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Biomedical subjects

R A deLemos

Publications and source records attributed to R A deLemos.

At least 19 recordsLinked to original sources
PubMed1996

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.

Bronchoalveolar Lavage↗
PubMed1995

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.

Adrenal Glands↗
PubMed1995

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)

Animals↗
PubMed1995

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.

Animals↗
PubMed1994

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.

Acute Disease↗
PubMed1994

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.

Animals↗
PubMed1993

Hormonal response of the premature primate to operative stress.

There are few data on the hormonal response to operation in the premature infant. Studies examining the response of newborn human infants have been performed on patients beyond the first few days of life, where some adaptation to postnatal life has occurred. This study evaluated the response of the newly born premature primate to surgical stress. Premature baboons (75% gestation) were intubated, mechanically ventilated and underwent thoracotomy at 2 hours of life with exposure of the ductus arteriosus (PDA). In group 1, formalin was infiltrated to keep the ductus patent. In group 2, the PDA was ligated. Controls had no operation. Blood was drawn at 0, 6, 24, 48, 72, and 96 hours of age. Echocardiograms were performed to confirm patency or closure of the ductus and to monitor cardiac function. Epinephrine, norepinephrine, renin, and cortisol levels were measured. Cortisol levels rose in all groups. Operation stimulated a marked increase in catecholamine and renin levels in both operative groups, which was more marked in the group with PDA ligation at 24 hours. These data reflect expected pathophysiology since early PDA ligation exerts additional hemodynamic demand on the heart. In conclusion, the premature primate is able to mount a significant and severity-dependent endocrine response to stress.

Animals↗
PubMed1993

A primate model of Ureaplasma urealyticum infection in the premature infant with hyaline membrane disease.

Cultures positive for Ureaplasma urealyticum in babies weighing < 1000 g have been associated with both chronic lung disease (CLD) and death, but no definite causality has been established. To further investigate the role of the organism in CLD, we colonized premature baboons with U. urealyticum and compared resulting pathology with that in uninoculated control animals. Using an established model of prematurity, the 140-day-gestation baboon, three animals were colonized with U. urealyticum via endotracheal tube. All had hyaline membrane disease, indistinguishable from disease in human infants, and U. urealyticum infection. Samples obtained from nasopharynx, trachea, pleural fluid, and, at necropsy, lung tissue produced positive cultures. Culture of blood from one animal yielded U. urealyticum. On pathologic examination, after 6 days of ventilation, all three of the infected animals had the specific pathologic finding of bronchiolitis with epithelial ulceration not seen in four uninfected control animals. Thus, U. urealyticum is capable of causing a pathologically recognizable pulmonary lesion in premature primates with hyaline membrane disease.

Animals↗
PubMed1993

Decreased pulmonary damage in primates with inhalation injury treated with high-frequency ventilation.

OBJECTIVE: This study compared two forms of high-frequency ventilation (HFV) with conventional volume ventilation (CON) in a primate model of inhalation injury to determine whether ventilatory mode was a determinant of pulmonary damage. SUMMARY BACKGROUND DATA: The authors previously reported that the prophylactic use of high-frequency flow interruption in patients with bronchoscopically diagnosed inhalation injury requiring mechanical ventilatory support resulted in a significant decrement in mortality. They hypothesized that a reduction in ventilatory mode induced pulmonary damage was in part responsible for their clinical results. METHODS: Fifteen adult baboons were randomized to one of three ventilatory modes (CON, high-frequency flow interruption [HFFI], or high-frequency oscillatory ventilation [HFO]) after moderate smoke injury. Ventilatory support was tailored to the same physiologic endpoints. After 7 days, the animals were killed and pulmonary pathologic changes were scored and compared. Repetitive physiologic and biochemical data were compared using analysis of variance for repeated measures. RESULTS: Physiologic endpoints were achieved in CON and HFFI, but not in HFO. Hemodynamic variables did not differ between CON and HFFI. The barotrauma index was greater in CON compared to HFFI (p < 0.05), despite similar PO2, FIO2, AA gradient, and PCO2. Animals treated with HFFI had significantly less parenchymal damage than those treated with CON (p = 0.03) or HFO (p = 0.0008). CONCLUSIONS: The prophylactic use of HFFI led to a significant decrement in ventilatory mode induced pulmonary damage and offers an explanation for the decreased mortality in inhalation injury patients treated with HFFI.

