a randomized prospective trial of hyperbaric oxygen in a referral burn center population

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Title: A randomized prospective trial of hyperbaric oxygen in a referral burncenter population.

Authors: Brannen AL; Still J; Haynes M; Orlet H; Rosenblum F; Law E; ThompsonWO

Author's Address: Augusta Regional Medical Center, Georgia, USA.

Source: The American Surgeon [Am Surg] 1997 Mar; Vol. 63 (3), pp. 205-8.Clinical Trial; Journal Article; Randomized Controlled Trial

English

Country of Publication: UNITED STATES NLM ID: 0370522 PublicationModel: Print Cited Medium: Print ISSN: 0003-1348 (Print) Linking ISSN:00031348 NLM ISO Abbreviation: Am Surg Subsets: MEDLINE

Hyperbaric Oxygenation*Burns/*therapyAdult; Burns/mortality; Burns/surgery; Chi-SquareDistribution; Female; Humans; Length of Stay; Male; MiddleAged; Regression Analysis; Survival Analysis; Treatment Outcome

Various studies of the effect of hyperbaric oxygen (HBO) in a widevariety of disease entities have been carried out. In the treatment of

burns, animal and human studies have yielded somewhat contradictoryresults. Controlled studies in humans are limited. A randomized study onthe effect of HBO was conducted involving 125 burn patients admittedwithin 24 hours of injury who were matched by age, burn size, andpresence or absence of inhalation injury. Patients in the treatment armreceived oxygen at two atmospheres of pressure for 90 minutes twice aday for a minimum of 10 treatments and a maximum of one treatmentper total body surface per cent burn. The control group was treated in asimilar fashion, except for the absence of HBO. There were nostatistically significant differences between the two groups for theoutcome measures of mortality, number of operations, and length of stay for the survivors. In this large clinical trial, we were unable to

demonstrate any significant benefit to burn patients from the use of HBO.



Date Created: 19970307 Date Completed: 19970307 Latest Revision:20041117

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A RANDOMIZED PROSPECTIVE TRIAL OF HYPERBARICOXYGEN IN A REFERRAL BURN CENTER POPULATION

Various studies of the effect of hyperbaric oxygen (HBO) in a wide variety of disease entities have been carried out. In the treatment of burns, animal andhuman studies have yielded somewhat contradictory results. Controlled studiesin humans are limited. A randomized study on the effect of HBO was conductedinvolving 125 burn patients admitted within 24 hours of injury who werematched by age, burn size, and presence or absence of inhalation injury.Patients in the treatment arm received oxygen at two atmospheres of pressurefor go minutes twice a day for a minimum of 10 treatments and a maximum of one treatment per total body surface per cent burn. The control group wastreated in a similar fashion, except for the absence of HBO. There were nostatistically significant differences between the two groups for the outcomemeasures of mortality, number of operations, and length of stay for thesurvivors. In this large clinical trial, we were unable to demonstrate anysignificant benefit to burn patients from the use of HBO.

HYPERBARIC OXYGEN (HBO) IS currently employed as an accepted treatmentin a variety of therapeutic situations (Grim et al.( n1)), includingdecompression sickness, acute carbon monoxide poisoning, acute cyanide

poisoning, chronic refractory osteomyelitis, acute gas embolism, gas gangrene,crush injuries, refractory anaerobic infection, radiation necrosis, preparation of radiated bone for grafting, treatment of skin grafts and flaps with questionableviability, and enhancement of healing in selected wound problems. A numberof studies have involved the use of HBO in attempts to improve the treatmentof burned individuals, but controlled studies are rare, both animal and human.We have carried out a randomized study of matched, paired patients at the



Burn Unit of Augusta Regional Medical Center involving 125 acutely burnedpatients.

Patients and MethodsAcutely burned patients admitted within 24 hours of injury were evaluated forinclusion into the study. The patients were randomized in pairs on the basis of

age, burn size, and the presence or absence of inhalation injury and wereassigned to receive either routine burn management or the same routine of burn care with the addition of HBO therapy. Patients received their first HBOtreatment within 24 hours of burn injury and were treated at two atmospheresof pressure for 90 minutes twice a day for a minimum of at least 10 treatmentsand a maximum of one treatment per per cent total body surface area (TBSA)burn. All patients received the maximum number of HBO treatments for theirburn size, unless treatments could not be given due to serious illness or someproblem preventing treatment in the chamber. The project was approved bythe Institutional Review Board of Humana Hospital Medical Center, which wassubsequently renamed Augusta Regional Medical Center (Augusta, GA).

