Plastic & Reconstructive Surgery Issue: Volume 99(6), May 1997, pp 1620-1625

Copyright: (C)1997American Society of Plastic Surgeons Publication Type: [Articles]

ISSN: 0032-1052 Accession: 00006534-199705000-00023

[Articles]

The Effect of Hyperbaric Oxygen Therapy on a Burn Wound Model in Human Volunteers Niezgoda, Jeffrey A. M.D.; Cianci, Paul M.D.; Folden, Blake W. R.N.; Ortega, Robin L. R.N.; Slade, J. Benjamin M.D.; Storrow, Alan B. M.D.

Author Information

Virginia Beach, Va., San Pablo and Fairfield, Calif., and San Antonio, Texas

From the Department of Hyperbaric Medicine at the David Grant Medical Center,Travis Air Force Base, the Department of Hyperbaric Medicine at Brookside Hospital, and the Joint Military Medical Command emergency Medicine Residency Program at the Wilford Hall Medical Center, Lackland Air Force Base. 1541 Lake James Drive; Virginia Beach, Va. 23464 Received for publication February 6, 1996; revised May 7, 1996. Presented at the American College of Emergency Physicians Research Forum, in San Francisco, California, on February 25-26, 1995.

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Air Force or the Department of Defense.

Abstract

A previous nonblinded study has suggested beneficial effects from hyperbaric oxygen treatment of superficial partial-thickness radiation burns in human volunteers. This protocol was designed to either confirm or challenge these previous findings in a randomized, blinded format. Twelve healthy, nonsmoking volunteers (7 males, 5 females) participated. All were screened for contraindications to hyperbaric oxygen therapy (acute sinusitis, otitis media, pneumonia, pregnancy, active cancer, pneumothorax) and given a single test hyperbaric exposure.

A standardized wound model was employed for the painless creation of a volar forearm lesion on volunteers by applying a suction device to form a blister, excising its epidermal roof, and irradiating the exposed dermis with ultraviolet light. Subjects were randomized into either a hyperbaric oxygen group (100% oxygen at 2.4 ATA, n=6) or the sea-level air-

breathing equivalent control group (8.75% oxygen at 2.4 ATA, n=6). Both groups then underwent standard hyperbaric therapy. The subjects, the hyperbaric oxygen chamber operators, and the monitoring clinicians were all blinded to the oxygen concentration administered. Each subject received two dives per day over a 3-day period. The wounds were studied noninvasively prior to treatment and once per day over 6 days for size, hyperemia, and exudation, with epithelialization as the endpoint. The averages for each measurement of the hyperbaric oxygen group versus the control group were computed by means of a one-tail t test; p was considered significant at less than 0.05.

Daily wound size, hyperemia, and exudation measurements were significantly different on day 2. The hyperbaric oxygen group showed a 42 percent reduction in wound hyperemia, a 35 percent reduction in the size of the lesion, and a 22 percent reduction in wound exudation (p values of 0.05, 0.03, and 0.04, respectively). No significant difference was noted for epithelialization.

Observed differences in wound size, hyperemia, and exudation were attributable to hyperbaric oxygen therapy. This study further supports earlier conclusions that hyperbaric oxygen therapy is beneficial in a superficial dermal wound.

----------------------------------------------

It is estimated that 2.5 million people in the United States sustain burns each year. In this group, 100,000 require hospitalization and 12,000 deaths are attributed to the burn trauma.2 Advances in burn wound therapy over the past few decades, particularly in the areas of critical care monitoring, resuscitation, and antibiotics, have improved the survival of burn victims significantly.3 However, minimizing burn severity, preserving partially injured tissue, and speeding recovery time remain continuing challenges.

A burn is a complex and dynamic injury characterized by a central zone of coagulation necrosis, bounded by a stasis zone, which in turn is surrounded by a zone of hyperemia. Hematologic changes in the area of trauma include platelet microthrombi and aggregation, hemoconcentration, red cell aggregation, and white cell adhesion to vessel walls.4 Although knowledge is limited regarding the exact mechanism of activation, these hematologic changes stimulate histamine and other vasoactive factors that cause increased vascular permeability and result in tissue edema. Intravascular fluid loss due to edema formation can lead to hypovolemia, hypotension, and decreased tissue perfusion. Poor tissue perfusion can potentiate a progressive ischemic process, with extension of the burn wound, since borderline cells are unable to maintain viability.5

