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Biomedical subjects

R A deLemos

Publications and source records attributed to R A deLemos.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1991

High-frequency oscillatory ventilation versus intermittent mandatory ventilation: early hemodynamic effects in the premature baboon with hyaline membrane disease.

We studied the hemodynamic consequences during the first 24 h of life in premature baboons (140 d) with hyaline membrane disease that were treated with high-frequency oscillatory ventilation (HFOV) or conventional intermittent mandatory ventilation (IMV). Cardiac output and organ blood flow were measured at three time-points using the radiolabeled microsphere technique. Seven of seven HFOV and six of eight IMV animals survived the 24-h period. By design, initial mean airway pressure (Paw) was higher in the HFOV group (p less than 0.01). HFOV Paw was progressively reduced during the study period because of improving oxygenation as measured by the arterial to alveolar oxygen ratio. In contrast, it was necessary to increase Paw in the IMV animals to maintain the arterial to alveolar oxygen ratio. By 23 h, the IMV group required higher Paw than the HFOV group (p less than 0.05) and had a lower arterial to alveolar oxygen ratio (p less than 0.05). We found no significant differences in left ventricular output, effective systemic flow, organ blood flow, or central venous pressure between the two groups at 3, 8, or 23 h. The HFOV strategy used in our study resulted in significant improvement in oxygenation during the initial 24 h of treatment without adverse effect on left ventricular output, cerebral blood flow, or central venous pressure. We conclude that when appropriate changes in Paw are made during HFOV in response to improvement in arterial oxygenation and changes in lung inflation as assessed by chest radiographs HFOV can be achieved without depressing cardiovascular dynamics more than during conventional therapy with IMV.

Animals↗
PubMed1991

High-frequency ventilation: issues of strategy.

Although each high-frequency ventilator has functional characteristics that are design related, it now appears that when used with similar treatment strategies and within their functional limitations, similar clinical outcomes can be realized. Optimized treatment protocols must vary depending on the pulmonary disease to be treated, with strategies during treatment for pulmonary injury different from those used in pulmonary injury prevention. It is still unclear whether any one particular high-frequency ventilator will have specific disadvantages that cannot be overcome by device modification and that are inherent in a particular HFV methodology. Experimental and clinical data suggest that HFV will contribute significantly in reducing neonatal pulmonary morbidity and aid in the prevention of chronic pulmonary disease.

Clinical Protocols↗
PubMed1990

Toxic effects associated with the administration of deferoxamine in the premature baboon with hyaline membrane disease.

We hypothesized that administration of the iron chelator deferoxamine would inhibit iron-catalyzed free radical generation and lessen the severity of oxygen-induced pulmonary injury. To evaluate its efficacy and safety in premature infants, we administered deferoxamine by intravenous infusion to five premature baboons with hyaline membrane disease supported with conventional ventilation and 100% oxygen for 6 days. Seven animals served as controls. Deferoxamine treatment was initiated at 10 mg/kg per hour but, after the precipitous death of the first animal, was progressively reduced to 1.25 mg/kg per hour in the other animals. Four of five deferoxamine-treated baboons developed cardiovascular collapse and all five died by 42 hours. Five of the seven control animals survived the 6-day experimental period. Since cardiovascular toxic effects have not previously been reported, these findings suggest unique vulnerability of the immature cardiovascular system to iron chelation.

Animals↗
PubMed1990

Left ventricular dysfunction following ligation of the ductus arteriosus in the preterm baboon.

We evaluated the effect of early closure of the patent ductus arteriosus (PDA) on cardiac performance in a preterm baboon model of hyaline membrane disease. Eleven baboon fetuses were delivered at 75% gestation, resuscitated, and treated with conventional ventilation. The animals were divided into two groups, and underwent left thoracotomy at 2 hr of age. Group 1 (N = 5) had ductal infiltration with formalin to maintain ductal patency. Group 2 (N = 6) had ductal ligation. Hemodynamic parameters were compared between groups before and after surgical intervention. Examination of cardiovascular function was performed at intervals over a 24-hr period using two-dimensional, M-mode, and pulsed Doppler echocardiography. Ventricular performance was significantly worse in the ligation animals as demonstrated by reduced left and right ventricular outputs and reduced left ventricular shortening. However, pulmonary disease and arterial blood gases were not different. Early ligation was also associated with significantly increased systemic vascular resistance. We conclude that early ductal ligation leads to impaired ventricular performance in the premature primate. We hypothesize that the PDA may protect the immature ventricle by preventing pressure overload during adaptation to postnatal life.

Animals↗
PubMed1990

Acute inhalation toxicity of soman and sarin in baboons.

