1. current concepts in topical therapy for chronic sinonasal.pdf

8/14/2019 1. Current Concepts in Topical Therapy for Chronic Sinonasal.pdf

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REVIEW ARTICLE

Current Concepts in Topical Therapy for Chronic Sinonasal

Disease

Richard J. Harvey, MD, Alkis Psaltis, MD, Rodney J. Schlosser, MD, and Ian J. Witterick, MD

ABSTRACT

Introduction:There has been an explosion in the understanding of the mechanisms of chronic sinonasal inflammation. Multiple

approaches to control and modify the inflammatory reaction in chronic rhinosinusitis have led to many new agents being introduced

topically to the sinonasal cavities. This article aims to provide an evidence-based approach to the science behind topical

management of sinonasal disease.

Methods: The literature on delivery device, position, surgical state, and pharmaceutical and mechanical concepts of topical

therapy to the paranasal sinuses is reviewed.

Results: High-volume irrigation under positive pressure and in head-down positions is important for effective delivery and

mechanical action of topical solutions. Unoperated paranasal sinuses appear to receive very limited topical therapy. Enhanced

steroid therapy and surfactants appear to be the most promising pharmaceutical approaches. Future novel therapies may include

enhancers of the innate immune system. The effect of antibiotic additives is difficult to establish as this might be treating a disease-modifying state rather than the underlying pathology.

Conclusions: Topical therapies, applied after surgery, are likely to represent the mainstay of future management for chronic

inflammatory rhinosinusitis.

SOMMAIRE

Introduction: La comprehension des mecanismes de linflammation nasosinusale chronique a fait des pas de geant. De

nombreuses recherches visant a limiter et a modifier la reaction inflammatoire dans la rhinosinusite chronique ont mene a

lelaboration de nombreux nouveaux agents a application topique dans les cavites nasosinusales. Larticle vise a presenter une

approche fondee sur des donnees probantes, a la science qui sous-tend le traitement topique des affections nasosinusales.

Methode: Nous avons passe en revue la documentation sur les dispositifs dadministration, la position de la tete, letat du

traitement chirurgical ainsi que les principes pharmaceutiques et mecaniques du traitement topique des affections des sinus

paranasaux.Resultats: Une irrigation a grand volume, sous pression positive, et la tete en position declive sont des facteurs importants dune

administration efficace et de laction mecanique des solutions topiques. Il semble que les sinus paranasaux non operes soient tres

peu soumis au traitement topique. Lamelioration du traitement par les sterodes et les agents de surface seraient les deux voies les

plus prometteuses de la pharmacotherapie. Les nouveaux traitements pourraient comprendre des stimulateurs du systeme

immunitaire naturel. Enfin, leffet de ladjonction dantibiotiques est difficile a evaluer etant donne que ces medicaments pourraient

agir sur un etat modifiant levolution de la maladie plutot que sur laffection sous-jacente.

Conclusions: Les traitements topiques postoperatoires constitueront probablement, a lavenir, la clef de voute de la prise en

charge de la rhinosinusite inflammatoire chronique.

Key words: antibiotic, biofilm, endoscopic sinus surgery, irrigation, sinusitis, steroid, surfactant, topical

Richard J. Harvey:Department of Otolaryngology/Skull Base Surgery, St

Vincents Hospital, Darlinghurst, Sydney, NSW, Australia, and

Department of OtolaryngologyHead and Neck Surgery, Royal

Adelaide Hospital, Adelaide, SA, Australia; Alkis Psaltis: Department of

OtolaryngologyHead and Neck Surgery, Royal Adelaide Hospital, Adelaide,

SA, Australia; Rodney J. Schlosser: Department of OtolaryngologyHead

and Neck Surgery, Medical University of South Carolina, Charleston, South

Carolina; Ian J. Witterick: Department of Otolaryngology-Head and Neck

Surgery, University of Toronto, Toronto, Ontario.

Address reprint requests to: Richard J. Harvey, MD, Department of

Otolaryngology/Skull Base Surgery, St Vincents Hospital, Victoria Street,

Darlinghurst, Sydney, NSW 2010, Australia; e-mail: richard@

richardharvey.com.au.

DOI 10.2310/7070.2009.090161

# 2010 The Canadian Society of Otolaryngology-Head & Neck Surgery

Journal of Otolaryngology-Head & Neck Surgery, Vol 39, No 3 (June), 2010: pp 217231 217


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There has been a recent explosion in the understandingof the mechanisms of chronic sinonasal inflamma-tion. Multiple approaches to control and modify the

inflammatory reaction in chronic rhinosinusitis (CRS)

have led to many new agents being introduced topically to

the sinonasal mucosa. Current research into irrigation

dynamics and delivery device has expanded over the past 3

years. A range of products have become available to deliver

solutions topically to the nose (Table 1). There is a

scientific basis behind topical delivery; however, it is often

obscured by marketing information and commercial

interests. Distribution research behind nebulizers, sprays,

irrigations, and other delivery techniques has been

performed.

