Serum cortisol levels in very low birth weight infants of substance-abusing mothers.

OBJECTIVE: Recently, hypoadrenalism was described in extremely low birth weight infants. We have been measuring serum cortisol levels in very low birth weight (VLBW) infants to assess their adrenal function. It was noticed that infants of substance-abusing mothers (ISAM) had unusually high serum cortisol levels. To our knowledge, there are no data regarding serum cortisol levels in VLBW ISAM. The objective of our study was to determine if serum cortisol levels of VLBW ISAM are different from serum cortisol levels in VLBW infants without a history of maternal substance abuse. METHODS: We reviewed medical records of infants with birth weight between 400 and 1300 gm who were born between July 1994 and June 1995. Seven ISAM who had serum cortisol levels drawn before 48 hours of life were identified. Seven infants matched for gestational age, antenatal steroid exposure, and birth weight served as control infants. Clinical characteristics, serum cortisol levels, and clinical outcome were compared between the two groups. Serum cortisol levels of all infants were measured by radioimmunoassay. RESULTS: The mean birth weight of the ISAM group was 834 gm (range 480 to 1175 gm), and the mean gestational age was 27.4 weeks. The mean birth weight of the control group was 921 gm (range 525 to 1230 gm) with a mean gestational age of 27.8 weeks. The mean serum cortisol level of the ISAM group was 65.3 micrograms/dl (range 11.9 to 144 micrograms/dl); it was significantly higher than that of the control group (mean cortisol level of 20.5 micrograms/dl; range 4.9 to 62.7 micrograms/dl) (p = 0.01, two-tailed). CONCLUSION: Our data suggest that maternal substance abuse significantly increases serum cortisol levels in VLBW infants. Studies in larger scale are needed to confirm our findings and to correlate cortisol levels in this group of patients with clinical outcome.

Low serum cortisol in term newborns with refractory hypotension.

OBJECTIVES: The aim of this study is to measure baseline serum cortisol levels and clinical response to glucocorticoid therapy in a group of term infants with refractory hypotension. STUDY DESIGN: Seven term newborns with refractory hypotension were included. Serum cortisol levels were drawn before initiation of glucocorticoid therapy and measured by either fluorescence polarization immunoassay or radioimmunoassay. Baseline blood pressures, heart rate, and inotropes doses were recorded at baseline, then 4, 8, 12, 24, 48, 72, and 96 hours after glucocorticoid therapy. Urine output and volume expanders the infants received were recorded 24 hours before and after glucocorticoid therapy. Dexamethasone was used at a starting dose of 0.2 mg/kg per day divided every 12 hours. The statistical analysis was done using analysis of variance with repeated measures and paired t-test. RESULTS: Serum cortisol levels of the infants ranged from 2.0 to 15.4 micrograms/dl. After initiation of glucocorticoid therapy, there was significant improvement of blood pressure. Vasopressors were rapidly weaned and discontinued within 72 hours. In three of seven infants, no volume expanders were required after initiation of steroids, and none needed volume expanders after 2 days. Urine output increased significantly within 24 hours. All infants survived. CONCLUSIONS: Glucocorticoids improved pressure and stabilized clinical conditions of a group of term newborns with refractory hypotension. Serum cortisol levels of these infants were relatively low. We speculate that a subset of critically ill term infants has relative adrenal insufficiency and glucocorticoid therapy may be essential.

The effects of IL-10 on proinflammatory cytokine expression (IL-1beta and IL-8) in hyaline membrane disease (HMD).

