Gross and Histologic Placental Abnormalities Associated With Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To elucidate particular placental pathology findings that are associated with hypoxic ischemic encephalopathy (HIE) and determine which patterns are associated with adverse fetal/neonatal outcomes. STUDY DESIGN: Multi-institutional retrospective case-control study of newborns with HIE (2002-2022) and controls. Four perinatal pathologists performed gross and histologic evaluation of placentas of cases and controls. RESULTS: A total of 265 placentas of neonates with HIE and 122 controls were examined. Infants with HIE were more likely to have anatomic umbilical cord abnormalities (19.7% vs 7.4%, P = .003), fetal inflammatory response in the setting of amniotic fluid infection (27.7% vs 13.9%, P = .004), and fetal vascular malperfusion (30.6% vs 9.0%, P = <.001) versus controls. Fetal vascular malperfusion with maternal vascular malperfusion was more common in those who died of disease (P = .01). CONCLUSION: Placental pathology examination of neonates with HIE may improve our understanding of this disorder and its adverse outcomes.

Establishing a regional registry for neonatal encephalopathy: impact on identification of gaps in practice.

BACKGROUND: Neonatal encephalopathy (NE) continues to be a significant risk for death and disability. To address this risk, regional guidelines were developed with the support of a malpractice insurance patient safety organization. A NE registry was also established to include 14 centers representing around 50% of deliveries in the state of Massachusetts. The aim of this study was to identify areas of variation in practice that could benefit from quality improvement projects. METHODS: This manuscript reports on the establishment of the registry and the primary findings to date. RESULTS: From 2018 to 2020, 502 newborns with NE were evaluated for Therapeutic Hypothermia (TH), of which 246 (49%) received TH, representing a mean of 2.91 per 1000 live births. The study reports on prenatal characteristics, delivery room resuscitation, TH eligibility screening, and post-natal management of newborns with NE who did and did not receive TH. CONCLUSIONS: The registry has allowed for the identification of areas of variation in clinical practices, which have guided ongoing quality improvement projects. The authors advocate for the establishment of local and regional registries to standardize and improve NE patient care. They have made the registry data collection tools freely available for other centers to replicate this work. IMPACT: Malpractice insurance companies can take an active role in supporting clinicians in establishing clinical practice guidelines and regional registries. Establishing a collaborative regional neonatal encephalopathy (NE) registry is feasible. Data Collection tools for a NE registry have been made publicly available to be adopted and replicated by other groups. Establishing a regional NE registry allowed for the identification of gaps in knowledge, variations in practice, and the opportunity to advance care through quality improvement projects.

BOston Neonatal Brain Injury Dataset for Hypoxic Ischemic Encephalopathy (BONBID-HIE): Part I. MRI and Manual Lesion Annotation.

Hypoxic ischemic encephalopathy (HIE) is a brain injury that occurs in 1 ~ 5/1000 term neonates. Accurate identification and segmentation of HIE-related lesions in neonatal brain magnetic resonance images (MRIs) is the first step toward predicting prognosis, identifying high-risk patients, and evaluating treatment effects. It will lead to a more accurate estimation of prognosis, a better understanding of neurological symptoms, and a timely prediction of response to therapy. We release the first public dataset containing neonatal brain diffusion MRI and expert annotation of lesions from 133 patients diagnosed with HIE. HIE-related lesions in brain MRI are often diffuse (i.e., multi-focal), and small (over half the patients in our data having lesions occupying <1% of brain volume). Segmentation for HIE MRI data is remarkably different from, and arguably more challenging than, other segmentation tasks such as brain tumors with focal and relatively large lesions. We hope that this dataset can help fuel the development of MRI lesion segmentation methods for HIE and small diffuse lesions in general.

Attitudes toward a novel breastfeeding-mediated drug and nutrient delivery system: A qualitative study.