The general therapeutic goal of topical management

may lie between potentially competing actions of mechan-

ical and pharmaceutical intervention. The mechanical

removal of mucus, antigen, pollutants, inflammatory

products, and bacteria/biofilms is often targeted with

topical approaches. These interventions often rely on high-

volume positive pressure solutions to provide shearing

forces with additives to alter air surface liquid (ASL)

tension. However, the same approach may not be

appropriate for delivery of pharmaceutical preparations.

Complete sinus distribution, long mucosal contact time

with local absorption, and minimal wastage are common

desired properties.

The over-the-counter (OTC) market for topicalsinonasal treatments is likely to grow exponentially over

the next few years. Increasingly, the pharmaceutical

options have also expanded. Antibiotics, such as mupir-

ocin, and steroids are often added to solutions. The

science, or lack thereof, behind many of the OTC agents

and pharmaceutical additions to saline is not widely

published. Potential adverse risks also need to be balanced

with greater local intervention. The influence of pre- and

postsurgical distribution efficacy is an important factor

that significantly changes how these solutions should be

used. This article aims to provide a systematic and

evidence-based approach to the science behind the topical

management of sinonasal disease.

Management Concepts for Topical Therapies

There are several mechanisms by which local topical

irrigations may have effect. Saline alone has been

thought to have several beneficial properties.14

Additives in saline have all too easily been credited with

therapeutic gain in uncontrolled studies,5 but the

efficacy may be due to saline or simply mechanical

effects alone. Three main driving forces exist in CRS

(Figure 1). There is an interacting triad of intrinsic

mucosal inflammation, local infection, and mucociliary

dysfunction. This includes multiple eosinophillic sub-

types; systemic IgE, local IgE, aspirin-sensitive airways

disease, leukotriene abnormalities, asthma, superantigen,

and other T-cell-driven eosinophilic inflammation.

Infection may be a primary event or opportunisticowing to ulcerated mucosa or dysfunctional mucociliary

transport.6 Infection for many sufferers will be a disease-

modifying event rather than the primary driving

pathology.6 Finally, mucociliary dysfunction is predo-

minantly an acquired event. There are clinical correlates

of a patient skewed to one mechanism. Mucoceles are

generally without infection or inflammation. They may

be an example of pure mucociliary dysfunction or simple

obstruction without abnormal cilia but still impaired

mucocilary clearance. Likewise, grade 4 polyps, present-

ing only with nasal obstruction very late in the clinical

history with few other symptoms, is likely to be the

result of an underlying immunologic abnormality with

intrinisic mucosal inflammation and retained mucocili-

ary function without infection. Finally, patients who

respond solely to culture-directed antimicrobial therapy

may have simple mucosal infection with limited or easily

reversible mucociliary dysfunction without primary

intrinsic mucosal inflammation. Within this framework,

the majority of patients develop CRS from a combina-

tion of factors, and ostial obstruction is not the primary

problem; thus, simply restoring ventilation is probably

Table 1. Summary of Delivery Techniques

Delivery Pressure Delivery Volume

Positive pressure High volume

Squeeze bottle

Pressurized sprays

Pulsatile jetBulb syringe

Low volume

Pump sprays

Atomization

Negative or low pressure High volume

Nasal inhalation

Neti pot

Low volume

Drops

Nebulizer

Catheter instillation

218 Journal of Otolaryngology-Head & Neck Surgery, Volume 39, Number 3, 2010


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of limited benefit. The majority of recalcitrant patients

in our experience have aerated sinuses but persistent

mucosal disease (Figure 2).

Topical therapies may act by replacing mucociliary

clearance, where deficient, and removing inflammatory

mucus. They can prevent infection by protecting ulcer-

ated and inflamed mucosa. Antiinflammatory and anti-

biotic additives are likely to further modify the disease

triangle.

Distribution of Topical Therapies

Surgery

Distribution of topical solution to the unoperated sinuses is

limited,7and in the setting of CRS with mucosal edema, it is

probably only in the order of , 2% of total irrigation

volume.8 Nebulization is also ineffective with , 3% sinus

penetration.9 A fundamentally held belief among those

treating CRS patients is that endoscopic sinus surgery (ESS)

improves the delivery of topical medications to the sinonasal

mucosa,10,11 yet only recent evidence exists to support this

claim.7,12 ESS is essential to effectively allow topical

distribution to the sinuses. The frontal and sphenoid sinuses

are essentially inaccessible prior to surgery7 (Figure 3), and

an ostial size of 4+ mm is required to even begin seeing

penetration to the maxillary sinus.12 For those with mucosal

edema and chronic inflammation, distribution is probably

worse.8 Additionally, there is a significant difference in the

way in which ESS is delivered across institutions as some

post-ESS cavities are opened widely, whereas others practice

techniques to simply dilate or create very conservative

Figure 1. The pathophysiologic interaction of intrinsic mucosal inflammation, microbial flora, and mucociliary dysfunction. Current topicaltherapies can affect all three interacting processes: the ability to substitute for loss of mucociliary clearance and alter mucus rheology, delivery ofsteroids to intrinsic mucosal inflammation, and antimicrobial therapies. Reproduced with permission from the Division of Rhinology, St VincentsHospital.

