CFD Guided Optimization of Nose-to-Lung Aerosol Delivery in Adults: Effects of Inhalation Waveforms and Synchronized Aerosol Delivery.

PURPOSE: The objective of this study was to optimize nose-to-lung aerosol delivery in an adult upper airway model using computational fluid dynamics (CFD) simulations in order to guide subsequent human subject aerosol delivery experiments. METHODS: A CFD model was developed that included a new high-flow nasal cannula (HFNC) and pharmaceutical aerosol delivery unit, nasal cannula interface, and adult upper airway geometry. Aerosol deposition predictions in the system were validated with existing and new experimental results. The validated CFD model was then used to explore aerosol delivery parameters related to synchronizing aerosol generation with inhalation and inhalation flow rate. RESULTS: The low volume of the new HFNC unit minimized aerosol transit time (0.2 s) and aerosol bolus spread (0.1 s) enabling effective synchronization of aerosol generation with inhalation. For aerosol delivery correctly synchronized with inhalation, a small particle excipient-enhanced growth delivery strategy reduced nasal cannula and nasal depositional losses each by an order of magnitude and enabled ~80% of the nebulized dose to reach the lungs. Surprisingly, nasal deposition was not sensitive to inhalation flow rate due to use of a nasal cannula interface with co-flow inhaled air and the small initial particle size. CONCLUSIONS: The combination of correct aerosol synchronization and small particle size enabled high efficiency nose-to-lung aerosol delivery in adults, which was not sensitive to inhalation flow rate.

A narrative review on trans-nasal pulmonary aerosol delivery.

The use of trans-nasal pulmonary aerosol delivery via high-flow nasal cannula (HFNC) has expanded in recent years. However, various factors influencing aerosol delivery in this setting have not been precisely defined, and no consensus has emerged regarding the optimal techniques for aerosol delivery with HFNC. Based on a comprehensive literature search, we reviewed studies that assessed trans-nasal pulmonary aerosol delivery with HFNC by in vitro experiments, and in vivo, by radiolabeled, pharmacokinetic and pharmacodynamic studies. In these investigations, the type of nebulizer employed and its placement, carrier gas, the relationship between gas flow and patient's inspiratory flow, aerosol delivery strategies (intermittent unit dose vs continuous administration by infusion pump), and open vs closed mouth breathing influenced aerosol delivery. The objective of this review was to provide rational recommendations for optimizing aerosol delivery with HFNC in various clinical settings.

Nasal high flow higher than 60 L/min in patients with acute hypoxemic respiratory failure: a physiological study.

BACKGROUND: Nasal high flow delivered at flow rates higher than 60 L/min in patients with acute hypoxemic respiratory failure might be associated with improved physiological effects. However, poor comfort might limit feasibility of its clinical use. METHODS: We performed a prospective randomized cross-over physiological study on 12 ICU patients with acute hypoxemic respiratory failure. Patients underwent three steps at the following gas flow: 0.5 L/kg PBW/min, 1 L/kg PBW/min, and 1.5 L/kg PBW/min in random order for 20 min. Temperature and FiO2 remained unchanged. Toward the end of each phase, we collected arterial blood gases, lung volumes, and regional distribution of ventilation assessed by electrical impedance tomography (EIT), and comfort. RESULTS: In five patients, the etiology was pulmonary; infective disease characterized seven patients; median PaO2/FiO2 at enrollment was 213 [IQR 136-232]. The range of flow rate during NHF 1.5 was 75-120 L/min. PaO2/FiO2 increased with flow, albeit non significantly (p = 0.064), PaCO2 and arterial pH remained stable (p = 0.108 and p = 0.105). Respiratory rate decreased at higher flow rates (p = 0.014). Inhomogeneity of ventilation decreased significantly at higher flows (p = 0.004) and lung volume at end-expiration significantly increased (p = 0.007), but mostly in the non-dependent regions. Comfort was significantly poorer during the step performed at the highest flow (p < 0.001). CONCLUSIONS: NHF delivered at rates higher than 60 L/min in critically ill patients with acute hypoxemic respiratory failure is associated with reduced respiratory rate, increased lung homogeneity, and additional positive pressure effect, but also with worse comfort.