Deficient expression of the counterregulatory cytokine IL-10 by lung inflammatory cells may facilitate chronic inflammation and the pathogenesis of hyaline membrane disease (HMD), in premature infants. To determine if pathways which regulate proinflammatory cytokines in response to human recombinant IL-10 (rIL-10) were functional in the lungs of these neonates, bronchoalveolar lavage (BAL)-derived lung inflammatory cells (predominantly macrophages and neutrophils) from infants with HMD were cultured in the presence of lipopolysaccharide (LPS) and increasing concentrations of (rIL-10). The expression of IL-1beta and IL-8 protein was assessed 24 h later. IL-10 protein was also measured from the BAL aspirates of these newborns at 4-day intervals over the first month of life. In cell culture IL-1beta expression was inhibited by rIL-10 in a dose-dependent fashion while IL-8 expression was inhibited by higher concentrations of rIL-10. IL-10 protein was undetectable from BAL fluid of the premature infants sampled over 28 days. The results demonstrate that lung inflammatory cells, which do not express IL-10 in vivo, are capable of responding to rIL-10 in cell culture with reduction of IL-1beta and IL-8 expression. These data support the rationale for the development of rIL-10 as a potential anti-inflammatory agent in the treatment of HMD.

Subgaleal hemorrhage in a premature infant with congenital diaphragmatic hernia following vacuum-assisted delivery.

An infant with congenital diaphragmatic hernia was delivered by vacuum extraction, with a resultant subgaleal hemorrhage that excluded him from ECMO. The literature regarding vacuum-assisted delivery and birth trauma is reviewed in the context of congenital anomalies that may require ECMO support, and recommendations for perinatal management are suggested.

C-reactive protein levels in the extremely premature infant: case studies and literature review.

Sepsis continues to be a significant source of morbidity and mortality in the neonatal intensive unit. At the same time, we need to contain medical costs and prevent the rapid growth of resistant organisms by limiting unnecessary antibiotic use. Among laboratory indexes studied as indirect indicators of the presence and resolution of infection and inflammation, C-reactive protein (CRP) has gained more recent widespread use. CRP usually increases in a delayed manner with the onset of inflammation and decreases as inflammation resolves. We follow serial CRP values in our neonatal intensive care unit from the start of a sepsis evaluation until antibiotic therapy is withdrawn. We describe two extremely low birth weight patients who improved clinically with therapy and whose CRP levels normalized in the face of continued positive blood cultures. The implications for the use of CRP in deciding when to halt therapy in premature infants are discussed.

Differential regulation of IL-8 by IL-1beta and TNFalpha in hyaline membrane disease.

Mechanisms that regulate cytokine-mediated inflammation in the lungs of preterm infants, including factors which regulate production of the chemokine IL-8, remain poorly defined. Sequential bronchoalveolar lavage samples were obtained from preterm newborns with hyaline membrane disease over a 28-day period. Bronchoalveolar lavage cell cytokine relationships were evaluated and the differential regulation of IL-8 by IL-1beta and TNFalpha was studied in a short-term culture system. In vivo, IL-8 and IL-1beta protein levels correlated closely with each other and with macrophage counts. In cell culture, exogenous anti-IL-1beta antibody led to a 40% maximum inhibition (approximately) of IL-8 production by lipopolysaccharide stimulated lung inflammatory cells. Comparable amounts of exogenous anti-TNFalpha antibodies achieved a 15% maximum inhibition (approximately) of IL-8 production. Anti-IL-1beta and anti-TNFalpha antibodies in combination did not inhibit IL-8 production beyond that achieved by anti-IL-1beta antibody alone. These results, in preterm newborns, support the concept of lung inflammation mediated in part by a macrophage, IL-1beta, and IL-8 cell cytokine pathway. The results also suggest that factors other than IL-1beta and TNFalpha regulate IL-8 expression in the lungs of preterm infants.

Renal tolerance with the use of intralipid-amphotericin B in low-birth-weight neonates.

