Frank L. Mannino

Exogenous human surfactant for treatment of severe respiratory distress syndrome: A randomized prospective clinical trial

We performed a randomized, prospective clinical trial comparing intratracheal administration of human surfactant with conventional treatment with intermittent mandatory mechanical ventilation alone for treatment of severe respiratory distress syndrome in preterm infants of less than 30 weeks gestation. Twenty-two infants (mean gestational age 27.0 weeks, mean birth weight 987 gm) were given surfactant, and 23 infants (mean gestational age 27.2 week, mean birth weight 1055 gm) received intermittent mandatory ventilation. Infants given surfactant required less FiO2 during the first week, had lower mean airway pressure during the first 48 hours, and had improved ventilatory index and a/A PO2 ratio. Death or the occurrence of bronchopulmonary dysplasia was significantly less among infants given surfactant (P = 0.019). Pneumothorax, pulmonary interstitial emphysema, and need for FiO2 greater than or equal to 0.3 for greater than 30 days was significantly less in the surfactant group. This trial confirms the efficacy of treatment with human surfactant in preterm infants with severe respiratory distress syndrome.

Congenital skin defects and fetus papyraceus

Two unrelated infants with congenital skin defects (aplasia cutis congenita) involving the trunk and limbs, each with an associated monozygotic twin fetus papyraceus, are described. Evidence from these two cases and a review of the literature indicate that congenital skin defects of other body areas, as represented by these two children, is a specific pattern of malformation distinct from isolated small congenital skin defects involving the vertex of the scalp. The frequent occurrence of fetus papyraceus in patients with congenital skin defects of other body areas suggests a common etiology for these two phenomena.

Consequences of dichotomization

Dichotomization is the transformation of a continuous outcome (response) to a binary outcome. This approach, while somewhat common, is harmful from the viewpoint of statistical estimation and hypothesis testing. We show that this leads to loss of information, which can be large. For normally distributed data, this loss in terms of Fishers information is at least 1-2/pi (or 36%). In other words, 100 continuous observations are statistically equivalent to 158 dichotomized observations. The amount of information lost depends greatly on the prior choice of cut points, with the optimal cut point depending upon the unknown parameters. The loss of information leads to loss of power or conversely a sample size increase to maintain power. Only in certain cases, for instance, in estimating a value of the cumulative distribution function and when the assumed model is very different from the true model, can the use of dichotomized outcomes be considered a reasonable approach.

Thoracoabdominal motion in newborns during ventilation delivered by endotracheal tube or nasal prongs

Preterm infants have asynchronous thoracoabdominal motion (TAM) secondary to a highly compliant chest wall and different lung mechanics compared to term infants. We compared TAM during continuous positive airway pressure (CPAP) administered through an endotracheal tube (ETT‐CPAP) or nasal prongs (nasal‐CPAP), and during synchronized intermittent mandatory ventilation administered by nasal prongs (nasal‐SIMV) in 14 preterm newborn infants. Asynchrony of TAM was quantified by measuring relative motion of chest wall and abdomen with strain gauges and calculating phase angles (θ).

Stroke in neonates

Five neonates with large cerebral infarctions of arterial origin are presented. Four had severe focal seizures on the first day of life. The fifth, a premature infant, was asymptomatic. The diagnoses were made by computed tomography (CT) scans between 5 and 12 days of life; CT scans obtained in the first few days of life were normal. In the fifth infant, the infarct was hemorrhagic and was also noted by cranial ultrasound. Three of the infants had a history of trauma to the head or neck during labor and birth. Only one was severely asphyxiated at birth. Two apparently are doing well at 1 year of age. Cerebral infarcts of arterial origin in neonates probably have been missed in living patients in the past, but now are recognized in the newborn period by properly timed CT examination.

Improved oxygenation during synchronized intermittent mandatory ventilation in neonates with respiratory distress syndrome: A randomized, crossover study

In a randomized, crossover study, we compared arterial partial pressure of oxygen and of carbon dioxide between consecutive periods of conventional and synchronized intermittent mandatory ventilation (SIMV). We studied spontaneously breathing infants with an endotracheal tube in place. The infants were < 12 hours of age, had a diagnosis of respiratory distress syndrome, and had an arterial/alveolar oxygen ratio of < 0.25. The infants had a mean birth weight of 1077 gm and gestational age of 28 weeks. The mean rate of asynchrony on intermittent mandatory ventilation (IMV) was 52% (range, 36% to 76%), and on SIMV was < 1%. Infants were randomly assigned to IMV or SIMV as their initial ventilator mode and underwent ventilation for four 15-minute periods, and crossed over to the alternate mode after each period. Ventilator settings and the fraction of inspired oxygen were not changed between modes. At the end of each period, arterial blood gas measurements were obtained; 26 paired comparisons were made between modes. The mean arterial partial pressure of oxygen was significantly higher during SIMV than during IMV (mean, 61.5 vs 53.3 mmHg; p < 0.01). The mean arterial partial pressure of carbon dioxide was slightly lower during SIMV than during IMV (mean, 42.7 vs 41.3 mm Hg; p < 0.05). The improvement in oxygenation demonstrated with SIMV may allow a reduction in ventilator pressure or oxygen exposure in this group of infants, who are at risk of having complications of ventilation.

Bacterial diversity in two Neonatal Intensive Care Units (NICUs).

