Comparison of efficacy of cryotherapy and chlorhexidine to oral nutrition transition time in chemotherapy-induced oral mucositis Y. ERDEN, MASTER, NURSE, Department of Fundamentals of Nursing, Faculty of Healthy Science, Ataturk € University, Erzurum, & G. IPEKCOBAN, PHD, ASSISTANT PROFESSOR, Department of Fundamentals of Nursing, Faculty of Healthy Science, Ataturk University, Erzurum, Turkey € ERDEN Y. & IPEKCOBAN G. (2016) European Journal of Cancer Care Comparison of efficacy of cryotherapy and chlorhexidine to oral nutrition transition time in chemotherapyinduced oral mucositis The aim of this study was to compare the efficacy of cryotherapy and chlorhexidine to oral nutrition transition time in chemotherapy-induced oral mucositis. This randomised controlled trial with random assignments to the experimental and control groups was conducted with cancer patients. Study data were collected from 90 cancer patients. The first experimental group (n = 30) received chlorhexidine mouthwash, the second experimental group (n = 30) received oral cryotherapy and the control group (n = 30) received routine care. To collect data we used the ‘Mucositis Rating Index’. Changes in patients’ oral mucosa in each group were checked and oral feeding transition periods were recorded. There was an important statistical difference between the times of transition to oral nutrition for patients (P < 0.01). Oral nutrition transition time of patients in the first experimental group who had applied chlorhexidine was shorter than in other groups. Following the tests, we detected a significant shortening in oral nutrition transition time of patients in first group who used chlorhexidine gargle as compared to the second group and control group. There was no significant difference between cryotherapy application and control group. In parallel with these findings, we detected that the degree of oral mucositis decreased. INTRODUCTION Mucositis can occur frequently in cancer treatment (Bhatt et al. 2010; Worthington et al. 2011) and reduces quality of life. It affects the inlet region of gastrointestinal tract and is a biological complex process in response to some toxicity (Kwong 2004; Naidu et al. 2004; Lalla et al. 2008; Krishna et al. 2011). Notably, it is seen as a potential side effect of the short-term intravenous administration of combined chemotherapeutic agents (Epstein & Schubert 2003; C avusoglu 2007). The oral mucosa and normal saliva activity are two major barriers that prevent the invasion of microorganisms (Eren et al. 2007). Mucosa is affected by many chemotherapeutic agents because of its high mitotic activity. Chemotherapy medications that lead to the development of oral mucositis include methotrexate; antimetabolites such as 5-fluorouracil, dactinomycin, adriamycin; antibiotics such as bleomycin; and alkaloids like vinblastine (Naidu et al. 2004; Eren et al. 2007; Svanberg et al. 2007; Bensinger et al. 2008). Drugs that cause ulcerations in the oral cavity are more likely to be antimetabolites such as methotrexate and 5- fluorouracil (Rocke et al. 1993; Baydar et al. 2005). Severe ulcerative mucositis causes deterioration of mucosa and development of opportunistic infections in mouth. These infections can lead to complications such as bacteremia and sepsis (Eren et al. 2007). Mucositis negatively affects Correspondence address: Y. Erden, Department of Fundamentals of Nursing, Faculty of Healthy Science, Ataturk University, Erzurum, € Turkey (e-mail: [email protected]). Accepted 4 March 2016 DOI: 10.1111/ecc.12495 European Journal of Cancer Care, 2016 © 2016 John Wiley & Sons Ltd Original Article
daily functions, feeding and the patients’ quality of life (C avusoglu 2007; Svanberg et al., 2007). In addition, mucositis can cause intolerance to treatment and reduction or skipping of chemotherapy doses (Peterson & Cariello 2004; Sonis 2004; C avusoglu 2007; Volpato et al. 2007; Lalla et al. 2008). This painful inflammation and ulceration causes discomfort that makes it difficult for affected patients to eat, swallow, speak or perform oral hygiene measures. These effects in turn might result in weight loss, dehydration (Qutoba et al. 2013). An awareness of prevention and control strategies is fundamental to managing oral mucositis properly. The nurse is responsible for providing appropriate care management to guarantee the quality of care given to the patient and their safety. Therefore, the nursing team needs to be regularly involved in continuing education, to keep up-to-date about clinical practice grounded in scientific evidence (Manzi et al. 2016). Oral mucositis increases the requirement for total parenteral nutrition and contributes to increased use of narcotic analgesics (Treister & Sonis 2008). Many pharmacological and non-pharmacological methods have been tested to cope with the side effects of chemotherapy, to