rl

Intranasal phenylephrine-surfactant treatment isnot beneficial in otitis media with effusion

Deborah Johnson a, Sujana S. Chandrasekhar b,*, Alan J. Mautone a

International Journal of Pediatric Otorhinolaryngology (2008) 72, 1085—1089

www.elsevier.com/locate/ijpo

aUMDNJ-New Jersey Medical School Department of Pediatrics, United StatesbNew York Otology and Mount Sinai School of Medicine, 364 East 69th Street, New York,NY 10021, United States

Received 22 December 2007; received in revised form 21 March 2008; accepted 25 March 2008

KEYWORDSOtitis media;Eustachian tube;Intranasal treatment;Phenylephrine;Surfactant;Animal model

Summary

Background: Otitis media is the most common reason for non-well-child visits to theprimary care physician. Various treatments are in use to try to ameliorate the painarising from Eustachian tube (ET) dysfunction. One such treatment is topical pheny-lephrine spray, despite clinical evidence disputing its use. Previous research by thislaboratory has demonstrated the beneficial effect of topical surfactant treatment inreducing ETopening pressure, allowing the tube to open. This study is designed to testthe effectiveness of topical phenylephrine, delivered with surfactant, in reducingdays of effusion in OME, in an animal model.Methods: OME was generated by injecting Klebsiella pneumoniae lipopolysaccharideinto the right bullae of 28 gerbils. After frank OME resulted, the animals were dividedinto four groups. Group 1 received no treatment or propellant spray alone (placebo).Group 2 received intranasal surfactant spray once daily. Group 3 received intranasalsurfactant-phenylephrine spray once daily. Group 4 received intranasal surfactant-phenylephrine spray twice daily. All animals were evaluated on a daily basis by bothotomicroscopy and tympanometry, and treatment was ceased when the ear returnedto normal appearance. Evaluations were continued for a total of 30 days. Chi-squaredanalysis with significance set at .05 was performed.Results: In the untreated and placebo groups, middle ear effusion resolved at 16.25days by otomicroscopy and 28.26 days by tympanometry. In Group 2 (surfactantalone), effusion resolved at 10.57 days and 15.71 days, respectively. In Group 3(surfactant-phenylephrine once daily), effusion resolved at 15.67 days and 28.33days. In Group 4 (surfactant-phenylephrine twice daily), effusion resolved at 18.67days and 28.33 days. These results were statistically significant.Conclusions: Intranasal phenylephrine-surfactant treatment is shown to be at leastineffective, and possibly detrimental, in the resolution of OME, in this animal model.

* Corresponding author. Tel.: +1 212 249 3232; fax: +1 212 249 3287.E-mail address: newyorkotology@gmail.com (S.S. Chandrasekhar).

0165-5876/$ — see front matter # 2008 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.ijporl.2008.03.019

1086 D. Johnson et al.

The hypothesis is that surfactant potentiates the drying effect of phenylephrine at theET by allowing it to get to the ET more easily; in addition, the drying effect ofphenylephrine prevents full surfactant action. We believe that these results can beextrapolated to humans and that phenylephrine should be avoided in these cases.# 2008 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

The clinical management of otitis media with effu-sion (OME) remains a challenge. Widely acceptedguidelines advocate avoidance of antibiotic therapyfor this condition as far as possible in children overage 2 years [1]. It is therefore left to the clinician totry other measures to counteract the discomfortfrom changed middle ear pressure and MEE-asso-ciated hearing loss, so as to allow time for naturalclearance of disease. Systemic non-prescriptioncold remedies containing antihistamines and/ordecongestants are frequently used by caregiversdespite lack of evidence of efficacy [2] and seriousconcerns regarding safety [3]. Another commonlyused remedy is intranasal decongestant spray, basedon anecdotal experience of both physician andpatient/parent, and despite lack of clinical evi-dence demonstrating benefit in OME [4—9]. Thepresent animal study examines the intranasal useof the decongestant phenylephrine combined withaerosolized surfactant (previously shown by ourstudies to be effective alone) in the resolution ofOME.