Amphotericin B is still the first-line therapy for neonatal fungal infections. With several comparative trials of intralipid-based amphotericin B (IL-AmB) demonstrating its clinical effectiveness and reduced renal toxicity in adults, we examined the renal tolerance and infection outcome in low-birth-weight infants in our 48-bed NICU treated with IL-AmB. Over 2 years, 52 patients (58 courses) received > or = 10 days of IL-AmB. Nineteen charts (23 episodes) were randomly accessed and reviewed. Mean birthweight = 747 grams, gestational age = 25.6 weeks, total IL-AmB dosage = 19.8 +/- 3.3 mg/kg (n = 23); 20 of these episodes were fungal culture positive (9 fungemias). Only one patient (who died during therapy) had a rise in creatinine of > 0.3 mg/dL. Overall, serum creatinine decreased significantly after Day 10 of IL-AmB therapy, from 0.93 +/- 0.42 mg/dL at baseline, to 0.54 +/- 0.24 after 19 days of therapy (p < 0.0001). Serial urine output, serum potassium and potassium supplementation data showed no significant differences from baseline. No interruption of therapy nor infusion reactions occurred. Only one death occurred attributable to fungal infection. Intralipid-amphotericin B may provide an effective alternative in the antifungal therapy of low birthweight neonates, without nephrotoxicity. Further prospective, comparative trials are warranted.

Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn.

BACKGROUND: Although inhaled nitric oxide (iNO) causes selective pulmonary vasodilation and improves oxygenation in newborn infants with persistent pulmonary hypertension, its effects are variable. We hypothesized (1) that the response to iNO therapy is dependent on the primary disease associated with persistent pulmonary hypertension of the newborn (PPHN) and (2) that the combination of high-frequency oscillatory ventilation (HFOV) with iNO would be efficacious in patients for whom either therapy alone had failed. METHODS: To determine the relative roles of iNO and HFOV in the treatment of severe PPHN, we enrolled 205 neonates in a randomized, multicenter clinical trial. Patients were stratified by predominant disease category: respiratory distress syndrome (n = 70), meconium aspiration syndrome (n = 58), idiopathic PPHN or pulmonary hypoplasia (excluding congenital diaphragmatic hernia) ("other": n = 43), and congenital diaphragmatic hernia (n = 34); they were then randomly assigned to treatment with iNO and conventional ventilation or to HFOV without iNO. Treatment failure (partial pressure of arterial oxygen [PaO2] < 60 mm Hg) resulted in crossover to the alternative treatment; treatment failure after crossover led to combination treatment with HFOV plus iNO. Treatment response with the assigned therapy was defined as sustained PaO2 of 60 mm Hg or greater. RESULTS: Baseline oxygenation index and PaO2 were 48 +/- 2 and 41 +/- 1 mm Hg, respectively, during treatment with conventional ventilation. Ninety-eight patients were randomly assigned to initial treatment with HFOV, and 107 patients to iNO. Fifty-three patients (26%) recovered with the initially assigned therapy without crossover (30 with iNO [28%] and 23 with HFOV [23%]; p = 0.33). Within this group, survival was 100% and there were no differences in days of mechanical ventilation, air leak, or supplemental oxygen requirement at 28 days. Of patients whose initial treatment failed, crossover treatment with the alternate therapy was successful in 21% and 14% for iNO and HFOV, respectively (p = not significant). Of 125 patients in whom both treatment strategies failed, 32% responded to combination treatment with HFOV plus iNO. Overall, 123 patients (60%) responded to either treatment alone or combination therapy. By disease category, response rates for HFOV plus iNO in the group with respiratory syndrome and the group with meconium aspiration syndrome were better than for HFOV alone or iNO with conventional ventilation (p < 0.05). Marked differences in outcomes were noted among centers (percent death or treatment with extracorporeal membrane oxygenation = 29% to 75%). CONCLUSIONS: We conclude that treatment with HFOV plus iNO is often more successful than treatment with HFOV or iNO alone in severe PPHN. Differences in responses are partly related to the specific disease associated with PPHN.

Undetectable interleukin (IL)-10 and persistent IL-8 expression early in hyaline membrane disease: a possible developmental basis for the predisposition to chronic lung inflammation in preterm newborns.

