Clinical Radiology (1988) 39, 291-294

The Effect of Chlorhexidine and Benzydamine Mouthwashes on Mucositis Induced by Therapeutic Irradiation L. P. SAMARANAYAKE, A. G. ROBERTSON*, T. W. MacFARLANE, I. P. HUNTER, G. MacFARLANE*, D. S. SOUTARI and M. M. FERGUSON:I:

Department of Oral Medicine & Pathology, Glasgow Dental Hospital & School, 378 Sauchiehall Street, Glasgow G2, *Institute of Radiotherapeutics and Oncology, Western Infirmary, Glasgow Gll , tPlastic Surgery Unit, Canniesburn Hospital, Glasgow G61 and SDepartment of Oral Medicine & Oral Surgery, School of Dentistry, University of Otago, Dunedin, New Zealand

A variety of mouthwashes are frequently used in the management of irradiation-induced mucositis. Ben- zydamine has recently been introduced for alleviating this condition. Its efficacy as a mouthwash was compared with chlorhexidine in two groups of patients receiving radiotherapy for oral carcinoma. Mucositis and pain were recorded over a 6 week period and oral carriage of Candida species, coliforms and Staphylococcus aureus was assessed using an oral rinse technique. There was no significant difference in the mucositis scores, overall pain scores or the yeast and bacterial species isolated between the two treatment groups. However, 58% (7 out of 12) and 92% (12 out of 13) patients reported oral discomfort when rinsing the mouth with chlorhexidine and benzydamine, respectively. In both groups, the most common coliform isolated was Klebsiella pneumoniae and the carriage of yeasts was significantly greater than that of coliforms. These results indicate that, although the individual patient acceptance of chlorhexidine is better than benzydamine, there is little difference between the two mouthwashes both in controlling pain and mucositis or in the oral carriage of the micro-organisms studied.

Therapeutic irradiation of the oral-pharyngeal region for the treatment of malignant tumours frequently leads to the troublesome side effects of mucositis, xerostomia and ageusia. While mucositis and ageusia arise in the acute phase of radiotherapy, xerostomia tends to be a later complication (Bernhoft and Skaug, 1985). If muco- sitis is very severe it may be necessary to rest the patient from irradiation resulting in prolongation of treatment time and consequential reduction in therapeutic effect (Kirk et al., 1975). Therefore, if the patient is to have the optimal response, it is important to prevent interrup- tions to radiotherapy by minimising mucositis.

Topical applications of various descriptions (e.g. chlorhexidine gluconate, povidone-iodine, sodium bicarbonate, saline, aspirin, gentian violet) are fre- quently used in the management of irradiation-induced mucositis as they are thought to be useful in maintaining acceptable standards of oral hygiene and reducing inflammation in such compromised individuals. Benzydamine hydrochloride has recently been intro- duced as beneficial in the management of oral mucositis (Kim et al., 1986). This is a non-steroidal drug that reportedly possesses topical analgesic, anaesthetic, anti-

Correspondence to: Dr L. P. Samaranayake, Department of Oral Medicine and Pathology, Glasgow Dental Hospital and School, 378 Sauchiehall Street, Glasgow G2 3JZ, Scotland

inflammatory and antimicrobial properties (Hunter, 1978; Kotokoa et al., 1979; Whiteside, 1982). Benzydamine is structurally unrelated to other non- steroidal anti-inflammatory drugs although its action is also believed to be mediated by suppressing prostaglan- din synthesis (Lisciana et al., 1968).

The effects of benzydamine in patients with pharyngitis and tonsillitis (Froom and Boisseau, 1979) and aphthous stomatitis (Yankell et al., 1981) have been studied and its anaesthetic activity found to be superior to placebo rinses. The use of benzydamine was studied by Epstein and Stevenson-Moore (1986) in 29 patients with irradiation induced mucositis in a double-blind, placebo-controlled trial; it was associated with a statistically significant relief of pain.

