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Biomedical subjects

Thomas H Shaffer

Publications and source records attributed to Thomas H Shaffer.

At least 37 records · Page 2Linked to original sources
PubMed2005

Recombinant human Clara cell secretory protein in acute lung injury of the rabbit: effect of route of administration.

OBJECTIVE: To test the hypothesis that intratracheal instillation of Clara cell secretory protein (CC 10) to the lung may afford greater protection than intravenous administration from ventilator-induced lung inflammation. DESIGN: Interventional laboratory study. SETTING: An academic medical research facility in northeastern United States. SUBJECTS: Sedated, lavage-injured juvenile rabbits. INTERVENTIONS: A total of 18 juvenile rabbits were anesthetized, ventilated, injured with saline lavage (Pao2 of <100 mm Hg; respiratory compliance of <0.50 mL.cm H2O.kg and <50% baseline), and randomized to receive intratracheally administered surfactant plus no recombinant human CC 10 (rhCC 10, control), intravenous rhCC 10, or intratracheal rhCC 10. MEASUREMENT AND MAIN RESULTS: Arterial blood chemistry and pulmonary mechanics were monitored; plasma and urine were collected serially. After 4 hrs of ventilation, lungs were lavaged and harvested. Surfactant function was analyzed from bronchoalveolar lavage samples (surfactometry); rhCC 10, interleukin-8, and lung myeloperoxidase concentrations were measured. Pao2, oxygenation index, ventilatory efficiency index, and respiratory compliance were not different across time or group beyond injury. Surfactometry data identified no differences as a function of group or time. Plasma, bronchoalveolar lavage, and lung interleukin-8 concentrations, lung myeloperoxidase concentrations, and inflammatory cell counts in the alveolar and interstitial spaces of intravenous and intratracheal groups were lower than in the control group (p < .05) but not statistically different from each other. Concentrations of rhCC 10 in lung, bronchoalveolar lavage, and plasma were greater in the intratracheal group than in the intravenous group (p<.05). Urine rhCC 10 concentrations were greater for the intravenous group than for the intratracheal group (p<.05) at 1, 3, and 4 hrs after treatment. No group differences in histomorphometry were noted. CONCLUSIONS: Both intravenous and intratracheal rhCC 10 delivery, after surfactant therapy, effectively decrease lung inflammation vs. surfactant alone. While supporting the physiologic profile, intratracheal instillation results in greater, maintained lung and plasma rhCC 10 pools compared with intravenous administration. As such, intratracheal instillation of rhCC 10 may afford more prolonged protection against lung inflammation than intravenous administration.

Animals↗
PubMed2004

Regulation of apical surface fluid and protein secretion in human airway epithelial cell line Calu-3.

We evaluated the relationship between apical surface fluid (ASF) and protein secretion in Calu-3 cells grown at an air-liquid interface. Calu-3 monolayers responded to forskolin, a cystic fibrosis transmembrane regulator (CFTR) channel agonist, by secreting a significant amount of ASF. Such a response from Calu-3 monolayers was not observed with CFTR channel blockers glybenclamide and DPC. Other ion channel mediators, PGF-2alpha, PMA, DNDS, and DIDS, had no effect on Calu-3 ASF secretion. Forskolin decreased Calu-3 protein secretion and glybenclamide increased protein secretion. Similarly, forskolin decreased Calu-3 lysozyme secretion, whereas glybenclamide and DPC increased lysozyme secretion. We observed significant changes in Calu-3 fluid and protein secretions with ion channel mediators known to alter CFTR activity. Our results demonstrate a functional link between fluid and protein secretions in Calu-3 apical surface and suggested a possible involvement of CFTR in these processes.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2004

Tracheal gas insufflation-augmented continuous positive airway pressure in a spontaneously breathing model of neonatal respiratory distress.