Adult baboons (Papio sp.; 8-12 kg) were anesthesized with sodium pentobarbital (20 mg/kg iv). The animals were instrumented for measurement of mean blood pressure (MBP), pulmonary artery pressure (PAP), ECG, arterial and mixed venous blood gases, lung volumes, lung pressures, and efferent phrenic nerve activity. Bronchoalveolar lavage (BAL) was performed. Studies were done prior to exposure, at intervals during the first 4 hr postexposure, and at 4 and 28 days after exposure. Control animals received a sham exposure to 2-propanol (N = 5). Soman (pinacolyl methylphosphonofluoridate) at 13.14 micrograms/kg (2 X LD50) was vaporized into the upper airway in a second group of animals (N = 5), and sarin (isopropyl methylphosphonofluoride) 30 micrograms/kg (2 X LD50) was vaporized into a third group of animals (N = 4). Controls showed no change in any parameter either immediately after diluent exposure or during the monitoring period. Soman and sarin produced a decline in MBP and bradyarrhythmias that were reversed with atropine. Apnea occurred in all soman- and sarin-exposed animals within 5 min postexposure, and was associated with absence of phrenic nerve signal. Ventilation was mechanically supported until the animal could maintain normal arterial blood gases during spontaneous breathing. BAL studies revealed an increase in total white cell population and neutrophils at 4 hr in all three groups. There were signs of impaired hemodynamics and persistent lung injury for 4 days that resolved by 28 days after exposure. In conclusion, inhalation of soman and sarin in the baboon is associated with cardiac arrhythmias, development of apnea, and a significant decrease in MBP. Inhalation exposure also resulted in a persistent influx of neutrophils and hypoxemia.

Administration, Inhalation↗
PubMed1990

Proximal, tracheal, and alveolar pressures during high-frequency oscillatory ventilation in a normal rabbit model.

To study the effect of different high-frequency oscillatory ventilation parameters on airway pressure, we measured oscillatory pressure amplitude ([Paw[) and mean airway pressure (Paw) at three sites in open-chested normal rabbits: proximal, trachea, and alveolus. Five animals were studied to test a new pleural capsule design, which was then used in two groups of animals to measure right upper (n = 4) or middle (n = 5) lobe alveolar pressures. Animals were randomly sequenced through combinations of frequency (10, 15, and 20 Hz) and fractional inspiratory time (Ti) (0.3 and 0.5) while normoxic and eucapnic. During capsule testing, we noted that alveolar pressures increased (p less than 0.05) with increasing capsule mass, suggesting that compressive forces from the capsule may alter the capsule measurement. We thus used a low-mass (430 mg) transducer system in the rabbit high-frequency oscillatory ventilation experiments. Using multifactorial analysis of variance, we found significant main effects of Ti on Paw, and of measurement site on both [Paw[ and Paw (all p less than 0.009). Frequency did not influence variations in either [Paw[ or Paw. For both Ti settings, alveolar upper lobe Paw was lower compared with that of the middle lobe (p less than 0.0005). Lengthening Ti (0.3 to 0.5) increased tracheal Paw in each capsule group (p less than 0.0005). At Ti = 0.5, tracheal Paw exceeded Paw measured proximally (p less than 0.05). Our data support in vivo alveolar Paw inhomogeneity and demonstrate significant changes in pressures within the lung related to Ti during high-frequency oscillatory ventilation.

Analysis of Variance↗
PubMed1990

High-frequency oscillatory ventilation and extracorporeal membrane oxygenation for the treatment of acute neonatal respiratory failure.

Forty-six (92%) outborn and four (8%) inborn term or near-term neonates were admitted for extracorporeal membrane oxygenation (ECMO) treatment to a neonatal intensive care unit between July 1, 1985, and November 1, 1987. All infants had PAO2-PaO2 greater than or equal to 600 mm Hg in spite of aggressive conventional ventilatory and pharmacologic therapy. All patients were offered rescue treatment with high-frequency oscillatory ventilation (HFOV), and only if there was no improvement in PAO2-PaO2 with HFOV were infants treated using ECMO. Four patients died before receiving an adequate trial of HFOV and before emergency ECMO support could be initiated; 21 patients, all of whom survived to hospital discharge, responded to HFOV; 25 patients ultimately required ECMO therapy for cardiopulmonary support, with 22 (88%) surviving to discharge. Neonates responding to HFOV were of slightly younger gestational age (38 +/- 2 weeks vs 40 +/- 2 weeks, mean +/- SD; P less than .001) and more frequently had clinical evidence of pneumonia (11 of 21 vs 2 of 25; P less than .002). There was no statistically significant difference in outcome with respect to the number of ventilator days, hospital days, or survival between patients responding to HFOV and patients who required ECMO. Morbidity was increased in ECMO patients, with bleeding abnormalities, seizures, and renal failure occurring more frequently than in HFOV-treated infants. Overall, 92% (46 of 50) of the patients were treated with a staged protocol using HFOV before ECMO. A total of 46% (21 of 46) responded to HFOV treatment alone and did not require ECMO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Extracorporeal Membrane Oxygenation↗
PubMed1989

Alpha-myosin heavy chain cDNA structure and gene expression in adult, fetal, and premature baboon myocardium.