There is apparently no data available comparing the usefulness of benzydamine with more widely used mouthwashes in the management of side effects of radiotherapy. Hence the main aim of this study was to compare the efficacy of benzydamine and chlorhexidine in alleviating irradiation-induced mucositis, by carrying out a single-blind trial in two groups of patients undergo- ing post-operative radiotherapy for squamous carcin- oma of the oral cavity. The opportunity was also taken to assess, quantitatively and qualitatively, the oral car- riage of yeasts, coliforms and Staphylococcus aureus in these two groups, as colonisation by these micro-orga- nisms had been documented in patients receiving cyto- toxic therapy (Main et al., 1984; Samaranayake et al., 1984).

A placebo mouthwash was not included in this study because of the ethical consideration of withholding what was believed to be appropriate treatment.

METHODS

Twenty-five patients were randomly allocated to use either benzydamine or chlorhexidine mouthwashes while receiving radical radiotherapy for squamous car- cinoma of the oral cavity (60 Gy in 30 fractions over 6 weeks, or 54 Gy in 18 fractions over 6 weeks). The majority had already undergone radical surgery and insertion of a free flap in their oral cavities (Robertson et al., 1986).

In the chlorhexidine group there were two females and 10 males: the age range was 46 to 72 years, with a median age of 66 years. In the benzydamine group there were two females and 11 males: the age range was 54 to 82 years, with a median age of 70 years. For the duration of radiotherapy the patients were instructed to rinse the

292 CLINICAL RADIOLOGY

mouth with 15 ml of either 0.15% w/v benzydamine hydrochloride ('Difflam', Carnegie Medical) or 0.2% w/v aqueous chlorhexidine gluconate (Hibitane-ICI Pharmaceuticals) for 30 s twice daily.

Acidic taste was measured on both lateral margins of the tongue using a digital meter, calibrated from 0 to 1400 units as described by Grant et al. (1987).

Mucositis was graded subjectively as - nil, mild, moderate, severe or ulceration (graded as 0, 1,2, 3 or 4) and the values over all attendances were then calculated to yield the average mucosal rating. Pain associated with inflammation was measured by the patient using a 100 mm analogue scale, with 'no pain' being given a zero score and 'unbearably severe pain' a score of 100. All patients were reviewed weekly when symptoms and signs were recorded.

Microbiological samples were taken by an oral rinse technique (Samaranayake et al., 1986) which consisted of instructing the patients to rinse the mouth with 10 ml of 0.1 M phosphate buffered saline, (PBS) pH 7.2, for 60 s. The rinse was then expectorated back into a univer- sal container, transported to the laboratory and con- centrated by centrifugation at 17 000 g for 10 rain. The deposit thus obtained was resuspended in 1 ml of PBS to yield a concentrated oral rinse. Twenty-five microlitres of the latter was inoculated onto each of Sabouraud's dextrose agar (for yeast counts), MacConkey's agar (for coliform counts) and blood agar plates (for Staphylococ- cus aureus counts) using spiral inoculation (Waish et al., 1985).

After 48 h incubation at 37~ the number of colony forming units on Sabouraud's dextrose agar was esti- mated using a colony counter (Gallenkamp, Leicestershire); the yeasts were identified by sugar fer- mentation (Lodder, 1970) and germ-tube techniques (MacKenzie, 1962). After 18 h incubation at 37~ Staphy lococcus aureus were identified using the coagulase test, and the coliforms by Analytical Profile Index (API Laboratory Products, Basingstoke).

sensation. Furthermore, four of 13 in the benzydamine group required to have their radiotherapy treatment prolonged due to oral symptoms compared with one of 12 in the chlorhexidine group.

Diminished taste acuity was noted on the non-oper- ated side of the tongue in 22 out of the 25 patients studied. All patients who experienced ageusia during radiotherapy recovered 60 to 174 days after cessation of treatment.

During the period of study, a total of 101 rinse sam- ples were collected from patients who were receiving chlorhexidine, while 79 samples were obtained from the benzydamine group. The smaller number of samples collected from the latter group was due to discontinua- tion of the mouthwashes by six patients in the later stages of the trial due to unpleasant side effects.