Respiratory distress syndrome (RDS) in neonates is characterized by labored breathing and poor gas exchange, often requiring ventilatory support. Continuous positive airway pressure (CPAP) is a preferred intervention to support spontaneous ventilatory efforts by sustaining lung volume recruitment, while it prevents derecruitment during exhalation by maintaining end-expiratory pressure. However, CO2 retention during CPAP often results in the need for mechanical ventilation. Since tracheal gas insufflation (TGI) promotes CO2 elimination by reducing prosthetic dead space, we hypothesized that TGI used with CPAP may reduce the need for more invasive therapies. The objective of this study was to evaluate the physiologic effect of TGI with CPAP in a spontaneously breathing model of acute lung injury with respect to gas exchange and pulmonary mechanics. Nineteen spontaneously breathing neonatal pigs (2.4 +/- 0.4 kg) were anesthetized, sedated, instrumented, and placed on CPAP at 5 cmH2O. All piglets were injured with intravenous oleic acid (0.08 ml/kg), and then randomized to receive CPAP with TGI (TGI; n = 9) or CPAP alone (control; n = 10). FiO2 was titrated at 0.05 every 15 min during the protocol to maintain SaO2 > 93%. Vital signs, arterial blood gases, pulmonary mechanics, and thoracoabdominal motion (TAM) were evaluated 30 min after injury and at 1-hr intervals for 4 hr. Following the 4-hr measurement, the piglets were sacrificed and the lungs were grossly examined. After initiation of treatment, we found that the PaCO2 was lower (33.1 +/- 5.0 vs. 47.0 +/- 10.3 mmHg; P < 0.01), while the oxygenation indices were greater (PaO2, SaO2, a/A ratio; P < 0.01) in the TGI group than with control animals. Subsequently, the pH was greater (7.45 +/- 0.08 vs. 7.36 +/- 0.08; P < 0.01) and closer to baseline values with TGI. By 4 hr, the FiO2 was titrated lower (0.37 +/- 0.06 vs. 0.49 +/- 0.15; P < 0.05) and ventilation was accomplished with a lower minute ventilation (MV) in the TGI group than in the control group (445 +/- 113 vs. 581 +/- 223 ml/kg/min; P < 0.01). Respiratory compliance was greater with TGI than control (0.76 +/- 0.13 vs. 0.63 +/- 0.11 ml/cmH2O/kg; P < 0.01), whereas resistance and TAM were similar between groups. We conclude that the use of TGI with CPAP in the treatment of RDS results in improved gas exchange and pulmonary mechanics. As such, TGI-augmented CPAP may prevent infants from requiring more invasive ventilation by reducing CO2 retention.

Animals↗
PubMed2004

Protein composition of apical surface fluid from the human airway cell line Calu-3: effect of ion transport mediators.

BACKGROUND: Analysis of the protein components of airway secretions is a potential means of detecting and characterizing biochemical alterations associated with airway diseases. METHODS: We evaluated airway protein secretions using the airway epithelial cell line Calu-3 grown at an air-liquid interface. To observe changes in apically secreted proteins, we analyzed the protein content of apical surface fluid (ASF) washings of Calu-3 monolayers treated with ion transport mediators. RESULTS: Immunoassay screening for antibacterial and inflammatory proteins indicated the presence of measurable levels of lysozyme and IL-8 in Calu-3 ASF. RT-PCR and immunoassay studies indicated that Calu-3 cells do not produce clara cell 10 kDa protein (CC10). The total protein secretion of Calu-3 was not altered by bradykinin, but amiloride and adenosine significantly increased Calu-3 protein secretion. Lysozyme secretion was not altered by bradykinin, but amiloride and adenosine significantly reduced lysozyme secretion. IL-8 secretion was not altered by bradykinin or adenosine, but amiloride significantly decreased IL-8 secretion. CONCLUSION: Our results demonstrate the presence of antibacterial protein lysozyme and the pro-inflammatory cytokine IL-8 in Calu-3 ASF and that ion transport mediators such as bradykinin, amiloride and adenosine influence the secretion of Calu-3 ASF proteins.

Adenosine↗
PubMed2004

Association of interleukin-8 with inflammatory and innate immune components in bronchoalveolar lavage of children with chronic respiratory diseases.

