Evaluation of a prostacyclin analog in prevention of pulmonary oxygen toxicity.

Prolonged exposure to high concentrations of oxygen can result in significant lung injury, although newborn animals are tolerant relative to adults. We previously reported that relative O2 tolerance in the rabbit is lost by 10 days of age, and is coincident with a decline in lung prostacyclin. In the current study we administered iloprost, a stable prostacyclin analog, by continuous infusion to maturing rabbits exposed to greater than 95% oxygen. Compared to vehicle-treated controls, iloprost-treated rabbits had significantly lower protein in bronchoalveolar lavage fluid at 84 h, a smaller percentage of neutrophils at 65 and 84 h, and lower mortality at 96 h. The partial protection against pulmonary oxygen toxicity afforded by iloprost is likely due to its membrane stabilizing effect, and its inhibitory actions on neutrophil migration, activation, production of oxygen radicals and proteolytic enzymes.

Evaluation of a leukotriene receptor antagonist in prevention of hyperoxic lung injury in newborn rabbits.

Prolonged exposure to hyperoxia can result in significant lung injury and has been associated with the development of bronchopulmonary dysplasia. Leukotrienes (LT) recruit polymorphonuclear leukocytes (PMN) to the lung, increase vascular permeability, and have therefore been postulated to play a role in the pathogenesis of hyperoxic lung injury. This study investigates ICI 198,615 (ICI), an LTD4 and LTE4 receptor antagonist in preventing hyperoxic lung injury in newborn rabbits. Matched littermates of 7-day-old rabbits received ICI (0.1 or 1.0 microM/kg/h) or vehicle alone, were exposed to greater than 95% O2, and sacrificed after 48, 72, 84 and 96 h of exposure. Bronchoalveolar alveolar lavage fluid (BAL) of the left lung was analyzed for white cell count, differential, absolute number of PMNs, total protein, and cyclooxygenase products 6-keto-PGF1 alpha, and thromboxane B2. Lung water was quantified utilizing the right lung. Results demonstrated no significant differences between the ICI groups or between the ICI groups and controls. In conclusion, the administration of the LTD4 and LTE4 receptor antagonist ICI 198,615 was insufficient to reduce the formation of pulmonary edema, reduce mortality or attenuate hyperoxic lung injury. These experiments suggest that a number of other mediators may be involved in the hyperoxic lung injury process and that the functional inhibition of a portion of the arachidonic acid cascade was not sufficient to either prevent or attenuate hyperoxic lung injury in newborn rabbits.

Oleic acid lung injury increases plasma prostaglandin levels.

To determine whether lung injury causes increased plasma prostaglandin (PG) levels, 35 rabbits received oleic acid and 35 served as controls. Half of each group also received 4 ml/kg of Intralipid over one hour and at least five in each subgroup received indomethacin 7.5 mg/kg. Arterial and venous plasma concentrations of PGE2, 6-keto-PGF1 alpha, and PGF2 alpha-M were measured. Venous PGE2 was significantly higher in the oleic acid-injured than in the normal lung group, 1560 +/- 270 (Mean +/- SEM) versus 880 +/- 140 pg/ml (p less than .05). Plasma levels were reduced by 50% with indomethacin, but PGE2 levels remained significantly higher than in the normal lung group, 850 +/- 180 versus 480 +/- 60 for arterial (p less than .05) and 820 +/- 140 versus 480 +/- 80 for venous (p less than .05), respectively. PGF2 alpha-M levels were significantly higher in the lung injury group, 240 +/- 50 versus 50 +/- 40 pg/ml for arterial (p less than .05) and 220 +/- 50 versus 95 +/- 40 for venous (p less than .05), respectively. These lung injury-related increases in PGE2 and PGF2 alpha-M appear related both to increased pulmonary production and to decreased pulmonary clearance. With Intralipid infusion, however, arterial PGE2 increased by 500 +/- 260 pg/ml compared to baseline (p less than .05) with no change in venous PGE2, indicating in this instance that the increase in arterial PGE2 levels is related to increased pulmonary production.

Failure of non-selective inhibition of arachidonic acid metabolism to ameliorate hyperoxic lung injury.