There are significant experimental data supporting the adjunctive use of hyperbaric oxygen therapy for burn injuries. Microscopically, hyperbaric oxygen is thought to preserve the microcirculation in the partially injured tissue, thereby decreasing the overall size and depth of the wound.6 The potential benefits of hyperbaric oxygen therapy in burn patients include edema reduction, marginally viable tissue preservation, enhanced host defenses, wound closure promotion, morbidity and mortality reduction, shortened hospitalization, and hospital cost reduction.7-18

Clinical reports and various series of nonrandomized burn patients treated with hyperbaric oxygen provide mostly favorable data. However, most burn unit physicians contend that there is insufficient objective evidence to justify hyperbaric oxygen use in burn treatment plans. Our literature review found no large, well-controlled, randomized, blinded, prospective studies evaluating hyperbaric oxygen therapy in burn patients.

Objective

Decreased edema formation, less wound exudation, and diminished wound margin hyperemia have been reported in a human burn model(ultraviolet-irradiated suction blister wound) following hyperbaric oxygen treatment.1,19,20 This protocol was designed to confirm or challenge these previous findings by conducting a double-blind, randomized study to provide a more objective assessment of hyperbaric oxygen utility in burn patients.

Design

Setting

This study was conducted by the Department of Hyperbaric Medicine at the David Grant Medical Center, Travis Air Force Base, the Western Regional Medical Center for the United States Air Force. This facility supports the largest multiplace hyperbaric chamber in the United States and is specifically designed to conduct double-blinded research studies by means of a specialized gas mixer that allows simultaneous delivery of 100% oxygen and sea-level air-equivalent specialty gas through blinded protocol boxes. Our protocol was approved by the Surgeon General's Clinical Investigation Committee.

Participants

Informed consent was obtained from 12 healthy, nonsmoking volunteers (7 males, 5 females). All were screened for contraindications to hyperbaric therapy (acute sinusitis, otitis media, pneumonia, pregnancy, active cancer, pneumothorax) and given a single hyperbaric exposure to ensure tolerance of pressurization. The first 12 volunteers met these inclusion criteria and tolerated the test of pressure.

A previously described standardized wound model was employed for the painless creation of a lesion on the volar forearm of the volunteers.20 In this burn model, the volar aspect of the subject's nondominant forearm was cleansed with ethyl alcohol (70%), and a blister chamber (a rigid, transparent, airtight apparatus connected to a suction device with a 5-mm circular perforation on one surface) was applied to the forearm. Continuous suction was applied to the blister chamber and skin site for 135 minutes at a pressure of 400 mmHg below atmospheric pressure. Following this, the epidermis of the formed blister was sharply excised with a no. 11 scalpel blade. The forearm was then covered with aluminum foil, exposing only the blister wound bed, and selectively irradiated with a mineral light lamp (Model R-52-G, Ultra Violet Products, Inc., San Gabriel, Calif.)(range of

radiation wavelength: 200 to 400 nm, peak 254 nm) from a distance of 10 cm for 30 minutes. The wound was then covered with a hydrocolloid dressing, which was renewed daily. Subjects were randomized into either the hyperbaric oxygen group (100% oxygen at 2.4 ATA) or the sea-level air-breathing equivalent control group (8.75% oxygen at 2.4 ATA) and treated with standard hyperbaric therapy within 2 hours of creating the wound. The hyperbaric schedule was twice-daily treatments on days 1, 2, and 3, for a total of six dives. The treatment pressure of 2.4 ATA was reached by pumping air into the chamber over a 5-minute period. Once at treatment depth, either 100% oxygen or the 8.75% oxygen mixture was administered through a tight-fitting aviator's mask or a clear vinyl hood for three 30-minute periods. These 30-minute periods were separated by 10-minute air breaks, during which the subjects removed their masks or hoods.

The chamber air-breathing periods are standard protocol to minimize the potential for oxygen toxicity. Because of increased nitrogen onloading by the control group and the associated risk of developing decompression sickness during chamber ascent, all protocol subjects inhaled 100% oxygen during chamber ascent as a preventive measure. The subjects, the hyperbaric oxygen chamber operators, and the monitoring clinicians were all blinded to the oxygen concentration administered.