BACKGROUND: The host inflammatory response and innate immunity play a complex role in respiratory diseases. METHODS: We evaluated the levels of inflammatory mediators and antibacterial proteins in children who required bronchoscopy and bronchoalveolar lavage fluid (BALF) for clinical indications such as chronic tracheostomy (n=15) and chronic suppurative lung disease (n=8). RESULTS: Our results suggested the presence of interleukin-1beta (IL-1beta) and IL-8 as major inflammatory mediators in BALF samples. The level of the antibacterial protein sIgA was higher than lactoferrin and lysozyme. BALF IL-8 levels significantly correlated with the presence of IL-1beta, IL-6, IL-10, IL-16, sIgA and lysozyme. BALF IL-8 levels did not correlate with the levels of immunomodulatory and anti-inflammatory clara cell 10 kDa protein (CC10) or lactoferrin. CONCLUSION: This study suggests that patients with high levels of BALF IL-8 could potentially have high levels of IL-6, IL-10, IL-16, lysozyme and sIgA. Evaluating the inflammatory mediators (IL-8) in relation to other BALF protein components provides insight into understanding the role of inflammatory mediators in the regulation of host defense and the response to lung inflammation and injury.

Biomarkers↗
PubMed2004

Liquid ventilation: an adjunct for respiratory management.

Although significant advances in respiratory care have reduced mortality of patients with respiratory failure, morbidity persists, often resulting from iatrogenic mechanisms. Mechanical ventilation with gas has been shown to initiate as well as exacerbate underlying lung injury, resulting in progressive structural damage and release of inflammatory mediators within the lung. Alternative means to support pulmonary gas exchange while preserving lung structure and function are therefore required. Perfluorochemical (PFC) liquids are currently used clinically in a number of ways, such as intravascular PFC emulsions for volume expansion/oxygen carrying/angiography and intracavitary neat PFC liquid for image contrast enhancement or vitreous fluid replacement. As a novel approach to replace gas as the respiratory medium, liquid assisted ventilation (LAV) with PFC liquids has been investigated as an alternative respiratory modality for over 30 years. Currently, there are several theoretical and practical applications of LAV in the immature or mature lung at risk for acute respiratory distress and injury associated with mechanical ventilation.

Adult↗
PubMed2004

Airway structure, function and development in health and disease.

Until they are fully mature, the airways are highly susceptible to damage. Factors that may contribute to vulnerability of immature airways and the occurrence of bronchopulmonary dysplasia (BPD) in preterm neonates include decreased contractility of smooth muscles of the airway, which leads to generation of lower forces, and immaturity of airway cartilage, leading to increased compressibility of developing airways. Mechanical ventilation has little effect on adult airways, but affects the dimensions and mechanical properties of preterm and newborn airways. Techniques for clinical evaluation of airway function include: (i). measurements of airway function during tidal breathing (airway resistance and reactivity are significantly elevated in infants with BPD); (ii). forced expiratory flow measurements [small-airway obstruction in infants with BPD is indicated by markedly reduced maximal volume measurements (Vmax)]; (iii). radiography procedures (plain radiographs, fluoroscopy, computed tomography and virtual bronchoscopy); and (iv). endoscopy procedures (rigid or flexible bronchoscopy, with or without measurement of oesophageal pressure). Imaging has demonstrated an excessively decreased airway cross-sectional area during exhalation in infants with BPD and acquired tracheomegaly in very preterm infants who had received mechanical ventilatory support. To further advance our understanding of how the airways develop, and to design less damaging protocols for mechanical ventilation in preterm neonates, basic laboratory studies of airway ultrastructure need to be performed and the results correlated with clinical pulmonary function studies.

Animals↗
PubMed2003

Continuous tracheal gas insufflation during partial liquid ventilation in juvenile rabbits with acute lung injury.