To examine cardiac myosin gene structure and expression in a non-human primate model for human heart development and disease, we have constructed a cDNA library from baboon atrium and used baboon beta-myosin heavy chain (beta-MHC)* cDNA probes to isolate atrial MHC clones. The nucleotide sequence of one such clone, lambda BMHC alpha 3, contains sequences that encode part of the light meromyosin region (LMM) and the 3' untranslated region of the baboon alpha-MHC. To study cardiac MHC gene transcription, we constructed probes from the baboon alpha-MHC cDNA for S1 nuclease analyses of RNA from atria and ventricles. To examine translational regulation of cardiac MHC gene expression, we used monoclonal antibodies (MAb) against specific alpha- and beta-MHC epitopes for Western blot analyses. In atria and ventricles from adult baboons, we detected predominantly alpha- and beta-MHC gene transcripts, respectively. In ventricles from fetal baboons at two stages of development (140 and 160 days gestation), we also detected predominantly beta-MHC gene transcripts and isoforms. To investigate changes induced by parturition, we obtained ventricles from baboons that were prematurely delivered at 140 days gestation and supported for 10 days in an extrauterine environment. In contrast to adult and fetal patterns, we observed an increase in alpha-MHC transcripts and isoforms in ventricles of premature baboons. Because alpha-MHC gene expression is increased in premature baboons (total age of 150 days) compared to their older 160 day fetal counterparts, the induction of ventricular alpha-MHC synthesis must have resulted from factor(s) associated with parturition or prolonged mechanical ventilation rather than at predetermined stages of gestational development.

Amino Acid Sequence↗
PubMed1989

A comparison of ventilation strategies for the use of high-frequency oscillatory ventilation in the treatment of hyaline membrane disease.

To assess the efficacy of high frequency oscillatory ventilation (HFOV) in the management of infants with hyaline membrane disease (HMD), we compared two HFOV strategies with conventional positive pressure ventilation with positive end expiratory pressure (PPV) for 24 h in premature baboons (140 d gestation). Three out of 14 PPV, five out of five HFOV-E (begun at birth; 15 Hz; I:E 1:2), and none of 10 HFOV-L (begun after 3 h PPV; 10 Hz; I:E 1:2) were killed at 24 h for morphologic examination. Physiologic (Paw, Pa/AO2, IO2, B.P., pulse, blood gases) data on all animals in each group were assessed at each 3 h interval and over time. Intergroup differences in radiographs at 0 and 24 h and in morphology were quantitatively assessed by comparison with a panel of standards. All animals had radiographic HMD. Initial Paw was set higher with HFOV-E (16.8) than PPV or HFOV-L (14.1, 14.1). PPV baboons required increasing Paw to maintain constant Pa/AO2. Six out of 14 PPV animals developed airleak and three out of three had morphologic HMD. In contrast Pa/AO2 was higher in both HFOV groups at lower Paw by 24 h. None of 15 HFOV animals developed airleak. HFOV-E lungs had dramatic differences in morphology with uniform saccular opening and decreased edema and hyaline membranes compared to PPV. HFOV-L had less dramatic effects because of lower Paw and delayed application. Early use of HFOV at a high Paw favorably alters the course of HMD. Unless closely monitored, this strategy results in lung overinflation which may adversely affect venous return and cardiac output.

Animals↗
PubMed1989

Pathologic features of various ventilatory strategies.

Five pathologic findings have been found to be associated with ventilatory-induced lung injury in the premature baboon model of hyaline membrane disease. They are: (1) tracheal and major bronchial lesions, (2) small airway changes, (3) inflation pattern aberrations, (4) bronchoalveolar hemorrhage, and (5) air leak problems. The use of immediate high frequency oscillatory ventilation (HFOV) prevents the bronchiolar overdistension (small airway), atelectasis (inflation pattern), and air leak problems. The lesions in the trachea and large bronchi of prematures all show injury secondary to prolonged intubation, but after HFOV the lesions are no worse than those seen in PPV-treated tracheas. HFOV does increase the incidence of bronchoalveolar hemorrhages, and this lesion plus some of the non-pulmonary complications will require further investigation.