Surfactant is a ubiquitous term for surface activesubstances (phospholipids) that occur on mucosalsurfaces in the respiratory system, including theEustachian tube (ET). Specifically, surfactant is aphosphatidylcholine with fatty acid residues of var-ious chain lengths and saturations. Surfactants thatare on the market at this time are all isolated fromnatural, including animal, sources. The surfactantused in this laboratory is a completely syntheticpreparation of dipalmitoyl phosphatidylcholine(DPPC) in a 200:1 ratio with cholesterol palmitate(CP) [10]. It is not yet commercially available.

Our laboratory has previously shown that surfac-tant decreases ET passive opening pressure (POP) byits property of rapid spread over the mucosal sur-face of the ET, lowering the surface tension of itslining layer and decreasing adhesion of the tubewalls, thereby allowing the tube to open more read-ily [11]. In the healthy-ear mouse model, mean POPof the ET was reduced from 43 to 30 mmHg; in thehealthy-ear gerbil model, mean ET POP fell from41.5 to 31.5 mmHg. These reductions were statisti-cally significant ( p < .05). In ears with artificiallyinduced OME, intranasal surfactant treatment sig-

nificantly reduced time of middle ear effusion, froman average of 16 to 10.6 days when given once daily,and 16—8.6 days when administered twice daily(p < .05) [12]. Both the healthy ear animal studyand the OME animal study proved the efficacy ofanterior intranasal surfactant treatment at thenasopharyngeal ET orifice.

Having shown the positive benefits of intranasalsurfactant spray on ET POPand on resolution of MEE,and given the existing clinical predilection for treat-ment with non-prescription intranasal decongestantsprays for OME, the current paper examines whetherintranasal phenylephrine solution administeredalong with surfactant is in fact beneficial in clearingMEE.

2. Materials and methods

After Institutional Research Board and Animal CareFacility approvals were obtained, 28 gerbils (Mer-iones unguiculatus) were studied. Intraperitonealinjection of pentobarbital 50 mg/kg and buprenor-phine 0.03 mg/kg was the method of anesthesia forthe initial examination and induction of OME. OMEwas induced by injecting Klebsiella pneumonia lipo-polysaccharide into the right bulla of each animal.Intraperitoneal administration of ketamine 75 mg/kg and xylazine 4 mg/kg was used for all subsequentinterventions and examinations. Inhalational anes-thetics were specifically not used in order to avoidconfounding results on that basis. The otomicro-scopy grading scale described by Fulghum in 1985was modified and used for this study [13]. Grade 0indicates completely normal; grade 1, mild hyper-emia; grade 2, cloudy middle ear with faint ossicles;grade 3, increased cloudiness with retraction of thetympanic membrane (TM); and grade 4 describes abulging TM with exudate present. Dosages of sur-factant and phenylephrine used were similar tothose appropriate for human application.

Animals were divided into four groups when theeffusion reached Fulghum grade 3 or 4. Group 1,consisting of nine animals, received either no treat-ment or propellant spray alone with no medication.This group was initially divided as 1A (no treatment)and 1B (propellant alone); as there was no differ-ence in outcome between them, they were com-

Intranasal phenylephrine-surfactant treatment is not beneficial in otitis media with effusion 1087

Fig. 1 Days to OME resolution by otomicroscopy and bytympanometry in the four groups. *Intranasal aerosolizedsurfactant alone once daily resulted in significantly fewerdays of MEE than control ( p < .001) **Intranasal aeroso-lized phenylephrine-surfactant twice daily resulted insignificantly more days of MEE than control when mea-sured by otomicroscopy ( p < .001); otherwise therewas no difference between control and phenylephrine-surfactant.