The wounds were studied noninvasively with regard to daily size, hyperemia, and exudation. Standardized photographs of the wounds were used to document wound size, progression of healing, and wound epithelialization. These photographs were magnified (x100), and the islets of neoepithelialization and peripheral invagination were graphed daily for computer analysis. Laser-Doppler flowmetry (Laserflo BPM2, Vasomedics, Inc., St. Paul, Minn.) was conducted on all wounds to assess wound blood flow (read as blood perfusion measurement units, BPM) and hyperemia. Laser-Doppler flowmetry was accomplished following creation of the suction blister wound, prior to initiating hyperbaric oxygen, and again each day after completion of the second hyperbaric treatment. Wound exudation was evaluated daily by comparing the change in weight of the hydrocolloid dressing placed over the wound with a control dressing placed identically on the opposite forearm. The hydrocolloid dressings were protected from the external environment by a thin plastic occlusive overdressing. The hydrocolloid dressings were weighed before application and upon removal and at the same time each day. Wound photography, Laser-Doppler flowmetry, and wound exudation measurements continued daily until the endpoint of wound epithelialization was reached. Evaluation of the wound appearance was made 6 months and 1 year following completion of the study.

Results

Daily wound size, hyperemia, and exudation measurements showed the greatest difference between the groups on day 2. In comparing wound hyperemia, the hyperbaric oxygen group showed a 42 percent reduction in Laser-Doppler flowmetry measurements on day 2 with blood perfusion measurement values of 14.4 for the hyperbaric oxygen group and 25.0 for the control group (Fig. 1). Comparison of these data points using a one-tail t test found statistical significance (p value of 0.05). Analysis of wound size showed a

35 percent reduction in the size of the lesion on day 2, hyperbaric oxygen group 6.1 mm and control group 9.5 mm(p=0.03) (Fig. 2). A 22 percent decrease in wound exudation also was noted on day 2, hyperbaric oxygen group 0.188 gm and control group 0.304 gm (p=0.04) (Fig. 3).

There was no significant difference found for any of the wound parameters on the other days. Assessments of wound appearance made at 6 months and 1 year after completion of the study showed no evidence of scarring. Minimal skin discoloration noted at 6 months completely resolved at 1-year follow-up.

Discussion

Maintaining microvascular integrity, minimizing edema formation, and providing the oxygen substrate necessary to sustain cellular viability are the rationale for hyperbaric oxygen use in thermal burns. These beneficial effects may prevent conversion of partial- to full-thickness injury and preserve the viability of the dermal elements, thereby leading to a more rapid epithelialization. These favorable outcomes have been demonstrated on a cellular level as well as in animal and human studies.6,7,10,11,21

Preservation of adenosine triphosphate (ATP) has been demonstrated in areas subjacent to partial-thickness burn injury.10,11 A significant body of data from animal studies supports the efficacy of hyperbaric oxygen in thermal injury.

Animal models have demonstrated reduction of edema formation, improved healing time, reduced infection, improvement of microvasculature, decreased inflammatory response, earlier return of capillary patency, and decreased progression to full-thickness burn injury in hyperbaric oxygen-treated animals when compared with controls.6,7,10,11,21 Human studies have suggested decreased death rates for patients with total body surface area burns of 35 to 75 percent, reduced fluid requirements, reduced mean length of hospitalization, decreased need for surgery related to burn treatment, and a curtailed total hospital cost for patients treated with hyperbaric oxygen compared with controls.17,18,22,23

A criticism of the preceding studies is the general lack of blinded or randomized designs. Few hyperbaric chamber facilities are equipped to provide blinded hyperbaric oxygen and placebo treatments. Furthermore, acute burns are not standardized wounds, and consequently, conclusions drawn from the treatment of nonstandardized groups may be biased.

A benign, standardized, and reproducible open wound can be created by using a model. For use in human subjects, the wound should be inflicted painlessly and leave no cosmetically undesirable scar. An ultraviolet-irradiated suction blister burn wound model meeting these criteria was established for use in human volunteer subjects.20 This model was studied extensively by means of video microscopy. A progression of microcirculatory changes including red blood cell stagnation, formation of microthrombi, and resulting

extravasation and edema formation has been documented and may parallel the transition that occurs in the conversion of a partial-thickness to a full-thickness thermal injury.19,20

By utilizing this human burn wound model, our investigation was conducted in a controlled and scientific manner, and the information we collected can be used to better assess the efficacy of a hyperbaric oxygen treatment regimen. By combining this controlled burn wound model with a hyperbaric facility equipped to conduct blinded hyperbaric treatments, we succeeded in conducting the first prospective, randomized, double-blinded trial of hyperbaric oxygen therapy in human subjects to report positive statistical significance.

