Endoscopic grading systems for nasal polyps: are we comparing apples to oranges?

Endoscopic grading of nasal polyps (NP) is typically a coprimary endpoint in clinical trials evaluating treatments for chronic rhinosinusitis with nasal polyps (CRSwNP). However, a consensus on the most effective way to grade nasal polyps has not been reached. Different scales have been used, hampering the interpretation of data across trials. This review compares the characteristics of NP grading systems used in registration trials for approved NP treatments. These fundamental differences in grading systems make quantitative comparison of outcomes between trials inaccurate and potentially misleading. In lieu of a universal grading system, reporting the baseline distribution of polyp grades (unilateral and/or summed/total grades), as well as changes from baseline over time by baseline grade may help improve interpretability of outcomes and reduce inaccuracy when attempting cross-trial comparisons and making therapeutic decisions.

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.

EXHANCE-3: a cohort study of the exhalation delivery system with fluticasone for chronic sinusitis with or without nasal polyps.

BACKGROUND: Inhaled nasal corticosteroid sprays (INS) are often inadequate to treat chronic rhinosinusitis (CRS). The exhalation delivery system with fluticasone (EDS-FLU; XHANCE®) may improve outcomes in CRS by increasing medication delivery to target superior/posterior anatomic sites. This study assessed safety and efficacy of EDS-FLU in a large population with moderate-to-severe CRS with or without nasal polyps (CRSwNP, CRSsNP). METHODS: Prospective, multicenter, 12-week, single-arm study of EDS-FLU 372 Â#181;g twice daily (BID) at 38 U.S. sites. Safety was assessed by adverse-event evaluations, nasal endoscopy, and ocular examinations. Efficacy was serially assessed by outcomes including nasal endoscopy (Lund-Kennedy Score, polyp grade), patient- and physician-reported outcomes (22-item Sinonasal Outcome Test [SNOT-22]), study-defined surgical indicator assessment, and Patient Global Impression of Change (PGIC). RESULTS: 705 comparatively refractory subjects were enrolled, 603 CRSsNP and 102 CRSwNP [moderate-to-severely symptomatic; baseline SNOT-22 ~43, high rates of prior INS use (92.3%) and/or prior surgery (27.5%)]. More than 90% reported improvement on treatment by PGIC. SNOT-22 scores improved substantially and similarly in patients with NP (-23.7) and without NP (-24.4). Among patients with baseline Lund-Kennedy edema scores >0, 33.3% (CRSwNP) and 54.8% (CRSsNP) had complete resolution of edema. In CRSwNP patients, 48% had polyp elimination in ?1 nostril, 63% had ?1-point improvement in polyp grade, mean bilateral polyp grade decreased from 2.9 to 1.6, and study-defined surgical eligibility decreased. EDS-FLU was generally well tolerated, with a safety profile similar to conventional INS sprays when used to treat CRS CONCLUSION: EDS-FLU 372 #181;g BID in the treatment of CRS with or without polyps was safe, well-tolerated, and produced substantial improvement across a broad range of both objective and subjective measures.

Intranasal sumatriptan powder delivered by a novel breath-actuated bi-directional device for the acute treatment of migraine: A randomised, placebo-controlled study.

INTRODUCTION: Intranasal sumatriptan is an option for the treatment of migraine; however, nasal delivery using conventional spray pumps is suboptimal. METHODS: Adult subjects (n = 117) with migraine were enrolled in a multicentre, randomised, double-blind, parallel group, placebo-controlled study. A single migraine attack was treated in-clinic with sumatriptan 10 mg, sumatriptan 20 mg or placebo administered intranasally by a novel bi-directional powder delivery device when migraine was moderate or severe. RESULTS: A greater proportion of subjects who received sumatriptan were pain-free at 120 minutes compared with those who received placebo (10 mg/20 mg sumatriptan vs. placebo = 54%/57% vs. 25%, P < .05). Significant benefits were also observed for pain relief at 120 minutes (84%/80% vs. 44%, P < .001/.01) and as early as 60 minutes (73%/74% vs. 38%, P < .01) and for 48 hours sustained pain-free (P < .05). Treatment-related adverse events were rare, with a metallic taste being the most commonly reported (10%/13%). CONCLUSIONS: Sumatriptan nasal powder administered using the new device during a migraine attack was effective and well tolerated.

Preliminary efficacy of fluticasone delivered by a novel device in recalcitrant chronic rhinosinusitis.