Deposition of drugs in the nose and sinuses with an exhalation delivery system vs conventional nasal spray or high-volume irrigation in Draf II/III post-surgical anatomy.

BACKGROUND: Endoscopic sinus surgery is often performed to improve delivery of topical medication into sinus cavities. Intranasal steroids are guideline recommended in post-surgical patients, and experiments with cadavers suggest that surgery improves delivery of drug into sinuses. Exhalation delivery systems (EDS) use a new mechanism for intranasal delivery and have been shown to reach superior/posterior regions of the nasal cavity better than nasal sprays in unoperated patients. METHODS: Silicone casts of the nasal cavity and sinuses from a patient after Draf II, and then Draf III, were made from high-resolution computed tomography (CT) data using 3D printing. Internal surfaces were coated with liquid-sensitive, color-changing gel. Color changes were evaluated following conventional nasal spray delivery (0.1 mL x 2) (Nasonex), EDS delivery (0.1 mL x 2) (XHANCE), and high-volume, low-flow (HVLF) delivery (80 mL) with head tilted either 45° or 90°. RESULTS: Conventional nasal spray deposited liquid only in anterior nasal segments. EDS deposited liquid throughout the nasal cavity, in surgically opened ethmoid and maxillary spaces, at entrances of the frontal sinuses in Draf II geometry, and into frontal sinuses in Draf III. Tilted 45° HVLF delivery enters the maxillary sinuses but not the frontal sinuses or the ethmoid region. At full 90° inclination, HVLF delivery reaches most of the frontal and maxillary sinuses but not the roof and posterior wall of the ethmoid region. CONCLUSIONS: HVLF and EDS produced a deep intranasal/intrasinal deposition in the silicone cast compared with conventional nasal spray delivery; both deposited liquid inside the surgically opened sinuses. HVLF offers the benefit of lavage, whereas EDS may be more efficient and convenient.

Subunit-based mucosal vaccine delivery systems for pulmonary delivery - Are they feasible?

Pulmonary infections are the most common cause of death globally. However, the development of mucosal vaccines that provide protective immunity against respiratory pathogens are limited. In contrast to needle-based vaccines, efficient vaccines that are delivered via noninvasive mucosal routes (such as via the lungs and nasal passage) produce both antigen-specific local mucosal IgA and systemic IgG protective antibodies. One major challenge in the development of pulmonary vaccines using subunit antigens however, is the production of optimal immune responses. Subunit vaccines therefore rely upon use of adjuvants to potentiate immune responses. While the lack of suitable mucosal adjuvants has hindered progress in the development of efficient pulmonary vaccines, particle-based systems can provide an alternative approach for the safe and efficient delivery of subunit vaccines. In particular, the rational engineering of particulate vaccines with optimal physicochemical characteristics can produce long-term protective immunity. These protect antigens against enzymatic degradation, target antigen presenting cells and initiate optimal humoral and cellular immunity. This review will discuss our current understanding of pulmonary immunology and developments in fabricating particle characteristics that may evoke potent and durable pulmonary immunity.

High flow nasal therapy in perioperative medicine: from operating room to general ward.