bined into a single control group. In group 2, sevenanimals received intranasal surfactant spray (5 mg/spray) once daily. In group 3, six animals receivedintranasal surfactant-phenylephrine spray (4.1 mgsurfactant and 90 mg phenylephrine/spray) oncedaily. In group 4, six animals received intranasalsurfactant-phenylephrine spray twice daily. The sur-factant compound used was synthetic dipalmitoylphosphatidylcholine with cholesterol palmitate in a200:1 ratio (DPPC:CP). The 18% decrease in surfac-tant dosage in the group 3 and 4 animals is due to theaddition of phenylephrine and to a limitation on thesize of the metering valve used, thereby fixing thedelivery volume of each spray. The investigators feltthat the valve size should remain the same through-out the study to eliminate possible issues with thevolume of propellant actuated per spray from ani-mal to animal between groups. The amount ofsurfactant delivered per spray is an amount suffi-cient to twice cover the entire surface area of theadult human nasopharynx, so that more than enoughsurfactant was delivered to every animal to exert itseffect.

All animals were evaluated on a daily basis byboth otomicroscopy and tympanometry, using a GSI1723 middle ear analyzer with a probe tone of660 Hz and sensitivity equal to 1. Microscopic obser-vations were made using a Zeiss OPMI-1 microscope,with the observer blinded to group assignment. Theeffusion was considered clinically resolved when theear returned to Fulghum grade 0, and treatment wasceased. Both types of observations were continuedfor 30 days. Tympanometric resolution essentiallyparalleled, but trailed, otomicroscopic resolutionconsistently in all cases. In other words, MEEresolved visually before tympanometric pressuredid, but tympanometric resolution was predictableand consistent. This confirmed otomicroscopicvalidity.

Chi-squared analysis with a significance level setat p = .05 was performed.

3. Results

In group 1 (the control group) MEE resolved in anaverage of 16.25 days by otomicroscopy and 28.26days by tympanometry. In group 2 (surfactantalone), MEE resolved in an average of 10.57 daysby otomicroscopy and 15.71 days by tympanometry.This difference between control and surfactanttreatment was statistically significant (p < .001).In group 3 (surfactant-phenylephrine once-daily),MEE resolved in an average of 15.67 days by otomi-croscopy and 28.33 days by tympanometry. Therewas no difference compared to the control group. In

group 4 (surfactant-phenylephrine twice-daily), theeffusion took significantly longer to resolve byotomicroscopy–—18.67 days instead of 16 days(p < .001), but was no different from control bytympanometry. The results are shown in Fig. 1.

4. Discussion

One group has looked at increasing pressure in themiddle ear and ET as a mode of therapy with equi-vocal or poor results [14,15]. The current experi-mental design of intranasal actuation of a metereddose inhaler does not employ increased pressure or amechanical mechanism in the nasal passage or ET.This is confirmed by the lack of difference in ET POPor OME outcome between control groups 1A (notreatment) and 1B (propellant alone). Additionally,the propellant has no preservatives and no anti-microbial effect.

The surfactant system is exquisitely conservedacross species and is perhaps the most geneticallyconsistent system among all vertebrates; however,its function of providing alveolar stability andincreasing lung compliance is a function that islimited to mammalian species, hence, surfactantmust have a more ubiquitous and fundamental func-tion [16]. Studies of nebulized (not aerosolized)surfactant to treat otitis media found a less thanadequate effect [17]. A review article on surfac-tants and ET pointed out that other studies ofsurfactant therapy were unable to deliver a dosesufficient enough to demonstrate a positive effect,but that our method did deliver a more than ade-quate dose of surfactant to be effective [18].

1088 D. Johnson et al.

Few other authors have investigated the poten-tial for topical phenylephrine treatment in ET–—related middle ear disease.

A study of 44 infants with the common cold andnegative ear pressures (but not OM) were giveneither intranasal phenylephrine or placebo [4].There was no improvement in middle ear pressuresfrom intranasal phenylephrine administration. AnOME study of 152 children with persistent MEE fol-lowing AOM conducted in 1984 [7] showed no dif-ference in rates of clinical and tympanometric curebetween intranasal phenylephrine and placebo inthe 52% of patients who were able to complete thestudy. The authors note that 30% of the patientsdropped out, mainly for inability to tolerate themedication. Based on lack of efficacy as well asdifficulties in administration, the authors concludethat there is limited, if any, role for topical decon-gestants in OME.

