Extubation Readiness Practices and Barriers to Extubation in Pediatric Subjects.

BACKGROUND: Invasive mechanical ventilation is a lifesaving intervention that is associated with short- and long-term morbidities. Extubation readiness protocols aim to decrease extubation failure rates and simultaneously shorten the duration of invasive ventilation. This study sought to analyze extubation readiness practices at one institution and identify barriers to extubation in pediatric patients who have passed an extubation readiness test (ERT). METHODS: We performed a retrospective chart review of all pediatric subjects admitted between April 2017 and March 2018, and who were on mechanical ventilation. Exclusion criteria were cardiac ICU admission, tracheostomy, chronic ventilator support, limited resuscitation status, and death before extubation attempt. Data with regard to the method of ERT and reasons for delaying extubation were collected. RESULTS: There were 427 subjects included in the analysis with 69% having had an ERT before extubation. Of those, 39% were extubated per our daily spontaneous breathing trial (SBT) protocol, and the daily SBT failed in 30% but they had passed a subsequent pressure support and CPAP trial on the same day. The most common reasons for failing the daily SBT were a lack of spontaneous breathing (30% [75/252]), being intubated < 24 h (24% [60/252]), breathing frequency outside the target range (22% [55/252]), and not meeting tidal volume goal (14% [34/252]). The most common documented reasons for delaying extubation despite passing daily SBT were planned procedure (29% [26/90]), neurologic status (23% [21/90]), and no leak around the endotracheal tube (18% [16/90]). The median time between passing ERT and extubation was 7 h (interquartile range, 5-10). CONCLUSIONS: In our institution, there was variation in extubation readiness practices that could lead to a significant delay in liberation from invasive ventilation. Adjustment of our daily SBT to tolerate a higher work of breathing, such as higher breathing frequencies and lower tidal volumes, and incorporating sedation scoring into the protocol could be made without significantly affecting extubation failure rates.

Progression of Respiratory Support Following Pediatric Extubation.

OBJECTIVES: High-flow nasal cannula and noninvasive positive pressure ventilation have become ubiquitous in contemporary PICUs. Practice patterns associated with the use of these modalities have not been well described. In this study, we aimed to describe the use of high-flow nasal cannula and noninvasive positive pressure ventilation in children after extubation and analyze the progression of usage in association with patient factors. Our secondary aim was to describe interventions used for postextubation stridor. DESIGN: Single-center retrospective cohort study. SETTING: A 36-bed quaternary medical-surgical PICU. PATIENTS: Mechanically ventilated pediatric patients admitted between April 2017 and March 2018. Exclusions were patients in the cardiac ICU, patients requiring a tracheostomy or chronic ventilatory support, and patients with limited resuscitation status. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data regarding respiratory modality use was collected for the first 72 hours after extubation. There were 427 patients included in the analysis; 51 patients (11.9%) were extubated to room air, 221 (51.8%) to nasal cannula, 132 (30.9%) to high-flow nasal cannula, and 23 (5.4%) to noninvasive positive pressure ventilation. By 72 hours, 314 patients (73.5%) were on room air, 52 (12.2%) on nasal cannula, 29 (6.8%) on high-flow nasal cannula, eight (1.9%) on noninvasive positive pressure ventilation, and 24 (5.6%) were reintubated. High-flow nasal cannula was the most used respiratory modality for postextubation stridor. Multivariate analysis demonstrated that longer duration of invasive mechanical ventilation increased the odds of initial high-flow nasal cannula and noninvasive positive pressure ventilation use, and a diagnosis of cerebral palsy increased the odds of escalating from high-flow nasal cannula to noninvasive positive pressure ventilation in the first 24 hours post extubation. CONCLUSIONS: High-flow nasal cannula is commonly used immediately after pediatric extubation and the development of postextubation stridor; however, its usage sharply declines over the following 72 hours. Larger multicenter trials are needed to identify high-risk patients for extubation failure that might benefit the most from prophylactic use of high-flow nasal cannula and noninvasive positive pressure ventilation after extubation.

Marmosets as a preclinical model for testing "off-label" use of doxycycline to turn on Flt3L expression from high-capacity adenovirus vectors.

We developed a combined conditional cytotoxic, i.e., herpes simplex type 1-thymidine kinase (TK), plus immune-stimulatory, i.e., fms-like tyrosine kinase ligand-3-mediated gene therapy for glioblastoma multiforme (GBM). Therapeutic transgenes were encoded within high-capacity adenoviral vectors (HC-Ad); TK was expressed constitutively, while Flt3L was under the control of the TetOn regulatable promoter. We previously assessed efficacy and safety in intracranial GBM rodent models. But, since this approach involves expression of a cytokine within the brain, we chose the nonhuman primate, i.e., Callithrix jaccus (marmoset) as it has been established that its immune response shares similarities with man. We characterized the safety, cell-type specific expression, and doxycycline (DOX)-inducibility of HC-Ad-TetOn-Flt3L delivered within the striatum. We used allometrically scaled DOX doses delivered orally, twice daily for one month, mimicking the route and duration of DOX administration planned for the GBM trial. Flt3L was effectively expressed within astrocytes, microglia, oligodendrocytes, and neurons. No evidence of brain or systemic toxicities due to the treatment was encountered. Our data indicate that DOX doses equivalent to those used in humans to treat infections can be safely used "off-label" to turn "on" therapeutic gene expression from HC-Ad-TetOn-Flt3L; providing evidence for the safety of this approach in the clinic.

Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma.

Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L). Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression "on" or "off" according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1×10(8), 1×10(9), or 1×10(10) viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1×10(9) vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and underpin further developments for its implementation in a phase I clinical trial for glioma.