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Hyperbaric oxygen as an adjuvant treatment for malignant otitis externa

  1. John S Phillips1,*,
  2. Stephen EM Jones2

Editorial Group: Cochrane ENT Group

Published Online: 31 MAY 2013

Assessed as up-to-date: 4 APR 2013

DOI: 10.1002/14651858.CD004617.pub3


How to Cite

Phillips JS, Jones SEM. Hyperbaric oxygen as an adjuvant treatment for malignant otitis externa. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD004617. DOI: 10.1002/14651858.CD004617.pub3.

Author Information

  1. 1

    Norfolk and Norwich University Hospital NHS Trust, Department of Otolaryngology, Norwich, UK

  2. 2

    Ninewells Hospital, ENT Department, Dundee, UK

*John S Phillips, Department of Otolaryngology, Norfolk and Norwich University Hospital NHS Trust, Colney Lane, Norwich, NR4 7UY, UK. john.phillips@mac.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 31 MAY 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Malignant otitis externa is a potentially fatal infection of the external auditory canal. This condition was originally described by Chandler in 1968 (Chandler 1968) and is also known as necrotising external otitis (Kraus 1988). Diagnosis is made upon clinical, microbiological and radiological grounds. For the purpose of this review, we define malignant otitis externa broadly as "a necrotising infection of the external ear canal including surrounding soft tissue and bone" (Hickham 1996).

Patients with this condition are typically elderly, diabetic men but other groups have been described (Giamarellou 1992). The precise aetiology of this condition is unknown, but theories related to altered host immunity, local tissue microangiopathy (Doroghazi 1981) and even altered cerumen biochemistry (Driscoll 1993) have been proposed. The disease originates in the external auditory canal and spreads through the osteocartilaginous junction to involve the soft tissues beneath the temporal bone. Initially osteomyelitis of the skull base ensues, followed by involvement of the facial and other cranial nerves. Malignant otitis externa is also complicated by parotitis, mastoiditis, jugular vein thrombosis, meningitis and death (Giamarellou 1992). Diagnosis is made on clinical grounds and is suspected in any diabetic or immunocompromised patient with pseudomonal otitis externa, especially when pain is a prominent feature. Technicium bone scanning has been described as the single most useful diagnostic tool (Parisier 1982), but other forms of radiological imaging play a role in indicating disease progression (Hickham 1996). The mortality for this condition has been reported to be as high as one-third (Chandler 1972), but when cranial nerves are affected it may be as high as 80% (Aldous 1973).

Traditionally the mainstay of treatment for malignant otitis externa has been prolonged antibiotic therapy (Strauss 1982), stringent diabetes control (Resouly 1982), repeated debridement of necrotic tissue and sometimes aggressive surgical management (Reines 1980). Hyperbaric oxygen is gradually gaining acceptance as a beneficial adjunctive therapy and has been recommended whenever a therapeutic pressure chamber is available (Shupak 1989). There are 24 centres offering such facilities in the United Kingdom. Hyperbaric oxygen is available for and currently being used in the treatment of many other medical conditions. Hyperbaric oxygen treatment is the administration of 100% oxygen for respiration at pressures above 1 atmosphere absolute (ATA). Hyperbaric oxygen treatment involves placing the patient in a compression chamber, increasing the environmental pressure within the chamber and administering 100% oxygen for respiration. In this way, it is possible to deliver a greatly increased partial pressure of oxygen to the tissues. Typically, treatments involve pressurisation to between 2 and 3 atmospheres absolute (ATA) for periods between 60 and 120 minutes once or twice daily. A typical course might involve 15 to 30 such treatments (HMP 1994). In the United Kingdom, 30 sessions of hyperbaric oxygen would typically cost GBP 3000, i.e. GBP 100 per session or GBP 50 per hour (Laden 2005). Complications and side effects of hyperbaric oxygen treatment include barotraumas to the ear, round window blowout, 'sinus squeeze', visual refractive changes, numb fingers, dental problems, claustrophobia, seizures and pulmonary oxygen toxicity (HMP 1994). In general these effects are either very rare or are only temporary. It is postulated that hyperbaric oxygen treatment works by elevating the oxygen partial pressure from hypoxia to normal or above normal levels, which amplifies the oxygen diffusion gradient into the avascular tissues (Mader 1980). This is a prerequisite for efficient leukocyte function (Hohn 1976) and has been shown to promote fibroblastic division, collagen production and capillary angiogenesis, thus enhancing soft tissue and bone healing (Hunt 1972).