prevent opportunistic infections and to provide pain relief for the patient. Two of these methods are cryotherapy and chlorhexidine mouthwash. Cryotherapy is the local cooling of tissues for treatment and prophylaxis purposes (Saadeh 2005). When cryotherapy is used during application of short-term chemotherapy agents, it causes vasoconstriction in the oral cavity and the distribution of the drug among the cells decreases with a resulting decreased risk of oral mucositis formation (Baydar et al. 2005; Karagozo € glu & Ulusoy 2005; Katrancı et al. 2012). Besides being used in oncology, cryotherapy is also used in the treatment and symptom control of many diseases in traumatology, rheumatology and neurology (Karagozo € glu & Ulusoy 2005). Chlorhexidine is an antimicrobial agent that is widely used in clinics to treat oral mucositis and candida infections in the mouth (Costa et al. 2003). Chlorhexidine is a broad-spectrum antiseptic agent and it is effective on Gram-positive bacteria, Gram-negative bacteria and fungi (C avusoglu 2007; Yılmaz 2007). The antibacterial effect of chlorhexidine continues for 12 h. Chlorhexidine has a unique role in many oral care protocols for prevention of oral mucositis with 0.12% chlorhexidine solution shown to prevent microbial colonisation (Keefe et al. 2007). Diagnosis, prevention and treatment of oral mucositis in clinics are very important. However, in nursing practice, there are insufficient evidence-based guidelines about the prevention and treatment of oral mucositis. Evidencebased guidelines are very important for nurses who are at the centre of patient care. One of the most important problems in patients with oral mucositis is their inability to take food orally. One of the most important factors that affects the transition time to oral nutrition in patients with oral mucositis is the degree of infection and inflammation. If the degree of oral mucositis is low and if it is treated quickly, the transition time to oral nutrition decreases (Anderson et al. 1998). Another important factor that affects the transition time to oral nutrition in patients with oral mucositis is providing appropriate protein support for the acceleration of wound healing. Thus, parenteral or enteral glutamine, vitamins and mineral supplements will accelerate wound healing and the transition to oral feeding (Cawley & Benson 2005). Nurses play an active role in the management of oral mucositis by using the appropriate diagnostic tools for the identification of oral mucositis and they need evidencebased guidelines to support this type of care. The aim of this experimental study was to compare the efficacy of cryotherapy and chlorhexidine to oral nutrition transition time in chemotherapy-induced oral mucositis. MATERIALS AND METHODS Design and sample The study was a randomised controlled trial with a random assignment to the first experimental group (n = 30) receiving chlorhexidine mouthwash, the second experimental group (n = 30) receiving oral cryotherapy, or a control group (n = 30) receiving routine care. At the same time patients received antibiotics due to ulcerations in the mouth. This study was conducted with cancer patients who were hospitalised and receiving chemotherapy at Medical Oncology and Hematology clinics of Erzurum Ataturk University Research and Application Hospital. All subjects had grade 3–4 oral mucositis because of chemotherapy and all of them were unable to take food orally. A total of 90 patients who had similar characteristics were included in the study. Instrument Data were collected using a form prepared by the researchers that contained questions regarding gender, education level, presence of a systemic disease, cigarette use, nutrition, dentist visits prior to treatment, receipt of mouth care education, tooth brushing habits, presence of prosthesis, mouth dryness, loss of appetite, cancer stage and length of disease (Baydar et al. 2005; Karagozo € glu & 2 © 2016 John Wiley & Sons Ltd ERDEN & IPEKCOBAN
Ulusoy 2005; Papadeas et al. 2007; Sorensen et al. 2008). In addition, the World Health Organization mucositis scale (Table 1) was used for assessing the patients’ oral mucositis (Gori et al. 2007). Studies indicate that symptoms of mucositis develop 5–10 or 7–14 days following chemotherapy, and they decrease within 2–3 weeks after chemotherapy (Karagozo € glu & Ulusoy 2005; C avusoglu 2007; C elkan 2007). Thus, mucositis assessment was also conducted in our study at 7, 14 and 21 days after chemotherapy as based on the WHO mucositis assessment scale. Ethical consideration Oral consent was obtained from the patients for their participation in the study before the questionnaire forms were administered. The patients were also informed verbally about the study. Participation was voluntary and the patients could withdraw from the study at any time without giving