We are interested in determining whether premature birth alters expression of counterregulatory cytokines which modulate lung inflammation. Production of proinflammatory cytokines tumor necrosis factor alpha. IL-1 beta, and IL-8 is regulated in part by the antiinflammatory cytokine IL-10. For preterm newborns with hyaline membrane disease, deficiencies in the ability of lung macrophages to express antiinflammatory cytokines may predispose to chronic lung inflammation. We compared the expression of pro- and antiinflammatory cytokines at the mRNA and protein level in the lungs of preterm and term newborns with acute respiratory failure from hyaline membrane disease or meconium aspiration syndrome. Four sequential bronchoalveolar lavage (BAL) samples were obtained during the first 96 h of life from all patients. All patients rapidly developed an influx of neutrophils and macrophages. Over time, cell populations in both groups became relatively enriched with macrophages. The expression of proinflammatory cytokine mRNA and/or protein was present in all samples from both patient groups. In contrast, IL-10 mRNA was undetectable in most of the cell samples from preterm infants and present in the majority of cell samples from term infants. IL-10 concentrations were undetectable in lavage fluid from preterm infants with higher levels in a few of the BAL samples from term infants. These studies demonstrate that 1) IL-10 mRNA and protein expression by lung inflammatory cells is related to gestational age and 2) during the first 96 h of life neutrophil cell counts and IL-8 expression decrease in BAL from term infants, but remain unchanged in BAL samples from preterm infants.

Decreased alveolarization in baboon survivors with bronchopulmonary dysplasia.

In this study, 12 male baboons were delivered by hysterotomy at 75% of gestation. The development of a nonlethal baboon model permitted a study of lung growth and development in long-term survivors. Control animals were ventilated with clinically appropriate oxygen for the 21 d study period. BPD animals were ventilated with PPV and an FIO2 of 1.0 for 7 d, followed by an FIO2 of 0.8 for 14 d. They survived for 33 wk, at which time a right lower lobe lobectomy was performed. Controls showed normal well-alveolated lungs, whereas BPD lungs showed enlarged airspaces focally, nonclassifiable as alveoli, alveolar ducts, or respiratory bronchioles. Volume densities of alveoli were decreased significantly (p = 0.0009), and enlarged airspaces were significantly increased (p = 0.0003) in the BPD group compared with controls. Alveolar counts verified a significant decrease in alveoli (p = 0.004), and the internal surface area was significantly decreased (p = 0.05) in BPD treated animals compared with controls. These data document that a mild to moderate BPD lesion results in a significant and permanent loss of alveoli and a significant increase in enlarged, unclassifiable airspaces, which together result in a decreased total internal surface area in baboons that survive with their disease.

Surfactant protein-A deficiency in a primate model of bronchopulmonary dysplasia.

Pathophysiologic and biochemical (surfactant protein and phospholipid) features were studied in a baboon model of hyperoxia-induced bronchopulmonary dysplasia (BPD) and superimposed infection. A total of 20 baboons were delivered by hysterotomy at 76% of gestation (140 d of gestational age) and were randomized into four groups, consisting of two control and two injury groups. Animals constituting a group that was managed on a pro re nata (PRN) basis were ventilated with clinically appropriate oxygen for the 16-d experimental period and served as ventilatory controls. They underwent an initial period of 42 h during which they demonstrated evidence of hyaline membrane disease (HMD), but began recovery at 42 h and by Day 6 appeared to have maximally recovered. At the time of these animals' killing, concentrations of surfactant proteins, messenger ribonucleic acids (mRNAs), and phospholipids were similar to those of normal adult baboons. Gestational control animals were delivered and killed without ventilation at 156 d gestational age. Surfactant protein-A (SP-A) and phospholipid concentrations in these animals' lavage fluids were about 10% of those in the PRN animals. Animals with BPD were subjected to positive-pressure ventilation and an FIO2 of 1.0 for 11 d, followed by 5 d of an FIO2 sufficient to maintain PaO2 at 40 to 50 mm Hg. The animals with BPD and infection were treated in the same way as the BPD group, except that 10(8) Escherichia coli were instilled intratracheally on Day 11, concomitantly with the reduction in FIO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Severe retinopathy of prematurity in extremely low birth weight infants after short-term dexamethasone therapy.