The objective of this study was to determine the attitudes and impressions of breastfeeding mothers and healthcare practitioners towards a device concept integrating breastfeeding with infant drug and nutrient administration. This was an exploratory qualitative study involving 20 breastfeeding mothers and 6 healthcare practitioners from the Suffolk and Middlesex County areas of Massachusetts, USA each individually interviewed. Interview transcription of the semi-structured interviews by an independent service began during data collection, and data coding into major themes continued until and after data saturation was reached. Repeated medication delivery with a reusable product was highlighted as a potential use case for the device concept; ease of use and cleaning as well as cost, familiarity with the method, and infant response were identified as critical considerations. Participants questioned device suitability with liquid formulations (as opposed to non-liquid), while potential advantages over alternative medication delivery technology like oral syringes were identified, including a more "natural" feeling. Most participants had prior knowledge of, or personal experience with, devices like commercially available nipple shields. Attitudes towards the NSDS were not determined by experience with nipple shields, however. The participants' prior exposure to nipple shields is in contrast to related studies in Kenya and South Africa where commercial nipple shields were not widely known and where specific concerns surrounding potential community stigma to an unknown device were raised by participants.

Treatment of Neonatal Seizures: Comparison of Treatment Pathways From 11 Neonatal Intensive Care Units.

OBJECTIVE: Seizures are a common neonatal neurologic emergency. Many centers have developed pathways to optimize management. We evaluated neonatal seizure management pathways at level IV neonatal intensive care units (NICUs) in the United States to highlight areas of consensus and describe aspects of variability. METHODS: We conducted a descriptive analysis of 11 neonatal seizure management pathways from level IV NICUs that specialize in neonatal neurocritical care including guidelines for electroencephalography (EEG) monitoring, antiseizure medication (ASM) choice, timing, and dose. RESULTS: Study center NICUs had a median of 70 beds (interquartile range: 52-96). All sites had 24/7 conventional EEG initiation, monitoring, and review capability. Management pathways uniformly included prompt EEG confirmation of seizures. Most pathways included a provision for intravenous benzodiazepine administration if either EEG or loading of ASM was delayed. Phenobarbital 20 mg/kg IV was the first-line ASM in all pathways. Pathways included either fosphenytoin or levetiracetam as the second-line ASM with variable dosing. Third-line ASMs were most commonly fosphenytoin or levetiracetam, with alternatives including topiramate or lacosamide. All pathways provided escalation to continuous midazolam infusion with variable dosing for seizures refractory to initial medication trials. Three pathways also included lidocaine infusion. Nine pathways discussed ASM discontinuation after resolution of acute symptomatic seizures with variable timing. CONCLUSIONS: Despite a paucity of data from controlled trials regarding optimal neonatal seizure management, there are areas of broad agreement among institutional pathways. Areas of substantial heterogeneity that require further research include optimal second-line ASM, dosage, and timing of ASM discontinuation.

Voxelwise and Regional Brain Apparent Diffusion Coefficient Changes on MRI from Birth to 6 Years of Age.

Background A framework for understanding rapid diffusion changes from 0 to 6 years of age is important in the detection of neurodevelopmental disorders. Purpose To quantify patterns of normal apparent diffusion coefficient (ADC) development from 0 to 6 years of age. Materials and Methods Previously constructed age-specific ADC atlases from 201 healthy full-term children (108 male; age range, 0-6 years) with MRI scans acquired from 2006 to 2013 at one large academic hospital were analyzed to quantify four patterns: ADC trajectory, rate of ADC change, age of ADC maturation, and hemispheric asymmetries of maturation ages. Patterns were quantified in whole-brain, segmented regional, and voxelwise levels by fitting a two-term exponential model. Hemispheric asymmetries in ADC maturation ages were assessed using t tests with Bonferroni correction. Results The posterior limb of the internal capsule (mean ADC: left hemisphere, 1.18 ×103µm2/sec; right hemisphere, 1.17 ×103µm2/sec), anterior limb of the internal capsule (left, 1.11 ×103µm2/sec; right, 1.09 ×103µm2/sec), vermis (1.26 ×103µm2/sec), thalami (left, 1.17 ×103µm2/sec; right, 1.15 ×103µm2/sec), and basal ganglia (left, 1.26 ×103µm2/sec; right, 1.23 ×103µm2/sec) demonstrate low initial ADC values, indicating an earlier prenatal time course of development. ADC maturation was completed between 1.3 and 2.4 years of age, depending on the region. The vermis and left thalamus matured earliest (1.3 years). The frontolateral gray matter matured latest (right, 2.3 years; left, 2.4 years). ADC maturation occurred earlier in the left hemisphere (P < .001) in several regions, including the frontal (mean ± standard deviation) (left, 2.16 years ± 0.29; right, 2.19 years ± 0.31), temporal (left, 1.93 years ± 0.22; right, 1.99 years ± 0.22), and parietal (left, 1.92 years ± 0.30; right, 2.03 years ± 0.28) white matter. Maturation occurred earlier in the right hemisphere (P < .001) in several regions, including the thalami (left, 1.63 years ± 0.32; right, 1.45 years ± 0.33), basal ganglia (left, 1.79 years ± 0.31; right, 1.70 years ± 0.37), and hippocampi (left, 1.93 years ± 0.34; right, 1.78 years ± 0.33). Conclusion Normative apparent diffusion coefficient developmental patterns on diffusion-weighted MRI scans were quantified in children aged 0 to 6 years. This work provides knowledge about early brain development and may guide the detection of abnormal patterns of maturation. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Rollins in this issue.