Animals↗
PubMed1989

Role of lung injury in the pathogenesis of hyaline membrane disease in premature baboons.

To test the hypothesis that hyaline membrane disease (HMD) has a multifactorial etiology in which barotrauma plays a major role, we compared the immediate institution of high-frequency oscillatory ventilation (HFOV; 15 Hz, n = 5) with positive-pressure ventilation with positive end-expiratory pressure (PPV; n = 7) in premature baboons (140-days gestation) with HMD. Measurements of ventilation settings and physiological parameters were obtained and arterial-to-alveolar O2 (PaO2-to-PAO2) ratio and oxygenation index [(PaO2/PAO2)-to-mean airway pressure ratio (IO2)] were calculated. At death (24 h), static pressure-volume (PV) curves were performed, and phospholipids (PL) and platelet-activating factor (PAF) were measured in lung lavage fluid. Morphological inflation patterns were analyzed using a panel of standards. By design, mean airway pressure was initially higher (19 vs. 13 cmH2O) in the HFOV animals. PaO2-to-PAO2 ratio and IO2 progressively deteriorated in the PPV animals and then stabilized at significantly lower levels than with HFOV. PV curves from HFOV animals had significant increases in lung volume at maximum distending pressure, deflation volume at 10 cmH2O, and hysteresis area compared with PPV, which showed no hysteresis. Seven of seven PPV and only one of five HFOV animals had morphological findings of HMD. PL amount and composition in both groups were consistent with immaturity, even though the quantity was significantly greater in the PPV group. PAF was present (greater than or equal to 0.10 pmol) in six of seven PPV and in the only HFOV animal with HMD. We conclude that HFOV protected PL-deficient premature baboons from changes in gas exchange, lung mechanics, and morphology typical of HMD in this model.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Influence of ventilatory technique on pulmonary baroinjury in baboons with hyaline membrane disease.

To assess the influence of ventilatory technique on pulmonary baroinjury in experimental hyaline membrane disease, we randomized 24 premature baboons to six treatment groups according to ventilator (PPV, positive pressure ventilator; HFO, high frequency oscillator; HFI, high frequency flow interrupter) and O2 therapy FIO2 as clinically indicated, or FIO2 1.0). PaCO2 was adjusted by varying pressure amplitude, and for PPV, also by rate (less than 60/min). HFO and HFI were set at a frequency of 10 Hz. Animals were cared for with standard NICU techniques until death or sacrifice at 11 days. One animal died at delivery and was excluded from data analysis. There were no intergroup differences in Paw, Pa/AO2, PaCO2 or oxygenation index (IO2 = [Pa/AO2]/Paw) prior to death of the first study animal at 13 h. Animals who subsequently developed airleak had higher Paw, lower Pa/AO2 and lower IO2 during this period. The degree of airleak was significantly less with HFO compared to PPV or HFI. The effect of O2 exposure did not appear different with respect to the degree of airleak or the frequency of severe tracheal injury, although survival was shortened. Severe tracheal injury was more frequent with HFI compared to PPV or HFO. BPD was found only in 100% O2 exposed animals surviving greater than 1 wk. Management of premature baboons with HFO and appropriate O2 resulted in less severe airleak, 100% survival, and no evidence of severe tracheal injury or BPD. These outcomes were not achieved with clinically similar strategies using PPV or HFI.

Animals↗
PubMed1988

Tracheal and bronchial injury in high-frequency oscillatory ventilation and high-frequency flow interruption compared with conventional positive-pressure ventilation.

We compared the histopathologic changes in the airways of premature baboons treated with conventional positive-pressure ventilation (PPV) with those seen after high-frequency oscillatory ventilation (HFOV) and high-frequency flow interruption (HFFI). Twenty-six animals were treated with ventilation for 24 hours (five PPV, 10 HFOV, 11 HFFI), and 18 were treated with ventilation for 96 hours (six PPV, six HFOV, six HFFI). A semiquantitative scoring system was used to grade tissue changes in the trachea, carina, and both main-stem bronchi. Alterations were produced by all forms of mechanical ventilation. The degree of injury was similar and relatively mild for the PPV- and HFOV-treated animals at both 24 and 96 hours. Eleven of 17 baboons treated with HFFI ventilation (8/11 at 24 hours; 3/6 at 96 hours) had severe airway damage characterized by diffuse submucosal necrosis, extensive hemorrhage, dense polymorphonuclear leukocyte infiltration, sloughed epithelium, focal basophilia, and intraluminal debris. HFOV resulted in no greater degree of airway damage than did PPV. The use of HFFI, with the particular strategy we employed, resulted in a far greater degree of damage than either PPV (P less than 0.01) or HFOV.

Animals↗