Aaron B. Cullen

Intra-tracheal delivery strategy of gentamicin with partial liquid ventilation

Patients with pulmonary infection often present with ventilation and perfusion abnormalities, which can impair intravenous antibiotic therapy. Intra-tracheal (i.t.) administration has met with obstacles, such as inadequate delivery to affected lung regions and the disruption of gas exchange. We hypothesized that i.t. administration of a gentamicin (G)/perfluorochemical (PFC) suspension (G/PFC) would effectively deliver and distribute gentamicin to the lung, while maintaining gas exchange and non-toxic serum levels. In addition, we sought to compare serum G and lung levels and distribution of G when G/PFC is administered at the initiation of partial liquid ventilation (PLV) vs. during PLV. To test this hypothesis, 17 newborn lambs were ventilated by PLV with perflubron (LiquiVent) for 4 h using three different G (5 mg kg-1) administration techniques: i.t. slow-fill (SF) (n = 6; G/PFC over 15 min at start of PLV), i.t. top-fill (TF) (n = 6; G/PFC 10-65 min after start of PLV), intravenous (i.v.) (n = 5, aqueous injection at start of PLV). Serum levels of gentamicin were obtained 1, 15, 30 and 60 min after administration, and hourly there after for the remainder of the protocol (4 h). Arterial blood gas and pulmonary function measurements were obtained throughout the protocol. At the conclusion of the protocol, representative samples from each lung lobe, the brain and kidney were homogenized and assayed for gentamicin. All results are presented as the mean +/- SEM; P < 0.05. Over time, serum gentamicin levels were greatest (P < 0.05) in i.v. (11.0 +/- 2.3 micrograms ml-1), followed by TF (2.3 +/- 0.1 micrograms ml-1) and SF (0.8 +/- 0.1 microgram ml-1). The percentage of the administered dose remaining in the lungs after 4 h was greater (P < 0.05) following i.t. delivery (SF 23.8 +/- 4.3%, TF 13.7 +/- 2.5%) as compared to i.v. (3.7 +/- 0.5%). These findings suggest that for a given dose of G, both SF and TF delivery methods of G/PFC can enhance pulmonary, relative to systemic, antibiotic coverage.

The impact of mechanical ventilation on immature airway smooth muscle: functional, structural, histological, and molecular correlates.

Preterm infants exposed to mechanical ventilation often develop airway dysfunction and bronchopulmonary dysplasia. The mechanisms of mechanical ventilation-induced airway injury are currently unknown. This study correlates the age-related effects of mechanical ventilation on airway function with structural alterations at the tissue, cellular, ultrastructural, and molecular levels. Mechanically ventilated and nonventilated tracheal rings were obtained from premature and newborn lambs. In tissue baths, the passive and active length-tension relationships and dose-response characteristics of the tracheal rings were determined. Fixed tracheal rings were digested and the resulting isolated smooth muscle cells measured. Rings were analyzed by light and electron microscopy. Additionally, protein was extracted from the tracheal smooth muscle and myosin heavy chain isoforms were separated by SDS-polyacrylamide gel electrophoresis and analyzed by densitometry. Mechanical ventilation resulted in a significant decrease of both the slope of the passive length-stress relationship and of maximal force generation, with both effects being most pronounced in the newborn age group. These age-related functional alterations correlated with a decrease in smooth muscle cell length and a disruption of ultrastructural architecture, which were also most pronounced in the older groups. Furthermore, mechanical ventilation resulted in epithelial denudation at all ages. There were no acute statistically significant effects of mechanical ventilation on myosin heavy chain isoform expression. This study demonstrates age-related effects of mechanical ventilation on the passive and active characteristics of tracheal function and provides a structural analysis of potential mechanisms. The mechanisms behind these functional differences involve ultrastructural changes in cell length, tissue matrix, and disruption of epithelial integrity. These findings help elucidate the pathogenesis of ventilator-induced airway injury.

Thermal Stability and Transition Studies With a Hybrid Warming Device for Neonates

OBJECTIVE: The use of both warmer beds and incubators is common in neonatal intensive care units (NICU), and transferring between these two warming devices is a routine and necessary event. This study was designed to evaluate the efficacy of a new hybrid-warming device, the Versalet™, in transitioning a preterm animal from a warmer bed to an incubator mode and back.STUDY DESIGN: Nine premature lambs were randomized, following delivery, to receive thermal support from a conventional warming bed and an incubator (control group), or from the Versalet™ (study group) in the warmer bed and incubator modes. Core and various surface temperatures, as well as physiological parameters were measured first during warming in the radiant warmer bed mode, Versalet™ or Resuscitaire™ and then during transition to the incubator mode, Versalet™ or Isolette™, and then back to the warmer bed mode.RESULTS: The animals remained stable during all the transitions. Despite careful planning, adverse events occurred in the control group during transfers. There were no significant differences in the temperature or physiologic profiles during any of the transitions in either group.CONCLUSION: Compared with the standard warming technique used in NICUs (separate warmer bed and incubator), the Versalet provides similar thermal and cardiovascular stability without adverse events during transition to different modes of warming. The degree to which this device would contribute to ease of management and improved outcomes in humans needs to be evaluated in a clinical trial.

Temperature and Heater Responses during Transition between Radiant and Incubator Thermal Environment in Newborn Preterm Lambs

Objective: Although both incubators and radiant warmer beds can provide thermal support to infants in the neonatal intensive care unit, the transition between devices can be a stressful event. The goal of this study was to evaluate a new device that combines these methods of warming and converts between them without requiring physical movement of the infant. Study Design: Twin preterm lambs received thermal support from a radiant warmer bed and an incubator (control), or from the VersaletTM 7700 Care Center (treatment) in the warmer and incubator configurations. Temperature of each lamb, as well as device heater power, were monitored every 2 min before, during, and after the transition. Physiological parameters were monitored every 15 min. Results: There was a significant difference in response time between closed-open and open-closed conditions for both groups. More adverse events occurred in the control group during transfers. There were no differences in temperatures or physiological variables during transitions in either group. Conclusions: These data suggest the Versalet provides similar thermal stability to traditional devices, with fewer adverse events associated with the lack of physical movement between warming configurations. The impact of this device on the care of the preterm neonate will be evaluated in a clinical trial.