With advances in neonatal intensive care survival of extremely low birth weight (< 1 kg) infants has increased significantly over the past decade. Dexamethasone is used increasingly for the prevention and treatment of chronic lung disease in these infants. The impact of dexamethasone therapy on the incidence or severity of retinopathy of prematurity (ROP) remains controversial. We conducted a retrospective study to evaluate the association between short-term dexamethasone treatment and severe ROP in extremely low birth weight infants. From October 1989 to December 1992, 309 very low birth weight infants were admitted to the neonatal intensive care unit. A total of 266 infants (86%) survived until hospital discharge. Of these, 90 weighed less than 1 kg. Thirty-eight of 90 infants received short-term dexamethasone therapy for chronic lung disease and the remaining 52 infants did not. Infants treated with dexamethasone and those not treated with dexamethasone were comparable in birth weight (820 vs 828 gm), gestational age (26.5 vs 26.9 weeks), inborn (11 vs 14), and occurrence of sepsis (13/38 vs 21/52). Infants treated with dexamethasone required longer periods of mechanical ventilation (44 +/- 23 vs 26 +/- 15 days, p < 0.001), had longer duration of supplemental oxygen (57 +/- 28 vs 29 +/- 23 days, p < 0.001), had higher incidence of patent ductus arteriosus (28/38 vs 18/52, p < 0.0003), and required surfactant therapy more often for respiratory distress syndrome (17/38 vs 11/52, p < 0.01), when compared with infants who did not receive dexamethasone. Severe ROP developed in 16 infants (stage III or higher); 12 of these were in the dexamethasone-treated group (p < 0.003). Thirteen infants required cryotherapy; nine were from the dexamethasone-treated group (p < 0.13). This study demonstrates an apparent association between the incidence of severe ROP and dexamethasone therapy. Prospective, randomized, controlled studies are needed to correct for differences in severity of cardiorespiratory illness to establish whether a causal role exists for steroid therapy in ROP. Until such studies are available, careful consideration must be given to indications, dosage, time of initiation, and duration of treatment with dexamethasone in extremely low birth weight infants.

SP-A deficiency in primate model of bronchopulmonary dysplasia with infection. In situ mRNA and immunostains.

The surfactant protein secretory cells in airway and alveolar epithelium were studied in premature baboons with bronchopulmonary dysplasia and superimposed infection. PRN animals were delivered by hysterotomy at 140 d gestational age and ventilated on clinically appropriate oxygen for a 16-d experimental period. To assess 0 time and sacrifice time gestational parameters, 140 and 156 d were studied. BPD animals were delivered at 140 d and ventilated with positive-pressure ventilation and an FIO2 of 1.0 for 11 d followed by 5 d of oxygen sufficient to maintain PAO2 at 40 to 50 mm Hg. BPD-infected animals were comparably ventilated and treated like the BPD group except that 10(8) E. coli organisms were endotracheally instilled on Day 11. In situ hybridization studies for mRNA expression of SP-A, SP-B, and SP-C revealed that an SP-A mRNA deficiency, present at 140 d, persisted in the BPD and BPD-infected groups, whereas SP-A mRNA was abundant in PRN and 156 d gestation control groups. SP-B and SP-C mRNA expression in the two hyperoxically injured groups was particularly extensive in cells around peribronchiolar and perivasicular sites. Immunostaining with SP-A, SP-B, and SP-C antibodies showed variable staining patterns. The study clearly demonstrates that a deficiency of SP-A mRNA expression persists in chronic lung injury and that variable protein staining patterns are manifested depending upon the underlying pathology.