Twenty-three out of the 25 patients harboured both yeasts and coliforms intra-orally on one or more occa- sions during the period of study. There was no signifi- cant difference in the yeast species isolated between the two treatment groups (Table 2). Approximately 67% of the yeasts isolated from both groups were Candida albicans. The remainder of the yeast isolates comprised: Saccharomyces cerevisiae, isolated six times; Candida parapsi losis , isolated twice and Candida glabrata and Candida pseudotropical i s , each isolated once. Combina- tions of two different yeast species were isolated from five of the 23 patients who harboured yeasts (Table 2).

The coliforms isolated from both treatment groups, are shown in Table 3. The two different mouthwash regimes did not significantly affect the oral coliform carriage either qualitatively or quantitatively. The most common coliform isolated was Klebsiel la p n e u m o n i a e , found in 72% of the patients. Combinations of two coliforms were isolated in 13 out of 23 patients who harboured coliforms, except in one case where three 'coliform' species were isolated. Whenever coliforms were isolated they invariably co-existed with yeasts.

Among both treatment groups the yeast carriage rate was significantly greater than the coliform carriage rate

RESULTS

The average pain scores, mucositis scores and the coliform and candidal carriage rates for the two treat- ment groups are shown in Table 1. Although there was no significant difference in the overall mucosal ratings, 12 out of 13 patients using benzydamine recorded oral discomfort while washing the mouth as compared with seven out of 12 in the chlorhexidine group. In addition, the patients who used chlorhexidine continued to use it for the 6 week period while only six of the 13 who used benzydamine managed to continue the regime for the full period. The remaining seven patients discontinued its use during the final 2 weeks as it caused nausea or discomfort which was usually described as a 'stinging'

Table 1

Evaluated criteria Patient group

Chlorhexidine Benzydamine (12 patients) (13 patients)

Average pain score 11 Average mucosal rating 22 Candidal carriage rate 72% Coliform carriage rate 56%

12 23 66% 47%

Table 2 - The identity and frequency of the yeast species isolated from different treatment groups

Yeast species Number of occasions isolated

Chlorhexidine Benzydamine Total

C. albicans I0 10 20 Saccharomyces cerevisiae 4 2 6 C. parapsilosis 0 2 2 C. glabrata 1 0 1 C. pseudotropicalis 0 1 I Mixed yeast isolates 3 2 5

Table 3 - The identity and frequency of the coliform species isolated from different treatment groups

Coliform species Number of occasions isolated

Chlorhexidine Benzydamine Total

Klebsiella pneumoniae 10 Pseudomonas aeruginosa 3 Enterobacter cloacae 3 Klebsiella oxytoca 2 Escherichia coli 3 Klebsiella ozonae 2 Proteus mirabilis 1 Pseudomonas maltophila 1 Acinetobacter calcoaceticus 1 Serratia liquefaciens 1

8 18 5 8 3 6 2 4 1 4 1 3 2 3 1 2 0 1 0 1

MOUTHWASHES FOR RADIATION MUCOSITIS 293

(P<0.05) during this period. When the yeast carriage rate and the coliform carriage between the two mouth- wash regimes were compared no significant difference could be demonstrated (Tables 1 and 2). In addition to these organisms Staphylococcus aureus was isolated from six patients at different times, Streptococcus pyo- genes (Lancefield Group A) twice and Streptococcus dysgalactiae (Lancefield Group C) once.

DISCUSSION

The lack of a significant difference between the car- riage rate of yeasts, coliforms and Staphylococcus aureus when using the two different mouthwash regimes indicate that neither antiseptic is effective in controlling the intra-oral colonisation of these opportunistic pathogens. However, as the role played by these micro- organisms in the pathogenesis of oral mucositis is not clear the efficacy of the mouthwashes could be com- pared by other evaluated criteria such as loss of taste and pain.