Measurements of wound size, hyperemia, and exudation showed the greatest difference between the groups on day 2. The hyperbaric oxygen group showed a 42 percent reduction in wound hyperemia (p = 0.05), a 35 percent reduction in the size of the lesion (p = 0.03), and a 22 percent reduction in wound exudation (p = 0.04). Statistical calculations were made utilizing a one-tail t test, based on our null hypothesis that hyperbaric treatment would show no benefit. We did not consider it a possibility that the hyperbaric oxygen group would do worse.

There was no significant difference between the groups in reaching reepithelialization, the endpoint for the study, or in the wound measurements on any day other than day 2, although a general trend favored the hyperbaric oxygen group for the endpoint as well as the other wound parameters studied. The lack of significance noted here may be attributed to the small size of the blister wound and that all wounds healed relatively quickly regardless of the treatment strategy.

Additionally, to protect against decompression sickness, all subjects received 100% oxygen during dive ascent. This oxygen exposure may have decreased additional expected differences. Although more rapid burn healing has been reported,12 additional burn wound model subjects would be needed to determine the effects of hyperbaric oxygen on this parameter.

Of special interest was the obvious increase in wound size predominantly noted in the control group on day 2. This finding, also noted in previous studies,1 was likely due to wound edema caused by irradiation-induced microvascular damage and extravasation. The edema produced a raised and convex wound contour that forced the wound margins laterally. The microvascular damage and edema formation in this model may parallel changes found in the transition zone that occurs between a partial-thickness and full-thickness burn.1

There was a minimal associated risk of developing decompression sickness during chamber ascent in the control group, secondary to increased nitrogen onloading. As a preventative measure against decompression sickness, all protocol subjects inhaled 100% oxygen during chamber ascent. Although both the hyperbaric oxygen and control groups received 100% oxygen during the 20-minute ascent from 45 ft of sea water to the surface, this oxygen exposure to the control group may have contributed to a diminution of the

differences between the study groups, as previously noted. A solution for this potential bias would be to conduct the study at 2.0 ATA (30 ft of sea water). At this depth, the subjects would not have a requirement for decompression sickness prophylaxis or oxygen breathing on ascent.

This study was conducted with hyperbaric treatments administered twice daily so as not to disrupt regularly scheduled patient treatments. The Undersea and Hyperbaric Medical Society advocates treatment of a burn injury with three hyperbaric dives within the first 24 hours of the injury, followed by twice-daily dives.24 Following a more aggressive hyperbaric oxygen treatment schedule may have added additional benefit to the hyperbaric oxygen group.

Conclusions

We suggest that observed differences in wound size, hyperemia, and exudation were attributable to hyperbaric oxygen therapy. This study supports earlier conclusions that hyperbaric oxygen is beneficial in a superficial dermal wound. Other protocols utilizing this burn wound model to study other wound-healing parameters are warranted. This protocol is the first prospective, randomized, double-blinded trial of hyperbaric oxygen therapy in human subjects to report statistical significance. These data support additional clinical trials and utilization of hyperbaric oxygen therapy for wound healing.

Jeffrey A. Niezgoda, M.D.

1541 Lake James Drive; Virginia Beach, Va. 23464

REFERENCES

1. Hammarlund, C., Svedman, C., and Svedman, P. Hyperbaric oxygen treatment of

healthy volunteers with UV-irradiated blister wounds.Burns 17: 296, 1991.

Bibliographic Links

2. Deitch, E. A. The management of burns. N. Engl. J. Med. 323: 1249, 1990.

3. Feller, I., Tholen, D., and Cornell, R. G. Improvements in burn care,

1965-1979. J.A.M.A. 244: 2074, 1980. Bibliographic Links

4. Boykin, J. V., Eriksson, E., and Pittman, R. N. In vivo microcirculation of a

scald burn and the progression of postburn dermal ischemia. Plast. Reconstr.