A five parameter tubal function study of 40 chil-dren with patent tympanostomy tubes treated withintranasal oxymetazoline decongestant spray or pla-cebo showed no effect from the nasal decongestant[9]. A much later study of eighty children withpatent tympanostomy tubes evaluated similarlywith a series of ET function tests after either xylo-metazoline decongestant nose drops or saline pla-cebo nose drops also revealed no effect [6]. Bothauthors concluded that topical nasal decongestion isnot effective in improving ET function in childrenwho already have poor ET function, but that efficacyin more physiologically normal ETs was not known.

In 34 individuals with normal ears, intranasaldecongestant application resulted in a positiveeffect on tubosonometrically evaluated ET function[19]. Another study examined 36 primarily adultpatients with dry central TM perforations and noactive or subacute OM who were given either pla-cebo or xylometazoline applied directly to thenasopharyngeal orifice of the ET [8]. Tubal patencyafter xylometazoline treatment was significantlyimproved only as measured by the Valsalva maneu-ver, and no effect was seen by either aspiration ordeflation ET function tests. The authors concludedthat a topical decongestant will improve ET functiononly at unphysiologically high pressures.

The 2004 Clinical Practice Guideline on OMEdeveloped by the American Academies of Pediatrics,Family Physicians and Otolaryngology-Head andNeck Surgery states unequivocally that ‘‘antihista-mines and decongestants are ineffective for OMEand are not recommended for treatment [1].’’

The current study shows that intranasal pheny-lephrine delivered in concert with surfactant is noteffective in improving ET function in OME. In addi-tion, the increase in days of effusion seen clinically

(otomicroscopically) with twice-daily phenylephr-ine treatment was statistically significant. Althoughthis difference disappeared by the time the tympa-nometry returned to normal, it raises concerns thatintranasal treatment of OME with phenylephrine isnot only not beneficial, but may actually be harmfulin prolonging the MEE. We have shown that theaddition of phenylephrine to surfactant at leastnegates the positive effect of surfactant at the ETorifice. As surfactants work best on moist mucosalsurfaces, we postulate that this negative effectoccurs because phenylephrine is vasoconstrictiveand dries mucosal surfaces, thereby dramaticallyreducing surfactant’s property of rapid spread toreach the ETorifice. It appears that, especially withrepeated application, the drying effect of pheny-lephrine outweighs surfactant’s ability to spreadalong the moist surface of the nose, and inhibitssurfactant’s ability to transport itself and the phe-nylephrine to and through the ET orifice.

5. Conclusions

This paper shows that the use of intranasal pheny-lephrine in OME in an attempt to assist ET function isnot beneficial and may be detrimental. It is hopedthat this information will aid the reader in discoura-ging patients from using this commonly employedmodality.

Acknowledgment

The authors wish to thank Natarajan Venkatayan,MD for his invaluable assistance in the animallaboratory.

References

[1] R.M. Rosenfeld, L. Culpepper, K.J. Doyle, K.M. Grundfast, A.Hoberman, M.A. Kenna, et al., American Academy of Pedia-trics Subcommittee on Otitis Media with Effusion; AmericanAcademy of Family Physicians; American Academy of Oto-laryngology—Head and Neck Surgery. Clinical PracticeGuideline: Otitis Media with Effusion, Otolaryngol. HeadNeck Surg. 130 (Suppl. 5 May) (2004) S95—S118.

[2] G.H. Griffin, C. Flynn, R.E. Bailey, J.K. Schultz, Antihista-mines and/or decongestants for otitis media with effusion(OME) in children, Cochrane Database Syst. Rev. (4 October18) (2006), CD003423.

[3] Infant Deaths Associated with Cough and Cold Medications–—Two States, 2005, CDC, MMWR January 12, 2007, 56 (01) 1—4.

[4] R.B. Turner, P.M. Darden, Effect of topical adrenergic decon-gestants on middle ear pressure in infants with commoncolds, Pediatr. Infect. Dis. J. 15 (7) (1996 July) 621—624.

