Jay I. Peters

Inhaled nanoparticles—A current review

The field of nanotechnology may hold the promise of significant improvements in the health and well being of patients, as well as in manufacturing technologies. The knowledge of this impact of nanomaterials on public health is limited so far. This paper briefly reviews the unique size-controlled properties of nanomaterials, their disposition in the body after inhalation, and the factors influencing the fate of inhaled nanomaterials. The physiology of the lung makes it an ideal target organ for non-invasive local and systemic drug delivery, especially for protein and poorly water-soluble drugs that have low oral bioavailability via oral administration. The potential application of pulmonary drug delivery of nanoparticles to the lungs, specifically in context of published results reported on nanomaterials in environmental epidemiology and toxicology is reviewed in this paper.

Influence of particle size on regional lung deposition – What evidence is there?

The understanding of deposition of particles in the respiratory tract is of great value to risk assessment of inhalation toxicology and to improve efficiency in drug delivery of inhalation therapies. There are three main basic mechanisms of particle deposition based primarily on particle size: inertial impaction, sedimentation and diffusion. The regional deposition in the lungs can be evaluated in regards to the aerodynamic particle size, in which particle density plays a significant role. In this review paper, we first introduce the available imaging techniques to confirm regional deposition of particles in the human respiratory tract, such as planar scintigraphy, single photon emission computed tomography (SPECT) and positron emission tomography (PET). These technologies have widely advanced and consequently benefited the understanding of deposition pattern, although there is a lack of lung dosimetry techniques to evaluate the deposition of nanoparticles. Subsequently, we present a comprehensive review summarizing the evidence available in the literature that confirms the deposition of smaller particles in the smaller airways as opposed to the larger airways.

Effects of prolonged controlled mechanical ventilation on diaphragmatic function in healthy adult baboons

OBJECTIVE To study diaphragmatic strength and endurance after a prolonged period of mechanical ventilation. DESIGN Prospective animal study. SETTING Animal research laboratory. SUBJECTS Seven uninjured adult baboons (Papio cynocephalus) were anesthetized with ketamine, sedated, paralyzed, and mechanically ventilated. Animals were monitored with pulmonary arterial and peripheral arterial catheters. INTERVENTIONS Mechanical ventilation was provided for 11 days with an FIO2 of 0.21 and tidal volume of 15 mL/kg. Pulmonary function tests, including lung volumes, arterial blood gases, and chest radiographs were also monitored. Nursing care procedures included frequent turning, chest physiotherapy, and endotracheal suction. Antacids and prophylactic antibiotics (intravenous penicillin, topical polymyxin B, and gentamicin sulfate) were administered. In three animals, fishhook electrodes were surgically placed around both phrenic nerves on both day 0 and after 11 days of mechanical ventilation for diaphragmatic stimulation. On day 0, the electrodes were removed after phrenic nerve stimulation studies were performed. After 11 days of mechanical ventilation, animals were electively killed and full autopsy performed. MEASUREMENTS AND MAIN RESULTS Hemodynamic and pulmonary function parameters were measured at baseline and every day during the 11 days of mechanical ventilation. Diaphragmatic strength and endurance were measured on days 0 and 11. Diaphragmatic endurance was determined by an inspiratory resistive loading protocol. There were no significant changes in hemodynamics, lung volumes, or gas exchange during the period of mechanical ventilation. On day 7, the chest radiographs showed patchy lobar atelectasis in six animals, which cleared by day 11 in all but two of the animals. Lung pathology showed mild, focal pneumonitis. By day 11, maximum transdiaphragmatic pressure had decreased by 25% from day 0 and diaphragmatic endurance had decreased by 36%. CONCLUSIONS Eleven days of mechanical ventilation and neuromuscular blockade in healthy baboons resulted in nonsignificant changes in hemodynamics, oxygenation, and/or lung function. However, significant impairment in diaphragmatic endurance and strength were seen. Based on these results, it is likely that prolonged mechanical ventilation by itself impairs diaphragmatic function independent of underlying lung disease.

