Study design and participants

This study is reported according to the CONSORT guidelines for the presentation of clinical trials [20]. This randomized, controlled, three-arm parallel-group study was performed at the Interdisciplinary Center for Treatment and Research in Balneology in Southern Germany. Participants were recruited via announcement in local newspapers and by sending written information about the study to local physicians, hospitals and pharmacies. Participants were eligible for inclusion if aged ≥ 18 years, had a diagnosis of arterial hypertension with an office systolic BP (SBP) of 140–180 mm Hg, and diastolic BP (DBP) of 90–110 mm Hg (grade 1 and 2 hypertension according to ESH/ESC guidelines 2013 [21]), had no change of antihypertensive medication in the last four weeks and no indication to change medication within the next four weeks. Exclusion criteria were severe disease - heart failure grade 3 or 4, peripheral arterial disease grade 3 or 4, unstable angina, renal failure, creatinine > 1.5 mg/dl - that might limit the patient’s capacity to participate in the study or make other treatments necessary, secondary hypertension, acute infection, fever, reasons against use of public baths such as open wounds, ITW (>1 per week) in the past two months, pregnancy and participation in other interventional studies. Written informed consent was obtained from all the participants before inclusion; ethical approval was given by local Ethics Committee (Ethics-Commission Medical Center University of Freiburg; No. 111/12). Clinical trial authorization was obtained from the Federal Institute for Drugs and Medical Devices (BfArM, Germany) and the Regional Council Freiburg. The study was prospectively registered in the German Clinical Trials Register (DRKS00003980) and conformed to the principles of the Declaration of Helsinki and to the GCP guidelines of the European Community.

Interventions

After completion of all baseline measurements participants were randomly allocated to one of two intervention groups (Bath1, resp. Bath2) or the control group (relaxation). Both bathing groups started ITW (34.0–36.0 °C) for 45–60 min four times a week for four weeks. Treatment locations were three spa centers in South-West Germany (Bad Krozingen, Freiburg and Bad Bellingen) with a comparable water mineral content (see Additional file 1: Table S1) and temperature. All participants were instructed to have head-out ITW (minimum deeper than axilla). After 4 weeks, one bathing group (Bath2) continued with four baths a week for another 20 weeks, while the other bathing group reduced to one bath a week (Bath1). The control group was advised to practice relaxation at home four times a week for 45–60 min for 24 weeks. Patients were provided with a relaxation CD, teaching them progressive muscle relaxation according to Jacobson, with some elements of awareness produced by RH to treat his patients. All groups were given written information on non-pharmacological methods to reduce BP edited by [22] and were advised to follow the instructions.

Outcome measures: CVD parameters and blood biochemistry

The primary outcome was BP measured after 4 and 24 weeks ITW, respectively, and has been reported previously [19]. Here, we report on the secondary clinical outcomes of CVRF: BMI, waist circumference, blood lipids, fasting blood glucose and C-reactive protein (CRP). Body weight was measured by using a digital scale (Soehnle professional, no. 7701; self-calibrating), height was measured by using a telescopic mechanical height rod (Seca, no. 2251721009), waist circumference was measured at the umbilical level using an inelastic measuring tape on the bare skin and recorded to the nearest 0.1 cm. The tape was snugged horizontally around the abdomen passing across the umbilicus without causing compression on the skin. Measurement was performed at the end of normal expiration. Blood samples were collected for total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride and CRP (all measured in serum, centrifuged 30 min after taking blood) and fasting blood glucose (NaF-Plasma). Analyses were done at the Institut für Klinische Chemie und Laboratoriumsmedizin (IKCL), Medical Center University of Freiburg (certified by Deutsche Akkreditierungsstelle DAkkS according to ISO 9001:2008).

Randomization and blinding

Randomization codes (single block of 60 patients) were generated by an independent statistician (SS). Because several participants withdrew consent after randomization but before being informed about their allocation, a further six participants were randomized in a single block. Enrolment (JN) was done directly after informed consent was obtained from the patients. Study IDs were assigned chronologically. In order to conceal allocation, SS was informed and added the study ID in chronological order in the randomization list. SS had no interaction at all with the patients. On their next visit, patients received a sealed, opaque envelope informing them of their allocated treatment.

Statistical analyses and sample size

Efficacy parameters were analyzed based on the intention-to-treat (ITT) population, defined as all allocated participants, applying the last-observation-carried-forward (LOCF) approach to impute missing data. Baseline differences between the three groups were assessed by either univariate analyses of variance (ANOVA) or by Chi² tests. To compare the effectiveness of ITW, a one-way between-groups analysis of covariance (ANCOVA) was conducted. The analysis model was built with group allocation as the independent variable, BMI, waist circumference, blood lipids, fasting blood glucose and CRP as the dependent variables, and the corresponding baseline scores as covariates. Prior to the analysis, we made sure that the specific assumptions for normality and homogeneity of variance for the one-way ANCOVA were met.

We report P-values and the respective partial eta² as effect size. A sample size calculation was performed for the primary outcome BP and resulted in 20 patients per group. Analyses were performed using SPSS version 20 (SPSS, Chicago IL). Data management and analyses were performed blinded to treatment allocation (SS, TW).