We have previously reported that bronchoalveolar lavage fluid cyclo-oxygenase products of arachidonic acid (AA) metabolism increase prior to the development of significant hyperoxic lung injury. To further assess the role of AA metabolites in the development of hyperoxic lung injury, we have utilized this same model of hyperoxic lung injury and administered either indomethacin (an inhibitor of the cyclo-oxygenase pathway of AA metabolism) or dexamethasone (inhibitor of AA release). A total of 46 adult rabbits were exposed to greater than 95% oxygen for 65 hours. Fourteen animals were given either 2 or 3 mg/kg/day indomethacin, 7 served as controls: 18 animals were given either 0.5 or 1.0 mg/kg/day of dexamethasone, 7 served as controls. The surviving animals were sacrificed after 65 hours of hyperoxia and bronchoalveolar lavage of the left lung was done; the right lung was examined by light microscopy. Treatment with indomethacin or dexamethasone failed to ameliorate the hyperoxic lung injury process. However, in both the indomethacin and dexamethasone treatment groups, significant suppression of 6-keto-PGF1 alpha, a PGI2 metabolite, was observed. Some suppression of TXB2 production was observed, but there was no evidence of any decrease in leukotriene production. We postulate that failure to ameliorate hyperoxic lung injury with either indomethacin or dexamethasone therapy was related to significant suppression of PGI2, a potentially protective AA metabolite, and/or to failure to significantly decrease production of potential pathogenic participants, such as TXA2 or LTB4.(ABSTRACT TRUNCATED AT 250 WORDS)

Fat emulsions and lung function.

IVFE infusion can impair lung function in healthy adults, premature infants, and adults with pre-existing lung injury, and in experimental animals with acute injury. Although all observed IVFE-related lung dysfunction was initially attributed to the temporally associated hyperlipemia, this explanation may in fact be correct only with fat overload syndrome. When serum triglyceride levels are in a more appropriate range, all subsequent studies have shown the same alterations in lung function unrelated to triglyceride increases and indomethacin-related blocking of lung function impairment, despite comparable serum triglyceride increases. Furthermore, our studies with Liposyn demonstrated the most significant increases in serum triglyceride levels, but the smallest PaCO2 and PaO2 changes. In general, the lung function abnormalities associated with IVFE infusion have thus been caused by increases in VA/Q inequalities. Although elucidation of the relationship between IVFE-related increased PG production and secondary VA/Q changes may be of significant physiologic import, the PaO2 and PaCO2 changes even with pre-existing lung injury have generally not been of sufficient magnitude to be of much clinical significance. The IVFE-related increases in plasma PG concentrations may, however, still have significant nonpulmonary clinical effects related to known or postulated consequences of increased plasma PG concentrations, including effects on ductus arteriosus patency, retinal and cerebral blood flow, and immune competence.

Respiratory pattern at hospital discharge in asymptomatic preterm infants.

Pneumogram (PG) recordings were performed in 87 very low birthweight (VLBW) asymptomatic infants just prior to hospital discharge to determine the relationships between: 1) a prior history of apnea of prematurity (AOP) and cardiorespiratory pattern; and 2) cardiorespiratory pattern at hospital discharge and postconceptional age. Apnea density (A6/D%) and longest apnea were significantly greater in those with (n = 66), versus without (n = 21) a prior history of AOP (P less than 0.05 and P less than 0.01, respectively). Although PG values for the 21 VLBW infants without a prior history of AOP did not differ significantly from those of full-term infants, for the 66 VLBW infants with a prior AOP history A6/D% (P less than 0.01), episodes of periodic breathing (P less than 0.05) and longest apnea (P less than 0.001) were significantly greater compared with full-term infants. Postconceptional age was significantly less in the VLBW infants with A6/D% values above, compared with those within the 95th percentile for normal infants (median age, 36 and 37.5 weeks; P = 0.01). Therefore, respiratory pattern abnormalities in asymptomatic VLBW infants ready for hospital discharge are related to a prior history of AOP and may be significantly higher than in full-term infants at the postconceptional ages at which hospital discharge now tends to occur.

Loss of oxygen tolerance in newborn rabbits: relationship to changes in eicosanoid and antioxidant levels.