Animals↗
PubMed1993

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.

Animals↗
PubMed1993

Effect of premature birth and survival on hepatic thyroxine 5'-monodeiodinase activity in baboons.

Plasma thyroid hormones and hepatic 5'-monodeiodinase type I (5'-MDI) activity were measured in a primate model of premature birth and survival. When prematurely delivered at 140 days (term gestation is 184 days), infant baboons developed hyaline membrane disease, had no surge in T3 and T4, temporarily developed hypothyroxinemia, and had extremely low T3 concentrations during the first 40 h of life. After 4 days, both plasma T4 and T3 levels progressively increased, but were still considerably lower at 16 days compared to those in normal term infants. Hepatic 5'-MDI activity was measured in the presence of dithiothreitol in fetal, premature, and infant baboons. Fetal baboons at 140 and 161 days gestation had 80% less 5'-MDI activity than term infants, but at 178-180 days gestation, near term, fetal hepatic 5'-MDI activity increased to levels similar to those in young adults. Interruption of in utero development by premature birth resulted in no change in hepatic 5'-MDI activity after 24 h, but within 6 days after delivery, hepatic 5'-MDI had significantly increased to levels observed in fetal baboons near term. Kinetic analysis revealed that fetal and premature 5'-MDI had different maximum velocities and similar apparent Km values. There was no significant difference in hepatic total, protein, or nonprotein sulfhydryl groups between 1- and 10-day-old premature (140 days gestation) baboons. These results suggest that premature birth does not limit the postnatal maturation of hepatic 5'-MDI activity.

Animals↗
PubMed1992

Rescue ventilation with high frequency oscillation in premature baboons with hyaline membrane disease.

We tested the hypothesis that high-frequency oscillatory ventilation can be efficacious in hyaline membrane disease (HMD) even after lung injury is established. We compared high frequency oscillatory ventilation (HFOV) rescue (n = 8; 15 Hz; I:E = 1:2) after 8 hours of positive pressure ventilation (PPV) with positive end-expiratory pressure, to continued PPV (control, n = 7) in premature baboons with HMD over a 24 hour period. Ventilator settings and physiologic parameters were recorded hourly. At necropsy (24 hours), lung status pressure-volume curves, alveolar phospholipids (PL), platelet activating factor-like activity (PAF), and lung water were determined. Roentgenographic and morphologic differences in lung inflation were quantified by standard techniques. No intergroup differences were found in heart rate, blood pressures, ventilator settings, FiO2, blood gases, or chest radiographs during the first 8 hours. Both groups had progressive physiologic disease. At 8 hours, HFOV-rescue animals, in contrast to controls, had immediate significant time-related improvements in Pa/AO2 (at the same Paw) and in oxygenation index (Pa/AO2/Paw) lasting for 16 hours. No significant intergroup differences in lung/body weight, lung water, lung mechanics, PL, PAF, or frequency of moderate to severe roentgenographic changes existed at 24 hours. Although all animals had morphologic evidence of HMD, saccular aeration was more uniform and airway dilatation less evident in HFOV rescue (P less than 0.0001). Based on the improved gas exchange, we conclude that HFOV rescue was efficacious in the "late' treatment of HMD, presumably because of the more uniform saccular aeration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The contribution of experimental models to our understanding of the pathogenesis and treatment of bronchopulmonary dysplasia.