BACKGROUND: High flow nasal therapy (HFNT) is a technique in which humidified and heated gas is delivered to the airways through the nose via small nasal prongs at flows that are higher than the rates generally applied during conventional oxygen therapy. The delivered high flow rates combine mixtures of air and oxygen and enable different inspired oxygen fractions ranging from 0.21 to 1. HFNT is increasingly used in critically ill adult patients, especially hypoxemic patients in different clinical settings. MAIN BODY: Noninvasive ventilation delivers positive pressure (end-expiratory and inspiratory pressures or continuous positive airway pressure) via different external interfaces. In contrast, HFNT produces different physiological effects that are only partially linked to the generation of expiratory positive airway pressure. HFNT and noninvasive ventilation (NIV) are interesting non-invasive supports in perioperative medicine. HFNT exhibits some advantages compared to NIV because HFNT is easier to apply and requires a lower nursing workload. Tolerance of HFNT remains a matter of intense debate, and it may be related to selected parameters. Patients receiving HFNT and their respiratory patterns should be closely monitored to avoid delays in intubation despite correct oxygenation parameters. CONCLUSION: HFNT seems to be an interesting noninvasive support in perioperative medicine. The present review provides anesthesiologists with an overview of current evidence and practical advice on the application of HFNT in perioperative medicine in adult patients.

Opportunities and challenges for intranasal oxytocin treatment studies in nonhuman primates.

Nonhuman primates provide a human-relevant experimental model system to explore the mechanisms by which oxytocin (OT) regulates social processing and inform its clinical applications. Here, we highlight contributions of the nonhuman primate model to our understanding of OT treatment and address unique challenges in administering OT to awake behaving primates. Prior preclinical research utilizing macaque monkeys has demonstrated that OT can modulate perception of other individuals and their expressions, attention to others, imitation, vigilance to social threats, and prosocial decisions. We further describe ongoing efforts to develop an OT delivery system for use in experimentally naïve juvenile macaque monkeys compatible with naturalistic social behavior outcomes. Finally, we discuss future directions to further develop the rhesus monkey as a preclinical test bed to evaluate the effects of OT exposure and advance efforts to translate basic science OT research into safe and effective OT therapies.

Not Just a Drop in the Bucket-Inversion of Oxymetazoline Nasal Decongestant Container Increases Potential for Severe Pediatric Poisoning.

Oxymetazoline is an over-the-counter nasal decongestant with potent alpha agonist properties. In overdoses as small as 1-2 mL, toxicity can be seen including bradycardia and respiratory depression. We demonstrated that inverting the container increased the volume delivered 20- to 30-fold compared with holding it upright in an in vitro model.

[Main progress on intranasal administration of traditional Chinese medicine].

Traditional Chinese medicine has a long history of intranasal administration. Compared with the other administration routes, intranasal administration has the benefits of fast absorption, high bioavailability, high brain-targeting and non-invasive. In the past few years we take "Xingnaojing" and "Tongqiao Sanyu formula" as model drug and studied pharmacokinetics of effective components of different polarities. MDCK/MDCK-MDR1 cells were used to simulate blood brain barrier to study the permeate behaviors of different drug and the mechanism of enhancing effects of aromatic medicine. Then a microemulsion (modified by mPEG2000-PLA) was prepared for intranasal administration, and the pharmacokinetics and investigated tissue distribution were studied by fluorescence imaging. The irritation of the drug and different preparations were studied on human nasal epithelial cell (HNEC) cell and living animals. In this paper, we reviewed the achievements and hope that it can provide constructive suggestions for the future research.

[Investigation of permeability of intranasal formulations using Side-Bi-Side horizontal diffusion cell]. / Nazális gyógyszerformák permeabilitási vizsgálata Side-Bi-Side horizontális cella alkalmazásával.

Nowadays the nasal route has received a great attention as a reliable administration for the systemic administration. In the Department of Pharmaceutical Technology, University of Szeged, the main research work is the design and development of innovative nasal formulations, which can open new possibilities for some well-known agents and may also help some drug-candidates delivery problems. The aim of this work was to present some reliable models for investigation of permeability, such as Spectra/Por Dialisys Membran, ZelluTrans/Roth Mini Dialyzer, µFLUX diffusion Cell, Navicyte Vertical and Horizontal Diffusion Chamber System and In-line Cell. In addition, the horizontal membrane diffusion model (Side-Bi-Side) was used to investigate in vitro and ex vivo studies of permeability of meloxicam in comparison with the vertical diffusion cell (Franz). The present study investigated the meloxicam in different dosage forms (powder, spray, gel). It was found that the Side-Bi-Side cell is suitable to test the nasal formulations, but the uniform distribution of the active substance cannot be ensured in donor place by increasing the viscosity of the compositions, therefore the Franz cell is recommended for investigation of nasal gel. Previous measurement cannot be found related to this topic.