Intranasal phenylephrine-surfactant treatment is not beneficial in otitis media with effusion 1089

[5] J. Jones, L. Greenberg, S. Groudine, S. Guertin, R. Hoffman,I. Hollinger, L. Mokhiber, M. Rosen, R. Ruben, D. Schaff,Clinical Advisory: Phenylephrine Advisory Panel Report, Int.J. Pediatr. Otolaryngol. 45 (1) (1998) 97—99.

[6] N. van Heerbeek, K.J. Ingels, G.A. Zielhuis, No effect of anasal decongestant on eustachian tube function in childrenwith ventilation tubes, Laryngoscope 112 (6 June) (2002)1115—1118.

[7] G.F. Hayden, J.E. Randall, J.C. Randall, J.O. Hendley, Topi-cal phenylephrine for the treatment of middle ear effusion,Arch. Otolaryngol. 110 (August 8) (1984) 512—514.

[8] J.H. Jensen, N. Leth, P. Bonding, Topical application ofdecongestant in dysfunction of the Eustachian tube: a ran-domized, double-blind, placebo-controlled trial, Clin. Oto-laryngol. Allied Sci. 15 (3 June) (1990) 197—201.

[9] T. Lildholdt, E.I. Cantekin, C.D. Bluestone, H.E. Rockette,Effect of a topical nasal decongestant on Eustachian tubefunction in children with tympanostomy tubes, Acta Otolar-yngol. 94 (1/2, July—August) (1982) 93—97.

[10] Patents: Composition And Method For Treatment of OtitisMedia. An aerosol composition for treating otitis media andto carry drugs to treat otitis media, Inventor: Alan J. Mau-tone, Patent Numbers: 6,156,294 and 6,676,930.

[11] S.S. Chandrasekhar, P.E. Connelly, N. Venkatayan, M. el-Sherif Ammar, M. Tabor, A.J. Mautone, Intranasal metereddose aerosolized surfactant reduces passive opening pres-sure of the eustachian tube: comparison study in twoanimal models, Otol. Neurotol. 23 (1 January) (2002)3—7.

[12] N. Venkatayan, P.E. Connelly, A.J. Mautone, Y.L. Trouble-field, S.S. Chandrasekhar, Dosage regimens of intranasalaerosolized surfactant on otitis media with effusion in ananimal model, Otolaryngol. Head Neck Surg. 124 (4 April)(2001) 388—393.

[13] R.S. Fulghum, R.P. Hoogmoed, J.E. Brinn, Longitudinal stu-dies of experimental otitis media with Haemophilus influ-enzae in the gerbil, Int. J. Pediatr. Otorhinolaryngol. 9(1985) 101—114.

[14] C.M. Alper, W.J. Doyle, Repeated inflation does not preventotitis media with effusion in a monkey model, Laryngoscope109 (7 Pt 1 July) (1999) 1074—1080.

[15] C.M. Alper, J.D. Swarts, W.J. Doyle, Prevention of otitismedia with effusion by repeated air inflation in a monkeymodel, Arch. Otolaryngol. Head Neck Surg. 126 (5 May)(2000) 609—614.

[16] C.B. Daniels, S. Orgeig, The comparative biology of pulmon-ary surfactant: past, present and future, Comp. Biochem.Physiol. A Mol. Integr. Physiol. 129 (1 May) (2001) 9—36.

[17] A.J. Nemechek, N. Pahlavan, D.N. Cote, Nebulized surfactantfor experimentally induced otitis media with effusion, Oto-laryngol. Head Neck Surg. 117 (5 November) (1997) 475—479.

[18] J.F. McGuire, Surfactant in the middle ear and eustachiantube: a review, Int. J. Pediatr. Otorhinolaryngol. 66 (1October 21) (2002) 1—15.

[19] L. Olen, J. Holmquist, Influence of nasal decongestants onEustachian tube function, in: Recent Advances in OtitisMe-dia: Proceedings of the Fifth International Symposium,Decker Periodicals, Toronto, (1993), pp. 83—85.

Available online at www.sciencedirect.com