Effect of ductal patency on organ blood flow and pulmonary function in the preterm baboon with hyaline membrane disease.

OBJECTIVE: To examine the effect of early ductal ligation vs. maintenance of ductal patency on vital organ perfusion and pulmonary function in premature baboons with hyaline membrane disease. DESIGN: Randomized, controlled interventional study to compare early ligation with formalin infiltration of the ductus arteriosus. SETTING: Animal care facility at a dedicated research foundation. SUBJECTS: Eighteen premature baboons delivered by hysterotomy at 140 +/- 2 day gestation. INTERVENTION: Nine premature baboons underwent formalin infiltration of the ductus arteriosus (group 1), and nine underwent ductal ligation (group 2). Surgical ligation or formalin infiltration was performed at 2 to 4 hrs of age. Animals were maintained on mechanical ventilation and ventilator parameters were adjusted to maintain PaO2 and PaCO2 within the physiologic range. MAIN OUTCOME MEASURES: Left ventricular output indexed to body weight and vital organ perfusion were measured at 24 hrs of age by the radiolabeled microsphere method. Lung mechanics, including lung wet/dry weight ratio, total lung water, static compliance and functional residual capacity were measured immediately following euthanasia. RESULTS: Total pulmonary blood flow was significantly lower (p = .0001) in group 2 (mean = 94 mL/min/kg), compared with group 1 (mean = 287 mL/min/kg). Systemic blood flow and effective pulmonary blood flow were higher in group 1 (p = .07). No significant difference between groups in absolute organ blood flow was noted, although flow as a percent of left ventricular index was significantly higher in all organs except the kidney in group 2. There was no difference in arterial blood gas values, parameters of mechanical ventilation, percent lung water, or postmortem measurement of lung mechanics between groups. CONCLUSION: Early ductal ligation did not result in improved cardiac output, increased organ blood flow, or improved pulmonary function. We postulate that gradual constriction of the ductus arteriosus may play an important role in successful cardiovascular adaptation in the premature infant. While it is clear that premature infants with symptomatic patent ductus arteriosus often benefit from ductal closure, we question the practice of prophylactic early ductal closure.

Failure of acute perinatal asphyxia or meconium aspiration to produce persistent pulmonary hypertension in a neonatal baboon model.

OBJECTIVE: Our purpose was to determine whether perinatal asphyxia or meconium aspiration, or both, can produce the physiologic and histologic pulmonary vascular changes associated with the meconium aspiration syndrome. STUDY DESIGN: Twenty neonatal baboons were studied in four groups: 1, control; 2, meconium aspiration; 3, asphyxia (intermittent cord compression); and 4, asphyxia with meconium aspiration. Animals were ventilated for 24 hours under ketamine, diazepam, and pancuronium. Data were analyzed by means of mixed model analysis of measures. RESULTS: Meconium significantly impaired oxygenation (p < 0.001), whereas concurrent asphyxia moderated this effect (p < 0.034). Meconium also increased the need for ventilatory support (p < 0.002). No animal had persistent pulmonary hypertension; neither systemic nor pulmonary systolic pressures differed statistically between the groups. No animal showed evidence of abnormal pulmonary arteriolar muscularization. CONCLUSION: Sublethal perinatal asphyxia or meconium aspiration were insufficient to produce either the physiologic or histologic changes of severe meconium aspiration syndrome. It is unlikely that intrapartum fetal distress alone can produce this syndrome in human neonates.

Total parenteral nutrition does not improve diaphragm development in premature baboons.