Harvey et al, Current Topical Therapy for Chronic Sinonasal Disease 219


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sinusotomies (Figure 4). A heterogeneous group of surgical

comparisons makes evaluating locally delivered therapies

difficult to assess,13 and the pracitce of minimal techniques

have populated without consideration of many of these

factors.14 In medically managing CRS, the use of expensive

and time-wasting topical therapies is probably not supported

prior to surgery.

Device

Nebulizers poorly penetrate the sinuses even after maximal

ESS,15 and large-volume squeeze bottles appear to have the

best efficacy post-ESS.7,1517 Presurgery, the distribution to

the sinuses is extremely limited regardless of the

device,7,8,12 and sprays are the least effective of all7 (see

Figure 3. Sprays have almost no sinusdistribution prior to surgery. Meansinus dispersion of radiographic con-trast is extremely limited without

surgical exposure of the sinus mucosa.In the frontal and sphenoid sinuses,this is especially true. Reproducedwith permission from the Division ofRhinology, St Vincents Hospital.

A B

C D

Figure 2. Postsurgical disease (A and

B). Rarely is lack of ventilation amajor factor. Most refractory patientshave air in the sinus, and ostialpatency is a poor measure of success.Objective evidence of inflammatoryresolution and symptom improve-ment are better outcomes. Thesepatients often result in a dramaticimprovement (C and D) with topicaltherapy. Reproduced with permissionfrom the Division of Rhinology, StVincents Hospital.



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Figure 3). Neti pots have some advantage in the unoperated

sinus as head position and retrograde flow allow penetra-

tion.7 Postsurgery distribution is superior with high-volume

positive pressure devices.7,12,18 Research into topical

distribution often quantifies penetration and surface areacovered but not volume, potential shearing action, or

mucosal contact time. From intrasinus video observation

within our own studies, there is a very significant difference

in fluid dynamics between irrigation techniques that is

difficult to quantify (Figure 5). Simple computed tomo-

graphy studies or endoscopic grading do not take into

account the increased hydrostatic forces seen with large-

volume positive pressure devices, such as a squeeze bottle,

when compared with large-volume, low-pressure devices,

such as the Neti pot. In addition, it is unknown if these

increased irrigation pressures are beneficial or not. Simple

low-volume sprays and drops have very poor distribution

and should be considered a nasal cavity treatment only,

especially prior to ESS.7 Although multiple devices and head

positions have been trialed, less than 50% of most low-

volume applications will reach the middle meatus.19

Position

The are incomplete data on the most effective positioning

for delivering fluid to the nasal cavity and paranasal

sinuses.7,1927 The majority of these studies involve

assessing the distribution of dye around the middle

turbinate with simple sprays and drops in presurgical

patients. Many commercial products recommend a head-

down, overthe-sink, noseto-the-ground position forirrigation (Figure 6). This is practical and makes runoff

easy to collect. Evidence of the efficacy in delivery of drops

to the middle meatus relative to head position demon-

strated that the Mygind and Ragan (left lateral and

supine positions) were superior to the Mecca and Head

Back positions in one study28 but was inconclusive in

others.19,27 The relevance of positioning with positive

pressure application may be less significant. However, even

with positive pressure high-volume irrigation, the head-

down or lateral position may lead to better frontal

distribution.7,29

Mechanical or Pharmaceutical Intervention?

There may be potential competing interests when it comes

to topical therapies. Large-volume positive pressure

irrigations appear to have the best distribution and would

most likely remove mucus and inflammatory secretions.

Unfortunately, they are also very inefficient at delivery of

pharmaceutical agents to the sinuses. Our research into

exposure and residual fluid remaining in the sinuses after

A B

Figure 5. Preendoscopic sinus sur-gery (ESS) high-volume positive pres-sure irrigation does allow some fluidto enter the maxillary sinus (A).However, the fluid only trickles invia the natural os (1), secondaryostium (2) and surgical antrostomy(3). Post-ESS fluid delivery is fast,with high shearing forces and thepotential for mechanical removal ofmucus (B).

A B

Figure 4. The right middle meatus asit will appear after (A) ostial dilatationand (B) formal endoscopic sinussurgery. The potential difference in

assisting topical delivery to the sinusmucosa is great and thus makesstudies into the efficacy of endoscopicscans surgery using a heterogeneousgroup of such patients very difficult tointerpret.