Malignant otitis externa is an uncommon condition associated with significant rates of morbidity and mortality (Shupak 1989). It is important to construct a systematic review to define the role of hyperbaric oxygen fully in the treatment of this condition.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

To assess the effectiveness of adjunctive hyperbaric oxygen treatment for malignant otitis externa.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials.

 

Types of participants

Adults (over 16) with malignant otitis externa.

 

Types of interventions

Any treatment(s) where hyperbaric oxygen was an adjuvant therapy versus the same treatment(s) alone.

 

Types of outcome measures

 

Primary outcomes

  1. Death.

 

Secondary outcomes

The secondary outcome measures were as follows.

  1. Time until clinical improvement. This was to be measured by resolution of pain and aural discharge.
  2. Time until radiological improvement. A variety of radiological techniques exist to measure the course of malignant otitis externa. Our intention was to allow improvement to be measured by whichever technique was deemed appropriate by the authors of the study.
  3. Recovery from cranial nerve palsies.

 

Search methods for identification of studies

We conducted systematic searches for randomised controlled trials. There were no language, publication year or publication status restrictions. The date of the last search was 4 April 2013, following previous search updates in 2011, 2008 and 2006.

 

Electronic searches

We searched the following databases from their inception for published, unpublished and ongoing trials: the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 3); PubMed; EMBASE; CINAHL; LILACS; KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Science; ISRCTN; ClinicalTrials.gov; ICTRP, Google Scholar and Google.

We modelled subject strategies for databases on the search strategy designed for CENTRAL. Where appropriate, we combined subject strategies with adaptations of the highly sensitive search strategy designed by The Cochrane Collaboration for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2, Box 6.4.b. (Handbook 2011)). Search strategies for major databases including CENTRAL are provided in Appendix 1.

 

Searching other resources

We scanned the reference lists of identified publications for additional trials and contacted trial authors where necessary. In addition, we searched PubMed, TRIPdatabase, Google and Google Scholar to retrieve existing systematic reviews relevant to this systematic review, so that we could scan their reference lists for additional trials. We searched for conference abstracts using the Cochrane Ear, Nose and Throat Disorders Group Trials Register.

 

Data collection and analysis

 

Selection of studies

The two review authors reviewed the articles found by the searches independently to identify studies of the types outlined above. We intended to resolve any disagreement by discussion. Should this have failed to resolve the disagreement then the final decision was to be made by JP.

 

Data extraction and management

We planned to extract data onto standardised, pre-piloted forms.

 

Assessment of risk of bias in included studies

Assessment of the risk of bias of the included trials was to be undertaken independently by the two review authors, with the following taken into consideration, as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011):

  • sequence generation;
  • allocation concealment;
  • blinding;
  • incomplete outcome data;
  • selective outcome reporting; and
  • other sources of bias.

We planned to use the Cochrane 'Risk of bias' tool in RevMan 5 (RevMan 2012), which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry: low, high or unclear (or unknown) risk of bias.

 

Data synthesis

We planned to perform statistical analysis using Review Manager 5. For dichotomous outcomes we would have calculated a risk ratio (RR). We intended to use a mean difference (MD) or standardised mean difference (SMD) for continuous outcomes as appropriate. We were to use a fixed-effect model where non-significant heterogeneity was found between studies. We were to use a random-effects model where great heterogeneity in studies was found.

We planned subgroup analysis of the following patient characteristics:

  • patients presenting with or without cranial nerve palsies;
  • patients presenting with or without diabetes.

We would have used study quality for sensitivity analyses.

Should trials be included in future updates of this review, we will apply these data collection and analysis methods.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

We identified no randomised controlled trials through the original searches for this review in 2004, nor at any of the update searches 2006, 2008, 2011 and 2013.

 

Risk of bias in included studies

Not applicable.

 

Effects of interventions

Using our search strategy we identified some relevant articles. None fulfilled the requirements of our protocol. We retrieved them in order to search the bibliographies for other articles which might fulfil our inclusion criteria, but we identified no further articles using this method. We could therefore enter no data for analysis.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

No randomised controlled trials were identified by our search strategy. The quality of the data identified was therefore not adequate to allow further discussion. We will, however, briefly describe the types of studies identified by our search strategy.

We found four case reports (Bath 1998; Lancaster 2000; Mader 1982; Shupak 1989) and five case series (Davis 1992; Lucente 1982; Lucente 1983; Robinson 1994; Tisch 2003), which included a total of 73 patients. These articles described the use of hyperbaric oxygen as adjuvant therapy with antibiotics in the majority of cases. In general, most regimens used 20 to 40 doses of hyperbaric oxygen treatment. Each treatment was of 90 minutes duration at 2.5 atmospheres absolute (ATA). Alternative regimens differed very little. There was no mention of any complications related to hyperbaric oxygen treatment.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

Implications for practice

The quality of the studies identified by our literature search was poor, lacking randomisation or other controls. In view of this the effectiveness of treatment with hyperbaric oxygen therapy compared with treatment with antibiotics and surgical debridement could not be statistically assessed in this review.

