Steven E. Zgleszewski

High dose dexmedetomidine as the sole sedative for pediatric MRI

Objective:  This large‐scale retrospective review evaluates the sedation profile of dexmedetomidine.

Dexmedetomidine for pediatric sedation for computed tomography imaging studies

Dexmedetomidine is a sedative with limited experience in the pediatric population. This is the first study that prospectively evaluates the sedation profile of a dexmedetomidine pilot program for pediatric sedation for radiological imaging studies. In March 2005, our hospital sedation committee approved the replacement of IV pentobarbital with dexmedetomidine as the standard of care for CT imaging. Detailed Quality Assurance (QA) data sheets collect relevant information on each patient, which is then logged into a computerized sedation database. After IRB approval, all QA data was accessed. Sixty-two patients with a mean age of 2.8 years (SD = 1.8, range 0.5–9.7) received IV (IV) dexmedetomidine administered as a 2 mcg/kg loading dose over 10 minutes, followed by repeat boluses of 2 mcg/kg over 10 minutes until target of Ramsay Sedation Score 4 (RSS) achieved. Patients were then maintained on 1 mcg/kg/hr infusion until imaging is completed. Repeated-measures ANOVA indicated that compared to pre-sedation values, the heart rate and mean arterial blood pressure decreased an average of 15% during bolus, infusion and recovery (P < 0.01). No significant changes were observed in respiratory rate or end-tidal CO2. Mean recovery time was 32 ± 18 minutes. Based on our pilot results, dexmedetomidine may provide a reliable and effective method of providing sedation.

Hemodynamic effects of dexmedetomidine sedation for CT imaging studies

Background:  Dexmedetomidine sedation for radiological imaging studies is a relatively recent application for this drug. Previous studies have demonstrated some haemodynamic effects of dexmedetomidine, however, the effects remain poorly described in children. The aim of this study was to better define the effect of age on heart rate (HR) and blood pressure changes in children sedated for CT imaging with dexmedetomidine.

Incidence and predictors of hypertension during high-dose dexmedetomidine sedation for pediatric MRI

This study reviewed the hypertensive response of a large population of children to high‐dose dexmedetomidine sedation with the aim of determining the incidence and predictors of hypertension.

Fetal lung development: Airway pressure enhances the expression of developmental genes

BACKGROUND/PURPOSE The mechanisms by which static airway pressures in the developing lung affect development are unknown. The in vitro murine fetal lung model with airway ligation reproduces the phenomenon of intraluminal airway pressure in developing lungs. We have applied the technique of differential display of mRNAs to fetal murine lungs that were maintained in organ culture with and without tracheal ligation. The goal of this investigation was to identify genes that are induced or enhanced by airway pressure during lung development. METHODS Fetuses were harvested from CD-1 mice on gestational day (Gd) 14. The lungs were removed and trachea either transected or ligated and organ cultured for 7 days. Total RNA was extracted from cultured unligated controls and ligated lungs. Reverse transcription (RT) of the purified total RNA from each pooled sample was performed with anchor primer H-T11G or C and one of 24 arbitrary primers followed by polymerase chain reaction (PCR) of the RT mixtures. PCR products were electrophoresed on a DNA sequencing gel. Differentially expressed cDNA bands of interest were cut from the dried gel. Each cDNA was then reamplified. Reamplified cDNAs were extracted, PCR amplified, cloned, and sequenced for homology to existing sequences in the GenBank database. RESULTS Sequencing identified 4 differentially expressed genes enhanced by tracheal ligation: hepatoma-derived growth factor (HDGF), ribosomal protein S24, stathmin, and parathyroid hormone (PTH). CONCLUSIONS Genes enhanced by airway pressure or tracheal ligation are mitogenic for fibroblasts, correlate with cell proliferation, regulate cell proliferation and differentiation, and may play a role in growth in distal lung and type II cell differentiation. Further work is necessary to identify the mechanisms by which these genes influence lung maturational processes.

An exaggerated hypertensive response to glycopyrrolate therapy for bradycardia associated with high-dose dexmedetomidine.