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irrigation suggests that less than 5% of the solution will

remain after standard squeeze bottle irrigation.30 With 96%

of the irrigation going to waste, combining the mechanical

and pharmaceutical aims of the therapy in one delivery may

be suboptimal. In addition, even when post-ESS positive

pressure irrigations reach the dependent sinuses, it is

unclear exactly how long such irrigations and any

pharmaceutical agents remain in the sinus cavity before

being cleared by mucociliary transport or gravity alone.

Saline: The Basis of All Irrigations

Topical saline appears to improve symptom control in

those patients with chronic sinonasal disease.1,31 Both

rhinitis and rhinosinusitis have been included in these

reviews together with pre- and postoperative patient

selection. Based on our current understanding of topical

distribution, this makes the results difficult to interpret.

Symptom control may merely be a result of better mucus

management in the nasal cavity or a potential therapeutic

change to pathology.

Nasal Mucosa: Protective or Cytopathic?

Traditional thinking portrays a mucosal protective effect by

saline irrigations, avoiding drying and excoriation. It has

been speculated that improved trophism of mucosa, as a

result of topical saline, would enhance mucosal defence by

increased specific IgA mediated defense.32 However, in vitro

observation has demonstrated deleterious morphologic

changes of healthy respiratory mucosa, including ciliary

loss, when exposed to hypotonic (0.3%) and hypertonic

(3%) saline on electron microscopic study.33 These changes

were not seen with isotonic saline. Host innate mucosal

defenses may also be removed by irrigation.3436 However,

there appears to be overwhelming support for symptom

benefit rather than adverse effects. The Cochrane study did

not demonstrate any serious adverse event in over 1650

patients in published trials.1

Enhanced Drug Delivery

There is evidence of a synergistic effect of hypertonic saline

and topical steroid delivery. Possible removal of the mucus

blanket alone may allow better steroid absorption.

Additionally, there is evidence that increased tight junction

permeability of respiratory mucosa occurs with saline andis not seen with equivalent mannitol osmolarity.37 Does

this lead to better intranasal steroid delivery? There is

evidence to support a synergistic saline and steroid benefit

from some clinical trials in rhinitis1,38 and from nebulized

therapy in asthma.39,40

Mucociliary Clearance

Mucociliary function is the combination of several factors.

Ciliary beat frequency (CBF) is only part of the equation.

Ciliary structure and orientation; areas of ciliary loss;changes in mucus rheology41 and to the gel and sol

characteristics of the mucus blanket; and effective ciliary

coupling with the gel layer42 will all be involved. Buffered

isotonic and hypertonic (3%) saline decreases saccharine

clearance time (SCT) by 24.1% and 39.6%, respectively.43,44

Additionally, 5% hypertonic saline reduced SCT, with no

change in 0.9% and 3% solutions in a further study.45 All

three of these studies were on healthy, normal adults.

Saline, especially hypertonic, appears to improve SCT.

It is unlikely to be a result of increased CBF. The reduced

SCT is likely to be a result of increased ionic load to the sol

layer46 with more favourable rheologic properties.47,48

Rehydration of the sol layer may change the viscoelastic

properties of the mucus blanket and allow more efficient

cilial action.47 Improved mucus transport has also been

demonstrated with other substances, including nonionic

solutions (glucose, mannitol, and urea).49

Effect on CBF

Although data exist for a positive effect on mucocillary

transport time,43,44 there is no direct evidence of enhanced

Figure 6. High-volume positive pressure squeeze bottle irrigationperformed with retrograde flow in contralateral nose postendoscopicsinus surgery offers the best fluid distribution to the sinuses fromrecent fluid dynamic research. Reproduced with permission from theDivision of Rhinology, St Vincents Hospital.



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CBF with saline. On the contrary, ciliostasis has been

observed with 3%, 7% and 14.4% saline solutions but not

with isotonic saline.50,51 Even isotonic saline has demon-

strated a reduction in CBF in some studies.51 Many

authors have attempted to dispel these data as a result of

sampling error or artificial exposure. In an attempt to

reproduce a clinically relevant situation, Wabitz and

colleagues exposed nasal mucosa to 3% and 0.9% saline

in healthy individuals, in vivo, and then harvested.48 The

assessment of CBF was made on the explanted mucosa.

There was no significant enhancement in CBF.

Nasal Provocation or Decongestion?