Characterization of Death in Infants With Neonatal Seizures.

BACKGROUND: Neonatal seizures are associated with death and neurological morbidity; however, little is known about how neonates with seizures die. METHODS: This was a prospective, observational cohort study of neonates with seizures treated at seven sites of the Neonatal Seizure Registry. We characterized the mode of death, evaluated the association between infant characteristics and mode of death, and evaluated predictors of death or transfer to hospice. RESULTS: We enrolled 611 consecutive neonates with seizures, and 90 neonates (15%) died before hospital discharge at a median age of 11 days (range: 1 to 163 days); 32 (36%) died in the first postnatal week. An additional 19 neonates (3%) were transferred to hospice. The most common mode of in-hospital death was death after extubation amidst concerns for poor neurological prognosis, in the absence of life-threatening physiologic instability (n = 43, 48%). Only one infant died while actively receiving cardiopulmonary resuscitation. In an adjusted analysis, premature birth (odds ratio: 3.06, 95% confidence interval 1.59 to 5.90) and high seizure burden (odds ratio: 4.33, 95% confidence interval 1.88 to 9.95) were associated with increased odds of death or transfer to hospice. CONCLUSION: In a cohort of neonates with seizures, death occurred predominantly after decisions to withdraw or withhold life-sustaining intervention(s). Future work should characterize how these decisions occur and develop optimized approaches to support families and clinicians caring for newborns with seizures.

SARS-CoV-2 can infect the placenta and is not associated with specific placental histopathology: a series of 19 placentas from COVID-19-positive mothers.

Congenital infection of SARS-CoV-2 appears to be exceptionally rare despite many cases of COVID-19 during pregnancy. Robust proof of placental infection requires demonstration of viral localization within placental tissue. Only two of the few cases of possible vertical transmission have demonstrated placental infection. None have shown placental expression of the ACE2 or TMPRSS2 protein, both required for viral infection. We examined 19 COVID-19 exposed placentas for histopathologic findings, and for expression of ACE2, and TMPRSS2 by immunohistochemistry. Direct placental SARS-CoV-2 expression was studied by two methods-nucleocapsid protein expression by immunohistochemistry, and RNA expression by in situ hybridization. ACE2 membranous expression in the syncytiotrophoblast (ST) of the chorionic villi is predominantly in a polarized pattern with expression highest on the stromal side of the ST. In addition, cytotrophoblast and extravillous trophoblast express ACE2. No ACE2 expression was detected in villous stroma, Hofbauer cells, or endothelial cells. TMPRSS2 expression was only present weakly in the villous endothelium and rarely in the ST. In 2 of 19 cases, SARS-CoV-2 RNA was present in the placenta focally in the ST and cytotrophoblast. There was no characteristic histopathology present in our cases including the two placental infections. We found that the placenta is capable of being infected but that this event is rare. We propose one explanation could be the polarized expression of ACE2 away from the maternal blood and pronounced paucity of TMPRSS2 expression in trophoblast.

Patient and Hospital Factors Associated With Unexpected Newborn Complications Among Term Neonates in US Hospitals.