Utility of intranasal Ketamine and Midazolam to perform gastric aspirates in children: a double-blind, placebo controlled, randomized study.

BACKGROUND: We performed a prospective, randomized, placebo-controlled study aimed to evaluate the efficacy and safety of a sedation protocol based on intranasal Ketamine and Midazolam (INKM) administered by a mucosal atomizer device in uncooperative children undergoing gastric aspirates for suspected tuberculosis. PRIMARY OUTCOME: evaluation of Modified Objective Pain Score (MOPS) reduction in children undergoing INKM compared to the placebo group. SECONDARY OUTCOMES: evaluation of safety of INKM protocol, start time sedation effect, duration of sedation and evaluation of parents and doctors' satisfaction about the procedure. METHODS: In the sedation group, 19 children, mean age 41.5 months, received intranasal Midazolam (0.5 mg/kg) and Ketamine (2 mg/kg). In the placebo group, 17 children received normal saline solution twice in each nostril. The child's degree of sedation was scored using the MOPS. A questionnaire was designed to evaluate the parents' and doctors' opinions on the procedures of both groups. RESULTS: Fifty-seven gastric washings were performed in the sedation-group, while in the placebo-group we performed 51 gastric aspirates. The degree of sedation achieved by INMK enabled all procedures to be completed without additional drugs. The mean duration of sedation was 71.5 min. Mean MOPS was 3.5 (range 1-8) in the sedation-group, 7.2 (range 4-9) in the placebo-group (p <0.0001). The questionnaire revealed high levels of satisfaction by both doctors and parents in the sedation-group compared to the placebo-group. The only side effect registered was post-sedation agitation in 6 procedures in the sedation group (10.5%). CONCLUSIONS: Our experience suggests that atomized INKM makes gastric aspirates more acceptable and easy to perform in children. TRIAL REGISTRATION: Unique trial Number: UMIN000010623; Receipt Number: R000012422.

An unexpected route for otolaryngology bacterial contamination with a Venturi atomizer.

BACKGROUND: The Venturi-principle atomizer is a commonly used device in otolaryngology practices. The purpose of this study is to evaluate the possible route of bacterial contamination from the nasal vestibule to the atomizer tip through the jet airflow created during the use of the Venturi atomizer. METHODS: Thirty nostrils from 15 enrolled volunteers were tested. The aerosols generated by spraying sterilized saline into the nostrils were collected using a specially made aerosol-collecting nozzle cap. The collected samples were sent for bacterial culture, and nasal vestibular swab cultures were performed for comparison. RESULTS: In the aerosol-exposed group, 18 out of 30 samples (60%) were positive for bacterial growth, confirming the bacterial contamination from the nasal vestibule to the atomizer tip through the reverse jet airflow. The bacteria species in 8 of the 18 positive samples were identical to those from the nasal swab culture results from the same nostril. CONCLUSION: In ordinary otolaryngology practices, there are significant risks for bacterial contamination from the nasal vestibule to the tip of the Venturi atomizer even without direct contact. Clinicians must be more aware of this pattern of contamination, which has not been reported in the existing literature.

Design of the PRINCESS trial: pre-hospital resuscitation intra-nasal cooling effectiveness survival study (PRINCESS).