There has been much speculation on the effect of

hypertonic solutions as a nasal decongestant or to reduce

edema.52

Many authors have suggested that an osmoticinfluence would improve nasal patency.53 The concept of

buffered hypertonic as a decongestant44 has not been

supported by scientific observation. In contrast, decreased

airspace measurements on rhinometry have been shown

after hypertonic saline exposure.54 At commonly used

concentrations, no statistical difference was observed in

rhinometric analysis of 0.9% and 3% saline solutions.43

Variable and inconsistent changes (6 100150%) in

rhinomanometric assessment to 0.9% saline and varying

tonicities of solutions have been demonstrated.55,56 No

relationship was found in either study.Contrary to decongestion, hypertonic saline can act as a

provocation to nasal mucosa. Additional secretions are first

seen at 3.6% in healthy patients.56 At even lower tonicity,

2.7% solution, nasal pain and discomfort were elicited in

healthy subjects.54 When solutions approach 5.4%, there is

significant sensation of nasal obstruction and corresponding

loss of airspace on acoustic rhinometry.54 Nebulized

hypertonic saline of 4.5% and 7% is used in asthma

provocation tests. The potential for saline to stimulate nasal

pain, secretion, and vasodilatation increases with tonicity.

Improvement in nasal patency is likely to be the result

of clearance of secretions rather that an osmotic effect.54

With higher concentrations, provocation is likely with

reduced airspace and increased sensation of obstruction.

There will also be a wide individual variation in thresholds

and tolerance.57

Mechanical Removal of Sinonasal Secretions,Antigens, or Biofilm

The potential for sprays to remove debris, mucus, or

antigen has always been implied. However, there is little

research to substantiate its effectiveness. There is only

indirect evidence through reduced antigen-specific IgE

levels in allergic rhinitis sufferers who used saline during

the allergy season.58 High-volume solutions appear to be

more effective in managing symptoms than simple

sprays,59 but with mixed groups of pre- and post-ESS

patients, the degree of benefit is still debatable. As a

potential adverse effect, positive pressure irrigations may

potentially seed antigens and inflammatory products

throughout the paranasal sinuses as demonstrated on the

positive pressure effects of nose blowing.60

The Additives

Mucoactive Agents: Surfactants

Amphipathic molecules possess the ability to be soluble in

both water and organic solutions. They form the basis of

surfactants. This affects both the solution and remaining

molecular load behaviour at airsurface interfaces.61

Pulmonary surfactant is the best known clinical example

of the importance of these amphipathic molecules.

Pulmonary surfactant greatly improves the efficiency of

mucocilial clearance by reducing the adhesiveness of

mucus to the respiratory epithelium. Acute respiratory

distress of the newborn is the case example of the

requirement of such agents in respiratory function.

Surfactants can have both mucoactive properties and

antimicrobial properties. Chemical surfactants can inter-

fere with microbial cell membrane permeability and cause

membrane disruption. These agents are often classified as

cationic, anionic, or zwitterionic (possessing nonadjacent

positive and negative charges) based on the charge of the

hydrophilic domain present in these molecules. Cationic

surfactants possess the most antimicrobial properties but

are also the most irritating.62

There are many commercially produced surfactants.

Synthetically produced detergents, soil wetting agents,

paints, antifogging solutions, and ski wax are all examples.

The combination of PEG-80 sorbitan laurate, cocamido-

propyl betaine, and sodium trideceth sulphate (commonly

known as Johnson & Johnson Baby Shampoo) has been

shown to have both antibiofilm-forming properties at 1%

solution and clinical efficacy in managing refractory CRS

patients.62 Surfactants may not be a direct therapy for

aggressive polypoid mucosal change that is dominated by

inflammatory T-helper (Th)2 response but for treating

crusting, thick mucus and chronic bacterial mucosal

colonization.



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Citric acid zwitterionic surfactant is currently under

study for potential antimicrobial activity.63 This agent

combines the calcium bridgedisrupting citric acid with

the surfactant caprylyl sulsbetaine. It was effective at

reducing bacteria-forming units within a sheep CRS model

but not as effective as topical mupirocin.64 There are

concerns regarding possible ciliary dysfunction from any

synthetic additive, and future combination solutions are

likely to lead to effective agents.

Alteration to the Innate Immunity

Components of the innate immune system are likely to

play a significant role in the normal defense and function

of sinus mucosa.34 High concentration of salt in this ASL is

thought to impair the activity of airway antimicrobial

factors and explain some of the pathogenesis in conditionssuch as cystic fibrosis (CF).65 Xylitol, a nonsoluble five-

carbon sugar, has been shown to reduce bacterial

colonization in healthy controls.65 This compound lowers

ASL salt osmolality, providing enhanced innate immunity

(salt sensitive) but no direct antimicrobial effect. Reduced

bacterial load has been demonstrated in a rabbit model on

maxillary sinusitis.66 There is great promise for additives

that enhance innate immunity, either directly or indirectly,

but combinations of hypertonic salt solution and xylitol

may potentially be counterproductive.

