The Effects of Cold Exposure Training and a Breathing Exercise on the Inflammatory Response in Humans: A Pilot Study

Abstract

Objective: We previously showed that a training intervention comprising a combination of meditation, exposure to cold, and breathing exercises enables voluntary activation of the sympathetic nervous system, reflected by profoundly increased plasma epinephrine levels, and subsequent attenuation of the lipopolysaccharide (LPS)-induced inflammatory response. Several elements of the intervention may contribute to these effects, namely, two different breathing exercises (either with or without prolonged breath retention) and exposure to cold. We determined the contribution of these different elements to the observed effects.

Methods: Forty healthy male volunteers were randomized to either a short or an extensive training in both breathing exercises by either the creator of the training intervention or an independent trainer. The primary outcome was plasma epinephrine levels. In a subsequent study, 48 healthy male volunteers were randomized to cold exposure training, training in the established optimal breathing exercise, a combination of both, or no training. These 48 participants were subsequently intravenously challenged with 2 ng/kg LPS. The primary outcome was plasma cytokine levels.

Results: Both breathing exercises were associated with an increase in plasma epinephrine levels, which did not vary as a function of length of training or the trainer (F(4,152) = 0.53, p = .71, and F(4,152) = 0.92, p = .46, respectively). In the second study, the breathing exercise also resulted in increased plasma epinephrine levels. Cold exposure training alone did not relevantly modulate the LPS-induced inflammatory response (F(8,37) = 0.60, p = .77), whereas the breathing exercise led to significantly enhanced anti-inflammatory and attenuated proinflammatory cytokine levels (F(8,37) = 3.80, p = .002). Cold exposure training significantly enhanced the immunomodulatory effects of the breathing exercise (F(8,37) = 2.57, p = .02).

Conclusions: The combination of cold exposure training and a breathing exercise most potently attenuates the in vivo inflammatory response in healthy young males. Our study demonstrates that the immunomodulatory effects of the intervention can be reproduced in a standardized manner, thereby paving the way for clinical trials.Trial Registration:ClinicalTrials.gov identifiers: NCT02417155 and NCT03240497.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.

Figures

FIGURE 1

Schematic overview of the procedures of the breathing exercises study. Dots indicate blood sampling from the arterial catheter at the corresponding time points.

FIGURE 2

Schematic overview of the procedures of the human endotoxemia study. Dots indicate blood sampling from the arterial catheter at the corresponding time points. LPS = lipopolysaccharide.

FIGURE 3

Arterial blood gas parameters and plasma epinephrine levels during the breathing exercises study: influence of breathing exercise. A, Oxygen saturation. B, Oxygen partial pressure (po2). C, pH. D, Carbon dioxide partial pressure (pco2). − retention: data obtained during the first breathing exercise on the experiment day (breathing exercise 1, Figure 1) from participants performing the breathing exercise without prolonged retention of breath. + retention: data obtained during the first breathing exercise on the experiment day (breathing exercise 1, Figure 1) from participants performing the breathing exercise with prolonged retention of breath. Data are presented as mean ± 95% confidence interval (panels A–D) or median and interquartile range (panel E) of 20 participants per group, and p values depicted in the graphs represent the between-group comparison calculated using linear mixed-models analysis (time by column factor). Epinephrine data were log-transformed before analysis. For comparisons that yielded time by column factor p values <.05, results of post hoc analyses performed using the Sidak multiple comparison test are reported in Table S1, http://links.lww.com/PSYMED/A820.

FIGURE 4

Arterial blood gas parameters and plasma epinephrine levels during human endotoxemia. A, pH. B, Oxygen saturation. C, pco2. D, Plasma epinephrine concentrations. The gray box indicates the period during which the trained participants practiced the breathing exercise (BRT and CBR groups only). Data are presented as mean ± 95% confidence interval (panels A–C) or median and interquartile range of 12 participants per groups. p Values depicted next to the legend represent the comparison of that group with the control group over time, calculated using linear mixed-models analysis on log-transformed data (time by column factor). Epinephrine data were log-transformed before analysis. Significant p values are shown in bold. For comparisons that yielded time by column factor p values <.05, results of post hoc analyses performed using the Sidak multiple comparison test are reported in Table S2, http://links.lww.com/PSYMED/A820. BRT = breathing exercise group; CBR = cold exposure and breathing exercise group; CEX = cold exposure group; CON = control group; pco2 = carbon dioxide partial pressure.

FIGURE 5

Cardiorespiratory parameters, tympanic temperature, and symptoms during human endotoxemia. A, Heart rate. B, MAP. C, Tympanic temperature. D, Score of self-reported symptoms. The gray box indicates the period during which the trained participants practiced the breathing exercise (BRT and CBR groups only). Data are expressed as mean ± 95% confidence interval of 12 participants per group. p Values depicted next to the legend represent the comparison of that group with the control group over time, calculated using linear mixed-models analysis (time by column factor). Significant p values are shown in bold. For comparisons that yielded time by column factor p values <.05, results of post hoc analyses performed using Sidak multiple comparison test are reported in Table S3, http://links.lww.com/PSYMED/A820. CON = control group; BRT = breathing exercise group; CBR = cold exposure and breathing exercise group; CEX = cold exposure group; MAP = mean arterial pressure.

FIGURE 6

Plasma concentrations of inflammatory cytokines during human endotoxemia. A, TNF-α. B, IL-6. C, IL-8. D, IL-10. The gray box indicates the period during which the trained participants practiced the breathing exercise (BRT and CBR groups only). Data are presented as mean ± 95% confidence interval of 12 participants per group. p Values depicted next to the legend represent the comparison of that group with the control group over time, calculated using linear mixed-models analysis (time by column factor). Significant p values are shown in bold. For comparisons that yielded time by column factor p values <.05, results of post hoc analyses performed using the Sidak multiple comparison test are reported in Table S4, http://links.lww.com/PSYMED/A820. BRT = breathing exercise group; CBR: cold exposure and breathing exercise group; CEX = cold exposure group; CON = control group; IL = interleukin; TNF = tumor necrosis factor.