Differences in pain experience occurred between the two groups during the mouthwash procedure; 92% of patients using benzydamine complained of pain in their mouth compared with 58% in the chlorhexidine group. In addition, more than half of the patients receiving benzydamine had to stop the regime due to the severity of pain or associated nausea while rinsing the mouth and this never occurred in the chlorhexidine group. Therefore, chlorhexidine seems to be more acceptable to patients than benzydamine although there is little difference in the overall pain scores between the two groups.

There appear to be no studies in the literature com- paring the use of benzydamine and chlorhexidine mouthwashes in irradiation-induced mucositis. Previous workers who compared benzydamine with placebo mouthwashes in identical groups of patients found a significant reduction in pain, compared with the placebo group (Sonis et al., 1985; Epstein and Stevenson-Moore, 1986). Nevertheless, the mucosal burning sensation associated with benzydamine rinses and resultant poor patient compliance due to this factor were noted by all workers, who consequently had to resort to dilute solu- tions. It is uncertain whether the discomfort was attributable to the drug itself or to the vehicle.

Candida albicans was the predominant yeast isolated in the present study confirming the results of Rosenthal and Wilkie (1965) and Martin et al. (1981). The oral carriage of multiple yeasts observed in 22% of the patients in this study is marginally greater than the 16% oral carriage rate seen in healthy individuals (Samaranayake et al., 1986). This indicated that neither mouthwash had a significant effect on oral yeast flora.

A total of nine genera of coliforms were isolated from the two groups (Table 3). Of these, Klebsiella species were isolated on 50% of the occasions. In the study of Martin et al. (1981) all isolates belonged to the genus Klebsiella. One reason for this discrepancy may be the improved sampling technique used in the present study which is more sensitive than those employed by earlier workers (Samaranayake et al., 1986). Using the oral rinse technique, 14 out of the 23 patients were found to carry two to three different coliform species in their oral cavity. Multiple coliform carriage in the oral cavity

either in irradiated patients or in otherwise com- promised individuals has not been documented. Our sampling technique may be more sensitive or it is possi- ble that the presence of a skin graft might influence the colonisation by these bacteria. That the coliforms invariably co-existed with yeasts is interesting in view of the recent in vitro data which suggest that enterobacteria such as Klebsiella and Escherichia coli promote yeast colonisation of epithelial surfaces (Makrides and Mac- Farlane, 1982; Centeno et al., 1983).

Pseudomonas species were isolated on 20% of the occasions from both groups under study as transient oral colonisers. As this micro-organism is a common cause of death from bacterial infections in cancer hospitals (Isselbacher et al., 1980) the presence of an oral reser- voir of putative pathogens in these patients may be relevant. Furthermore, the inability to suppress these coliforms despite the use of 'bactericidal' mouthwashes suggests that vigilance for bacteraemias or septicaemias caused by oral coliforms should be maintained by all who care for these patients.

In conclusion, the results of this study would suggest that there is little difference between chlorhexidine and benzydamine in controlling overall pain and mucositis, or the oral carriage of the Candida species, coliforms and Staphylococcus aureus. However, as individual patient acceptance of the chlorhexidine mouthwash is better the use of this in preference to benzydamine is justifiable in the management of irradiation-induced oral mucositis. However, there still remains a paucity of data on the efficacy of mouthrinses in this condition.

Acknowledgement. We are grateful to Carnegie Medical, Loughborough for supplying the Difflam Mouthwash used in this study.

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Hunter, KM (1978). A clinical evaluation of benzydamine hydro- chloride. Australian Dental Journal, 23, 164-166.

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Kirk, J, Gray, WM & Watson, WR (1975). Cumulative radiation effect. Part V. Time gaps in treatment regimes. ClinicalRadiology, 26, 159-176.

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Book Reviews

New Concepts in Cardiac Imaging 1987. Edited by Pohost, Higgins, Morganroth, Ritchie and Schelbert. Year Book Medical Publishers, Chicago, 1987, 397 pp. s

This book is the third in an annual series which provides critical reviews on selected topics in the developing areas of cardiac imaging. The editor-in-chief and the majority of contributors are based in the USA.

The book is divided into four main sections which are concerned with ultrasound methods, radionuclide methods, X-ray imaging tech- niques and magnetic methods.