 
Implications for research

Our findings demonstrate the need for a well-designed, randomised controlled trial to compare hyperbaric oxygen therapy with standard therapy. Any future trials would need to consider in particular the following.

  1. Appropriate sample size with the power to detect expected differences. Due to the infrequent diagnosis of malignant otitis externa it could be necessary to organise a multicentre trial.
  2. Careful definition and selection of target patients. It would be preferable to recruit patients who had not been previously treated for malignant otitis externa.
  3. Appropriate oxygen dose per treatment session. Of the studies analysed, hyperbaric oxygen was instituted at a variety of disease stages with varying pressures, frequencies and durations. For this reason there would be need for standardised treatment protocols for any proposed hyperbaric oxygen regime.
  4. Appropriate comparator therapy.
  5. Use of an effective sham therapy.
  6. Appropriate outcome measures, including all those listed in this review.
  7. Careful elucidation of any adverse effects and their duration.
  8. The cost-utility of the therapy.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

With thanks to Jenny Bellorini, Carolyn Dorée and Annette Foley for their assistance with this review.

Also:

Dr Michael Bennett MB BS, FANZCA, Dip DHM
Department of Diving and Hyperbaric Medicine
Prince of Wales Hospital
Barker Street
Randwick NSW 2031
Australia

and

Mr Gerard Laden
Technical and Research Director
Hull Hyperbaric Unit
Hull and East Riding Hospital
Lowfield Road
Anlaby
East Yorkshire
UK

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

This review has no analyses.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Appendix 1. Search strategies


CENTRALPubMedEMBASE (Ovid)CINAHL (EBSCO)

#1 OTITIS EXTERNA
#2 ((otitis OR auditory) AND externa*)
#3 "antrum otitis"
#5 #1 or #2 or #3
#6 maligna*
#7 necroti*
#8 necrosis
#9 #6 or #6 or #7 or #8
#10 #5 and #9
#11 HYPERBARIC OXYGENATION
#12 oxygen*
#13 hbot
#14 hbo
#15 #11 or #12 or #13 or #14
#16 #10 and #15
#1 "Otitis Externa"[Mesh]
#2 "antrum otitis"
#3 (otitis OR auditory) AND externa*
#4 #1 OR #2 OR #3
#5 maligna* OR necroti* OR necrosis
#6 #4 AND #5
#7 "Hyperbaric Oxygenation"[Mesh]
#8 oxygen*
#9 hbo OR hbot
#10 #7 OR #8 OR #9
#11 #6 AND #10
1 exp external otitis/
2 ((otitis or auditory) and externa*).tw.
3 "antrum otitis".tw.
4 1 or 2 or 3
5 (maligna* or necroti* or necrosis).tw.
6 HYPERBARIC OXYGEN/
7 (oxygen* or hbo or hbot).tw.
8 6 or 7
9 4 and 5 and 8
S1 (MH "Otitis Externa")
S2 TX (((otitis OR auditory) AND externa*))
S3 S1 or S2
S4 ((maligna* OR necroti* OR necrosis))
S5 S3 and S4
S6 (MH "Hyperbaric Oxygenation")
S7 TX ((oxygen* OR hbo OR hbot))
S8 S6 or S7
S9 (S6 or S7) and (S5 and S8)

Web of ScienceBIOSIS PreviewsCAB Abstracts (Ovid)ICTRP

#1 TS=("antrum otitis")
#2 TS=((otitis OR auditory) AND externa*)
#3 #2 OR #1
#4 TS=(maligna* OR necroti* OR necrosis)
#5 #4 AND #3
#6 TS=(oxygen* OR hbo*)
#7 #6 AND #5
#1 TS=("antrum otitis")
#2 TS=((otitis OR auditory) AND externa*)
#3 #2 OR #1
#4 TS=(maligna* OR necroti* OR necrosis)
#5 #4 AND #3
#6 TS=(oxygen* OR hbo*)
#7 #6 AND #5

NB this search was last updated in January 2011.
1 ((otitis or auditory) and externa*).tw.
2 "antrum otitis".tw.
3 1 or 2
4 (maligna* or necroti* or necrosis).tw.
5 (oxygen* or hbo or hbot).tw.
6 3 and 4 and 5
otitis AND externa* OR auditory AND externa* OR otitis AND antrum



 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 4 April 2013.