At our institution, high-dose i.v. dexmedetomidine is used to provide sedation for pediatric patients undergoing nonpainful radiological imaging studies. Some of these patients exhibit marked bradycardia (more than 20% deviation from the lowest age-adjusted normal values) while maintaining an arterial blood pressure within an acceptable normal range. We report on three cases wherein treatment of dexmedetomidine-induced bradycardia with i.v. glycopyrrolate (5.0 microg/kg) not only resulting in resolution of bradycardia but also resulting in an exaggerated increase of arterial blood pressure.

Influence of epidermal growth factor and transforming growth factor beta-1 on patterns of fetal mouse lung branching morphogenesis in organ culture

Transforming growth factor‐β (TGF‐β), a potent inhibitor of epithelial cell proliferation, and epidermal growth factor (EGF), a mitogenic polypeptide that binds to cell surface receptors, are important regulators of cell differentiation; however, their distinct role(s) in lung development and their mechanisms of action are not well understood. We evaluated the effects of these factors on lung morphogenesis in murine fetal lungs at gestational day 14 (time:zero) and again after 7 days in culture. Baseline controls were cultured after tracheal transection in supplemented BGJb medium, and other tracheally transected lungs were cultured following addition of EGF (10 ng/ml BGJb), TGF‐β1 (2 ng/ml BFJb), or with both in combination added to the medium.

Growth factors and dexamethasone regulate Hoxb5 protein in cultured murine fetal lungs

Studies on lung morphogenesis have indicated a role of homeobox( Hox) genes in the regulation of lung development. In the present study, we attempted to modulate the synthesis of Hoxb5 protein in cultured murine fetal lungs after mechanical or chemical stimuli. Murine fetuses at gestational day 14 (GD14) were removed from pregnant CD-1 mice, and lungs were excised and cultured for 7 days in BGJb media. The experimental groups were 1) untreated, unligated; 2) tracheal ligation; 3) supplemented media with either epidermal growth factor (EGF; 10 ng/ml), transforming growth factor (TGF)-β1 (2 ng/ml), dexamethasone (10 nM), EGF+TGF-β1, or EGF+TGF-β1+dexamethasone. After 3 or 7 days, the cultured lungs were compared with in vivo lungs. Immunoblotting signals at 3 days in culture were stronger than those at 7 days. Western blot analyses showed that ligation, EGF, TGF-β1, and EGF+TGF-β1 downregulated Hoxb5 protein to ∼20-70% of Hoxb5 protein levels in unligated, untreated cultured lungs. Furthermore, dexamethasone alone or in combination with EGF and TGF-β1 downregulated Hoxb5 protein by >90% ( P < 0.05) signal strength, similar to that seen in GD19 or in neonatal lungs. Immunostaining showed that Hoxb5 protein was expressed strongly in the lung mesenchyme at early stages in gestation. However, by GD19 and in neonates, it was present only in specific epithelial cells. A persistent level of Hoxb5 protein in the mesenchyme after EGF or TGF-β1 treatments or tracheal ligation was noted. Hoxb5 protein was significantly downregulated by EGF+TGF-β1, and it was least in lungs after dexamethasone or EGF+TGF-β1+dexamethasone treatment. The decrease in Hoxb5 protein was significant only in the groups with dexamethasone added to the media. Thus immunostaining results parallel those of immunoblotting. The degree of Hoxb5 downregulation by dexamethasone or EGF+TGF-β1+dexamethasone was similar to that seen in vivo in very late gestation, which correlated to the advancing structural development of the lung.

Efficiency of propofol versus midazolam and fentanyl sedation at a pediatric teaching hospital : a prospective study