Importance: Unexpected complications in term newborns have been recently adopted by the Joint Commission as a marker of obstetric care quality. Objective: To understand the variation and patient and hospital factors associated with severe unexpected complications in term neonates among hospitals in the United States. Design, Setting, and Participants: This cross-sectional study collected data from all births in US counties with 1 obstetric hospital using county-identified birth certificate data and American Hospital Association annual survey data from January 1, 2015, through December 31, 2017. All live-born, term, singleton infants weighing at least 2500 g were included. The data analysis was performed from December 1, 2018, through June 30, 2019. Exposures: Severe unexpected newborn complication, defined as neonatal death, 5-minute Apgar score of 3 or less, seizure, use of assisted ventilation for at least 6 hours, or transfer to another facility. Main Outcomes and Measures: Between-hospital variation and patient and hospital factors associated with unexpected newborn complications. Results: A total of 1 754 852 births from 576 hospitals were included in the analysis. A wide range of hospital complication rates was found (range, 0.6-89.9 per 1000 births; median, 15.3 per 1000 births [interquartile range, 9.6-22.0 per 1000 births]). Hospitals with high newborn complication rates were more likely to care for younger, white, less educated, and publicly insured women with more medical comorbidities compared with hospitals with low complication rates. In the adjusted models, there was little effect of case mix to explain the observed between-county variation (11.3%; 95% CI, 10.0%-12.6%). Neonatal transfer was the primary factor associated with complication rates, especially among hospitals with the highest rates (66.0% of all complications). The risk for unexpected neonatal complication increased by more than 50% for those neonates born at hospitals without a neonatal intensive care unit compared with those with a neonatal intensive care unit (adjusted odds ratio, 1.55; 95% CI, 1.38-1.75). Conclusions and Relevance: In this study, severe unexpected complication rates among term newborns varied widely. When included in the metric numerator, neonatal transfer was the primary factor associated with complications, especially among hospitals with the highest rates. Transfers were more likely to be necessary when infants were born in hospitals with lower levels of neonatal care. Thus, if this metric is to be used in its current form, it would appear that accreditors, regulatory bodies, and payers should consider adjusting for or stratifying by a hospital's level of neonatal care to avoid disincentivizing against appropriate transfers.

Mining multi-site clinical data to develop machine learning MRI biomarkers: application to neonatal hypoxic ischemic encephalopathy.

BACKGROUND: Secondary and retrospective use of hospital-hosted clinical data provides a time- and cost-efficient alternative to prospective clinical trials for biomarker development. This study aims to create a retrospective clinical dataset of Magnetic Resonance Images (MRI) and clinical records of neonatal hypoxic ischemic encephalopathy (HIE), from which clinically-relevant analytic algorithms can be developed for MRI-based HIE lesion detection and outcome prediction. METHODS: This retrospective study will use clinical registries and big data informatics tools to build a multi-site dataset that contains structural and diffusion MRI, clinical information including hospital course, short-term outcomes (during infancy), and long-term outcomes (~ 2 years of age) for at least 300 patients from multiple hospitals. DISCUSSION: Within machine learning frameworks, we will test whether the quantified deviation from our recently-developed normative brain atlases can detect abnormal regions and predict outcomes for individual patients as accurately as, or even more accurately, than human experts. Trial Registration Not applicable. This study protocol mines existing clinical data thus does not meet the ICMJE definition of a clinical trial that requires registration.

Unexpected term NICU admissions: a marker of obstetrical care quality?