Consent forms were signed by the patient or an appropriate family member.

Limitations on the availability of hyperbaric chamber space meant it was notpossible to make HBO therapy available to all patients on admission, so that,unless chamber space was available, the patient could not be included in thestudy. Therefore, the group randomized to receive HBO was treated on a

space-available basis. These patients were compared with a group of patientstreated in similar fashion and matched for age, burn size, square centimetersof excised area of burn, and presence or absence of inhalation injury selectedfrom the patient group not receiving hyperbaric therapy.

The primary outcome variable used in this analysis was length of stay (LOS).

Secondary variables included mortality and number of surgeries. The analysesof LOS and number of surgeries was performed on only the data from thesurviving patients, because the values of those who died were censored.Statistical analysis of the importance of the HBO treatment on LOS wasperformed using a two-stage stepwise regression; the first stage contained alist of possible covariates known to influence LOS (e.g., number of surgeries,per cent and depth of burn, and presence of inhalation injury). Following thedetermination of covariates in the first stage of the model analysis, anindicator variable to isolate the effect of HBO treatment was added to themodel as the second stage. Thus, the importance of HBO treatment on LOS

follows after a statistical adjustment of LOS due to covariates known to affect

LOS. This model is a modification of analysis of covariance, where the stepwiseregression algorithm is used to identify the best subset of covariates prior totesting for the factor of interest (in this case, the effect of HBO treatment). Thenumber of surgeries was analyzed using a similar approach. Analysis of mortality was conducted using a Chi2 statistic calculated from the 2 by 2contingency table. Differences in demographic statistics between the twogroups of patients by survival were assessed using 2 by 2 analysis of variancefor continuous variables and contingency tables for categorical variables.



ResultsThere were 125 patients enrolled in the study, with 63 receiving HBO therapyand 62 not receiving HBO (controls). One-third of patients received their firsttreatment within 8 hours after injury. Table 1 shows the means of demographic variables of the sample, split by survival within the two groups(HBO and control) regarding age, burn size, inhalation injuries, and squarecentimeter of excision. Although the number of deaths was small in each group(11 per cent), the age, per cent full-thickness burn and per cent TBSA burn of those who died were significantly larger in each group than those whosurvived. Inhalation injury was more likely among those who died, but squarecentimeters of excised burn wound was smaller among those who died than

among those who survived. There were no significant differences among theHBO group and the control group means, and there were no significantinteractions of treatment group by survival.

The primary outcome variable, LOS, was analyzed for the 111 survivingpatients, because those patients who died had censored values for their LOS.

Statistical analysis of covariance of LOS showed that LOS covaried moststrongly with number of surgeries, accounting for 70.2 per cent of the variance(P < 0.0001). Age was the next most important predictor, followed by per centTBSA burn and presence of inhalation injury. Taken as a set, these fourvariables accounted for 76.6 per cent of the variance. LOS increased withincreasing levels of each of the factors. No other variables, including treatmentwith HBO, were statistically significant in the presence of these four predictors.Forcing a treatment group variable into the model increased the r2 by only0.00065 and decreased the adjusted r2 from 0.756 to 0.755. The presence of inhalation injury added an average of 4.3 additional days to the patient's stay(P = 0.012). Estimates from the regression model are given in Table 2.

The number of surgeries covaried with per cent full-thickness burn (r2 = 0.518;P < 0.001) but no other covariates. Adding the effect of the treatment groupincreased the r2 by 0.001 and decreased the adjusted r2 from 0.513 to 0.510.Thus, the number of surgeries, adjusted for percentage full-thickness burn,was not different between the two treatment groups.

There is no difference in LOS, mortality, or number of surgeries between thecontrol and HBO-treated groups once these variables were adjusted for thepatient's condition.

Discussion

HBO therapy involves the inhalation of 100 per cent oxygen at a pressuregreater than that of atmospheric pressure at sea level. The mechanism of action is felt to be achieved by hyperoxygenation of the patient's blood. Otherconcomitant effects include vasoconstriction, fibroblast proliferation,enhancement of white cell killing of bacteria, and neovascularization of wounds.