BACKGROUND Many pediatric endoscopists are adopting propofol in their practices, with the expectation that propofol will increase their overall efficiency. OBJECTIVE AND SETTING To compare the efficiency of propofol versus midazolam and fentanyl by measuring elapsed times between initial intravenous administration and patient discharge at a pediatric teaching hospital. DESIGN Endoscopy times were prospectively collected for consecutive patients who were undergoing either anesthesiologist-administered propofol or endoscopist-administered midazolam and fentanyl. The effect of the type of sedation on these times was assessed by using multiple linear regression by adjusting for other candidate predictors, including concomitant use of other sedatives, endotracheal intubation by anesthesiologists, and the presence of fellow trainees. MAIN OUTCOME MEASUREMENTS Time to onset of sedation (time sedation started to scope in), procedure time (endoscope in to endoscope out), discharge time (endoscope out to hospital discharge), and total time (sedation started to hospital discharge). RESULTS The times for 134 children (mean age 12 +/- 5 years) to receive propofol sedation were compared with those of 195 children (13 +/- 5 years) who received midazolam and fentanyl. Midazolam and fentanyl cases disproportionately included EGDs (P < .001) and patients who were classified as American Society of Anesthesiologists I (P < .03). Patients who received propofol had shorter times until sedated, similar procedure times, longer discharge times, and comparable total times. Multivariate analyses confirmed that fellow participation prolonged the procedure times (P < .0001), and endotracheal intubation prolonged propofol times (P <. 01), but adjusting for these did not change the comparison results. CONCLUSIONS Anesthesiologist-administered propofol sedation in a pediatric teaching endoscopy unit may not lead to faster hospital times when compared with endoscopist-administered midazolam and fentanyl. These results are not explained by controlling for patient characteristics, the presence of a trainee, the sedative doses, or endotracheal intubation for airway management.

Effects of dexamethasone, growth factors, and tracheal ligation on the development of nitrofen-exposed hypoplastic murine fetal lungs in organ culture.

BACKGROUND/PURPOSE The addition of growth factors EGF (epidermal growth factor) plus TGFbeta1 (transforming growth factor beta1; E + T) or dexamethasone (DEX) to normal murine fetal lungs in culture enhances lung development. In addition, ligation of the airway in lungs in organ culture, enhances lung development. Nitrofen (2,4-dichlorophenyl-p-nitrophenylether) administration to pregnant mice results in pulmonary hypoplasia in the offspring with many similarities to human hypoplastic lung conditions. This study investigates the effects of growth factors, dexamethasone, and airway ligation on the development of hypoplastic fetal murine lungs in whole-organ culture. We hypothesized that E+T, DEX, or airway ligation will enhance the development and maturation of hypoplastic murine fetal lungs in vitro. METHODS Time-dated pregnant CD-1 mice were given nitrofen, 25 mg, intragastrically at gestational day (Gd) 8. The dams were killed on Gd 14, and the fetuses were removed. The hypoplastic fetal lungs were excised, and the tracheae were transected. The lungs were cultured in serum-free BGJb media in the presence or absence of E+T (10 ng/mL + 2 ng/mL, respectively) or DEX (10 nmol/L). Some lungs were cultured for 7 days with the tracheae ligated. RESULTS Gross morphology under a dissecting stereomicroscope showed that the lungs were larger after E+T, DEX, or tracheal ligation. Histologically, the untreated lungs had progressed from the pseudoglandular stage to a canalicular-like stage with poorly differentiated airways. The E+T-treated lungs had better developed airway branching and small acini; however, thick mesenchyme persisted. The ligated lungs had well-developed airway branching and acinar structures. After DEX treatment the lungs were most developed with very well defined airway branching and expanded acinar structures; however, there was no secondary septation. Ultrastructurally, the hypoplastic lungs at Gd 14 and after 7 days in culture had no glycogen in their epithelial cells, no defined acinar formation, and had damaged mitochondria. The E+T-treated or tracheally ligated lungs had abundant type II cells, secreted lamellar bodies (LBs), and showed infrequent tubular myelin. Mitochondrial damage was noted in these lungs as in the untreated lungs. DEX-treated hypoplastic lungs showed large acini. The acinar walls were thick; however, they had type II cells with abundant LBs and intact mitochondria. The airways were noted to have differentiated cell types. Surfactant secretions in acinar spaces showed tubular myelin structures. CONCLUSIONS E+T, tracheal ligation, or DEX accelerates lung development and maturation of hypoplastic fetal murine lungs compared with untreated controls. DEX had a greater effect with special reference to repair of mitochondrial damage. DEX not only accelerated lung development, but it may have reversed some of the effects nitrofen.