Surg. 66: 191, 1980. Request Permissions Bibliographic Links

5. Arturson, G. Pathophysiology of the burn wound.Ann. Chir. Gynaecol. 69: 178,

1980. Bibliographic Links

6. Ketcham, S. A., Thomas, A. N., and Hall, A. D. Angiographic Studies of the

Effect of Hyperbaric Oxygen on Burn Wound Revascularization. In J. Wada and T.

Iwa (Eds.), Proceedings of the Fourth International Congress of Hyperbaric

Medicine. London: Bailliere, 1970. P. 388.

7. Ikeda, K., Ajiki, H., Nagao, H., et al. Experimental and Clinical Use of

Hyperbaric Oxygen in Burns. In J. Wada and T. Iwa (Eds.),Proceedings of the

Fourth International Congress of Hyperbaric Medicine. Tokyo: Igaku Shoin, 1970.

P. 370.

8. Nylander, G., Nordstrom, H., and Eriksson, E. Effects of hyperbaric oxygen on

oedema formation after a scald burns. Burns Incl. Therm. Inj. 10: 193, 1984.

9. Sanders, J., and Gottlieb, L. The Effects of Hyperbaric Oxygen on Dermal

Ischemia Following Thermal Injury. In Proceedings of the American Burn

Association. New Orleans: American Burn Association, 1989. P. 21.

10. Stewart, R. J., Yamaguchi, K. T., Cianci, P., et al. Burn Wound Levels of

ATP after Exposure to Elevated Levels of Oxygen. InProceedings of the American

Burn Association. New Orleans: American Burn Association, 1989. P. 21.

11. Stewart, R. J., Yamaguchi, K. T., Cianci, P., et al. Effects of hyperbaric

oxygen on adenosine triphosphate in thermally injured skin. Surg. Forum 39: 87,

1988.

12. Hart, G. B., O'Reilly, R. R., Broussard, N. D., et al. Treatment of burns

with hyperbaric oxygen. Surg. Gynecol. Obstet. 139: 693, 1974.

13. Waisbren, B. A., Schultz, D., Collentive, G., et al. Hyperbaric oxygen in

severe burns. Burns Incl. Therm. Inj. 8: 176, 1982.

14. Grossman, A. R. Hyperbaric oxygen in the treatment of burns. Ann. Plast.

Surg. 1: 163, 1978. Request Permissions Bibliographic Links

15. Grossman, A. R., and Grossman, A. J. Update on hyperbaric oxygen and

treatment of burns. H.B.O. Rev. 3: 51, 1982.

16. Ray, C. S., Green, B., and Cianci, P. Hyperbaric oxygen therapy in burn

patients with adult respiratory distress syndrome.Undersea Biomed. Res.

16(Suppl.): 81, 1989.

17. Cianci, P., Lueders, H. W., Lee, H., et al. Adjunctive hyperbaric oxygen

therapy reduces length of hospitalization in thermal burns.J. Burn Care Rehabil.

10: 432, 1989.

18. Cianci, P., Williams, C., Lueders, H., et al. Adjunctive hyperbaric oxygen

in the treatment of thermal burns: An economic analysis. J. Burn Care Rehabil.

11: 140, 1990.

19. Svedman, P., Svedman, C., and Njalsson, T. Epithelialization and blood flow

in suction blister wounds on healthy volunteers. J. Invest. Surg. 4: 175, 1991.

Bibliographic Links

20. Svedman, C., Hammarlund, C., Kutlu, N., and Svedman, P. Skin suction blister

wound exposed to UV irradiation: A burn wound model for use in humans. Burns 17:

41, 1991. Bibliographic Links

21. Ketchum, S. A., III, Zubrin, J. R., Thomas, A. N., and Hall, A. D. Effect of

hyperbaric oxygen on small first, second and third degree burns. Surg. Forum 18:

65, 1967.

22. Niu, A. K., Yang, C., Lee, H. C., et al. Burns treated with adjunctive

hyperbaric oxygen therapy: A comparative study in humans.J. Hyperbaric Med. 2:

75, 1987.

23. Cianci, P., Lueders, H. W., Lee, H., et al. Adjunctive hyperbaric oxygen

therapy reduces the need for surgery in 40-80% burns.J. Hyperbaric Med. 3: 97,

1988.

24. Mader, J. T., (Ed.). Hyperbaric Oxygen Therapy: A Committee Report.

Bethesda, Md.: UHMS, 1989.

----------------------------------------------