Thermal Disparity among Fingers and Its Amelioration by CO2- Water Bathing in Connective Tissue Disease Patients

Objective. Correlation between a low finger temperature and thermal disparity among fingers was studied in connective tissue disease (CTD) patients. Whether the thermal disparity may be ameliorated by hand immersion in a warm carbon dioxide(CO2-) water bath was analyzed. Methods. CTD patients with suspected peripheral circulation disorder underwent a thermography test. From before to 30min after hand immersion in CO2-water (CO2 bathing; 1000 ppm CO2, 42 C, 10min), the nailfold temperatures were measured. The mean temperature (m-Temp) and the coefficient of variation of the temperature (CV = SD/m‐Temp of one hand; the mean of CVs of both hands was adopted as the indicator of thermal disparity) were monitored. The correlation between m-Temp and CV was also analyzed. Results. Forty-seven (45 females and 2 males) patients were included, 32 of whom had Raynaud’s phenomenon. The m-Temp was 30:8 ± 3:0°C at the baseline, increased to 35:3 ± 1:0°C immediately after CO2 bathing, and remained significantly higher than that at the baseline until 30min after (32:1 ± 1:9°C). The CV was 0:0291 ± 0:0247 at the baseline, decreased to 0:0135 ± 0:0039 immediately after CO2 bathing, and remained significantly lower than the baseline until 30min after (0:0163 ± 0:0143). Between m-Temp and CV, a negative correlation was observed throughout the measurements. Conclusion. Thermal disparity was observed at baseline measurement in CTD patients. Warm CO2 bathing markedly ameliorated the disparity, and this amelioration remained until after 30min. Throughout the observation, the lower the m-Temp, the more severe the thermal disparity among fingers.


Introduction
Peripheral vascular involvement is one of the major features associated with connective tissue diseases (CTDs). We previously reported that thermal disparity among fingers is a characteristic feature of conditions with disturbed peripheral circulation including Raynaud's phenomenon [1]. CO 2 has long been known to improve peripheral circulation, with its effect usually observed after exposure of the whole body for a certain number of days [2]. In this study, we evaluated whether exposure to warm water containing CO 2 may ameliorate the thermal disparity among fingers and whether this amelioration can be achieved after only a short period of exposure. These are intriguing issues, and their clarification might in turn elucidate the pathophysiology of some peripheral vasculature diseases.

Patients and Methods
Patients who visited the Japanese Red Cross Medical Center, were diagnosed as having a CTD, and were suspected of having peripheral circulation disorder as determined by their doctors in charge were included. They underwent a thermography test before and after immersing their hands in CO 2water. The test was performed within the routine clinical setting under the public health insurance system, and the results were retrospectively analyzed.
After acclimatization to room temperature (25°C) for 15 min, both hands were immersed into a 42°C CO 2 -water bath for 10 min (CO 2 bathing). The water contained 1,000 ppm CO 2 (Carbothera Onpar™, Mitsubishi Rayon Cleansui Co., Ltd., Japan). Before (-10 min) and 0, 3, 5, 10, 15, 20, and 30 min after CO 2 bathing, nailfold temperature (Temp) of the ten fingers was measured by thermography (INFRAEYE3000™, Nihonkoden, Japan). CO 2 bathing and Temp measurement were carried out in a sitting position with the hands placed at a level below the heart throughout the test.
As an indicator of thermal disparity among fingers, the coefficient of variation (CV) was adopted. CV was calculated as SD/mean temperature (m-Temp). In this study, the mean of right and left hand CVs was used throughout. The correlation between m-Temp and CV was also examined. Results were statistically analyzed by the paired t-test.
This work was supported by Research Award, Japanese Society of Balneology, Climatology and Physical Medicine, 2016. This study was approved by the Ethics Committee, Chiba Central Medical Center: H30-R19.
The time-course changes in Temp of each finger of one hand of a patient are shown in Figure 1 as a representative case. In this patient, the baseline Temp varied from finger to finger, resulting in a high CV at baseline. Then, after CO 2 bathing, the thermal disparity disappeared, and CV diminished.
When dividing the patients into two groups with a baseline CV lower and higher than the mean, 30 patients showed a lower CV. In these 30 patients, their mean CVs were similar in all the measurements and no significant difference was observed between the baseline CV and each CV after CO 2 bathing (data not shown). On the other hand, in all of the 17 patients with a CV higher than the mean at the baseline, CV decreased significantly after CO 2 bathing, and a statistically significant decrease from that at the baseline was observed in all the measurements. In this latter group, after the initial CV decrease, CV reincreased gradually, and from 15 min after CO 2 bathing until the last measurement, CV became significantly higher than that immediately after CO 2 bathing (data not shown).
The correlation between m-Temp and CV is shown in Figure 4 for each measurement. At the baseline, both m-Temp and CV differed from patient to patient; CV showed a tenfold difference. Patients with a higher CV showed a wide range of m-Temps. In patients with a lower CV, mostly a higher Temp was observed. Immediately after CO 2 bathing, data points appeared clustered; the patients with a lower Temp and/or a higher CV at the baseline showed a higher Temp and a lower CV. Then afterward, the data points gradually returned to their original positions prior to CO 2 bathing. However, Temp increase and CV decrease were still preserved 30 min after. Between m-Temp and CV, a significant correlation was observed in all the measurements (p < 0:05, at any measurement).