OBJECTIVE: To assess whether delivery of fluticasone propionate using a novel bi-directional delivery device (Opt-FP) offers therapeutic benefits in patients with chronic rhinosinusitis (CRS). METHODS: A prospective, single centre, randomized, double-blind, placebo (PBO)-controlled, parallel group study was conducted in adult subjects (n=20) with CRS without nasal polyps or only cobblestoned mucosa. Subjects received Opt-FP 400 µg or placebo twice daily for 12 weeks (n=10/group). Outcome measures included symptom scores, RSOM-31, CRS VAS, nasendoscopy, peak nasal inspiratory flow (PNIF) and magnetic resonance imaging (MRI). RESULTS: Endoscopy score for oedema showed a highly significant and progressive improvement (12 weeks (median scores): Opt-FP -4.0, PBO -1.0, p=0.015). PNIF increased significantly during Opt-FP treatment compared to placebo (4 weeks: p=0.006; 8 weeks: p=0.03). After 12 weeks MRI scores in the Opt-FP group improved against baseline (p=0.039) and a non-significant trend was seen versus placebo. The nasal RSOM-31 subscale was significantly improved with Opt-FP treatment (4 weeks: p<0.009, 8 weeks: p<0.016, 12 weeks: NS). Sense of smell, nasal discomfort and combined score were all significantly improved (p<0.05). The Opt-FP was well tolerated. CONCLUSIONS: The OptiNose breath-actuated bi-directional delivery device administering fluticasone propionate (400 µg b.i.d.) is an effective and well tolerated treatment for recalcitrant CRS.

Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial.

The neuropeptide oxytocin has shown promise as a treatment for symptoms of autism spectrum disorders (ASD). However, clinical research progress has been hampered by a poor understanding of oxytocin's dose-response and sub-optimal intranasal delivery methods. We examined two doses of oxytocin delivered using a novel Breath Powered intranasal delivery device designed to improve direct nose-to-brain activity in a double-blind, crossover, randomized, placebo-controlled trial. In a randomized sequence of single-dose sessions, 17 male adults with ASD received 8 international units (IU) oxytocin, 24IU oxytocin or placebo followed by four social-cognitive tasks. We observed an omnibus main effect of treatment on the primary outcome measure of overt emotion salience as measured by emotional ratings of faces (η2=0.18). Compared to placebo, 8IU treatment increased overt emotion salience (P=0.02, d=0.63). There was no statistically significant increase after 24IU treatment (P=0.12, d=0.4). The effects after 8IU oxytocin were observed despite no significant increase in peripheral blood plasma oxytocin concentrations. We found no significant effects for reading the mind in the eyes task performance or secondary outcome social-cognitive tasks (emotional dot probe and face-morphing). To our knowledge, this is the first trial to assess the dose-dependent effects of a single oxytocin administration in autism, with results indicating that a low dose of oxytocin can significantly modulate overt emotion salience despite minimal systemic exposure.

Low-dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment.

Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel 'Breath Powered' nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8 IU (international units) or 24 IU OT, 1 IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8 IU OT in comparison to both placebo and 24 IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.

A new method for the remote collection of nasal and exhaled nitric oxide.

STUDY OBJECTIVES: The present study introduces a method that has been developed to improve the remote collection and transportation of gas samples from the nose and lungs. DESIGN: Assessment of agreement between two methods of clinical measurements. SETTING: Noninvasive exhaled gas measurement at a respiratory research laboratory. PARTICIPANTS: Ten nonsmoking adult volunteers (median age, 44 years; age range, 33 to 53 years; men, 6; women, 4) were recruited. MEASUREMENTS AND RESULTS: Exhaled nitric oxide (ENO) and nasal nitric oxide (NNO) outputs were measured directly (on-line) and remotely (off-line). With the velum closed, lung air was exhaled at fixed flows (ie, 6, 8, and 10 L/min) (ENO) or room-air was aspirated through the nose in series at one fixed flow (ie, 5 to 8 L/min) (NNO). The off-line nitric oxide (NO) measurements were achieved by a gas collection tube system, which consisted of a flow control unit, a tube reservoir with one-way valves at both ends, and an interrupter valve allowing the trapping of gas inside the tube and eliminating the inclusion of "dead space." After clamping, the reservoir may store and transport the gas samples for delayed analysis. The coefficient of variation of three consecutive NO measurements was < 3% for both on-line and off-line ENO and NNO. The correlations between on-line and off-line measurements in both ENO and NNO outputs were high (r = 0.99; R(2) = 0.99), and, unlike previous studies using bag-collection, the ENO outputs for on-line and off-line measurements were in good agreement (Bland-Altman test) at all flows tested. CONCLUSIONS: The tube gas collection system eliminates the dead space and contamination during the gas sampling and permits the cost-effective and reliable off-line collection of both nasal and exhaled gas samples.