Antimicrobials

Until recently, only a paucity of studies existed examining

the efficacy of topical antimicrobial agents in the treatment

of CRS. With the emergence of bacterial biofilms as a

possible inciting or perpetuating agent in the inflamma-

tory process associated with CRS,67,68 interest in such

treatments has been rekindled. The attractiveness of topical

treatment lies in its theoretical ability to achieve much

higher local, yet systemically tolerated concentrations,

through the direct delivery of the agent to the site of

infection and limited systemic absorption. The evidence

for the efficacy of several of the more commonly used

topical antimicrobials is reviewed below.

Tobramycin

The use of topical tobramycin in CRS has been an extension

of its aerosolized use in the treatment of pseudomonal

pulmonary infections in CF patients. The highest level of

evidence to date, supporting its efficacy in CRS, was in a

nonrandomized controlled study in CF patients with

sinusitis.69 In this study, both nasal polyposis and the need

for revision surgery were significantly reduced in patients

treated with tobramycin irrigations. Although such efficacy

in symptomatic and endoscopic improvement has also been

replicated in a small, doubleblind, randomized controlled

trial (RCT), additional significant benefit over saline

irrigation alone was not observed at recommended human

clinical concentrations of 80 mg/mL.6,70 This finding is

further supported by a recent animal sinusitis model, which

reported equivalent evidence of histologic persistence of

disease in sinuses treated with this concentration of

tobramycin versus saline irrigation alone.71 Although the

authors found that increasing tobramycin concentration to

400 mg/mL6 significantly reduced histologic inflammation,

concerns have been raised about the possible adverse effects,

including otoxicity encountered at such high concentrations.

Amphotericin B

The pathogenic role of fungus in CRS remains debated,

with conflicting reports surrounding the efficacy of

amphotericin B as a treatment modality. Despite level I

evidence from a double-blind RCT by Ponikau and

colleagues demonstrating a significant improvement in

endoscopic, radiologic, and serologic findings in patients

treated with 250 mg/mL amphotericin B irrigations,72 such

findings have not been replicated by similar RCTs.73,74 A

recent in vitro study examining the activity of variousdoses of amphotericin B against fungal organisms may

help explain the discrepancy observed.75 This study

demonstrated that nasal amphotericin B irrigation is

ineffective in killing fungi in vitro at the Food and Drug

Administration (FDA)-approved concentration of 100 mg/mL,

with concentrations of 200 mg/mL or higher required for

effective fungicidal activity. Recent phase III FDA (and

unpublished) trials have failed to demonstrate a clinical

improvement in these patients. It appears unlikely that

current human studies will provide any further conclusions

made about the safety or efficacy of amphotericin B

irrigations at this stage.

Mupirocin

Mupirocins unique mechanism of action, low cross-

reactivity with other antibiotics, 100% stability in nasal

secretions, and insignificant systemic absorption have

made it the ideal theoretical choice for the management

of Staphylococcus aureusrelated CRS treatment failures.

Although no RCTs exist to date, in vitro laboratory,76 in

vivo animal,77 and, more recently, human cohort



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studies78,79 indicate promising results in relation to its

efficacy againstS. aureusrelated CRS. Indeed, the study by

Uren and colleagues showed that twice-daily irrigations

with 0.05% mupirocin resulted in a significant sympto-

matic and endoscopic improvement in more than three-

quarters of patients who had previously failed maximal

medical and surgical management.78 Part of mupirocins

efficacy in this subgroup of patients is thought to be

mediated by its unique antibiofilm action.76

Manuka Honey

Capiliano (Australia) and manuka (New Zealand) honeys,

derived from the floral source in tea trees (Leptospermum

spp), have antimicrobial properties,8082 and are the most

widely studied. Other honeys also have therapeutic

activity.80,83,84

Manuka honey has been used with successi n m an ag i ng i nf ec te d w ou nd s a nd u lc er s.8588

Methylglyoxal (MGO) is a derivative from the manuka

flowers and is thought to be significant in the antimicro-

bial activity of these honeys.89,90 The appropriate con-

centration is debatable. One in two dilution (50%) has

shown good antistaphylcoccal and antipseudomonal

activity to planktonic and biofilm bacteria.84 Lower

concentrations (, 5%) still have activity against coagulase-

negative staphylococci.91 With MGO isolated, there is a

minimum inhibitory concentration of 1.1 mM MGO

against Escherichia coli and S. aureus.

89

This correspondsto a 15 to 30% dilution (1.11.8 mM of MGO) of manuka

honey and would appear to represent an evidence-based

concentration for researchers pursuing this therapy.

Although the current evidence for the efficacy of topical

antimicrobial use in the treatment of CRS appears

promising, it is at best low level. Larger and better

designed RCTs are needed before definitive conclusions

can be made regarding the ideal dosing, safety, and efficacy

profiles of such agents. Until then, it is likely that topical

antimicrobial agents will remain out of the mainstream

management of this condition, being reserved for those

patients in whom all other treatment options have been

exhausted.

Antiinflammatories

There is growing evidence that a predominant feature of

CRS is a shift in mucosal immune response to a

proinflammatory action, whether Th1 or Th2 dominated.