Relative tolerance of newborn animals to hyperoxia has been reported. This study investigated the age limitation of oxygen tolerance and mechanisms for its loss. Developmental changes in lungs of normoxic New Zealand rabbits were studied on days 1, 3, 4, 5, and 10 of life. These were contrasted with newborn and 7-day-old rabbits exposed to greater than 95% O2 for 65 hours. Normoxic rabbits demonstrated a decrement in bronchoalveolar lavage (BAL) 6keto-PGF1a, thromboxane B2, and lower lung catalase, total glutathione, and superoxide dismutase with maturation. Newborns were more tolerant to oxygen than 7-day-old rabbits. Oxygen exposure beginning on day 1 did not result in identifiable lung damage. Exposure beginning on day 7 resulted in microscopic evidence of injury and significant increases in BAL white cells, neutrophils and protein, and a trend toward higher BAL LTB4 compared to normoxic age-matched controls. Antioxidants were higher in the hyperoxic 7 day-olds, but remained lower than values in hyperoxic newborns. These results suggest that loss of oxygen tolerance in maturing rabbits is related to a developmental decrement in antioxidants and prostacyclin.

Liposyn infusion increases plasma prostaglandin concentrations.

To determine whether Liposyn infusion results in increased plasma prostaglandin (PG) concentrations, the following study was performed in 33 adult rabbits with chronically implanted arterial and venous catheters. Plasma PG concentrations were determined by radioimmunoassay for two vasodilators, PGE2 and PGI2 (as measured by its metabolite 6-keto-PGF1 alpha), and two vasoconstrictors, thromboxane (TX) A2 and PGF2 alpha, as measured by their metabolites TXB2 and PGF2 alpha-M, respectively. A 1-hour infusion of Liposyn at 4 ml per kg resulted in statistically significant increases in arterial and venous concentrations of PGE2 and 6-keto-PGF1 alpha (p less than 0.001) and of TXB2 (p less than 0.04). There were no significant changes in PGF2 alpha-M plasma concentrations. Liposyn infusion also resulted in a small but statistically significant increase in PaO2 of 4.7 +/- 1.5 torr (p less than 0.01). It is concluded that Liposyn infusion results in statistically significant increases in plasma concentrations of PGE2, 6-keto-PGF1 alpha, and TXB2.

Monitoring of critically ill infants and children.

The strategies for monitoring infants and children in the intensive care setting differ from the strategies used to monitor adults. This article highlights the physiologic differences between infants and children and adults that affect these methods. The technical aspects of monitoring infants and children are also discussed.

Education of personnel involved in the transport program.

Inclusive in the demand for transport services is the need for an ongoing formal educational curriculum to ensure that a high standard of care is consistently provided to patients. Those who provide transport services must ensure that the staff has an adequate baseline level of training and licensure, an ongoing system of educational review, and the frequency of activity necessary to maintain skills. Team members should have an acceptable level of cognitive and technical skills to transport patients and perform needed procedures safely. Such skills may be acquired and maintained by participation in nontransport activities, through a didactic curriculum and a system of ongoing case review, through team members providing training to referring hospitals, and through a "buddy" system of supervised transport activities. While an ongoing educational curriculum and its structure remain constant, the content can and should be tailored to the type of patients transported, from the very low birth weight infant and pregnant mother to pediatric and adult patients.

Tuberculosis in infancy in the 1990s.

In 1990, 25,701 cases of tuberculosis (TB) were reported in the United States, the largest annual increase since 1953. Children younger than 15 years of age accounted for 1596 new cases. The resurgence of TB can largely be contributed to the HIV epidemic. The clinical course, diagnosis, therapy, and prevention of TB in the perinatal period and in infancy are discussed in view of the epidemics of HIV and TB in the adult population.

Cardiopulmonary resuscitation of the newborn. An update.

The abrupt transition from intrauterine to extrauterine life represents a series of profound physiologic changes. This process puts the baby at risk for asphyxia. At birth, the newborn is, therefore, more frequently in need of resuscitation than at any other age. This article reviews the rationale for the sequence and process of neonatal resuscitation, emphasizing recent changes in recommendations.

Neonatal cardiopulmonary resuscitation: the good news and the bad.

Many health care professionals all over the world have been taught neonatal cardiopulmonary resuscitation (CPR) using the neonatal CPR course based upon the work of Bloom and Cropley. The purpose of this article is to provide a retrospective review of the development of some of the neonatal CPR techniques, to discuss current techniques and to complement the dedication of this issue to Dr. Ronald Brown and Catherine Copley, MN, RN.

Caring for the graduate from the neonatal intensive care unit. At home, in the office, and in the community.