Nasal airway dimensions and lung function in awake, healthy neonates.

Possible relations between nasal airway dimensions and measures of lung function are not well established. It has been suggested that a major part of airway resistance is found in the nose. However, little is known about the shape of tidal flow volume (TFV) loops in relation to nasal caliber. We therefore investigated whether lung function assessed by tidal breathing in healthy newborn infants was affected by nasal airway dimensions. Nasal airway dimensions were measured in 17 healthy newborn babies (mean age, 2.7 days) by acoustic rhinometry before and immediately after lung function measurements. Lung function was evaluated by TFV loops and passive respiratory mechanics (single-breath occlusion technique), first with both nostrils open, and subsequently immediately after occlusion of the larger of the two nostrils, causing at least a 50% reduction in nasal minimum cross-sectional area (MCA). Neither the TFV expiratory ratios (time and volume to reach peak flow to total time and volume, respectively [t(PTEF)/t(E) and V(PTEF)/V(E), respectively]), nor resistance or compliance of the total respiratory system differed significantly regardless of whether one or both nostrils were open. With one nostril closed there were no significant effects on any of the measured lung function parameters. We conclude that in healthy awake neonates reducing the cross-sectional area of nasal dimensions by 50% does not affect TFV loops or passive respiratory mechanics.

Unilateral nasal nitric oxide measurement after nasal surgery.

This study was designed to validate and standardize a method for unilateral nasal nitric oxide (NO) measurement. Fourteen healthy volunteers and 11 patients who had undergone unilateral medial maxillectomy were enrolled. Nasal NO was measured unilaterally by means of a dual pump system, and bilateral nasal NO was measured by aspirating air through the nasal airway in series. The median unilateral NO output was 195 nL/min on the surgical side and 291 nL/min on the contralateral, surgically untreated side (p = .006). The NO output was not significantly different between nostrils in the control group (p = .82). With the bilateral technique, there was no significant difference between the surgery group and the healthy-subjects group (p = .72). The unilateral nasal NO technique is sensitive in determining unilateral differences in nasal NO production. The NO outputs from the nostrils were similar in normal subjects regardless of the nasal cycle, but were significantly lower on the operated side in the unilateral nasal surgery group.

Nasal airway dimensions in term neonates measured by continuous wide-band noise acoustic rhinometry.

The nasal airways of 94 healthy term infants (37-42 weeks gestational age) were examined by continuous wide-band noise acoustic rhinometry under standardized conditions on the second or third day postpartum. Validation of the flexible infant probe on tubular plastic models with dimensions similar to the nasal cavity of newborn infants showed a correlation coefficient of 0.98. The mean and standard deviation (SD) of the total minimal cross-sectional area (TMCA), the distance from the nostril to the MCA (DMCA) and the total volumes between the nostril and 45 mm into the nasal cavity (TVOL45) were 0.20 +/- 0.05 cm2, 0.76 +/- 0.29 cm and 2.14 +/- 0.39 cm3 respectively. In general, both anthropometric and rhinometric mean values were higher in males (n = 52) compared to females (n = 42), and the difference was statistically significant for TMCA and head circumference. We conclude that the technical properties, small size and flexible tube of the miniprobe make it uniquely suited for objective assessment of the nasal airways in infants and small children. The RHIN 2000/2100 miniprobe (S.R. Electronics Aps, Lynge, Denmark) is the first infant probe commercially available, making standardization and comparison of results easier.

Changes in nasal airway dimensions in infancy.