This moves away from the normal mechanical and innate

immunity that provides a stable healthy mucosa.6 The

antiinflammatory action of corticosteroids would appear

to be the obvious solution to help suppress this response.

Unfortunately, the evidence for the role of nasal steroid in

the management of CRS is weak. Most studies include

unoperated patients or a mixture of pre- and postsurgical

populations. This raises greater questions of what mucosa

we are actually treating in these studies. The potential for

recording an action on secondary turbinate reactivity in

CRS is great. Steroid sprays in unoperated patients lead to

almost no sinus distribution.7,92 So it is not surprising that

researchers using steroid postoperatively with direct

application to sinus mucosa have demonstrated bene-

fit9395 and those with a mixed or unoperated population

found less benefit.96,97 Topical fluticasone and high-dose

budesonide used in the postoperative period have the best

evidence for use.98 Budesonide 0.5 mg/2 mL respules

diluted in 240 mL squeeze bottle irrigation is the current

treatment under most recent investigation (Figure 7).Budesonide 0.25 mg once daily was shown to improve

quality of life as measured by SNOT-20 scores, with no

adrenal suppression.99 Although high-dose steroid appli-

cation has been shown to decrease polyps100 and is simple

and easy to deliver, steroid irrigations have yet to be

rigorously evaluated beyond safety and feasibility.99,101

Adverse Effects

Common adverse effects often overlooked include cost,

preparation time, and delivery effort. These are substantial

if nonreusable products are used and high-frequency

regimens are recommended. All of our current research

protocols rely on twice-daily or less delivery frequency. We

believe that more frequent topical therapies or irrigations

are simply not practical for managing a chronic disease.

There will also be a subset of patients who will find the

practice of nasal irrigation uncomfortable and have

burning sensations, nausea, or eustachian tube symptoms,

making tolerability low.

The use of saline is commonly regarded as low risk,

with minimal adverse effects. Its homeopathic background

has allowed widespread use without reporting of potential

unwanted side effects. A recent Cochrane Review sum-

marized the reported side effects from trials.1 No overall

risk ratio could be obtained from the published data;

however, reported rates from 5 to 32% were recorded.

Patient discomfort, itching, otalgia, sensation of nasal

obstruction, and nausea were experienced. No major

adverse events were noted in the trials. There was good

tolerance and acceptability of irrigation among most

participants.3,102



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Pain, Discomfort, and Provocation

With saline solutions used for nasal provocation testing, it

is not unexpected that a proportion of users will

experience some degree of discomfort, nasal burning,

or pain with their use. Hyperosmolar fluid generally

induces a greater reaction. Nasal pain and discomfort were

experienced in healthy subjects at 2.7% solutions in

challenge testing.54 Clinically, hypertonic solutions also

demonstrated greater burning and discomfort compared

with isotonic saline when delivered to viral rhinosinusitis

patients, 32% versus 13% (p, .05).53

Some commercial preparations contain a preservative,

benzalkonium chloride. Benzalkonium chloride has been

shown to induce short-term discomfort, but tolerance to

this response was achieved with repeated exposure.103

Apart from the concerns of its effects on nasal mucosa, itappears to be well tolerated. An RCT of benzalkonium

chloride versus placebo showed no difference in objective

testing (mucociliary clearance time, rhinomanometry,

smell test, and nasal secretion performance) or subjective

tolerability over 4 weeks of use.104

Provocation

Saline and hypertonic solutions have been shown to

increase both ionic and mucinous secretions.105,106 At

higher concentrations, these solutions can induce both the

sensation of nasal obstruction and a decrease in objective

airway space.54 Nasal eosinophil degranulation and hista-

mine release can also be induced with saline irrigation.57

Hypertonic (4.5%) saline solutions have demonstratedusefulness as a provocation tool in asthmatics.107 The

concurrent existence of asthma and CRS raises the possible

risk of exacerbation of hyperresponsive airway disease. Up

to 20% of asthmatic children may demonstrate hyperre-

sponsive effects to hypertonic saline when nebulized.108

Although there are concerns regarding induction of

bronchospasm,109 knowledge of particle size and deposi-

tion dictates that little exposure to the lower respiratory

tract is likely to occur.9 This is particularly so in sprays and

irrigations.

Mucosal Injury

Hypotonic solutions risk local mucosal cell damage.33

Acute otitis media was reported in several participants in

an abandoned water study.110 There is good evidence to

suggest that water-based therapies be avoided.