Near-fatal asthma: recognition and management

Purpose of review Near-fatal asthma continues to be a significant problem despite the decline in overall asthma mortality. The purpose of this review is to discuss recent advances in our understanding of the pathophysiology, diagnosis and treatment of near-fatal asthma. Recent findings Two distinctive phenotypes of near-fatal asthma have been identified: one with eosinophilic inflammation associated with a gradual onset and a slow response to therapy and a second phenotype with neutrophilic inflammation that has a rapid onset and rapid response to therapy. Patients who develop sudden-onset near-fatal asthma seem to have massive allergen exposure and emotional distress. In stable condition, near-fatal asthma frequently cannot be distinguished from mild asthma. Diminished perception of dyspnea plays a relevant role in treatment delay, near-fatal events, and death in patients with severe asthma. Reduced compliance with anti-inflammatory therapy and ingestion of medications or drugs (heroin, cocaine) have been associated with fatal or near-fatal asthma. Summary Near-fatal asthma is a subtype of asthma with unique risk factors and variable presentation that requires early recognition and aggressive intervention.

Pulmonary artery systolic pressures estimated by echocardiogram vs cardiac catheterization in patients awaiting lung transplantation

BACKGROUND At many lung transplant centers, right heart catheterization and transthoracic echocardiogram are part of the routine pre-transplant evaluation to measure pulmonary pressures. Because decisions regarding single vs bilateral lung transplant procedures and the need for cardiopulmonary bypass are often made based on pulmonary artery systolic pressures, we sought to examine the relationship between estimated and measured pulmonary artery systolic pressures using echocardiogram and catheterization, respectively. METHODS We retrospectively reviewed all patients in our program who had measured pulmonary hypertension (n = 57). Patients with both echocardiogram-estimated and catheterization-measured pulmonary artery systolic pressures performed within 2 weeks of each other were included (n = 19). We analyzed results for correlation and linear regression in the entire group and in the patients with primary pulmonary hypertension (n = 8) and pulmonary fibrosis (n = 8). RESULTS In patients with primary pulmonary hypertension, pulmonary artery systolic pressure was 94 +/- 27 and 95 +/- 15 mm Hg by echocardiogram and catheterization, respectively, with r(2) = 0.11; in patients with pulmonary fibrosis, 57 +/- 23 and 58 +/- 12 mm Hg with r(2) = 0.22; and in the whole group, 76 +/- 29 and 75 +/- 23 mm Hg with r(2) = 0.50. Thirty-two additional patients had mean pulmonary artery systolic pressure = 48 +/- 16 mm Hg by catheterization but either had no evidence of tricuspid regurgitation by echocardiogram (n = 22) or the pulmonary artery systolic pressure could not be measured (n = 10). CONCLUSIONS In patients with pulmonary hypertension awaiting transplant, pulmonary artery systolic pressures estimated by echocardiogram correspond but do not serve as an accurate predictive model of pulmonary artery systolic pressures measured by catheterization. Technical limitations of the echocardiogram in this patient population often preclude estimating pulmonary artery systolic pressure.

Effectiveness of statins in reducing the rate of severe sepsis : A retrospective evaluation

Study Objectives. To determine whether use of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) is associated with a reduced rate of severe sepsis, and to further characterize the effect of statins on the frequency of organ dysfunction in patients with severe sepsis.

Impact of obesity in asthma: evidence from a large prospective disease management study

BACKGROUND asthma and obesity continue to have a significant effect on public health. It is widely accepted that obesity may be an independent risk factor for asthma and affect asthma severity and quality of life (QOL). OBJECTIVE to examine the relationship between body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) and asthma severity, spirometry findings, health care utilization (HCU), and QOL. METHODS this 12-month prospective randomized controlled trial comparing disease management with traditional care enrolled 902 patients (473 pediatric and 429 adults) representing an underserved population. Data collected at baseline and at 6-month intervals included demographics, asthma severity, medication use, spirometry findings, and HCU. The QOL was assessed using the pediatric and adult versions of the Asthma Quality of Life Questionnaire and the 36-Item Short Form Health Survey. All HCU was determined by means of patient interview and extensive medical record review. Data were analyzed using negative binomial regression and analysis of variance. RESULTS in children, 45% were overweight/obese (17% with BMIs >85th percentile; 28% with BMIs ≥ 95th percentile). In adults, 58% were obese (BMIs ≥ 30). There was no relationship in children between BMI and severity of asthma, spirometry findings, QOL, or HCU. In adults, there was no relationship between BMI and asthma severity or HCU. Higher BMI was associated with a significant reduction in QOL (P < .001). The BMI had an inverse relationship with forced vital capacity but with no other spirometric values. CONCLUSIONS obesity was not associated with worse asthma severity, spirometry findings, QOL, or HCU in children. In adults with asthma, obesity was associated with lower forced vital capacity and QOL but not with severity or HCU.