To examine the hypothesis that combined treatment with tracheal gas insufflation (TGI) and partial liquid ventilation (PLV) may improve pulmonary outcome relative to either treatment alone in acute lung injury (ALI), saline lavage lung injury was induced in 24 anesthetized, ventilated juvenile rabbits that were then randomly assigned to receive (n = 6/group) 1) conventional mechanical ventilation (CMV) alone, 2) continuous TGI at 0.5 l/min, 3) PLV with perfluorochemical liquid, and 4) combined TGI and PLV (TGI + PLV), and subsequently ventilated with minimized pressures and tidal volume (Vt) to keep arterial Po(2) (Pa(O(2))) >100 Torr and arterial Pco(2) (Pa(CO(2))) at 45-60 Torr for 4 h. Gas exchange, lung mechanics, myeloperoxidase, IL-8, and histomorphometry [including expansion index (EI)] were assessed. The CMV group showed no improvement in lung mechanics and gas exchange; all treated groups had significant increases in compliance, Pa(O(2)), ventilation efficacy index (VEI), and EI, and decreases in PaCO(2), oxygenation index, physiological dead space-to-Vt ratio (Vd/Vt), myeloperoxidase, and IL-8, relative to the CMV group. TGI resulted in lower peak inspiratory pressure, Vt, Vd/Vt, and greater VEI vs. PLV group; PLV resulted in greater compliance, Pa(O(2)), and EI vs. TGI. TGI + PLV resulted in decreased peak inspiratory pressure, Vt, Vd/Vt, and increased VEI compared with TGI, improved compliance and EI compared with PLV, and a further increase in Pa(O(2)) and oxygenation index and a decrease in PaCO(2) vs. either treatment alone. These results indicate that combined treatment of TGI and PLV results in improved pulmonary outcome than either treatment alone in this animal model of ALI.

Analysis of Variance↗
PubMed2003

Long-term tidal liquid ventilation in premature lambs: physiologic, biochemical and histological correlates.

Chronic lung disease in infants continues to be problematic. Tidal liquid ventilation (TLV) improves lung mechanics and provides effective gas exchange. We hypothesized that premature lambs could be supported safely with TLV and evaluated 9 preterm lambs (132 days gestation) on TLV up to 72 h. Results (mean +/- SEM): pH 7.36 +/- 0.003, PaCO2 44 +/- 0.34 mm Hg, PaO2 170 +/- 4.8 mm Hg, compliance=1.65 +/- 0.24 ml/cm H2O/kg, mean arterial blood pressure=53 +/- 0.08 mm Hg, heart rate=189 +/- 1.5 bpm. Blood perflubron levels were 6.0 +/- 0.24 microg/ml over 24 h. Tissue perflubron levels increased from 81 +/- 7.0 microg/g at 24 h to 108 +/- 15 microg/g at 72 h (p<0.05). There was a difference in perflubron concentrations as a function of tissue (p<0.001) that correlated to lipid levels (r2=0.93, p<0.01). These data demonstrate that TLV is both safe and effective up to 72 h in premature lambs.

Animals↗
PubMed2003

Perfluorochemical (PFC) combinations for acute lung injury: an in vitro and in vivo study in juvenile rabbits.

Perfluorochemical (PFC) fluids of different physical properties were titrated and tested in vitro for physical properties that are appropriate for respiratory application. Two PFC liquids were studied: perfluoromethylcyclohexane (PP2), a liquid with high vapor pressure and low viscosity, and perfluoromethyldecalin (PP9), a fluid with low vapor pressure and high viscosity. Eighteen rabbits (2.05 +/- 0.07 kg; mean +/- SEM) were lung-lavaged and randomized: group I, control group; group II, partial liquid ventilation with 75% PP2 and 25% PP9; group III, partial liquid ventilation with 50% PP2 and 50% PP9; and group IV, partial liquid ventilation with 25% PP2 and 75% PP9. Ventilator volumes were kept constant during the 4-h experiment. Cardiopulmonary measurements were performed every 30 min. The lung histology was examined. The in vitro study showed PFC [viscosity/vapor pressure (in cS and mm Hg, respectively)] as follows: 100% PP2 (0.88/141); 100% PP9 (3.32/2.9); 75% PP2 and 25% PP9 (1.26/107); 50% PP2 and 50% PP9 (1.63/13.7); and 25% PP2 and 75% PP9 (2.21/4.4). The in vivo experiments found that combinations of moderate vapor pressure (groups 3 and 4) demonstrated good gas exchange, compliance, and histologic findings. Thus, combinations of PFC liquids can be formulated to modulate the physiologic outcome in acutely injured lungs, and may prove useful for alternative PFC liquid applications.