The preservative benzalkonium chloride has experi-

mentally induced nasal mucosal lesions in rat nasal

respiratory epithelium.111 Benzalkonium chloride, at

concentrations used in commercial sprays, can possibly

cause neutrophil inactivation.112 Mucociliary dysfunction

A B

C D

Figure 7. The postsurgical mucosallining before (A and B) and aftertopical therapy (C and D). Prominentcrusting and staphylococcal and pseu-domonal colonization are present (Aand B). High-dose steroid therapy inthe setting of mucosal bacterial infec-tion does not follow traditional con-cepts on bacterial management.However, the ability to downregulatea mucosa-damaging proinflamma-tory response and restore innateimmunity might underlie efficacy.



11/16

and nasal mucosal cell damage have also been reported

with benzalkonium exposure.111,113,114

Speculation exists that natural immunodefense mechan-

ism, lysozymes and secretatory immunoglobulins, will be

removed with saline irrigation.36 However, the impact of this

is unproven and, in the presence of active sinonasalinflammation, is difficult to assess. Innate immunity may

already be lowered, resulting in the diseased state.115

Cross-infection

The potential for bacterial contamination and sinus cross-

infection has been a source of concern for those less

enthusiastic about the routine use of nasal irrigations.

Contamination of storage devices and solution source does

occur. Bulb syringes and neti pots had moderate to many

bacterial colonies growing in 19.5% and 7% of containersafter 2 weeks.116 There was no statistical difference between

pots and bulb syringes. Spray bottles are also not immune to

the contamination. After 3 days of use, 90% of spray bottles

had a bacterial growth. Nearly half of the colonies were S.

aureus and Pseudomonas aeruginosa.117 The comparison

group in this study was nasal drop bottles, which had only

15% growth after 3 days. The minimal direct contact with

nasal drop bottles is likely to account for the lower rates.

Contamination of the nasal lining by pathogens from palmar

skin, originating from hand-based irrigation, has also been

reported.118

Higher levels of gram-negative rods are also seenin patients using irrigations compared with controls.119

What role these bacterial species might have in the

course of CRS is unclear. However, there is evidence of

direct contamination of the sinuses by a Pseudomonas

species that was confirmed in both nearby bottles and

sinks.120 Sinusitis related to Pseudomonascontamination

has been reported in both humans121 and animals.122

Similar outbreaks of Pseudomonas perichondritis from

contamination were reported in patients who had ear

piercings at a single shop with Pseudomonas colonies

growing in the disinfectant bottle and sinks.123 Other

aqueous environments, such as hydrotherapy pools124 and

antifog solutions,125 have also lead to cross-infection.

Especially in aqueous environments, the risk of container

contamination with Pseudomonas is possible. How this

might relate to pathologic significance in sinus cavities

routinely growingPseudomonasand other species is unclear.

Systemic Absorption

Systemic absorption of medication needs to be carefully

predicted. Adrenal suppression from topical steroid has

been reported93 but appears to be uncommon even with

high concentration irrigation.99 With only 2.5 6 1.5% of

the solution retained in the sinuses after a squeeze bottle

irrigation,30 there is only a 50 6 30 mg exposure of twice-

daily 1 mg budesonide nasal irrigation. Mucosal absorp-

tion may vary greatly between compounds. Ototoxicity

with topical tobramycin has been reported.126,127

Conclusion

Physicians are currently faced with a bewildering array of

topical therapies available for their patients with

rhinosinusitis. Topical therapies will continue to grow

in popularity owing to their ease, efficacy, and targeted

approach to the target organ in CRSthe sinonasal

mucosa. There is currently little evidence to support the

use of topical therapies delivered via low-volume devices,

such as nebulizers or sprays. Additionally, most topical

therapies used prior to ESS do not reach the paranasal

sinuses to any significant extent and are simply treating

nasal conditions, such as turbinate hypertrophy owing to

allergic or nonallergic rhinitis. As our knowledge of the

precise pathophysiology of the various subsets of CRS

grows, it will enable us to tailor topical therapies that are

specific for the type of CRS seen in each patient. The

pharmacologic additives used must be selected with a

purpose in mind, that is, targeted antimicrobials,

antiinflammatories, surfactants, or mucociliary modu-

lating agents, and one solution will likely not be the

treatment of choice for all CRS patients. Otolaryngologists

must have a comprehensive understanding of topical

therapies that are available, when to use specific agents,

and how to deliver them to provide maximal benefit to our

patients.

Acknowledgement

Financial disclosure of authors: No external funding was

received. Dr. Schlosser receives grant support from the

Flight Attendant Medical Research Institute, NeilMed, and

Xoran. Dr. Schlosser is a consultant for BrainLAB,

Medtronic Xomed, Gyrus, and Schering-Plough and serves

on the speakers bureau for GlaxoSmithKline. Dr. Harvey

has served on an advisory board for Schering-Plough and

has received grant support from NeilMed. Dr. Witterick is

on Advisory Boards for Schering-Plough and Abbott

Laboratories and a consultant for Alcon and Pharma-

science Inc. Dr. Psaltis has nothing to declare.

Financial disclosure of reviewers: None reported.



12/16

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