Infants in Neonatal Intensive Care Units (NICUs) are particularly susceptible to opportunistic infection. Infected infants have high mortality rates, and survivors often suffer life-long neurological disorders. The causes of many NICU infections go undiagnosed, and there is debate as to the importance of inanimate hospital environments (IHEs) in the spread of infections. We used culture-independent next-generation sequencing to survey bacterial diversity in two San Diego NICUs and to track the sources of microbes in these environments. Thirty IHE samples were collected from two Level-Three NICU facilities. We extracted DNA from these samples and amplified the bacterial small subunit (16S) ribosomal RNA gene sequence using ‘universal’ barcoded primers. The purified PCR products were pooled into a single reaction for pyrosequencing, and the data were analyzed using QIIME. On average, we detected 93+/−39 (mean +/− standard deviation) bacterial genera per sample in NICU IHEs. Many of the bacterial genera included known opportunistic pathogens, and many were skin-associated (e.g., Propionibacterium). In one NICU, we also detected fecal coliform bacteria (Enterobacteriales) in a high proportion of the surface samples. Comparison of these NICU-derived sequences to previously published high-throughput 16S rRNA amplicon studies of other indoor environments (offices, restrooms and healthcare facilities), as well as human- and soil-associated environments, found the majority of the NICU samples to be similar to typical building surface and air samples, with the notable exception of the IHEs which were dominated by Enterobacteriaceae. Our findings provide evidence that NICU IHEs harbor a high diversity of human-associated bacteria and demonstrate the potential utility of molecular methods for identifying and tracking bacterial diversity in NICUs.

Combined high-frequency oscillatory ventilation and intermittent mandatory ventilation in critically ill neonates

Combined high-frequency oscillatory ventilation (HFOV) and intermittent mandatory ventilation (IMV) was used in 12 neonates with inadequate gas exchange with conventional IMV. Diagnoses included diaphragmatic hernia with hypoplastic lungs, pneumonia, persistent fetal circulation, and severe respiratory distress syndrome. In most patients there was severe air leak. Within 10 hours of beginning HFOV-IMV the mean arterial PCO2 fell from 60 +/- 5 (means +/- SEM) to 38 +/- 2 mm Hg (P less than 0.01) and the mean IMV rate was reduced from 96 +/- 8 to 17 +/- 4 breaths per minute (P less than 0.001). The mean arterial-alveolar oxygen tension ratio rose from 0.05 +/- 0.01 to 0.09 +/- 0.01 (P less than 0.005). Mean airway pressure in the trachea was reduced from 16 +/- 2 to 10 +/- 3 cm H2O (P less than 0.05). Four patients died, three of whom had diaphragmatic hernias with hypoplastic lungs. Five of the eight survivors had mild bronchopulmonary dysplasia requiring supplemental oxygen. These studies demonstrate that in some neonates with respiratory failure who fail to respond to conventional IMV, combined HFOV-IMV can be successful.

Intrauterine latent herpes simplex virus infection: II. Latent neonatal infection.

Herpes simplex virus (HSV, probably type 2) antigen has been detected in endometria and abortion tissue (companion paper) and in placentae, umbilical cords, and fetal and neonatal organs by avidin-biotin complex immunohistochemical studies. HSV cytologic abnormalities were not detected in any of the 12 normal and 64 abnormal cases analyzed, nor was HSV detected by culture or electron microscopy in selected cases. Antigen was present in single epithelial and, rarely, mesenchymal cells of various organs. Clinically unexplained fetal or neonatal problems associated with HSV antigen positivity included intrauterine death, fetal growth retardation, cystic brain degeneration, hydrops, interstitial pneumonitis, necrotizing enterocolitis, hepatitis, encephalitis, myocarditis, and renal failure. Maternal floor infarct of placenta and calcifying funisitis are the manifestations of intrauterine HSV infection in most cases. Maternal history of HSV infection was uncommon. It is concluded that intrauterine HSV infection may persist in the fetus and neonate in a latent fashion without cytologic abnormalities or detectable virus. This latent infection may be associated with intrauterine and neonatal death, organ damage, and neonatal disease.

Plasma Thyroid Hormones in Premature Infants: Effect of Gestational Age and Antenatal Thyrotropin-Releasing Hormone Treatment

Thyroid hormones are important for both perinatal adaptation and long-term psychomotor development; however, there is limited information on the effects of extreme prematurity and antenatal TSH-releasing hormone (TRH) treatment on pituitary-thyroid function. In this study we assayed plasma triiodothyronine (T3) and TSH in infants who were part of a collaborative trial of antenatal maternal TRH therapy. Within the control population (n = 166), infants of 24-28-wk and 28-32-wk gestational age had comparable levels of T3 (0.94 and 1.06 nmol/L, respectively) and TSH (5.7 and 7.2 mU/L) at birth, but the increases at 2 h and subsequent T3 levels were less in the 24-28 wk versus 28-32-wk gestation infants. In the TRH-treated group (n = 131), T3 was lower in the first day for infants delivered 7-72 h after antenatal TRH compared with control infants. TSH at birth was ∼3.5-fold greater for infants delivered at 0-6 h after the last TRH dose compared with the control group and was suppressed in infants delivering at 7-36 h. T3 and TSH levels were not different between control and TRH-treated groups at 3-28 d of age. In TRH stimulation tests on d 28, control and TRH-treated groups had similar peak levels of TSH and incidence of exaggerated response (TSH ≥ 35 mU/L). We conclude that extremely premature infants have a reduced postnatal surge in TSH and T3 and maintain lower T3 concentrations, probably reflecting tertiary hypothyroidism. The stimulatory and suppressive effects of antenatal TRH treatment observed at birth are transient and do not affect pituitary-thyroid responsiveness at 28 d of age.