Analysis of Pulmonary Inflammation and Function in the Mouse and Baboon after Exposure to Mycoplasma pneumoniae CARDS Toxin

Mycoplasma pneumoniae produces an ADP-ribosylating and vacuolating toxin known as the CARDS (Community Acquired Respiratory Distress Syndrome) toxin that has been shown to be cytotoxic to mammalian cells in tissue and organ culture. In this study we tested the ability of recombinant CARDS (rCARDS) toxin to elicit changes within the pulmonary compartment in both mice and baboons. Animals responded to a respiratory exposure to rCARDS toxin in a dose and activity-dependent manner by increasing the expression of the pro-inflammatory cytokines IL-1α, 1β, 6, 12, 17, TNF-α and IFN-γ. There was also a dose-dependent increase in several growth factors and chemokines following toxin exposure including KC, IL-8, RANTES, and G-CSF. Increased expression of IFN-γ was observed only in the baboon; otherwise, mice and baboons responded to CARDS toxin in a very similar manner. Introduction of rCARDS toxin to the airways of mice or baboons resulted in a cellular inflammatory response characterized by a dose-dependent early vacuolization and cytotoxicity of the bronchiolar epithelium followed by a robust peribronchial and perivascular lymphocytic infiltration. In mice, rCARDS toxin caused airway hyper-reactivity two days after toxin exposure as well as prolonged airway obstruction. The changes in airway function, cytokine expression, and cellular inflammation correlate temporally and are consistent with what has been reported for M. pneumoniae infection. Altogether, these data suggest that the CARDS toxin interacts extensively with the pulmonary compartment and that the CARDS toxin is sufficient to cause prolonged inflammatory responses and airway dysfunction.

Investigation and control of aspergillosis and other filamentous fungal infections in solid organ transplant recipients.

Filamentous fungal infections are associated with high morbidity and mortality in solid organ transplant patients, and prevention is warranted whenever possible. An increase in invasive aspergillosis was detected among solid organ transplant recipients in our institution during 1991–92. Rates of Aspergillus infection (18.2%) and infection or colonization (42%) were particularly high among lung transplant recipients. Epidemiologic investigation revealed cases to be both nosocomial and community‐acquired, and preventative efforts were directed at both sources. Environmental controls were implemented in the hospital, and itraconazole prophylaxis was given in the early period after lung transplantation. The rate of Aspergillus infection in solid organ transplant recipients decreased from 9.4% to 1.5%, and mortality associated with this disease decreased from 8.2% to 1.8%. The rate of Aspergillus infection or colonization among lung transplant recipients decreased from 42% to 22.5%; nosocomial Aspergillus infection decreased from 9% to 3.2%. Cases of aspergillosis in lung transplant recipients were more likely to be early infections in the pre‐intervention period. Early mortality in lung transplant recipients decreased from 15% to 3.2%. Two cases of dematiaceous fungal infection were detected, and no further cases occurred after environmental controls. The use of environmental measures that resulted in a decrease in airborne fungal spores, as well as antifungal prophylaxis, was associated with a decrease in aspergillosis and associated mortality in these patients. Ongoing surveillance and continuing intervention is needed for prevention of infection in high‐risk solid organ transplant patients.

In vivo efficacy of aerosolized nanostructured itraconazole formulations for prevention of invasive pulmonary aspergillosis

ABSTRACT Aerosolized evaporative precipitation into aqueous solution and spray freezing into liquid nanostructured formulations of itraconazole as prophylaxis significantly improved survival relative to commercial itraconazole oral solution and the control in a murine model of invasive pulmonary aspergillosis. Aerosolized administration of nanostructured formulations also achieved high lung tissue concentrations while limiting systemic exposure.