Central Annals of Otolaryngology and Rhinology

Research Article *Corresponding author

Ng Yuk Hui, Department of Otolaryngology, Singapore General Hospital, Academia Building – 5th floor, 20 Comparison of Methylene Blue College Road, 169850 Singapore, Singapore, Tel: 65-6321-4469; Fax: 65 6226 2079; E-mail: Distribution in the Nasal Cavity Submitted: 10 October 2015 Accepted: 30 November 2015 and Paranasal Sinuses Using Published: 01 December 2015 ISSN: 2379-948X a Pulsed Versus Non-Pulsed Copyright © 2015 Ho et al. Nebuliser in the Cadaver OPEN ACCESS Carolina Rebelo van Schaik1, Danielle Ho2* and Ng Yuk Hui1# Keywords 1Otolaryngology Department, Singapore General Hospital, Singapore • Aerosol 2General surgery Department, Singapore General Hospital, Singapore • Intranasal administration #Both authors contribute equally • Methylene blue • • Paranasal sinuses Abstract Background: Topical steroid therapy is first line in treatment of chronic rhino . It is often combined with sinus surgery to improve distribution of medication to diseased mucosa. Despite having many delivery methods available, there is no conclusion on the most efficacious mode of penetration. This study aimed to evaluate whether a pulsed nebulised system significantly improves distribution to the Paranasal sinuses before and after sinus surgery compared to the conventional . Methods: Intranasal distribution of Methylene blue staining delivered with the PARI sinus device with and without pulsation was assessed in the nasal cavities of 4 frozen cadaver heads (8 sides), before and after sinus surgery. 2 independent observers graded the surface area covered by the dye using a scoring system. Results: There was no significant difference in the surface area of dye distribution to all sites prior to surgical intervention between the pulsed and non-pulsed nebulizer (p = 0.29). This finding was consistent post-surgery within the nasal sinuses and recesses (p = 1) except for a statistically significant increase in dye distributed by the pulsed nebulizer in the posterior ethmoid and sphenoid sinus after surgery (p = 0.046 at both sites). Conclusion: The pulsation does not significantly alter the distribution of dye within the nasal sinuses pre-operatively. After endoscopic sinus surgery there was significant increase in dye distributed by the pulsed nebulizer within the posterior ethmoid and sphenoid sinus. However, further work is needed to evaluate the impact of different contrast agents in similar studies.

INTRODUCTION complications of the active agent. The main limitation is the Chronic rhino sinusitis (CRS) is a prevalent condition affecting of the device. Many studies have been performed to evaluate the performancedelivery of of drops, to target sprays, tissue irrigation which depends and Nebulizers on the efficacy [8,9]. on the individual’s quality of life and has a billion-dollar economic However, there is no consensus as to a superior modality. burden12.5% of on the society US population [2-4]. [1]. It has significant adverse effects Nebulizers are one type of device available and it works by mucosa is a central tenet to the condition and topical steroids Inflammatory dysfunction of the nasal and Paranasal sinus [10]. Smaller particles are postulated to better penetrate the have proven to be a safe and effective treatment [5-7]. Steroids vaporising drugs and creating flow patterns in their delivery shown to improve symptoms and objective evidence of disease. sinuses while larger droplets are filtered by the nose [11]. down regulate pro-inflammatory gene expression and have been Topical therapy is an attractive route as it minimizes systemic Pulsating Nebulizers are a recent addition to the field introduced in the late-2000s. Pulsations are created by sound waves which Cite this article: van Schaik CR, Ho D, Hui NY (2015) Comparison of Methylene Blue Distribution in the Nasal Cavity and Paranasal Sinuses Using a Pulsed Versus Non-Pulsed Nebuliser in the Cadaver. Ann Otolaryngol Rhinol 2(12): 1078. Ho et al. (2015) Email: Central are superimposed onto aerosol stream. These pressure gradients different sites pre- and post-surgery. The level of statistical generated may propel the aerosol further within the poorly p Inc., Chicago, IL) was used for the analysis. Another crucial factor impacting on delivery of topical agents is significance was taken to be at < 0.05. SPSS version 17 (SPSS sinusventilated anatomy. Paranasal It has been sinuses demonstrated to facilitate that topical distribution therapy [12]. has RESULTS AND DISCUSSION limited access to sinus cavities in the unoperated nose [13]. Mean grades for dye deposition in the different sites pre- Sinus surgery is often coupled with medical therapy in patients between pulsating and non-pulsating nebulisation revealed no with symptoms refractory to isolated medical intervention [14]. operatively are illustrated in Table 1. Pre-surgery comparison Remodeling the nasal passage removes anatomical obstruction interest (p and theoretically improves access to diseased mucosa. Surgery significant differences in distribution of dye across all sites of is often not curative and immune modulation with steroids = 0.285). As expected, anterior nasal sites such as the is continued for symptom control and to minimize disease turbinates, UP and OC were better penetrated than posterior recurrence. and non-pulsed nebulisation consistently delivered dye to the olfactorysites in both cleft the before pulsating surgery, and with non-pulsating slightly better arm. results Both seenpulsed in This study aimed to establish whether the additional feature the pulsed arm (mean scores 4 ± 0 and 3.25±0.96 respectively). p = 0.180). deposition of nebulised medication pre- and post-sinus surgery. of pulsation would lead to significant improvement in intranasal This difference was not statistically significant ( MATERIALS AND METHODS with pulsation in the sinuses or recesses of interest collectively (p There was no significant difference in distribution of dye noted The distribution of dye administered via nebulisation was sinuses with or without pulsation. In addition, it was noted that studied in the nasal cavities of four fresh frozen cadaver heads in = 0.76). This finding was consistent between individual Paranasal the anatomy laboratory of Singapore General Hospital, Singapore, May 2015. Specimens presenting overt septal deviation, previous zeroTable dye was 2 demonstrates delivered to the post-operative PE and SS before deposition surgery. of dye in