BACKGROUND: Therapeutic hypothermia (TH, 32-34°C) has been shown to improve neurological outcome in comatose survivors of out-of-hospital cardiac arrest (OHCA) with ventricular tachycardia or fibrillation. Earlier initiation of TH may increase the beneficial effects. Experimental studies have suggested that starting TH during cardiopulmonary resuscitation (CPR) may further enhance its neuroprotective effects. The aim of this study was to evaluate whether intra-arrest TH (IATH), initiated in the field with trans nasal evaporative cooling (TNEC), would provide outcome benefits when compared to standard of care in patients being resuscitated from OHCA. METHODS/DESIGN: We describe the methodology of a multi-centre, randomized, controlled trial comparing IATH delivered through TNEC device (Rhinochill, Benechill Inc., San Diego, CA, USA) during CPR to standard treatment, including TH initiated after hospital admission. The primary outcome is neurological intact survival defined as cerebral performance category 1-2 at 90 days among those patients who are admitted to the hospital. Secondary outcomes include survival at 90 days, proportion of patients achieving a return to spontaneous circulation (ROSC), the proportion of patients admitted alive to the hospital and the proportion of patients achieving target temperature (<34°C) within the first 4 hours since CA. DISCUSSION: This ongoing trial will assess the impact of IATH with TNEC, which may be able to rapidly induce brain cooling and have fewer side effects than other methods, such as cold fluid infusion. If this intervention is found to improve neurological outcome, its early use in the pre-hospital setting will be considered as an early neuro-protective strategy in OHCA. TRIAL REGISTRATION: NCT01400373.

Effect of introducing the mucosal atomization device for fentanyl use in out-of-hospital pediatric trauma patients.

BACKGROUND: Pain associated with pediatric trauma is often under-assessed and under-treated in the out-of-hospital setting. Administering an opioid such as fentanyl via the intranasal route is a safe and efficacious alternative to traditional routes of analgesic delivery and could potentially improve pain management in pediatric trauma patients. OBJECTIVE: The study sought to examine the effect of introducing the mucosal atomization device (MAD) on analgesia administration as an alternative to intravenous fentanyl delivery in pediatric trauma patients. The hypothesis for the study is that the introduction of the MAD would increase the administration of fentanyl in pediatric trauma patients. METHODS: The research utilized a 2-group design (pre-MAD and post-MAD) to study 946 pediatric trauma patients (age <16) transported by a large, urban EMS agency to one of eight hospitals in Marion County, which is located in Indianapolis Indiana. Two emergency medicine physicians independently determined whether the patient met criteria for pain medication receipt and a third reviewer resolved any disagreements. A comparison of the rates of fentanyl administration in both groups was then conducted. RESULTS: There was no statistically significant difference in the rate of fentanyl administration between the pre-MAD (30.4%) and post-MAD groups (37.8%) (P = .238). A subgroup analysis showed that age and mechanism of injury were stronger predictors of fentanyl administration. CONCLUSION: Contrary to the hypothesis, the addition of the MAD device did not increase fentanyl administration rates in pediatric trauma patients. Future research is needed to address the barriers to analgesia administration in pediatric trauma patients.

A prospective randomised single-blinded clinical trial comparing the efficacy and tolerability of the nasal douching products Sterimar™ and Sinus Rinse™ following functional endoscopic sinus surgery.