Thirty-nine infants, previously examined as neonates, were re-examined at 1 year of age with continuous wide-band noise acoustic rhinometry using a specific probe optimized for infants, to determine the dimensional growth and maturation of nasal airway geometry in otherwise healthy infants. During the first year of life, the acoustically determined dimensions of the nasal airways increased significantly. The total minimal cross-sectional area increased by 67% (0.21 cm2-->0.35 cm2), the volume of the anterior 4 cm of the nasal airway by 36% (1.80 cm3-->2.44 cm3) and the distance to the minimum cross-sectional area by 19% (0.78 cm-->0.93 cm). The rhinometric values of male infants were significantly larger than those of females. However, after adjusting for the significantly larger anthropometric values of males, the difference disappeared, indicating that it was mainly due to body size and not directly to gender. A highly significant correlation (r=0.44, p < 0.006) was observed between the minimum cross-sectional area and head circumference, which anatomically are the most closely related rhinometric and anthropometric values. Furthermore, when differentiating between infants with or without signs of nasal congestion during the fortnight preceding the rhinometric evaluation, a reduction in the total volume of the anterior 4 cm (17% p <0.02) and minimum cross-sectional area (12%, ns) was observed after adjustment. We conclude that the optimized acoustic rhinometric probe is a useful investigative modality, permitting studies of upper airway physiology of healthy and diseased infants.

Aerodynamic influences on nasal nitric oxide output measurements.

Nitric oxide (NO) concentration in aspirated nasal air is flow-dependent. Nasal NO outputs calculated from steady-state plateaux at flows < 1 l/min are substantially smaller than those at flows > 2 l/min. This study aimed to determine the differences in NO output as calculated from the NO concentration plateaux in aspirated nasal air, resulting from different aspiration flows. Nasal NO was determined by chemiluminescent analysis of air obtained from the nasal passages in series during velopharyngeal closure in 8 healthy adults (flows: 0.2-3.7 l/min) and 5 with symptomatic allergic rhinitis (flows: 0.2-3.7 l/min). Mean NO output in the healthy subjects was stable at approximately 315 nl/l/min at flows of 0.2-0.7 l/min, and increased to a second steady output level of approximately 400 nl/l/min (+28%, p < 0.0001) at more physiological flow rates of 2.7 l/min and higher. The symptomatic subjects had substantially higher NO output at all flows (p < 0.001) (709.3 nl/min at 3.7 l/min) than the non-allergic subjects. The flow dependency of the nasal NO output may be explained by failure at low flows for the air stream to penetrate the peripheral parts of the complex nasal passages, and by the presence of a laminar flow regime in which a marginal lamina would tend to insulate the main stream from the mucosa. Thus, previously reported NO outputs obtained at low flows may underestimate nasal NO output compared to output at higher and more physiological transnasal airflow rates, thus affecting interpretation of results.

Accuracy of acoustic rhinometry.

OBJECTIVES: The objective of this study was to evaluate the ability of acoustic rhinometry (AR) (Rhin2100, Rhinometrics, Lynge, Denmark) to accurately determine the dimensions (cross-sectional areas and volumes) of the curved and complex slit-like geometry of the nasal airway. MATERIALS AND METHODS: A plastic model representing the replicate of a decongested nasal airway was produced by stereolithographic techniques from a 3-D MRI-scan. The exact dimensions of this model was determined from a high resolution CT-scan. Dimensions perpendicular to the curved course of the acoustic pathway were compared with dimensions inferred from parallel sections. The impact of sound loss to the paranasal sinuses and the ability to detect posterior volume changes was tested in the same model. RESULTS: The error in volume determination was < 14% for the MCA and < 8% for the volumes, whereas the error reached 52% for dimensions calculated from parallel sections in the coronal plane. The influence of the simulated maxillary sinuses depend primarily on the size of the ostia and may represent an important source of error for posterior measurements, in particular after decongestion. CONCLUSIONS: The accuracy of acoustically derived dimensions of the 3-D model depend on the orientation of the planes used to calculate the dimensions of the model. Volume estimates based on the smallest cross-sectional areas in points along the acoustic pathway correlate well with acoustically derived volumes, whereas single cross-sectional areas are more susceptible to error. Sound leakage to patent sinus ostia reduce the accuracy of posterior measurements.

Technical abilities and limitations of acoustic rhinometry optimised for infants.