We hypothesized that total parenteral nutrition accelerates growth and development of diaphragm muscle (DPH) in prematurely delivered baboons (140 days gestation). For 10 days after delivery by cesarean section, we administered parenteral nutrition containing glucose, electrolytes, and water or total parenteral nutrition containing lipids, amino acids, glucose, vitamins, and electrolytes. After 10 days of care, dorsolateral and ventrolateral (VL) costal DPH were sampled for histochemically determined mean fiber area (MFA) and fiber type percentages. We determined isolated bundle isometric tension (normalized for cross-sectional area), time to peak tension, half-relaxation time, force-frequency relationship, and fatigability. Neither sex nor nutritional treatment affected contractile properties. Differences among sexes and muscle sites, but not among nutritional treatments, were observed for histochemical characteristics. In females, the VL DPH had a lower percentage of type IIo fibers and a greater MFA of type IIc fibers than the dorsolateral DPH and a lower percentage of type IIo fibers and greater MFA of type IIc and IIo fibers than the VL DPH in males. Mean fiber cross-sectional area of VL DPH was significantly greater in females than males. The larger fibers in females than males suggest a stronger DPH in females. Earlier growth of type II fibers in females could contribute to a better outcome for female than male premature infants with hyaline membrane disease.

Long-term partial liquid ventilation (PLV) with perflubron in the near-term baboon neonate.

PURPOSE: The feasibility and safety of continuous long-term (4-5 day) partial liquid ventilation (PLV) using perflubron was demonstrated in newborn baboons. PLV, a potential therapy for adult and neonatal respiratory distress syndrome (RDS), is conventional mechanical ventilation (CMV) with the lung filled to about functional residual capacity with perfluorochemical liquid. PROTOCOL: As a pilot trial for a larger preclinical study focused on the safety of extended duration PLV, three near term baboons were studied. The animals were delivered by cesarean section, anesthetized, intubated and placed on CMV. The animals were given intratracheal perflubron (30 ml/kg) and maintained on PLV for 96 hours. The transition back to gas ventilation occurred, after draining, over the fifth day (hrs 96-120). RESULTS: Two of the animals were born with normal pulmonary function, while the third developed respiratory distress prior to PLV. All the animals were adequately supported with PLV using moderate ventilator settings and low concentrations of oxygen. Perflubron distribution was enhanced by periodic rotation of the animals. Preliminary histology show vacuolated alveolar macrophages and no evidence of edema or other significant changes in the lungs. Pulmonary function in the RDS animal, after PLV treatment, showed normal gas exchange and lung mechanics. CONCLUSIONS: Three near term baboons, one with clinical RDS, tolerated 4 days of PLV followed by 1 day of CMV without complications using practical clinical management methods.

Tissue inhibitor of metalloproteinase-1 mRNA is specifically induced in lung tissue after birth.

Interactions between extracellular matrix, proteins, metalloproteinases, and their inhibitors play a major role in determining the structure of the lung during in utero development and after birth. To better understand the molecular mechanisms underlying lung development and morphogenesis, expression of the tissue inhibitor of metalloproteinase (TIMP-1) gene was examined 1) through the course of late fetal development, 2) when normal fetal development was interrupted by premature birth and extrauterine survival, and 3) during exposure of prematurely delivered neonates to hyperoxia. Total RNA isolated from lung tissue of fetal baboons (Papio sp) at 140, 150, and 180 d of gestation (term gestation = 180 d); baboons prematurely delivered at 140 d of gestation, 1, 2, 6, and 10 d old; and premature baboons ventilated for 6 and 10 d with 100% oxygen was examined by Northern blot analysis. The results demonstrated that TIMP-1 mRNA, which is expressed at low levels during fetal development, undergoes a marked increase in abundance shortly after both premature and term birth. This parturition-induced pattern of gene expression appears to be tissue specific to the lung and, contrary to results reported for adult and neonatal animals, is not affected by ventilation of the premature lungs with 100% inspired oxygen. Although the physiologic consequences of TIMP-1 mRNA induction by birth are not yet known, these data suggest a possible role for TIMP-1 in postnatal adaptation of lung tissue.