BACKGROUND: Unexpected admissions of term neonates to the neonatal intensive care unit and unexpected postnatal complications have been proposed as neonatal-focused quality metrics for intrapartum care. Previous studies have noted significant variation in overall hospital neonatal intensive care unit admission rates; however, little is known about the influence of obstetric practices on these rates or whether variation among unanticipated admissions in low-risk, term neonates can be attributed to systemic hospital practices. OBJECTIVE: The objective of the study was to examine the relative effects of patient characteristics and intrapartum events on unexpected neonatal intensive care unit admissions and to quantify the between-hospital variation in neonatal intensive care unit admission rates among this group of neonates. STUDY DESIGN: We performed a retrospective cross-sectional study using data collected as part of the Consortium for Safe Labor study. Women who delivered term (≥37 weeks), singleton, nonanomalous, liveborn infants without an a priori risk for neonatal intensive care unit admission were included. The primary outcome was neonatal intensive care unit admission among this population. Multilevel mixed-effect models were used to calculate adjusted odds ratios for demographics (age, race, insurer), pregnancy characteristics (parity, gestational age, tobacco use, birthweight), maternal comorbidities (chronic and pregnancy-induced hypertension), hospital characteristics (delivery volume, hospital and neonatal intensive care unit level, academic affiliation), and intrapartum events (prolonged second stage, induction of labor, trial of labor after cesarean delivery, chorioamnionitis, meconium-stained amniotic fluid, and abruption). Intraclass correlation coefficients were used to estimate the between-hospital variance in a series of hierarchical models. RESULTS: Of the 143,951 infants meeting all patient and hospital inclusion criteria, 7995 (5.6%) were admitted to the neonatal intensive care unit after birth. In the fully adjusted model, the factors associated with the highest odds for neonatal intensive care unit admission included: nulliparity (adjusted odds ratio, 1.62 [95% confidence interval, 1.53-1.71]), large for gestational age (adjusted odds ratio, 1.59 [95% confidence interval, 1.47-1.71]), and small for gestational age (adjusted odds ratio, 1.60 [95% confidence interval, 1.47-1.73]). Induction of labor (adjusted odds ratio, 0.95 [95% confidence interval, 0.89-1.01]) was not associated with increased odds of neonatal intensive care unit admission compared with women who labored spontaneously. The events associated with higher odds of neonatal intensive care unit admission included: prolonged second stage (adjusted odds ratio, 1.66 [95% confidence interval, 1.51-1.83]); chorioamnionitis (adjusted odds ratio, 3.89 [95% confidence interval, 3.42-4.44]), meconium-stained amniotic fluid (adjusted odds ratio, 1.96 [95% confidence interval, 1.82-2.10]), and abruption (adjusted odds ratio, 2.64 [95% confidence interval, 2.16-.21]). Compared with women who did not labor, the odds of neonatal intensive care unit admission were lower for women who labored: adjusted odds ratio, 0.48 (95% confidence interval, 0.45-0.52) for women with no uterine scar and adjusted odds ratio, 0.83 (95% confidence interval, 0.73-0.94) for women with a uterine scar. There was significant variation in neonatal intensive care unit admission rates by hospital, ranging from 2.9% to 11.2%. After accounting for case mix and hospital characteristics, the between-hospital variance was 1.9%, suggesting that little of the variation was explained by the effect of the hospital. CONCLUSION: This study contributes to the currently limited understanding of term, neonatal intensive care unit admission rates as a marker of obstetrical care quality. We demonstrated that significant variation exists in hospital unexpected neonatal intensive care unit admission rates and that certain intrapartum events are associated with an increased risk for neonatal intensive care unit admission after delivery. However, the between-hospital variation was low. Unmeasured confounders and extrinsic factors, such as neonatal intensive care unit bed availability, may limit the ability of unexpected term neonatal intensive care unit admissions to meaningfully reflect obstetrical care quality.

Using clinically acquired MRI to construct age-specific ADC atlases: Quantifying spatiotemporal ADC changes from birth to 6-year old.

Diffusion imaging is critical for detecting acute brain injury. However, normal apparent diffusion coefficient (ADC) maps change rapidly in early childhood, making abnormality detection difficult. In this article, we explored clinical PACS and electronic healthcare records (EHR) to create age-specific ADC atlases for clinical radiology reference. Using the EHR and three rounds of multiexpert reviews, we found ADC maps from 201 children 0-6 years of age scanned between 2006 and 2013 who had brain MRIs with no reported abnormalities and normal clinical evaluations 2+ years later. These images were grouped in 10 age bins, densely sampling the first 1 year of life (5 bins, including neonates and 4 quarters) and representing the 1-6 year age range (an age bin per year). Unbiased group-wise registration was used to construct ADC atlases for 10 age bins. We used the atlases to quantify (a) cross-sectional normative ADC variations; (b) spatiotemporal heterogeneous ADC changes; and (c) spatiotemporal heterogeneous volumetric changes. The quantified age-specific whole-brain and region-wise ADC values were compared to those from age-matched individual subjects in our study and in multiple existing independent studies. The significance of this study is that we have shown that clinically acquired images can be used to construct normative age-specific atlases. These first of their kind age-specific normative ADC atlases quantitatively characterize changes of myelination-related water diffusion in the first 6 years of life. The quantified voxel-wise spatiotemporal ADC variations provide standard references to assist radiologists toward more objective interpretation of abnormalities in clinical images. Our atlases are available at https://www.nitrc.org/projects/mgh_adcatlases. Hum Brain Mapp 38:3052-3068, 2017. © 2017 Wiley Periodicals, Inc.

Management and outcomes of congenital chylothorax in the neonatal intensive care unit: A case series.