This study was performed after approval from the institutional difference in post-operative dye deposition between the pulsed reviewsinus surgery, board. polyposis and mucosal disease were excluded. andthe sinusesnon-pulsed and nebulisation recesses. Similarly, across all there sites was (p =no 1). significant However, comparisons of mean scores before and after surgery showed The cadavers were held upright and each nostril was an improvement in dye distribution in these less accessible nebulised with the contra lateral nostril plugged as stated in the instructions of the manufacturer. One nostril served as a of dye deposition after surgery in both non-pulsating and control while the other was subjected to pulsating nebulisation. pulsatingintranasal arms. sites. AIn comparison particular, PE between and SS pre-demonstrated and post-operative evidence Allocation was done randomly. Nebulisation was standardized mean scores for dye distribution in the pulsed and non-pulsed with 4ml 1:1 ratio of Methylene blue to 0.9% normal applied to each nostril for 2 ½ minutes. The pulsating aerosol inarm the is pulsed illustrated arm ( p in = Table0.046 for 3. Post-operatively,both sites). The increase a statistically in dye significant increase in dye deposition in the PE and SS was found was produced using the PARI Sinus Pulsating Aerosol System distributed with and without pulsation at other sites did not (PARIVideo GmbH, endoscopy Starnberg, of Germany). the nasal cavity was performed with a 0, 30 and 70 degree rigid endoscope to assess the deposition of dye. Two blinded, independent observers graded the deposition Table 1: of solution immediately after application based on surface area Site Pre-operative meansPulsation scores for all subsitesNo pulsation of interest.p- value stained with Methylene blue using a 5-point scale: 0 = none, 1 = Inferior turbinate 2.75 ± 0.5 2.25 ± 0.96 0.414 <1/3, 2 = 1/3, 3 = 2/3, 4 = complete. A consensus was made before Middle turbinate 2.25± 0.5 2.75± 0.5 0.157 inferior (IT), middle (MT) and superior turbinates (ST); uncinate Superior turbinate 2.5 ± 1.29 1.75± 0.96 0.257 assigning the final grade. The following sites were evaluated: Uncinate process 3.25± 0.5 2.75± 0.5 0.157 Olfactory cleft 4 ± 0 3.25± 0.96 0.180 process (UP), olfactory cleft (OC), ethmoidal bulla surface (EB) 0.75± 0.96 0.75± 0.96 1.00 antrostomy,and sphenoethmoid sphenoidectomy recess (SER). and Draf Each 2A frontal cadaver sinusotomy. subsequently underwent bilateral complete ethmoidectomy, type 2 maxillary Maxillary sinus 1.75± 0.5 1.5 ± 0.58 0.564 After dissection, deposition of solution was evaluated again Interior of anterior Ethmoidal bulla 0.5 ± 1 0.5 ± 1 1.00 using the abovementioned 5-point scale, focusing on distribution ethmoid Interior of posterior 0 ± 0 0± 0 1.00 sinus (SS), frontal sinus (FS); frontal recess (FR), interior of the ethmoid in less accessible sites, namely the maxillary sinus (MS), sphenoid Spheno-ethmoid recess 1.75± 0.96 2± 0.82 0.705 sinonasal cavities with normal saline, bilateral nebulisation was Sphenoid sinus 0 ± 0 0± 0 1.00 performedanterior (IAE) post-surgery. and posterior There ethmoids was no re-allocation (IPE). After of rinsing pulsation the and non-pulsation sides and the distribution of solution by Frontal sinus 0.25± 0.5 0± 0 0.317 Frontal recess 0.75± 0.96 0.75± 0.96 0.785 test was performed to compare distribution of solution between surface area was rated once again. Wilcoxon signed-rank sum Data are expressed as mean ± SD. Ann Otolaryngol Rhinol 2(12): 1078 (2015) 2/5 Ho et al. (2015) Email: Central

