Introduction
A majority of the patients who undergo treatment for cancer that involves radiation and/or chemotherapy are at risk of side-effects, such as nausea/vomiting [
1], diarrhoea [
2], reduced salivary flow, infections, dysphagia, xerostomia, dental caries, osteoradionecrosis, and oral mucositis (OM), of which the latter is acknowledged as one of the most severe side-effects [
3]. OM affects approximately 40% of patients who are treated with standard-dose chemotherapy, and up to 80% of those who receive high-dose chemotherapy [
4,
5]. One of the most severe and distressing symptoms of OM is oral pain [
6], although the symptoms of OM can also affect patient comfort, speech, nutritional status, and ability to tolerate medical treatment [
7]. In addition, OM is associated with weight loss, parenteral feeding, impaired quality of life [
8], and extended hospital visits [
9], and it is considered to have adverse effects on socio-economical well-being [
10].
A long-standing concern for patients with cancer of the blood or bone marrow (e.g., myeloma) who are scheduled to receive high doses of chemotherapy is the establishment of an effective and well-tolerated preventive treatment strategy to alleviate OM in conjunction with hematopoietic stem cell transplantation (HSCT). Current recommendations regarding the prevention of OM involve the use of recombinant human Keratinocyte Growth Factor-1 (Palifermin), low-level laser therapy (LLLT), and cryotherapy (CT) [
11].
In the field of haematology/oncology, CT using ice chips before, during, and after chemotherapeutic drug infusion has proven to be an effective treatment modality for alleviating OM [
12‐
15]. The presumed mechanism is vasoconstriction, which reduces the blood flow and thereby reduces tissue exposure to chemotherapeutic agents. Another hypothesis is that CT reduces the metabolic activity of the basal epithelial cells, resulting in lower absorption of the agent and reduced chemotherapy-induced damage [
14].
Despite the fact that CT efficiently reduces OM in conjunction with HSCT, this cooling method can have adverse events, such as chills, headache, numbness/taste disturbance, and teeth sensations [
16]. In addition, it is uncertain whether all parts of the oral cavity are cooled equally using this method. Moreover, a continuous supply of ice chips is needed during treatment sessions, and it is often the case that the water used to make the ice chips is of poor quality, creating a health risk [
17]. To date, ice chips have been the only documented preventive cooling method available in clinical practice for these patients, and alternative cooling methods have not been investigated. To address this deficit, we have developed an innovative disposable cooling device (intra-oral cooling device; CD) that comprises an enclosed channel system with a continuously circulating hypothermic medium.
The main objectives of the present study were to compare in a randomised cross-over trial with healthy subjects, the tolerability, temperature reduction, and cooling distribution profiles of the intra-oral cooling device and ice chips.
Procedure and data collection
Eligible subjects were examined in a dental office (ambient temperature 22 °C) located at the Department of Oral Medicine and Pathology Institute of Odontology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Prior to inclusion, each individual was provided with detailed information and instructions regarding the usage of the two cooling methods, and written informed consent was obtained. The length (in centimetres) and weight (in kilograms) were measured and the BMI was calculated for each subject. Subjects were asked to complete a form to gather information about their medical history. The participants used the cooling device and ice chips for a maximum of 60 min in two separate sessions at least 24 h apart.
Cryotherapy using the cooling device
The cooling device, which was available only in one size, was self-inserted under surveillance and adjusted by the subject until it felt comfortable. A staff member verified a good adaptation to the oral mucosa before the cooling was started.
Cryotherapy using ice chips
Subjects inserted an ounce of ice chips and were asked to move the ice chips around in the mouth so as to cool as large a part of the oral mucosa as possible. When a melted ice slurry was obtained, the subject gargled for a few seconds before swallowing or spitting out the slurry. If the ice had melted completely another table spoon of ice was inserted immediately.
Prior to and immediately after cryotherapy, the temperature level at eight intra-oral locations (right buccal mucosa, left buccal mucosa, upper labial mucosa, lower labial mucosa, anterior and posterior dorsal tongue, anterior ventral tongue, and hard palate) were measured using the FLIR E60(bx) system. Blood pressure (systolic and diastolic) and heart rate were measured in the left arm with the subjects in a sitting position using the Omron M3 Comfort digital monitor. Following each cooling session, the subjects answered the questions regarding completed cooling in the questionnaire.
In total, 700 thermographic images were captured using FlIR E60(bx). The images were analysed by a blinded observer using the FLIR tools and BioPix software for assessments of temperature reduction and cooling distribution, respectively.
The maximum, minimum, and mean temperatures were recorded for each of the eight intra-oral locations before and after the cooling session, using the FLIR tools software. In addition to the temperature data, the software assigned a colour to each temperature, which was subsequently used in BioPix to assess cooling distribution. The analysis with BioPix was, however, only performed on the thermographic images captured after cooling, by calculating the percentage of an image that was covered by a specific colour, equivalent to or less than the mean temperature achieved from the previous temperature analysis at each location.
For the statistical analysis, the average value, taking into account the mean for each intra-oral location, was calculated and used both for temperature reduction and cooling distribution results.