The rationale for use of HBO in burn patients includes the potential benefits of vasoconstriction, which may offset the vasodilation resulting from the acute



burn. This yields a decrease in the exudation of plasma into the intravascularspace, which may in turn inhibit the development of burn shock and decreasefluid requirements. HBO also counteracts hypoxia of the tissues, felt to be of benefit in controlling wound infection and in promoting re-epithelialization of the burn wound.

Animal experiments involving the use of HBO in burn wounds have beencarried out. Ketchum et al.( n2) noted that burn wound healing time wasincreased by 30 per cent in rabbits treated with HBO. Korn et al.( n3) foundfaster re-epithelialization of burn wounds and an earlier return of capillarypatency after hyperbaric therapy. Nylander et al.( n4) reported that rat scaldstreated with HBO had less tissue edema, faster repletion of adenosinediphosphate, reduced lactate levels, and preservation of phosphorylase.

Not all reports are favorable. Perrins( n5) reported no effect of HBO in a pigscald model. Niccole et al.( n6) reported no advantage in wound healingachieved by HBO when the modality was compared with topical antibiotics.

Human information is fairly limited. Wada et al.( n7) in 1965 reportedimproved healing of second-degree burns in coal miners treated with HBO forcarbon monoxide poisoning. Clinical series have been reported by a number of authors. Waisbren et al.( n8) showed a 75 per cent reduction in the need forgrafting. Cianci et al.( n9) showed reduced LOS for burns up to 39 per cent. Inanother study, Cianci et al.( n10) showed reduced need for surgery andgrafting and decreased cost to patients with 40 to 80 per cent burns.Hammarlund et al.( n11) showed reduced edema and decreased exudation of fluid from burn blister wounds. Grossman( n12) showed decreased LOS anddecreased mortality. Grube et al.( n13) found no benefit in his cases and noteda number of complications due to the hyperbaric therapy. Problems in various

studies have included temporary vision loss, pneumothorax, and perforated eardrums.

Controlled studies are difficult to design, and relatively few have been carriedout. As indicated, a number of authors have reported in controlled studiessatisfactory results with HBO in patients. It is recognized that the optimal way

to do a study of HBO in burn patients would be to enroll all comers whoconsent to the study. Then a sham treatment would be done in which thepatient was actually placed in the hyperbaric chamber and left there for sameperiod of time as the treated patient but with the HBO not running. This wouldbe the optimal blinded approach. It would, however, pose the ethical questions

of risk and additional painful manipulation to the untreated patient who had nopossibility of receiving benefit. Also, the lack of availability of chamber space atour institution precluded this study design. Therefore, the study model thatwas selected was based on having hyperbaric chamber time available foractual use when a patient was admitted. Patients treated were then matchedwith untreated controls, as indicated in the protocol, to achieve comparablepatient groups. As can be seen from the data, this matching of patients wasessentially successful, and the two groups were not significantly different withregard to age, burn size, presence or absence of an inhalation injury, and



areas of burn excision. We found no significant difference in mortality, with an11 per cent death rate in both groups. The requirement for surgery was thesame in both groups. Length of hospital stay was also the same statistically. Itis recognized that LOS depends on a great many factors, including such thingsas income level and availability of home care, which we did not attempt toevaluate. In our model, benefit as shown by improved mortality, decreasedLOS, and decreased need for surgery could not be demonstrated. The efficacyof HBO therapy when added to our conventional program of management didnot improve these parameters.

DISCUSSION

DR. ROBERT P. CARRAWAY (Birmingham, Alabama): Dr. Still has coveredthe animal and clinical studies indicating the beneficial effects of hyperbaricoxygen in the treatment of thermal injuries. Those studies have reportedpreservation of the microcirculation, more rapid epitheliazation, and areduction in the incidence infection, number of surgeries, length of hospital

stay, and mortality. In 1992, there was a report advocating the use of earlyHBO therapy for burns, but as Dr. Still pointed out, distance was a problem instarting early treatment. Dr. Still, were you able to see any change in thelength of stay in your patients receiving early HBO treatments? Did they get anearlier discharge from your burn center? Second, your treatment schedule of aminimum of 10 and a maximum of 1 treatment per per cent body surface areavaries from the standard recommendations. In considering your protocol, itappears the HBO survivors with 21 per cent total body surface area would havereceived 21 treatments and the nonsurvivors with 52 per cent total bodysurface area burns would have received 52 treatments. I was confused aboutyour rationale for the difference in the treatment times and how long your

patients received hyperbaric therapy. Could you help me understand thatbetter? And lastly, hyperbaric therapies have been shown in human studies toexert a positive beneficial effect on the burn wound by reducing edema andplasma extravasation. Controlled randomized studies have also showed

reduction in fluid requirements. Did you note similar changes in fluidrequirements in your HBO treated group?