Study population

Details of participant flow are given in the figure (Fig. 1). During enrolment between July 2012 and April 2013, we screened 1085 patients. Of this number, 1019 participants were excluded - 701 for not fulfilling the inclusion criteria (mainly not having elevated BP values) and 318 for various other reasons such as not accepting randomization to regular baths or no baths for 6 months. In the end, a total of 66 participants met the inclusion criteria and were randomized into the study. Of these, seven withdrew their consent before receiving their allocation and were excluded from ITT-analysis, resulting in a final sample of 59 participants. According to Fergusson et al. [23], this so-called post-randomization exclusion from the primary analysis may be legitimate if patients have not received the intervention. In this case, excluding patients does not introduce bias and may lead to a more informative analysis.

Safety, tolerability and compliance

Six (10.2 %) participants dropped out during the study, two in Bath1, one in Bath2 and three in the control group. The alleged reasons for leaving the study were discontent with the assigned group (n = 3) and adverse events. In group Bath1 there was one serious adverse event (apoplexy that occurred in a patient with preexisting cerebral apoplexy who had reduced the frequency of baths) and one adverse event (superficial thrombophlebitis). After a bicycle accident one participant from the control group discontinued the study. In any case there was no association between drop-out and treatment (ITW/relaxation).

Data monitoring

Data monitoring was done blind to treatment allocation, with double data entry by two independent persons for 20 % of the values (revealing one error in 1776 data cases).

Effects of treatment on CVRF

Intensity

The intensity of ITW used does not explain our negative results, because we investigated high and low intensity ITW.

Temperature

High temperature (≥37.0 °C) causes more vasodilation and enhances metabolism, the temperature of the water (34.0–36.0 °C) may therefore have been too low. However, there is only little evidence for a cardiovascular influence and the results are inconsistent. In a small trial with eight patients with diabetes mellitus type 2 [24] bathing in hot tubs at 38.0–40.0 °C for 30 min per day, six times per week for three weeks resulted in a mean weight loss of 1.7 kg, and a decrease of fasting blood glucose from 182 mg/dl to 159 mg/dl. A Japanese RCT using hot baths (40.0 °C; 20 min once a fortnight) found no significant effect on BMI, waist circumference, serum lipids or blood glucose in healthy subjects [25]. A Hungarian study found no significant reduction in plasma lipids or CRP in 42 ambulatory patients with degenerative musculoskeletal disease after 15 baths at 38.0 °C over 3 weeks compared to baseline [16].

Exercise

It may also be necessary to combine ITW (32.0 °C) with exercise. This was shown in a 12-week randomized controlled trial in which a large significant reduction of BP (office SBP −36 mm Hg, DPB −12 mm Hg; 24-h ambulatory SBP −17 mm Hg, DBP −9 mm Hg) was observed in patients with resistant hypertension [12]. In a 10-week study (water aerobic training program using 55 min sessions 3 days per week) with 40 hypertensive men (grade 1 and 2), a reduction of SBP of 11.71 mm Hg and of DBP of 5.9 mm Hg compared to baseline was observed [11]. It appears that the exercise component is even more important than immersion; at least, this is what a randomized controlled study with 52 post-menopausal hypertensive women, which found no difference between the effect of water-based exercise compared to land-based exercise suggests [26].

Complex therapies

It may also be necessary to combine ITW with more complex therapies such as spa therapies. A 3-week Zelen double consent randomized controlled trial (N = 257) in France [27] found that a complex spa therapy with ITW (daily bubble bathing, water manual massages, mud therapy, water pool exercise, drinking of mineral water, nutrition and physical activity counseling) significantly reduced BMI (mean BMI loss after 14 months follow-up was 1.91 kg/m² [95 % CI: 1.46; 2.35]; P < 0.001). In a randomized, controlled trial from Poland [28] 50 overweight and obese patients (BMI = 43.8) presented a significant weight reduction with an average loss of 7 % of their initial weight and other CVRF such as total cholesterol, LDL-cholesterol, triglycerides and blood glucose after a 3-week spa therapy consisting of 15 daily mineral (4 % NaCl) thermal baths (31.0 °C) in a swimming pool and mud packs and a 1000 kcal diet. Similar results were shown in a 3-week non-randomized, controlled trial (N = 199) with ITW as part of complex spa therapy (cardiopulmonary endurance training, individually adjusted diet, education programme on CVRF and physical and balneological treatment related to other diseases). The spa therapy significantly reduced BMI (P < 0.001), mean arterial BP (P = 0.002), apolipoprotein B (P = 0.015), fasting insulin (P = 0.035) and fibrinogen (P = 0.950) [18].

In our study, ITW was combined with written information about a healthier lifestyle. We expected high motivation or adherence to a healthier lifestyle. However, this intervention did not seem to be intense enough. This may be explained by the fact that the participants relied completely on the effects of ITW or the relaxation technique. Another explanation for the minimal effect over time in all three treatment groups may be that unspecific effects such as regression to the mean were minimized in our trial, as there was a 1-week gap between the time of inclusion and baseline. One trial in Germany investigating spa therapy including ITW in mineral water found that 50 % of the moderate effects on CVRF happened during the first day of treatment [29].