OBJECTIVES: To compare the efficacy and tolerability of two commonly used nasal douching products, low-volume high-pressure Sterimar™ and high-volume low-pressure Sinus Rinse™ following functional endoscopic sinus surgery. DESIGN: Prospective randomised single-blinded study. SETTING: Tertiary referral centre. PARTICIPANTS: Thirty-one patients, undergoing functional endoscopic sinus surgery for chronic rhinosinusitis with and without polyps, were recruited for the study. The patients acted as their own comparators self-administering each douche three times daily into one randomly allocated nostril for a period of 12 weeks following the surgery. MAIN OUTCOME MEASURES: The primary outcome measure was a blinded objective endoscopic assessment of each operated side using a modified Lund-Kennedy endoscopic assessment tool undertaken at 2, 4 and 12 weeks postoperatively. As secondary outcome measures, the patients were asked to express a preference between the two products based on perceived effectiveness and ease of use. RESULTS: Compared with the preoperative scores, there was a statistically significant improvement in the SNOT-22 score at all three postoperative time points (P < 0.001). Compared with week 2, there was a statistically significant reduction in the modified Lund-Kennedy endoscopic scores (P < 0.05) for both Sterimar™ and Sinus Rinse™ at weeks 4 and 12. When comparing Sterimar™ with SinuRinse™, there was a statistically significant lower modified Lund-Kennedy score at 2 and 4 weeks postoperatively for the side treated with Sinus Rinse™ (P ≤ 0.05), indicating a more favourable outcome. However, this difference was not apparent at 12 weeks postoperatively (P = 0.66). At all time points, patients perceived Sinus Rinse™ to be more effective than Sterimar™ (P < 0.0001), but there was no significant difference in the patients' preference for either product (P > 0.05). CONCLUSION: High-volume low-pressure saline irrigation is recommended as an efficacious, easy to use and well-tolerated adjunct to endoscopic sinonasal toilet in the early postoperative period following functional endoscopic sinus surgery.

Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies.

BACKGROUND: Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia. OBJECTIVE: The aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD). METHODS: A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18-64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT®) and the single-staircase Snap & Sniff® Odor Detection Threshold Test (S&S-T). Nasal tolerability, including nasal examinations and a quantitative, self-administered nasal symptom questionnaire (NSQ), was also assessed. Data were analyzed using analyses of covariance. RESULTS: Of 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT® and S&S-T results, intranasal administration of esketamine had no effect on the odor identification or threshold test scores compared with placebo nasal spray + oral AD. Similarly, repeated administration with esketamine nasal spray had no meaningful impact on assessments of nasal function. No dose-response relationship was observed between esketamine doses and the olfactory test scores. Esketamine nasal spray was well tolerated, as indicated by responses on the NSQ and negative nasal examination findings. CONCLUSION: Findings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16-100 weeks) studies. CLINICAL TRIAL REGISTRATION: TRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.

Pharmacokinetic study and brain tissue analysis of Zolmitriptan loaded chitosan nanoparticles in rats by LC-MS method.

INTRODUCTION: Migraine has recently become a major interest to the neuroscientists. Zolmitriptan is an effective medicine used in the treatment of migraine. The nasal spray was prepared from Zolmitriptan loaded chitosan nanoparticles and evaluated for pharmacokinetic properties. METHODS: In this study male Wistar albino rats weighing between 200 and 250 g were taken and divided into 4 groups with 6 rats in each group. Nasal spray containing Zolmitriptan loaded Chitosan nanoparticles were administered nasally (using specific inhalation mask) at a dose of 0.5 mg/kg as a test formulation and compared with the control groups which received either water for injection or marketed standard drug (Zolmist) or standard drug solution at a same dose. The pharmacokinetic parameters such as Cmax, Tmax, and brain tissue analyses for accumulation of drug were performed for Zolmitriptan by LC-MS method. RESULTS: Amount of drug in the plasma from the test formulation, standard marketed drug (Zolmist) and standard drug solution was found to be 41.37 ±â€¯2.31, 34.76 ±â€¯4.22 and 23.74 ±â€¯2.42 ng/ml at 10 min respectively, which indicated significantly (p < 0.05) greater amount of drug being delivered from the test formulation compared to the both standard groups. The amount of the drug (Zolmitriptan) present in brain tissue (Olfactory lobe) was found to be 15 ±â€¯0.08, 13 ±â€¯0.14 and 8 ±â€¯0.13 ng/g at 60 min for test formulation, marketed standard and standard drug solution respectively which indicates significantly (p < 0.05) higher amount of drug absorption in brain tissue from the test formulation compared to both the standard groups. CONCLUSION: Pharmacokinetics studies of nasal spray containing Zolmitriptan loaded chitosan nanoparticles proved rapid onset of action in animals and is promising in treatment of migraine.