The ultrasound section looks at the developing areas of exercise assessment using Doppler flow methods and contrast echocardio- graphy. A section on ultrasound evaluation of cardiac masses offers nothing really new but it is a very well written review chapter.

The radionuclide section has an interesting section on left ventricu- lar diastolic function and a section on indium-Ill platelet imaging. Both these methods are currently limited in their clinical application. Positron emission tomography does, of course, offer more oppor- tunities but the technology is complex and expensive. In the X-ray imaging field a re-evaluation of the role of digital angiography in cardiac diagnosis is undertaken, bringing the reader up to date in what is available from this technique. Cine CT is also discussed and although it offers exciting possibilities, complexity and expense are major limit- ing factors.

Magnetic resonance imaging occupies a sizeable section with real time, echo planar imaging offering the possibility of very fast image acquisition. As yet, paramagnetic contrast medium agents appear to be limited in their clinical applications. There is an interesting final chapter on the potential hazards of magnetic resonance techniques, none, as yet, having been convincingly demonstrated in the clinical context.

As cardiac radiology is developing at a rapid rate, it is important for those making decisions about future directions to be up to date with the advancing technologies that are available. Limited resources mean that we must select the techniques most likely to be clinically important and it is this type of book that allows such decisions to be formulated. It seems from this volume that Indium platelet imaging, contrast echocardiography and paramagnetic contrast agents have all got some way to go. Digital cardiac imaging seems to offer much and will no doubt be increasingly applied, particularly when the storage problems are completely solved. Positron emission tomography and Cine CT are both potentially very useful but unfortunately are unlikely to have widespread application in the UK for some time due to the enormous expense involved in setting up the equipment.

This book, with a strong American flavour, will be of use to all those concerned with development of cardiac imaging but is unlikely to be of

great interest to radiology trainees or to radiologists without a specific interest in cardiac disease.

R. P. Wilde

Radiology of the Pediatric Chest. By Alvin H. Felman. McGraw-Hill, New York, 1987, 484 pp. s

There can be few radiologists who do not have to report on radio- graphs and other images of children's chests. Good radiographic tech- nique is a prerequisite for accurate interpretation but even when this is fulfilled many will greet the task with some foreboding. The publica- tion of this American book will do much to ease those worries.

The book is divided into a number of sections. The first discusses congenital abnormalities of the respiratory tract and oesophagus with the second section reviewing pulmonary disorders in the neonate. The mediastinum includes chapters on the thymus, neoplasms and infec- tions. There is only limited space for heart disease in this book which is primarily concerned with pulmonary disease but this section does contain a chapter on tumours of the heart and pericardium and another on tumour-like cardiac conditions such as TAPVD and aneurysmal patent ductus arteriosus. The fourth section examines radiological disease patterns namely overaeration, bronchial wall thickening, con- ditions which mimic pulmonary oedema, and major airway disease. Four chapters on pulmonary infections and infestations comprise sec- tion five. Section six covers interstitial lung disease, pulmonary tumours, chest trauma and the inevitable group of miscellaneous conditions which are difficult to include elsewhere.

Although the bulk of the book is plain film radiography there are a considerable number of CT scans and the place of more invasive investigations is fully discussed. Computed tomography, ultrasound and MRI are reviewed in three separate chapters written by Dr Mer- vyn Cohen. Computed tomography and ultrasound are frequent ancillary investigations with well-defined roles and although I cannot agree with the view that the use of MRI is now commonplace and indispensable that particular chapter is stimulating. I am disappointed that the last section on chest imaging does not include a chapter on nuclear medicine but occasional references are made to it throughout the earlier part of the book.

The book is subtitled 'Clinical and Pathological Correlations' and the inclusion of pathological descriptions of diseases and the pathophysiology of disease processes has enhanced the value of the book. Dr Felman writes in a humorous style which makes the book even more enjoyable. It should certainly be on the shelves of all department libraries and, I would hope, in the personal possession of radiologists involved with children's chest disease.

S. Chapman