Animals↗
PubMed2002

Physicochemical properties of perfluorochemical liquids influence ventilatory requirements, pulmonary mechanics, and microvascular permeability during partial liquid ventilation following intestinal ischemia/reperfusion injury.

OBJECTIVE: To test the hypothesis that the physicochemical properties of perfluorochemical liquid used in partial liquid ventilation can influence ventilatory requirements, pulmonary mechanics, microvascular permeability, and vasoactive mediator release in the abnormal lung. DESIGN: Prospective, controlled animal study. SETTING: Research laboratory in a university setting. SUBJECTS Male Sprague-Dawley rats: sham and intestinal ischemia/reperfusion injury. INTERVENTIONS: Treatment with perfluorochemical partial liquid ventilation (PLV: PP-5 or H-130) or conventional mechanical ventilation (CMV) over 60 mins of superior mesenteric artery occlusion and 60 mins of reperfusion. MEASUREMENTS AND MAIN RESULTS: Gas exchange, ventilatory requirements, and pulmonary mechanics were measured in vivo. Subsequently, pulmonary vascular resistance, microvascular permeability, and thromboxane were measured by using the isolated perfused lung preparation. PLV with PP-5 required significantly (p <.05) higher positive end-expiratory pressure resulting in increased mean airway pressures and pulmonary vascular resistance in both sham and intestinal ischemia/reperfusion injured animals compared with those treated with CMV or PLV H-130. PLV PP-5 also resulted in significantly (p <.05) lower respiratory compliance and greater microvascular permeability compared with sham animals. Following intestinal ischemia/reperfusion injury, PLV H-130 treated animals had significantly higher (p <.05) respiratory compliance than those treated with PLV PP-5 and a significantly lower (p <.05) intestinal ischemia/reperfusion-mediated increase in microvascular permeability than those treated with CMV or PLV PP-5. Thromboxane levels were significantly higher (p <.01) in injured animals treated with CMV or PLV PP-5 compared with comparably treated shams, were significantly lower (p <.01) in both PLV groups than CMV, and were further attenuated (p <.01) by PLV H-130 compared with PLV PP-5 animals. CONCLUSION: We conclude that PLV with perfluorochemical liquids attenuates pulmonary sequelae resulting from remote organ injury and that the extent of lung protection depends on the physicochemical properties of the perfluorochemical liquids.

Animals↗
PubMed2002

Distinct patterns of apoptosis in the lung during liquid ventilation compared with gas ventilation.

To determine whether liquid ventilation (LV) causes less cell injury and improves lung function compared with conventional gas ventilation (GV), we analyzed pulmonary physiological profiles, lung histology, and cell death in 110- and 120-day preterm lambs, which were randomized to receive either ventilation modality on FI(O(2)) = 1. LV lungs were well expanded with adequate pulmonary function, whereas GV animals exhibited marked atelectasis, poor pulmonary function, and increased mortality. Both ventilatory strategies induced marked lung cell apoptosis, but with distinct patterns of distribution. Although GV induced apoptosis of epithelium primarily in the lining and within the lumina of bronchioles, LV induced significant apoptosis much more homogeneously throughout lung parenchyma including alveoli and interstitial spaces. These studies suggest that although both forms of ventilation cause regional apoptosis, LV more effectively delivers oxygen and recruits the lung more homogeneously than GV.

Animals↗
PubMed2002

Managing our first breaths: a reflection on the past several decades of neonatal pulmonary therapy.