The extensive data from animal models of BPD and specific aspects of lung injury have helped to expand and refine the concept of pathogenesis introduced by Northway et al. Given the complexity and heterogeneity of the human illness, it is unreasonable to presume that any single model or research group could elucidate all of the features and interactions of this complex disease. Therefore, we have combined data from animal homologues of BPD with that available on specific injury mechanisms to construct a more comprehensive model of pathogenesis (Fig. 5). Of particular interest is the recent data suggesting that the accelerated maturation of the prematurely born infant is associated with specific defects in gene expression that might increase vulnerability to lung injury. Additional animal research is needed both to further refine this model of pathogenesis and to develop the basis for a more rationale approach to the prevention and treatment of BPD. Based on the research progress to date, we feel the priorities for the future should at the least include continued definition of the biochemical and molecular mechanisms underlying various types of lung injuries; evaluation of those mechanisms (and the consequences of their interruption) in a developmentally relevant setting; and further elaboration of the currently available BPD models to include factors (such as ante- and postpartum infections) that have not previously been part of these animal model systems. This approach, we feel, will complement human studies and ultimately lead to the prevention and better clinical management of this major health care problem.

Animals↗
PubMed1992

Prospective randomized comparison of high-frequency oscillatory and conventional ventilation in respiratory distress syndrome.

A prospective randomized trial with a crossover design was conducted to compare the efficacy and safety of two distinct strategies of high-frequency oscillatory ventilation (HFOV) to conventional intermittent mandatory ventilation (CV) in the management of respiratory distress syndrome. Only premature neonates with a birth weight less than 1.751 kg were eligible for enrollment into the study. Of 83 patients studied, 26 patients were assigned to CV-only, 27 to HFOV for 72 hours followed by CV (HFOV/CV), and 30 to HFOV-only until extubation. There was no difference among the three groups with respect to the incidence of pulmonary airleak, intraventricular hemorrhage, or death. The highest incidence of chronic lung disease was in the CV-only group. Although both HFOV groups had a lower incidence of chronic lung disease assessed at 30 days and 36 weeks postconception age, the difference was statistically significant only between the CV-only and HFOV-only groups (65% vs 30% at 30 days; P = .008; 38% vs 10% at 36 weeks postconception age, P = .013). These results suggest that use of HFOV as the predominant mode of ventilation in the management of respiratory distress syndrome is as safe as CV and can contribute to a decreased incidence of chronic lung disease. Furthermore, a short (72-hour) period of HFOV support does not provide the same advantage as continuous HFOV.

Analysis of Variance↗
PubMed1991

Cardiac output by Doppler echocardiography in the premature baboon: comparison with radiolabeled microspheres.

Pulsed-Doppler echocardiography (PDE) is a useful noninvasive method for determining left ventricular output (LVO). However, despite increasingly widespread use in neonatal intensive care units, validation studies in prematures with cardiopulmonary disease are lacking. The purpose of this study was to compare radiolabeled microsphere (RLM) and PDE measurements of LVO, using the critically ill premature baboon as a model of the human neonate. Twenty-two paired RLM and PDE measurements of LVO were obtained in 14 animals between 3 and 24 h of age. Average PDE LVO was 152 ml/min/kg (range, 40-258 ml/min/kg) compared to 158 ml/min/kg (range, 67-278 ml/min/kg) measured by RLM. Linear regression analysis of the paired measurements showed good correlation with a slope near unity (gamma = 0.94x + 4.20, r = 0.91, SEE = 25.7 ml). We conclude that PDE determinations of LVO compare well with those measured by RLM in the premature baboon. PDE appears to provide a valid estimate of LVO and should be useful in human prematures with cardiopulmonary distress.

Animals↗
PubMed1991

Ductal shunting and effective systemic blood flow following single dose surfactant treatment in the premature baboon with hyaline membrane disease.

We studied the hemodynamic effects of using natural surfactant in premature baboons with hyaline membrane disease (HMD). Study animals (n = 5) received a single dose of surfactant immediately after delivery and control animals (n = 8) did not. Using microspheres at 3, 8, and 23 h we found no significant differences in left ventricular output, effective systemic flow, systemic-to-pulmonary patent ductus arteriosus (PDA) shunting, or in cerebral or renal organ blood flow. However, both groups had large PDA shunts (fraction of LVO to lungs greater than 0.40-0.55 at 3 and 8 h) resulting in low systemic perfusion (less than 80 ml/min/kg). Single dose surfactant did not improve the myocardial dysfunction and low cerebral and renal blood flow which occur during treatment for HMD.

Animals↗