DateEventDescription

19 April 2013New citation required but conclusions have not changedNo relevant studies identified by full searches in April 2013.

4 April 2013New search has been performedNew searches run. Two references retrieved.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Protocol first published: Issue 1, 2004
Review first published: Issue 2, 2005


DateEventDescription

14 January 2011New search has been performedNew searches run January 2011. Eight references retrieved. We identified no new studies.

22 October 2008AmendedConverted to new review format.

22 October 2008New search has been performedThe literature search was repeated on 22 October 2008. We identified 11 articles, which included five review articles, two case reports and two case series. None of these articles were included in the update of our review as none of these studies were randomised controlled trials that abided with our inclusion criteria.

18 August 2006New search has been performedNew searches run June 2006. No new studies identified.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

JP - lead review author, protocol development, design of search strategy, review preparation, quality assessment, data extraction and analysis.

SJ - protocol development, review preparation, quality assessment, data extraction and analysis.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Internal sources

  • None, Not specified.

 

External sources

  • None, Not specified.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Should studies be included in future updates of this review we will now use The Cochrane Collaboration's 'Risk of bias' method for the assessment of study quality, as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).

References

Additional references

  1. Top of page
  2. AbstractRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Additional references
Aldous 1973
Bath 1998
Chandler 1968
Chandler 1972
Davis 1992
  • Davis JC, Gates GA, Lerner C, David MG Jr, Mader JT, Dinesman A. Adjuvant hyperbaric oxygen in malignant external otitis. Archives of Otolaryngology - Head and Neck Surgery 1992;118(1):89-93.
Doroghazi 1981
Driscoll 1993
  • Driscoll PV, Ramachandrula A, Drezner DA, Hicks TA, Schaffer SR. Characteristics of cerumen in diabetic patients: a key to understanding malignant external otitis?. Otolaryngology - Head and Neck Surgery 1993;109:676-9.
Giamarellou 1992
Handbook 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Hickham 1996
  • Hickham M, Amedee RG. Malignant otitis externa. Journal of the Louisiana State Medical Society 1996;148:511-3.
HMP 1994
  • Kindwall EP (ed). Hyperbaric Medicine Practice. Flagstaff AZ: Best Publishing Company, 1994.
Hohn 1976
  • Hohn DC, MacKay RD, Halliday B, Hunt TK. The effect of oxygen tension on the microbicidal function of leukocytes in wounds and in vitro. Surgical Forum 1976;27:18-20.
Hunt 1972
Kraus 1988
Laden 2005
  • Mr Gerard Laden, Technical and Research Director, Hull Hyperbaric Unit, Hull and East Riding Hospital, Lowfield Road, Anlaby, East Yorkshire, United Kingdom. Personal correspondence 2005.
Lancaster 2000
  • Lancaster J, Alderson DJ, McCormick M. Non-pseudomonal malignant otitis externa and jugular foramen syndrome secondary to cyclosporin-induced hypertrichosis in a diabetic renal transplant patient. Journal of Laryngology and Otology 2000;114(5):366-9.
Lucente 1982
Lucente 1983
Mader 1980
Mader 1982
Parisier 1982
  • Parisier SL, Lucente R, Som P, Hirschman S, Arnold I, Roftman J. Nuclear scanning in necrotising progressive 'malignant' external otitis. Laryngoscope 1982;92:1016-20.
Reines 1980
Resouly 1982
RevMan 2012
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.
Robinson 1994
  • Robinson S, Clark P. Necrotising (malignant) otitis externa. Australian Journal of Otolaryngology 1994;1(5):447-9.
Shupak 1989
  • Shupak A, Greenburg E, Hardoff R, Gordon C, Melamed Y, Meyer WS. Hyperbaric oxygenation for necrotizing (malignant) otitis externa. Archives of Otolaryngology - Head and Neck Surgery 1989;115:1470-5.
Strauss 1982
Tisch 2003
  • Tisch M, Lorenz KJ, Haarm M, Lampl L, Maier H. The treatment of necrotizing otitis externa with a combination of surgery, antibiotics, specific immunoglobulins and hyperbaric oxygen therapy. Results of the Ulm Treatment Concept [Otitis externa necroticans: Kombinierter Einsatz von chirurgischer Therapie, Antibiose, spezifischen Immunoglobulinen und hyperbarer Sauerstoff-therapie - Ergebnisse des Ulmer Therapiekonzepts]. HNO 2003;51(4):315-20.