Discussion
Disturbed peripheral circulation is one of the major features of CTDs. Not only the extremities but also internal organs including the lungs and intestines may also be involved in it, sometimes resulting in severe diseases such as pulmonary 3 International Journal of Vascular Medicine hypertension and pseudoileus. Recurrent vasoconstriction, narrowing, or obstruction may develop in small-caliber peripheral vasculatures; the possible pathogenetic mechanisms of which include autonomic nerve system dysfunction, vasculitides, and remodeling of the vascular structure. They are thought to develop usually unevenly from vessel to vessel. A notable case is Raynaud's phenomenon, in which the skin surface color and temperature differ markedly among fingers, not only at an attack but also even at the time without an attack (Figure 1). We have observed a thermal disparity in patients with Raynaud's phenomenon [1]. As an indicator of this thermal disparity, CV would be appropriate to be adopted.
In this study, we focused on thermal disparity. Here, we basically determined whether a low m-Temp, which is due to poor peripheral perfusion, is associated with a high CV. This association is clearly shown in Figure 4; at each measurement, a statistically significant negative correlation was observed between m-Temp and CV. An additional noteworthy observation is that at the baseline, three patients with a substantially low m-Temp did not show a very high CV (Figure 4, -10 min); it is considered that long-standing invasion might have led to diffuse vascular remodeling, resulting in a markedly low temperature in all fingers and consequently in a rather low CV. As far as we know, no study focusing on thermal disparity as an indicator of disturbed perfusion has been reported except for our previous report [1].
When adopting CV change to evaluate an effect of CO 2 bathing, only a 10 min exposure clearly decreased CV. Immediately after CO 2 bathing, simultaneously with an m-Temp increase, CV markedly decreased, as shown by the clustered data points in Figure 4. This likely reflected a greater increase in blood flow in fingers with disturbed perfusion. Another possible explanation is that cooling to the baseline Temp level after warm CO 2 bathing easily occurs in fingers with well-maintained perfusion. However, this is not likely because that as is shown in Figure 1, fingers with a primarily low Temp did not show a higher temperature than others with a primarily high Temp after CO 2 bathing. If flowmetry was also carried out in addition to thermometry, it might be helpful in analyzing the flow [3][4][5][6], although flowmetry has not been widely used in a routine clinical setting. The CV decrease was sustained until 30 min after CO 2 bathing (Figures 1 and 3). This sustained CV decrease was in contrast to the Temp increase; m-Temp finally decreased significantly 30 min after CO 2 bathing not only from m-Temp immediately after but also from m-Temp 3 min after bathing ( Figure 2). Amelioration of thermal disparity by CO 2 bathing was outstanding.
Therapies that can ameliorate the disparity would be beneficial and should be applied. Natural spring of CO 2 -water has long been known to have a warming effect and to cure vascular disorders ever since the Middle Ages [5]. In recent investigations, not only long-term but also short-term exposure to CO 2 -water has been examined. Ogoh et al. showed that lower-leg immersion in 38°C water containing 1000 ppm CO 2 for 20 min enhanced skin blood flow, possibly through endothelial-cell-mediated vasodilatation [7]. Finzgar [9]. Some of the studies compared the effect of CO 2 -water to tap water. Regarding the pathological aspect, Akahane et al. showed that a significantly larger number of capillaries were formed four weeks after muscle injury in rats with transcutaneous CO 2 therapy than in rats without it [10].
To the best of our knowledge, this is the first report of an effect of CO 2 bathing focusing on thermal disparity. Although infrared thermography has long been used in various studies, it has never been applied to study from this point of view [11][12][13][14][15]. As a limitation of this study, only a single exposure to CO 2 was carried out. Repeated bathing for a substantial duration might potentially reverse remodeling, resulting in recovery from vascular involvement that frequently develops in CTDs. Comparison to the effect with tap water will show a difference, as studies adopting both CO 2 and tap water have shown a better effect with the former.

Conclusion
In conclusion, this study showed that thermal disparity among fingers is a characteristically important finding of disturbed peripheral perfusion in CTD, that the lower the finger temperatures, the higher the thermal disparity, and that CO 2 bathing ameliorated the thermal disparity until after 30 min.

Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.