a reason. Approval was obtained from the Ethics Committee of the Medical Faculty, Ataturk University. Data analysis The data were recorded and analysed using Statistical Program for Social Sciences version 20 for Windows (SPSS Inc., Chicago, IL, USA). For the analysis of data, chisquare, ANOVA and independent sample tests were used. In the ANOVA, significant differences among subgroups of studied factors were tested using Duncan’s multiple range test. Statistical significance levels were set at P < 0.05. Nursing intervention Each subjects’ oral nutrition transition time was observed and recorded by the researcher for about 15 days. We sought the assistance of physicians for grading of oral mucositis and patients with a grade 3 or 4 oral mucositis were included in the study. Study group data were collected from patients in the study groups who had oral care with chlorhexidine twice a day and with cryotherapy once a day. Chlorhexidine mouthwash was applied six times a day to patients with grade 3 oral mucositis and it was applied eight times a day to patients with grade 4 oral mucositis. Tooth brushing was not recommended to patients with grade 3 and 4 oral mucositis because of possible ulcerations due to physical irritation (Can 2010). Control group data were collected from patients in the control group who followed standard oral care protocol (washing with plenty of water mouthwash). The observation period was 15 days because the duration of hospitalisation and discharge of patients was short in clinics where the research was conducted. This period is also compatible with the healing time of mucositis as reported in the literature (Spielberger et al. 2004; Stone et al. 2005; Worthington et al., 2011). All patients were trained in mouth cleaning before using the mouthwash. The duration of mouthwash needed to be 30 s and swallowing gargle and eating or drinking something immediately after the mouthwash was forbidden. The researcher checked patients every 2 days regarding whether they had applied chlorhexidine mouthwash correctly and, if necessary, chlorhexidine mouthwash was reapplied. Patients in other study group applied cryotherapy via ice cubes once a day. Ice cubes were packed by the investigator and they were stored in the refrigerator in each patient’s room. Ice cubes were prepared as small pieces and they were renewed every 2 days by the researcher. Patients applied the ice cubes once per day for 30 min. The researcher evaluated patients’ oral mucositis after the 7th and 14th day. RESULTS Sample description Among the patients in the control and experimental groups, 50.0% were women and 50.0% were men; 35.9% (Experimental Group 1: Chlorhexidine application), 33.3% (Experimental Group 2: Cryotherapy application) and 30.8% (control group) respectively, were elementary school graduates and did not have a smoking habit (83.3% in all three groups). The patients in the control and experimental groups were found to have diets heavy in protein (30.0%) and carbohydrates [33.3% (Experimental Group 1: Chlorhexidine application), 50% (Experimental Group 2: Cryotherapy application) and 36.7% (control group) respectively; the majority had mouth dryness (50%) and loss of appetite (53.3%; Experimental Group 2: Cryotherapy application), 50% (Experimental Group 2: CryotherTable 1. WHO mucositis scale Grade Description Grade 0 None Grade 1 Soreness, erythema Grade 2 Erythema, ulcers. Patient can swallow solid diet Grade 3 Ulcers, extensive erythema. Patient cannot swallow solid diet Grade 4 Mucositis to the extent that alimentation is not possible © 2016 John Wiley & Sons Ltd 3 Efficacy of cryotherapy and chlorhexidine
apy application) and 46.7% (control group)], and they did not have any other systemic diseases besides their oncologic problems (83.4%) (P > 0.05) (Table 2). In addition, none of the patients had gone to a dentist before chemotherapy, received education in oral care or used any oral care protocol. Disease-related characteristics Among the patients in the control and experimental groups, 33.3% had gastric cancer, 33.3% had colon cancer, 6.6% had pancreatic cancer, 16.9% had rectal cancer and 9.9% were diagnosed with a metastatic cancer of unknown location. The duration of the disease in the control group was found to be ‘9 months or more’ in 50.0% of the patients in Experimental Group 1 and 4– 8 months in 40.0% in Experimental Group 1 and control group; 46.7% of the control patients and 50.0% of the experimental group 1 patients had stage 4 disease (P > 0.05). The length of treatment varied from 1 to 3 months in 53.3% and 66.6% of the patients in the control group and in 63.3% of patients in the experimental group (P > 0.05) (Table 3). There was a statistical difference between the time of transition to oral nutrition for patients in experimental groups. Oral nutrition transition time of patients