Lung disease has been a leading cause of significant morbidity and mortality since neonates first drew breath. Over the past few decades, many treatment options have evolved to aid us in our ability to support neonatal breathing. The history of neonatal pulmonary care, both its successes and controversies, can teach us a great deal about the future of this dynamic field. As new developments occur, we constantly modify the therapies we offer to preterm and term infants. Understanding traditional therapeutic options and knowing what may be on the horizon can help caregivers to better match treatment plans with individual infants. This article reviews advances in mechanical ventilation, adjuvant therapies, and respiratory drugs through the past few decades and speculates on future directions in this field.

Humans↗
PubMedDate not supplied

Physiologic effects of CPAP: application and monitoring.

Although a wide array of respiratory care modalities has been employed to manage neonatal respiratory distress syndrome (RDS), the recent focus has emphasized strategies that correct lung pathophysiology while protecting the lung from further insult. Continuous positive airway pressure (CPAP) has remained a viable option for NICU infants since its introduction in 1971. Current methods of monitoring allow clinicians to troubleshoot and better understand the physiologic and clinical impact of administering CPAP to neonates with RDS. This article highlights the renewed interest in CPAP therapy and current methods of monitoring.

Continuous Positive Airway Pressure↗
PubMedDate not supplied

Inhaled nitric oxide therapy in the near-term or term neonate with hypoxic respiratory failure.

Inhaled nitric oxide (iNO) has altered the management strategy for treating near-term and term infants with hypoxic respiratory failure (HRF). There is a strong relationship between HRF and persistent pulmonary hypertension of the newborn (PPHN). PPHN is characterized by elevated pulmonary resistance, pulmonary vasoconstriction, and altered vascular reactivity. The resulting high pulmonary pressure may lead to HRF, which is defined as a relative deficiency of oxygen in arterial blood and insufficient minute ventilation. iNO improves oxygenation and decreases the need for extracorporeal membrane oxygenation. Although iNO therapy is effective, its efficacy can depend on the fine points of its use and on other care the infant is receiving. Even in NICUs that do not have iNO available, those who care for term infants with HRF must be familiar with its use and know when and how to transfer these infants and how to help families through this difficult period. Because iNO therapy will probably be used more frequently in nurseries over the next few years, more information on the safety and efficacy of its use in the broader neonatal population needs to be available.

Administration, Inhalation↗
PubMedDate not supplied

The neonatal respiratory pump: a developmental challenge with physiologic limitations.

Newborn lungs are particularly susceptible to pathophysiology. Respiratory distress commonly brings infants to the intensive care nursery. Premature birth compromises the infant's ability to respond to early lung dysfunction because of the reduced functional reserve available at younger gestational ages. The respiratory pump consists of respiratory musculature and the chest wall. The respiratory pump is the physiologic "machine" that responds to lung pathology. From gestation onward, components of the pump undergo developmental changes that influence its compensatory ability in the neonate. Careful observation of the synchrony of the chest wall and abdomen during spontaneous breathing efforts assists the caretaker in detecting respiratory compromise and impending respiratory failure. Noninvasive monitoring of respiratory patterns is a valuable tool for the neonatal caregiver, who must understand the developmental changes in the respiratory pump and be able to identify an infant's ineffective responses to lung pathophysiology.

Child Development↗
PubMedDate not supplied

Ventilator-induced airway injury: a critical consideration during mechanical ventilation of the infant.

The clinical management of respiratory failure in the newborn often focuses on lung parenchymal stiffness due to immaturity, surfactant deficiency, infiltrates, and other causes. However, health care personnel should also consider the airway, which plays an important role in gas exchange and lung mechanics. The airway can be easily injured, and an injured airway can significantly alter both the acute and chronic course of lung disease in infants. Further, there are developmental changes that affect the susceptibility of the neonatal airway to injury. Recognizing and preventing causes of airway injury can help to ensure optimal outcomes for the critically ill neonate.

Humans↗