Discussion
This study was conducted to compare the tolerability levels of an innovative cooling device and ice chips in healthy volunteers, as well as to investigate any adverse events. Overall, cooling was well tolerated, which is in accordance with a previous review article by Kadakia et al. [
18]. However, 16 of the 20 subjects preferred the intra-oral cooling device over the ice chips. For those who favoured the ice chips, three individuals frequently habitually chewed on ice chips and one experienced the cooling device as being too large, which is an issue that will be addressed in the future by creating three different sizes of the device.
Adverse events related to cryotherapy have, to the best of our knowledge, not been given prominence in previous studies, and therefore, have not been carefully evaluated. In the present study, several adverse events were reported for each of the cooling methods, with coldness, numbness, and teeth sensations being more frequently perceived in the cooling sessions with ice chips. This is not surprising, since ice chips at −0.5 °C were used and they were in direct contact with the oral mucosa and the teeth. In contrast, the cooling device is an enclosed channel system with circulating water at 8 °C, so there is no direct contact between the cold liquid and the surrounding tissues. The reason for using a water temperature of 8 °C was to avoid the addition of an anti-freeze coolant. Difficulties related to swallowing, rubbing discomfort, and poor fit were the most frequently reported adverse events for the cooling device, and these complaints may reflect the fact that only one size of the cooling device was available for this study. However, a study using devices of different sizes needs to be conducted to test this hypothesis. Furthermore, poor fit and rubbing discomfort are of great importance as they may cause sensitivity and damage to the oral mucosa, which would potentially worsen the OM. Therefore, a pilot study needs to be conducted with various sizes of the device in patients who are receiving myeloablative treatment, together with an assessment of adverse events. This would ensure that the adverse events experienced in healthy volunteers will not result in damage to the oral mucosa and exacerbation of OM.
Pain and nausea were also reported as adverse events for both methods, although these adverse events were reported more frequently in the sessions using ice chips. The nausea may be due to the volumes of water swallowed by the subjects as a consequence of the ice chips melting in the mouth, and the experienced pain is attributable to the low temperature of the ice. Nausea caused by the cooling device might be related to over-extension in some patients.
Regarding the adverse events noted, there is a clear trend towards design-related problems with the cooling device, whereas cold sensations and numbness accounted for the majority of the problems experienced with the ice chips. One major advantage of the cooling device over ice chips is that there is the possibility to refine and improve the design to achieve even better comfort, which is not possible for the ice chips.
This study also compared the effects of the cooling device and ice chips on mean temperature reduction, mean cooling distribution, and the association between oral cooling and systemic variables. In addition, we investigated the potential correlation between BMI and differences in temperature reduction and cooling distribution. However, analyses of the thermographic images did not show any statistically significant differences between the two methods.
This outcome can be explained in two ways. First, the FLIR tools software and BioPix are not specifically designed for investigating intra-oral temperatures, leading to a risk of misinterpretation. Second, although the same conditions were used for both cooling methods, the temperature of the oral mucosa recovers quickly, which means that there is a narrow time-window to capture the images at all eight intra-oral locations. This could cause distortions and further complicate the image analysis.
Ultimately, since the study was not dimensioned for these secondary end-points, there is a possibility of type II errors, i.e., the study does not have a sufficient sample size to be able to detect a difference between the methods. However, the possibility that ice chips are superior to the new cooling device and that the study failed to show this due to being underpowered seem unlikely, as the descriptive statistics actually point in the opposite direction, indicating superiority for the cooling device. These results, however, indicate that the same levels of temperature reduction and cooling distribution are achieved using water at 8 °C in the cooling device and ice chips at −0.5 °C.
The ANOVA did show two significant period effects, although since both treatments were equally affected by the period effects, these did not affect the estimates of differences between the two methods.
The ANOVA did not show any significant effect of sequence, which means that no significant implications of unequal carry-over effects were observed. Naturally, this may be a type II error due to lack of power to detect such a difference, given the limited sample size in the present study. However, we believe that there are good grounds to assume that there are no carry-over effects due to the nature of the present study. First, there are no changes in the underlying health conditions, since we are studying healthy volunteers. Second, none of the treatment effects, e.g., adverse events, such as teeth sensation or rubbing discomfort, are likely to be carried over to the second period.
Little is known about oral cooling and its possible associations with systemic variables. Baydar et al. observed no local or systemic side-effects associated with the use of cryotherapy with ice chips [
15]. In contrast, Svanberg et al. reported significantly higher (systolic) blood pressure levels following cryotherapy [
19].
Oral cooling did not show any statistically significant impact on any of the systemic variables, and BMI had no impact on oral cooling, which is not surprising since the majority of the subjects were within the normal range for BMI. These results are of importance for future clinical studies, as potential systemic effects can hamper medical rehabilitation after chemotherapy. However, further studies are needed to determine if there are genuine systemic effects following oral cryotherapy, particularly in patients who are undergoing myeloablative therapy. Furthermore, the same cooling capacity can be expected in subjects regardless of their BMI values.
The prospective randomised cross-over design, which allows all the subjects to test and evaluate both cooling methods, combined with blinded analyses of the thermographic images, provides reliable data and strengthens the impact of the present study. Another advantage is that subjective and objective parameters, as well as systemic associations were evaluated.
A limitation of the present study is that it was conducted on healthy dental students, which could have influenced the results, as they knew that the cooling device was a novel cooling method compared to ice chips. The cooling device might be tolerated differently by patients in clinical practice when used in cooling sessions that are longer than 60 min.