in the first experimental group who had applied chlorhexidine was shorter than in other groups (P < 0.01). DISCUSSION Discussion of effectiveness of chlorhexidine on oral nutrition transition time Oral mucositis is seen in more than 50% of patients who are given high-dose chemotherapy (Francesco 2005). According to data from the WHO, 10% of all mucositis is severe mucositis (grade 3 and 4). There is also an increased incidence of sepsis in patients with mucositis (Kannan et al. 1997) and thus treatment of this complication is important. There are no standard treatment Table 2. The distribution of the study patients’ socio-demographic and individual characteristics Characteristics Experimental Group 1 (Chlorhexidine application), N = 30 Experimental Group 2 (Cryotherapy application), N = 30 Control Group, N = 30 Test of significance S% S% S% P Age (years) 17–35 15 37.5 12 30 13 32.5 >0.05 36–50 3 13 11 47.8 9 39.1 51–66 12 44.4 7 25.8 8 29.6 Gender Female 15 50 15 50 15 50 >0.05 Male 15 50 15 50 15 50 Education lliterate 4 22.2 6 33.3 8 44.4 >0.05 Primary education 14 35.9 13 33.3 12 30.8 High school 10 35.7 9 32.1 9 32.1 License 2 40 2 40 1 20 Smoking Yes 5 16.7 5 16.7 5 16.7 >0.05 No 25 83.3 25 83.3 25 83.3 Nutrition Protein (P) 9 30 9 30 9 30 >0.05 Carbohydrate (C) 10 33.3 15 50 11 36.7 Vegetable (V) 5 16.7 5 16.7 5 16.7 P, C and V 6 20 1 3.3 5 16.7 Dry mouth Yes 15 50 15 50 15 50 >0.05 No 15 50 15 50 15 50 Lack of appetite Yes 16 53.3 15 50 14 46.7 >0.05 No 14 46.7 15 50 16 53.3 Systemic diseases Yes 5 16.6 5 16.6 5 16.6 >0.05 No 25 83.4 25 83.4 25 83.4 4 © 2016 John Wiley & Sons Ltd ERDEN & IPEKCOBAN
and care practices for prevention of oral mucositis in nursing, medicine and dentistry literature that include mucositis management. Except in some evidence-based practices, a specific agent or an educational technique has not been shown (Brown & Wingard 2004; Yılmaz 2007). It has been reported, however, that oral mucositis-induced problems can be reduced and prevented by moistening of the oral mucosa and removing dead tissue from mouth. In clinical practice guidelines created for the prevention and treatment of oral and gastrointestinal mucositis and in MASCC/ISOO (Multinational Association of Supportive Care in Cancer/International Society of Ocular Oncology), chlorhexidine mouthwash has been recommended (Rubenstein et al. 2004). In the transition to oral feeding, performing oral care with an appropriate antiseptic solution accelerates oral feeding transition time. Chlorhexidine mouthwash has an indispensable role in oral care protocols because of its antiseptic and antibacterial effect. In a study by Levy-Polack et al. (1998), it was determined that oral mucositis incidence significantly reduced in children with leukaemia who had oral care using chlorhexidine, povidone iodine and nystatin every day. Another study showed that tooth brushing and oral care with chlorhexidine reduced the incidence of chemotherapy-induced oral mucositis and its pain in children with cancer. Chlorhexidine was shown to reduce the duration and severity of oral mucositis in a study of 40 children (Cheng et al. 2004). Likewise, Luglie et al. (2002) found that chlorhexidine reduced the duration and severity of oral mucositis. Another study among patients with mechanical ventilator found that oral care with chlorhexidine reduced risk of nosocomial pneumonia (Boop et al. 2006). The findings of our study are thus similar to these studies. We detected that average oral nutrition transition time of patients in the first experimental group using chlorhexidine was 8.53 1.04 days; this finding was statistically significant (P < 0.05). There is no statistical difference between experimental group 2 and control group (P > 0.05); but there is statistical difference between experimental group 1 and control group (P < 0.01). Discussion of the effect of cryotherapy on oral nutrition transition time Oral cryotherapy is a popular application which is practical, inexpensive and easy to use. It has minimal side Table 3. The distribution of some disease-related characteristics of patients included in the study Parameters Experimental Group 1 (Chlorhexidine application), N = 30 Experimental Group 2 (Cryotherapy application), N = 30 Control Group, N = 30 Test of significance n % n % n % P Cancer type Gastric cancer 10 33.3 10 33.3 10 33.3 >0.05 Colon cancer 10 33.3 10 33.3 10 33.3 Pancreatic cancer 2 6.6 2 6.6 2 6.6 Rectal cancer 5 16.9 5 16.9 5 16.9 Unknown cause 3 9.9 3 9.9 3 9.9 Duration of disease 1–3 months 5 16.7 7 23.3 8 26.7 >0.05 4–8 months 10 33.3 12 40 12 40 9 months or more 15 50 11 36.7 10 33.3 Stage of disease Stage 2 5 16.7 5 16.7 5 16.7 >0.05 Stage 3 10 33.3 12 40 11 36.7 Stage 4 15 50 13 43.3 14 46.7 Length of treatment 1–3 months 16 53.3 20 66.6 19 63.3 >0.05 4–8 months 5 16.7 5 16.7 6 20 9 months or more 9 30 5 16.7 5 16.7 Oral nutrition transition time (x SD) 8.53 1.04b 12.13 1.81a 13.53 1.69a ** Total (x SD): 11.40 2.61. **P < 0.01 means values with different letters are significantly different. a: There is no statistical difference between experimental group 2 and control group (P > 0.05). b: There is statistical difference between experimental group 1 and control group (P < 0.01). © 2016 John Wiley & Sons Ltd 5 Efficacy of cryotherapy and chlorhexidine