This article focuses on recent progress in the understanding of optimal care for the neonatal intensive care unit (NICU) graduate in three domains that have relevance to primary care pediatricians: the concept of developmentally supportive care for the immature central nervous system of fragile premature infants; an understanding of the function and systems of community-based early intervention available for medically complex, developmentally challenged and at-risk infants; and the management of technology-dependent children at home.

Congenital and perinatal tuberculosis: discussion of difficult issues in diagnosis and management.

Tuberculosis (TB) has become more prevalent in women of childbearing age and, as well, more frequent in their children. This has occurred for a number of reasons, including: (1) women and children who have immigrated to this country from areas where TB is endemic, such as Mexico and Southeast Asia; (2) the development of multidrug-resistant organisms; (3) the increase seen in patients who live in congregate areas who are at higher risk for acquisition of TB; (4) more difficult access to adequate medical care; and (5) increases in adults and children who have become infected with human immunodeficiency virus. The focus of this review is on congenital and perinatally acquired TB including discussion of epidemiology, the stages of TB, the effects of TB infection and disease during pregnancy on the fetus and mother, congenital and perinatal TB, the potential role of the use of BCG vaccine in infants, and the emergence of multidrug-resistant TB on therapy of the pregnant mother and her fetus and the mother and her infant after delivery.

National survey of diagnosis and management of persistent pulmonary hypertension of the newborn.

The diagnosis and management of persistent pulmonary hypertension of the newborn remains controversial. A national survey was performed to analyze recent trends in the incidence, diagnosis, management, and survival of patients with persistent pulmonary hypertension of the neonate. Sixty-six institutions from all geographical regions responded. The overall admission incidence was 3.9% +/- 2.6%. Secondary persistent pulmonary hypertension of the neonate was more common than primary. Unexplained hypoxemia, ductal level right-to-left shunting, echocardiography, and a positive response to hyperventilation were all used frequently (in at least 79% of institutions) to diagnose persistent pulmonary hypertension of the neonate. The majority of institutions considered a positive response to hyperventilation to be determined by an increase of PaO2 by 30 mm Hg with a concomitant decrease in PaCO2 to 25 mm Hg. Approximately 70% of institutions use varying ventilator techniques (ie, with or without hyperventilation), but the majority use hyperventilation predominantly. Almost all (greater than 90%) institutions used muscle paralytic agents and pulmonary vasodilators. Tolazoline was the first choice of pulmonary vasodilator therapy. The overall survival rate of persistent pulmonary hypertension of the newborn was 77.4% +/- 13.4%. Survival rate did not differ between different geographic areas of the country. There was a trend noted for improved survival with less use of muscle paralyzing agents. Yet despite varying treatment protocols, survival rates are improving.

Delivery room management of meconium staining of the amniotic fluid and the development of meconium aspiration syndrome.

A 1-year prospective survey of obstetric and pediatric management of meconium staining of the amniotic fluid in 464 patients was undertaken. Pharyngeal suctioning before delivery was performed using bulb syringe (N = 130), De Lee suction catheter (N = 186), or both (N = 98); endotracheal intubation after delivery was also done in 413 instances. Using any of the three suctioning techniques, no differences were seen in Apgar scores, respiratory rates, presence or absence of meconium on or below the vocal cords, or development of meconium aspiration syndrome (MAS). If meconium was present on the vocal cords, it was present below the vocal cords in 76% of the cases. If no meconium was visualized, it was found below the vocal cords in only 7% of the cases. Of the 142 infants with meconium below the vocal cords, 10% developed MAS and all 14 survived.

An introduction to the structure and function of inflammatory mediators for clinicians.

As is apparent from a brief overview of some of the more important mediators involved in perinatal physiology and disease states, basic science research has provided many clinically relevant observations that, as discussed in other articles in this issue, have resulted in the discovery and development of clinically effective medications used daily in the care of the gravid mother and her fetus or neonate. In addition, an excellent base for the understanding of the mechanisms of the physiology of the maternal-fetal-placental unit has been established via extensive general and more focused research involving mediators.

Perinatal management of meconium staining of the amniotic fluid.

The pathogenesis of meconium passage and the pathophysiology of meconium aspiration are reviewed. Intrapartum and neonatal strategies for the prevention of meconium aspiration syndrome are presented in historical perspective, and newer interventions are appraised.