Table 2: p = recess. 0.046 at both sites) while the same comparison in the non-pulsed Post-operative means scores of Paranasal sinuses and frontal post-surgery in the pulsed arm was statistically significant ( Site Pulsation No pulsation p-value 2± 0.82 1.75 ± 0.96 0.317 arm was non-significant. Interior of anterior Maxillary sinus 2.5 ± 0.58 2.5 ± 0.58 1.00 ethmoid studyIn demonstrated the non-pulsed improved model, intranasal Manes et al.distribution used fluoresce of dye post- in to Interior of posterior compare pre- and post-FESS distribution of aerosol [15]. The 2± 0 1.75 ± 0.96 0.564 ethmoid noted in the middle meatus region (p Sphenoid sinus 1± 0 1.5 ± 0.58 0.157 surgery across all sites, with statistically significant difference = 0.044). When FESS Frontal sinus 1± 0.82 1 ± 1.41 1.00 frontalwas combined neo-ostium with was endoscopic reported (p modified = 0.001). Lothrop Despite differing procedure, in Frontal recess 1.75 ± 1.5 1.75 ± 0.96 1.00 a statistically significant improvement of drug delivered to the pulsed devices, the study reinforces that surgery is an important the extent to which surgery improves dye distribution by non- Data are expressed as mean ± SD. component to disease management and highlights that different Table 3: p-values for comparison of mean scores pre- and post- types of surgery may afford varying access to diseased mucosa. and frontal recess. operatively for pulsed and non-pulsed nebulisation in Paranasal sinuses for the topical treatment of chronic sinusitis. Valentine et al. Site Pulsation No pulsation comparedOther studies sinonasal have penetration analyzed the of efficacy nasal douching of pulsed to nebulisation the pulsed 0.102 0.194