effects and it is recommended for the treatment of mucositis (Aisa et al. 2005; Karagozo € glu & Ulusoy 2005); it is also situated in MASCC’s new guide. Many studies have shown that cryotherapy reduces the blood flow to oral mucosa in severe mucositis due to chemotherapy treatment. When cryotherapy is used with short-term intravenous chemotherapy agents, it causes local vasoconstriction so that oral mucosa blood flow slows down and distribution of the drug between cells decreases. Finally, the risk of oral mucositis decreases (Mead 2002). In Karagozo € glu and Ulusoy’s study, undertaken with 60 patients, administration of cryotherapy was started 5 min before intravenous administration of etoposide-, vinblastine- and cisplatincontaining chemotherapy regimens and then continued during the venous infusion. These researchers made their evaluations according to the patient mucositis assessment scale and a physician mucositis assessment scale after the first course. According to patient mucositis assessment scale, stomatitis incidence in their study group was 36.7% and stomatitis incidence in the control group was 90%. According to the physicians’ mucositis assessment scale, stomatitis incidence in the study group was 10% and stomatitis incidence in control group was 50%. These results were statistically significant (Karagozo € glu & Ulusoy 2005). Similarly, in a study by Rocke et al. (1993), the average oral mucositis value of 86 patients who applied cryotherapy for about 30 min was 0.73. A study of the treatment of oral mucositis by cryotherapy has not been found in the literature as yet. In this study, it was determined that average oral nutrition transition time of patients in the experimental group who applied cryotherapy was 12.13 1.81 days. We found that cryotherapy was ineffective for oral nutrition transition time in chemotherapy-induced oral mucositis. Cryotherapy reduces blood flow to the oral mucosa and blood cannot reach the tissues; therefore, the healing process of oral mucositis may be delayed and oral feeding may occur later. RECOMMENDATIONS The results obtained from this study can be summarised as follows: • Analyses of this study showed that the oral nutrition transition time of patients in the experimental group who applied chlorhexidine was shorter than the oral nutrition transition time of patients in the group who applied cryotherapy and the control group. In parallel with this finding it was found that the degree of oral mucositis reduced. According to this result: • Using chlorhexidine mouthwash for the prevention and treatment of oral mucositis should be offered. • Nurses must be trained about the identification, evaluation and prevention of oral mucositis. ACKNOWLEDGEMENTS We would like to thank directors of hospital, nurses and our participant patient for his/her role in the completion of this study. AUTHOR CONTRIBUTIONS Yasemin Erden, Gulay € _ Ipek C oban: study design. Yasemin Erden: data collection and analysis. Yasemin Erden, Gulay € _ Ipek C oban: manuscript preparation. FUNDING This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. CONFLICT OF INTEREST No conflict of interest has been declared by the author(s). REFERENCES Aisa Y., Mori T., Kudo M., Yashima T., Kondo S., Yokoyama A., Ikeda Y. & Okamoto S. (2005) Oral cryotherapy for the prevention of high-dose melphalaninduced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Supportive Care in Cancer Journal 13, 266–269. Anderson P.M., Schroeder G. & Skubitz K.M. (1998) Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer 1, 1433–1439. Baydar M., Dikilitas M., Sevinc A. & Aydogdu I. (2005) Prevention of oral mucositis due to 5-fluorouracil treatment with oral cryotherapy. Journal of the American Medical Association 7, 1161–1164. Bensinger W., Schubert M., Ang K.K., Brizel D., Brown E., Eilers J.G., Elting L., Mittal B.B., Schattner M.A., Spielberger R., Treister N.S. & Trotti A.M. (2008) 3rd. NCCN Task Force Report. Prevention and management of mucositis in cancer care. Journal of National Comprehensive Cancer Network 6, 1–21. Bhatt V., Vendrell N., Nau K., Crumb D. & Roy V. (2010) Implementation of a standardized protocol for prevention and management of oral mucositis in patients undergoing hematopoietic cell transplantation. Journal of Oncology Pharmacy Practice 16, 195–204. 6 © 2016 John Wiley & Sons Ltd ERDEN & IPEKCOBAN
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