A single session of hyperbaric oxygen therapy demonstrates acute and long-lasting neuroplasticity effects in humans: a replicated, randomized controlled clinical trial

Abstract

Purpose: Animal studies have demonstrated anti-inflammatory, and anti-nociceptive properties of hyperbaric oxygen therapy (HBOT). However, physiological data are scarce in humans. In a recent experimental study, the authors used the burn injury (BI) model observing a decrease in secondary hyperalgesia areas (SHA) in the HBOT-group compared to a control-group. Surprisingly, a long-lasting neuroplasticity effect mitigating the BI-induced SHA-response was seen in the HBOT-preconditioned group. The objective of the present study, therefore, was to confirm our previous findings using an examiner-blinded, block-randomized, controlled, crossover study design.

Patients and methods: Nineteen healthy subjects attended two BI-sessions with an inter-session interval of ≥28 days. The BIs were induced on the lower legs by a contact thermode (12.5 cm², 47C°, 420 s). The subjects were block-randomized to receive HBOT (2.4 ATA, 100% O₂, 90 min) or ambient conditions ([AC]; 1 ATA, 21% O₂), dividing cohorts equally into two sequence allocations: HBOT-AC or AC-HBOT. All sensory assessments performed during baseline, BI, and post-intervention phases were at homologous time points irrespective of sequence allocation. The primary outcome was SHA, comparing interventions and sequence allocations.

Results: Data are mean (95% CI). During HBOT-sessions a mitigating effect on SHA was demonstrated compared to AC-sessions, ie, 18.8 (10.5-27.0) cm² vs 32.0 (20.1-43.9) cm² (P=0.021), respectively. In subjects allocated to the sequence AC-HBOT a significantly larger mean difference in SHA in the AC-session vs the HBOT-session was seen 25.0 (5.4-44.7) cm² (P=0.019). In subjects allocated to the reverse sequence, HBOT-AC, no difference in SHA between sessions was observed (P=0.55), confirming a preconditioning, long-lasting (≥28 days) effect of HBOT.

Conclusion: Our data demonstrate that a single HBOT-session compared to control is associated with both acute and long-lasting mitigating effects on BI-induced SHA, confirming central anti-inflammatory, neuroplasticity effects of hyperbaric oxygen therapy.

Keywords: burns; hyperbaric oxygenation; inflammation; pathophysiology; secondary hyperalgesia.

Figure 1

CONSORT flow diagram showing the algorithm for enrollment and allocation of subjects. Notes: The intention-to-treat (ITT) number was 26, and the per-protocol (PP) number was 19 subjects. Abbreviations: AC, ambient pressure conditions; HBOT, hyperbaric oxygen therapy.

Figure 2

(A and B) Study setup. Notes: (A) Study algorithm. Each session followed the same study algorithm except for type of intervention: baseline assessments (0–20 min); burn injury (20–30 min); HBOT-/AC-intervention (30–130 min); and PI1-3 including measurements of skin-erythema (SE) and dermal-thickness (DT), and QST assessments, mechanical and thermal thresholds (130–150 min, 190–210 min, 250–270 min). HBOT-intervention included a compression phase (C; 30–35 min); a therapy phase of 100% O₂; 2.4 ATA (35–125 min); and a decompression phase (125–130 min). AC-intervention included control-therapy with 21% O₂, 1.0 ATA (30–130 min). Each subject received both treatments during two individual sessions but was randomized to either HBOT1-AC1 or AC2-HBOT2 sequence (Figure 2B). (B) Sequences, Sessions, and within-/between-sequence comparisons. Subject-flows were divided into "sequences" (Sequence 1: HBOT1+ AC1; Sequence 2: AC2+ HBOT2) and "sessions" (Session 1: HBOT1+ AC2; Session 2: AC1+ HBOT2). Within-sequence comparisons are comparisons of data within the same sequence (green lines) (HBOT1 vs AC1; AC2 vs HBOT2) whereas the between-sequence comparisons are comparisons of data between sequences (red lines) (HBOT1 vs HBOT2; AC1 vs AC2). Abbreviations: AC, ambient pressure conditions; HBOT, hyperbaric oxygen therapy; PI, post-injury; QST, quantitative sensory testing.

Figure 3

(A and B) Changes in secondary hyperalgesia areas. Notes: (A) Present study (n=19). Dot-line diagram illustrating the individual subject’s changes in secondary hyperalgesia areas (SHA) during ambient pressure conditions sessions (AC) and hyperbaric oxygen therapy sessions (HBOT). The mean values of AC- and HBOT-sessions were 32.0 cm² (20.1–43.9 cm²) and 18.8 (10.5–27.0 cm²; paired t-test: P=0.021), respectively, indicated by red lines. SHA-values are baseline corrected, calculated as AUC and presented as cm². Negative values are results of corrections with baseline values in two subjects perceiving a baseline, pre-burn SHA (cf. "Protocol violations"). (B) Combined data (n=36). Dot-line diagram illustrating the combined data. The mean values of AC- and HBOT-sessions were 40.9 cm² (31.8–50.0 cm²) and 26.4 (19.7–33.0 cm²; paired t-test: P=0.0018), respectively, indicated by a red line. Abbreviations: AC, ambient pressure conditions; HBOT, hyperbaric oxygen therapy; SHA, Secondary hyperalgesia areas.

Figure 4

(A and B) Protective, preconditioning effect of hyperbaric oxygen therapy on secondary hyperalgesia areas. Notes: (A) Present study (n=19). Box-plots of secondary hyperalgesia areas (SHA; mean [95% CI]) during Sequence 1 (HBOT1-AC1) and Sequence 2 (AC2-HBOT2). The SHA are baseline corrected, calculated as AUC and presented as cm². A significant difference between the HBOT- and AC-sessions was seen in Sequence 2 (P=0.019), indicating a preconditioning effect of HBOT. No difference was seen between the HBOT- and AC-sessions in Sequence 1 (P=0.56). (B) Combined data (n=36). A significant difference between the HBOT- and AC-sessions was seen in Sequence 2 (P=0.0001), indicating a preconditioning effect of HBOT. No difference was seen between the HBOT- and AC-sessions in Sequence 1 (P=0.55). Data were compared using the paired t-test. Abbreviations: AC, ambient pressure condition sessions; AUC, area-under-the-curve; HBOT, hyperbaric oxygen therapy session; SHA, Secondary hyperalgesia areas.