IMPORTANCE: Congenital chylothorax is a rare condition with pulmonary and multiorgan system effects, for which there are no standardized treatment recommendations. Collective review of known cases offers some conclusions and suggestions for treatment. OBJECTIVE: The aim of this study was to present a case series of 5 patients who were treated in the neonatal intensive care unit with chylothorax. METHODS: We describe 5 infants who were diagnosed prenatally with hydrops fetalis and postnatally had clinically significant congenital chylothorax. RESULTS: Treatment guidelines specific to congenital forms of chylothorax have not yet been developed, although there are consistent trends across our cases. Four of the 5 infants in this study have survived to date. Chylothorax was treated with chest tube placement and chylous fluid drainage, scrupulous attention to fluid balance, mechanical ventilation, and nutritional management and, in 3 cases, with octreotide infusions. Some of the infants also required treatment for immunodeficiency and altered coagulation pathways. None of the infants underwent surgical thoracic duct ligation. INTERPRETATION: Aided by the advantage of prenatal diagnosis, many cases of congenital chylothorax can be successfully treated by a combination of nutritional and medical management as well as careful attention to fluid and electrolyte balance and avoidance of infection, thereby avoiding the need for surgical ligation of the thoracic duct.

Management of the critical airway when an EXIT procedure is not an option: A case report.

Perinatal imaging facilitates detection of congenital head and neck masses to plan fetal procedures which secure the airway. Ex utero intrapartum therapy (EXIT) procedures are preferred to protect the neonatal airway. Herein we present a case in which a neonate with a large oropharyngeal lymphovascular malformation was delivered and the airway successfully managed without an EXIT procedure using a multidisciplinary approach. Preparations for the non-EXIT delivery and critical airway management are described.

BRAF V600E-Positive Multisite Langerhans Cell Histiocytosis in a Preterm Neonate.

Hemorrhagic pustules with a "blueberry muffin" appearance accompanied by respiratory failure in a neonate present a challenging differential diagnosis that includes infections and neoplasms. We present a case of multiorgan, multisite Langerhans cell histiocytosis (LCH), positive for the oncogenic BRAF V600E mutation, in a preterm neonate. Infants with LCH pose a diagnostic challenge due to their heterogeneous presentations. This case is unusual in that the newborn presented with severe multiorgan involvement. Due to the rare incidence, wide spectrum of clinical manifestations, and high mortality rate, clinicians must maintain a high index of suspicion for LCH.

An in vitro study to investigate the use of a breath-actuated, small-volume, pneumatic nebulizer for the delivery of methacholine chloride bronchoprovocation agent.

BACKGROUND: Current American Thoracic Society and American Association for Respiratory Care guidelines for the delivery of aerosol agents such as methacholine chloride (MC) for bronchoprovocation testing require the use of pneumatic jet nebulizers that have well-defined droplet size and mass output. A recently developed disposable, breath-actuated nebulizer (AeroEclipse) may offer bronchoprovocation testers an alternative to existing devices. METHODS: We studied the performance of 5 AeroEclipse nebulizers with regard to mass of MC delivered with various MC solution concentrations and numbers of inhalations, using a model of adult tidal breathing. Each nebulizer was operated with compressed air (8 L/min at 50 psig) and an initial fill of 2 mL. MC solutions with mass concentrations of 0.25, 0.98, 3.85, and 15.70 mg/mL were tested. The total mass of MC delivered was determined after 5, 10, and 15 complete breathing cycles, by assaying the MC collected on a filter placed at the nebulizer mouthpiece. The aerosol droplet size distribution, fine droplet fraction (FDF) (percentage of droplets < 4.8 microm diameter), and fine droplet mass (FDM) (mass of droplets < 4.8 microm diameter) were determined by laser diffractometry, using physiologically normal saline as a surrogate for MC solution. RESULTS: The mean +/- SD FDM collected in 5 breathing cycles was 654 +/- 29 microg with the 15.70 mg/mL solution, 158 +/- 9 microg with the 3.85 mg/mL solution, 37 +/- 3 microg with the 0.98 mg/mL solution, and 7 +/- 2 microg with the 0.25 mg/mL solution. FDM showed a linear correlation (r(2) = 0.9999) with MC concentration, within the range studied. FDM also showed a linear correlation (r(2) = 0.999) with the number of breathing cycles. For instance, with the 15.70 mg/mL solution, FDM was 654 +/- 29 microg with 5 breathing cycles, 1,228 +/- 92 microg with 10 breathing cycles, and 1,876 +/- 132 microg with 15 breathing cycles. CONCLUSIONS: Although the bronchoprovocation test procedure had to be slightly modified from the guidelines to accommodate the operation of the AeroEclipse's breath-actuation feature, our measurements indicate that a predictable dose of MC, within the useful range for bronchoprovocation testing, can be delivered to an adult patient breathing tidally. The green indicator on the AeroEclipse could be used to coach the patient to inhale for a specific period, thereby controlling MC delivery per breathing cycle.