The objective of this model study was to validate in detail the technical capabilities as well as the limitations of a new rhinometric probe optimised for infants in order to improve reliability of measurements and reduce the risk of misleading conclusions. The repeatability was excellent (CV < 0.6%) and the reproducibility was high (CV% < 4%) provided the ambient conditions were fairly stable. The repeatability declined when external noise levels were above 60 dB SPL, and variation in temperature and pressure reduce reproducibility. The accuracy of the minimum cross-sectional area (MCA) as well as the volume corresponding to the nasal cavity in infants (VOL4), was acceptable (% error < 12%) as long as the MCA was larger than 30-40% of the probe dimensions and the cross-sectional area of the cavity posterior to the MCA did not exceed the MCA by a factor of more than 3-4. Variation in the position of the MCA within the anterior 2 cm has minimal influence on the posterior measurements provided the shape and length of the MCA are unaltered. Rods inserted into the tubular model to simulate the slit-like shape of the nasal passage did not reduce the accuracy, which is essential to the clinical value of acoustic rhinometry. Recommendations and guidelines designed to enhance the reliability of acoustic measurements in infants are presented.

Aspiration flow optimized for nasal nitric oxide measurement.

The aim of the present study was to evaluate some of the factors which may influence the reliability of nasal NO measurements, and to optimize methods suitable for children and adults. Nasal nitric oxide (NO) output was determined by chemiluminescent analysis of aspirated samples in 16 adults and 6 children. With the velopharyngeal aperture closed, stable NO levels were obtained at flows ranging form 0.9 to 6.2 L/min. NO output averaged 401.0 +/- 145.4 nL/min./M2 in 6 children, 338.2 +/- 92.3 in 7 adult females and 268.6 +/- 70.2 in 9 adult males. Nasal NO output was independent of flow provided a stable plateau of NO value was reached. In this study, the optimal range of flows was 3.2-5.2 L/min. in adults and 2.2-3.2 L/min. in children. This enables selection of the most favorable flow to be chosen for individual subjects and situations.

Necrotizing fascitis of the head and neck--report of three cases and review of the literature.

Necrotizing fasciitis (NF) of the head and neck is a rare but potentially life-threatening soft tissue infection primarily affecting the superficial fascial planes. It is caused by group A streptococci or by a synergistic combination of aerobe and anaerobe micro-organisms. If proper treatment is delayed, the infection may cause extensive necrosis of overlying skin, extend to deeper planes and produce severe systemic toxicity. Recent reviews suggest that cervical and facial NF should be considered separate clinical entities with different clinical features and prognosis. In both, early diagnosis with prompt, aggressive surgical and medical treatment is essential to a successful outcome. Three cases of NF of the neck secondary to peritonsillar/parapharyngeal infections are presented and the main characteristics of 117 well-characterized cases of cervical and facial NF are reviewed.

Computational simulation of accumulation of expired air in the infant cot.

Accumulation and re-breathing of CO2 in expired air has been suggested as one possible explanation for the strong association between prone sleeping position and sudden infant death syndrome (SIDS). This preliminary study applying a modern computational fluid dynamics (CFD) program to simulate the aerodynamics in an infant cot supports the idea that accumulation of expired air may occur in the prone position. The literature dealing with the potential association between re-breathing of accumulated CO2 and SIDS is briefly reviewed.

[AIDS. A threat and a challenge of our time]. / AIDS. Vår tids trussel og utfordring.

PIP: The development of the acquired immunodeficiency syndrome (AIDS) epidemic in Europe is following the same course as it did in the US but is delayed by about 3 years. If this time is used properly, it may be possible to stop the epidemic at an early stage. The special epidemiology of the disease, the long incubation period, prejudice, and taboo concerning sexuality have constrained constructive and open debate on strategies and approaches. By mid-1986, 21,302 AIDS cases had been registered in the US for a prevalence rate of 88/million and 11.654 deaths had resulted. In Europe, 2,542 AIDS cases had been registered by mid-1986 for a prevalence rate varying between 0 and 17.4/million in various countries. Of the total number, 67% were homosexual or bisexual men, 10% misusers of needles, 4% hemophiliacs, and 2% transfusion related. In Norway in mid-1986, 25 persons had contracted AIDS for a prevalence rate of 6.0/million; 20 of these are dead. Over 70% of those contracting AIDS die within 2 years, for a cumulative lethality in the US and Europe as a whole slightly 50%. 20 of the Norwegian AIDS patients belonged to the homo/bisexual male risk group; 1 was a hemophiliac; 1 a blood recipient; 1 an injection misuser; and 1 was heterosexually infected. Average survival from time of diagnosis was about 6 months. Over 300 persons in Norway have been found human immunodeficiency virus (HIV) antibody positive and the actual number of infected is calculated at 2,500. By the mid-1990s AIDS may become the most common cause of death in Norway.^ieng