants awaiting lung transplantation. Changes in FiO2 and radiographic scores were analyzed with respect to neuromuscular blockade status. RESULTS: FiO2 consistently increased 0.20 (SD 0.11) during high-frequency ventilation without neuromuscular blockade (p = 0.02) and decreased 0.14 (SD 0.11) during high-frequency ventilation with neuromuscular blockade (p = 0.05). Chest radiographic appearance, quantified by an expansion/aeration index, consistently deteriorated without neuromuscular blockade (p = 0.01) and consistently improved with neuromuscular blockade (p = 0.03). Changes in FiO2 correlated with changes in radiograph scores (r = 0.7, p < 0.001). CONCLUSIONS: High-frequency ventilation with neuromuscular blockade optimizes oxygenation for SP-B--deficient infants. This ventilatory strategy should be considered while awaiting the diagnosis of SP-B deficiency or lung transplantation.

Retinal and intraventricular cerebral hemorrhages in the preterm infant born at or before 30 weeks' gestation.

PURPOSE: To determine the prevalence of retinal hemorrhages and their association with cerebral intraventricular hemorrhages (IVH) in low-birth-weight preterm neonates born at or before 32 weeks' gestation. METHODS: We prospectively studied a consecutive series of 22 neonates (24-30 weeks' gestation; mean gestational age, 27 weeks; mean weight, 1065 g) admitted to the neonatal intensive care unit. Anterior segment and indirect ophthalmoscopic examination, as well as cranial ultrasonographic examination, were performed on day 1 and day 10 of life. The prevalence of retinal and intraventricular hemorrhage was tested statistically for association with obstetric and neonatal clinical variables. RESULTS: The prevalence of retinal hemorrhage was 9% (2/22; 95% CI, 3%-21%) on day 1 and 2% (1/22) on day 10. The prevalence of IVH was 27% (6/22; 95% CI, 9%-46%): 14% (3/22) on day 1 and 23% (5/22) on day 10. Retinal hemorrhages occurred with greater frequency in neonates born to women who had intrauterine infection (chorioamnionitis, P =.043) and low umbilical cord pH levels (P =.027). No association was found between the presence of retinal hemorrhage and IVH (P = 1.000), mode of delivery (ie, vaginal vs cesarean section, P = 1.000), birth weight (P =.476), or gestational age (P = 1.000). The presence of subconjunctival hemorrhage was associated with IVH (P =.046). CONCLUSIONS: Retinal hemorrhages occur in less than 10% of low-birth-weight neonates, ie, a prevalence one half that observed in term neonates (22%). The hemorrhages tend to resolve without sequelae in the first 10 days of life and occur more commonly in infants born to women with uterine infection. Retinal hemorrhages in very premature neonates are not predictive of IVH-related brain damage.

Review of the literature on calyceal diverticula, a hypothesis concerning its etiology and report of 17 cases.

The literature on calyceal diverticula is reviewed, the embryological aspects and pathogenesis are discussed and commented upon, and the ""congenital vasocentric'' theory of the authors is elaborated. The study includes the analysis of 17 cases seen over twenty years at the Department of Urology, Semmelweis University Medical School, Budapest.

Idiopathic bladder hyperactivity treated with Ditropan (oxybutynin chloride).

Ditropan (oxybutynin chloride), a tertiary amine with slight anticholinergic and marked "papaverine-like" direct spasmolytic effects has been administered to 25 patients with idiopathic hyperactive bladder function. The drug reduced voiding frequency and abolished urgency. Control cystometry confirmed a significant increase in bladder capacity. Oral dryness was a tolerable side effect.

Experience with the Peponen capsule in the management of benign prostatic hyperplasia.

Sixty patients in Stages I and II of benign prostatic hyperplasia were treated with Peponen capsule. Out of them 26 took the drug for 10 months, 22 for at least 7, and 12 for at least 4 months. The daily dosage was 3 x 2 capsules in the first month and 3 x 1 capsule for the rest of the time. On the ground of urodynamic test results and changes in subjective complaints, more than 80% of the patients experienced improvement. The therapy intensified the uroflow, appeased dysuria, the difficult and painful discharge, and reduced the frequency of nocturnal urination.

Experience with the Direx Tripter X-1 shock-wave lithotripter.

The authors give account of the experience they gained with the Direx Tripter X-1 (ESWL) apparatus. In a random material they succeeded to render 81.5% of the patients stone free within three months. They judge the apparatus suitable for in situ treatment of pelvic and ureteric stones and for the monotherapy of staghorn calculi. It is easy to handle, inexpensive to buy and maintain but noisy to operate, moreover the patient has to be anaesthetized. All in all it is highly useful in the treatment of renal lithiasis.

[Complex therapy of cystine calculi]. / A cisztinkövesség komplex terápiája.

Authors report their experiences with management of cystine urolithiasis between 1975-1992. 61 patients were observed and treated with dietotherapy, medicaments, open surgery, percutaneous nephrolithotomy and extracorporeal shock wave lithotripsy. Difficulties of treatment of this rare stone have been demonstrated with data of 3 patients (lack of screening and early diagnosis, unsystematic prophylaxis, formation of large stones).

[Successful shock wave monotherapy of coral-shaped calculi in the kidney calix]. / Teljes veseüregrendszert kitöltö korallkö sikeres lökéshullám kezelése.

Authors reported about two patients with staghorn calculi, who have been treated by extracorporeal shock wave monotherapy by Direx Tripter-X-1 Lithotripter. They used in the first case percutaneous nephrostomy, in the second double J catheter as auxiliary method. Patients were treated 3 and 4 time, and they were stone free at three month follow up.