Size analysis of a pressurized metered dose inhaler-delivered solution formulation by an Aerosizer-LD time-of-flight aerosol particle size spectrometer.

In a previous study, an Aerosizer-LD time-of-flight (TOF) aerosol spectrometer was shown to underestimate significantly the aerodynamic size of airborne particles produced following actuation of a suspension-based formulation delivered from a pressurized metered-dose inhaler (pMDI) via a nonelectrostatic valved holding chamber (VHC). It was postulated that the nonspecific nature of the particle detection system in terms of chemical composition was responsible for the inclusion of smaller non-drug-containing excipient particles in the measured size distribution data from this analyzer. This limitation may not apply to certain solution formulations in which the only particles remaining after the evaporation of propellant and volatile excipient (solubilizer) are composed of pure drug substance. Such a formulation (QVAR, HFA-formulated beclomethasone di-propionate [BDP]) has recently become available, and the present investigation was therefore designed to test this hypothesis. Aerosizer-LD measured mass-weighted size distribution data for QVAR had a mass median aerodynamic diameter (MMAD) close to 1.1 microm, very similar to published data for this parameter, based on measurement of the aerosol by cascade impactor followed by drug-specific assay. However, the Aerosizer-LD underestimated the spread of the size distribution significantly. The causes are believed to be a combination of two separate effects: (1) lack of sensitivity of the particle detection system to particles finer than about 0.7 microm aerodynamic diameter and (2) preferential removal of particles larger than the MMAD, either by evaporation of residual solvent (ethanol) or by inertial/gravitational deposition in the sampling arrangement upstream of the measurement zone.

Performance of large- and small-volume valved holding chambers with a new combination long-term bronchodilator/anti-inflammatory formulation delivered by pressurized metered dose inhaler.

The treatment of both the bronchoconstriction and inflammatory aspects of asthma simultaneously by a single pressurized metered dose inhaler (pMDI) represents a significant advance in convenience to the patient. However, a valved holding chamber (VHC) may still be needed to reduce the coarse component of the dose that is likely to deposit in the oropharyngeal region, and a small sized device may offer significant advantages to the patient from the standpoint of compliance with therapy. VHCs representing small (adult AeroChamber Plus with mouthpiece, 149-mL) and large (Volumatic, 750-mL) devices have been compared in an in vitro evaluation with Seretide/Advair (hydro-fluoro alkane [HFA]-formulated fluticasone propionate [FP = 125 microg/dose] and salmeterol xinafoate [SX = 25 microg/dose]) by Andersen Mark-II eight-stage impactor operated at 28.3 L/min following compendial methodology. Fine particle fraction, based on the size range from 1.1 to 4.7 microm aerodynamic diameter, from either large or small VHCs with either component (69-79%) was similar [p > or = 0.08], and significantly greater than that from the pMDI alone (approximately 40%) [p < 0.001]. Fine particle dose emitted by the VHCs for SX (8.2 +/- 0.8 microg for the AeroChamber Plus and 7.7 +/- 0.5 microg for the Volumatic) were comparable, and also similar to the fine particle dose delivered by the pMDI when used without a VHC (7.6 +/- 0.6 microg). Fine particle doses for the FP component delivered by the two VHCs (46.4 +/- 3.4 microg for the AeroChamber Plus and 46.3 +/- 2.7 microg for the Volumatic) were equivalent, but were slightly greater than the corresponding fine particle dose from the pMDI alone (39.1 +/- 2.6 microg). However, this difference (approximately 20%) is close to the limit of resolution based on intermeasurement variability and is unlikely to have clinical significance, given the interpatient variability seen with inhaled drug therapy. It is therefore concluded that either of these VHCs has equivalent in vitro performance with this combination formulation in terms of the portion of the dose emitted from the pMDI that is likely to reach the receptors in the lungs.