MaxillaryInterior of sinus anterior ethmoid 0.102 0.066 Interior of posterior ethmoid 0.046* 0.066 outcomesPARI Sinus across device indices using Methylene such as intensity blue as ofa stain stain, [10]. percentage The study of reported that nasal douching resulted in significantly better Sphenoid sinus 0.046* 0.063 stain as well as circumference stained (p < 0.001 for all indices). However, other studies using different formulations demonstrate Frontal sinus 0.083 0.180 that pulsed nebulizer is a non-inferior device [12,17,18]. Frontal recess 0.285 0.102 * p-value < 0.05 intranasal deposition using 81mKr-gas imaging [12]. Compared to aMoller non-pulsating et al. evaluated system which the effect resulted of pulsating in < 5% total airflow Kr-gas on activity detected in the sinuses, pulsation increased penetration the advantage of using a pulsed device versus a conventional reach statistical significance. This study was designed to assess release of 81mKr-gas activity after the device was switched off; sinuses before and after surgery. theto about authors 48%. hypothesized The pulsating that airflowthis delayed also resultedeffect could in sustained augment nebulizer in the distribution of medication to the Paranasal The difference in sinonasal distribution of dye between aerosol deposition. pulsed and the non-pulsed nebulizer in the pre-operative setting p = 0.285). The results The same study assessed deposition efficiency of Tc99m- was not statistically significant (Table 1, inaccessible in both arms (p = 1). Of note, there was consistent [12].diethylene With pulsating triamine aerosol pentaacetic delivery, acid total (99m deposition Tc-DTPA) in the aerosol nasal illustrate that MS, IAE, IPE and SS in particular were equally deposition pre-operatively within the OC with both pulsed cavitydissemination (including with sinuses) pulsating was airflow 71 ± 17% compared of the tonebulized a nasal spraydose, and 6.5 ± 2.3% of the total nose activity penetrated to the sinuses. result in the pulsed arm (4 ± 0 and 3.25 ± 0.96 respectively, p and non-pulsed nebulization, with a non-significant improved with the nasal spray. was not well penetrated by nebulisation before and after surgery However, there was no significant activity detected in the sinuses [15].= 0.180). This Thissuggests finding that differs further from studies another are studyneeded where to ascertain the OC In another study, comparing pulsating aerosols and nasal whether nebulization may be advantageous to patients with CRS and prominent olfactory symptoms such as hyposmia. Thespray, pulsating 99mTc-DTPA aerosol wasdelivered used 9.7±2.0% to compare of the difference nasal dose in to drug the This study also found no difference in distribution of dye delivery in the posterior nasal spaces and Paranasal sinuses [17]. between the two arms in the post-operative setting (Table 2, p = 1). However, this study demonstrates that surgery does enhance pulsatingmaxillary andaerosols sphenoid may sinusesbe superior while to the the nasal nasal pump spray resulted and is ina deposition of particles within the nasal sinuses. Table 2 illustrates promisingnon-significant therapeutic sinus deposition. option [12,18]. It was similarly concluded that that mean dye deposition across all sites is improved after surgery. Of note, prior to surgery, there was zero dye noted in A number of important limitations are present in this study. The small sample size makes this a pilot study and results cannot and non-pulsating arm was 2 ± 0 and 1.75 ± 0.96 respectively; be generalized to a bigger population. However inferential atthe the IPE SS, and 1 SS.± 0 Post-surgery, and 1.5 ± 0.58 mean for scores pulsating at IPE and for non-pulsating the pulsating statistics still has value to detect a large effect size even if the sample size is limited. In our small sized sample, there was no improvesarm respectively. distribution This offinding medication is in agreement to the sinuses with [other 9,13, studies15,16]. that suggest that functional endoscopic sinus surgery (FESS) subsitessignificant post-surgery. advantage in Fordelivery that of reason medication we postulate using the that pulsed the feature before and after surgery, except in the most posterior Interestingly, the improved deposition of dye in the IPE and SS Ann Otolaryngol Rhinol 2(12): 1078 (2015) 3/5 Ho et al. (2015) Email: Central pulsating feature allows for deeper penetration when there is conventional Nebuliser in our sample. Surgery enhances dye distributed by the pulsed Nebuliser in certain subsites. However, limitation in our study was the use of Methylene blue dye as a additional work is needed to assess the use of different surrogate surrogatea sufficiently to measure enlarged drug pathway. deposition. We hypothesise Mathematical that modeling a main markers in similar studies to better evaluate such devices. of aerosolised particle deposition proposes three factors to determine particle deposition within the sinus: particle size, size ACKNOWLEDGEMENTS of the sinus ostium and pressure gradient. It is widely accepted Ms. Stephanie Fook- Chong, Institutional Senior Statistician. that particle size affects distribution and Hyo et al. concluded that and Team, Anatomy Laboratory of Singapore General Hospital. PARI GmbH for the loan of the device used in this study. Zayar Min the ideal particle size for delivery to the maxillary sinus would REFERENCES suggestsbe 3-10μm that [19]. particle The size PARI generated Sinus produces by the device aerosol is particlesunlikely to of 1. Hamilos DL. Chronic rhinosinusitis: epidemiology and medical bea mass a limiting median factor aerodynamic in particle diameter distribution. (MMAD) Methylene of 3.2 μm.blue This has management. 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Cite this article van Schaik CR, Ho D, Hui NY (2015) Comparison of Methylene Blue Distribution in the Nasal Cavity and Paranasal Sinuses Using a Pulsed Versus Non-Pulsed Nebuliser in the Cadaver. Ann Otolaryngol Rhinol 2(12): 1078.

Ann Otolaryngol Rhinol 2(12): 1078 (2015) 5/5