I feel the investigators have made a contribution in the treatment of burnsusing HBO. The population that they have studied is such that the per centburn is small, and it confirms the fact that individuals with burns less than 20per cent do not require HBO. Finally, I do not feel that your study addresseslarger burns.

DR. JOSEPH STILL (Closing Discussion): Dr. Carraway, we did not analyzethe 16 patients who were treated within the defined 8-hour period, thinkingthat the number was too small to be significant. The number of treatmentsthat we chose was on a basis of Dr. A. Lynne Brannen's desire to provide

patients with as much hyperbaric exposure as possible, and so we picked theone treatment per 1 per cent body burn. I am not sure why he didn't use thethree treatments in the first 24 hours, except again to say that most of our



patients didn't arrive in time to receive three treatments within the first 24hours. We were very impressed when we started using HBO. There wasdefinitely less fluid loss, the patients were drier, and they appeared to healearlier. At the present time, we are investigating fluid requirements in patientstreated with and without HBO and we should have that information availablewithin a year.

TABLE 1. Means of Demographic Variables, by HBO Treatment andSurvival

Survival

HBO-Treated Group

Variable Yes No

Number of patients 55 7

Females 9 3

Males 46 4

Means

Age 29.5 44.9

Full-thickness burn 7.8 36.4

Partial burn (% TBSA) 13.4 15.7

Total burn (% TBSA) 21.6 52.1

Inhalation injuries (%) 17 (31) 6 (86)

cm2 excised burn 1,447 859

Survival

Control Group

Variable Yes No P Value(*)

Number of patients 56 7

Females 15 4

Males 41 3

Means

Age 32.7 49.4 0.012

Full-thickness burn 6.7 45.0 0.001

Partial burn (% TBSA) 14.2 7.9 ns

Total burn (% TBSA) 20.9 52.9 0.001

Inhalation injuries (%) 17 (30) 5 (71) 0.001

cm2 excised burn 1,436 705 ns

(*) Significance of difference in means between survived group

and nonsurvived group. There were no significant differences

among the HBO group and the Control group means.

TABLE 2. Regression Estimates for Length of StayVariable b SE b Beta t Sig t

Age(years) 0.155 0.038 0.194 4.09 0.0001

Total percentage burn 0.166 0.065 0.136 2.54 0.0124



Inhalation injury(*) 4.273 1.851 0.115 2.31 0.0229

Number of operations 6.288 0.453 0.745 13.89 0.0001

Constant -3.018 2.012

R2 0.765

Standard error 8.526

b, regression coefficient; SE b, standard error of b; Beta,

standardized regression coefficient (b/SE b); t, t test ofhypothesis b (or Beta) = 0; Sig t, P value of the t test.

(*) Inhalation injury: 0, no injury; 1, injury.

REFERENCES ( n1.) Grim P. Gottlieb L, Boddie A, et al. Hyperbaric oxygen therapy: State of the art review. JAMA, 1990;263:2216-20.

( n2.) Ketchum F, Thomas A, Hall AEL. Proceedings of the Fourth International Congress on Hyperbaric Medicine. Williams & Wilkins Co., 1970, pp 383-394.

( n3.) Korn HN, Wheeler ES, Miller TA. Effect of hyperbaric oxygen on second

degree bum wound healing. Arch Surg, 1977; 112:732.

( n4.) Nylander G, Nordstrum H, Ericksson E. Effect of hyperbaric oxygen onedema formation after a scald burn. Burns Including Therm Inj 1984;10:1993-6.

( n5.) Perrins D. Failed attempt to limit tissue distruction in scalds of pig skinwith HBO: Proceedings of the Fourth International Congress on Hyperbaric Medicine. Tobyo Ijaku Shirn 1970;381.

( n6.) Niccole M, Thornton J, Danet R, et al. Hyperbaric oxygen in burnmanagement under controlled studies. Surgery 1977;727-33.

( n7.) Wada J, Ikeda K, Kagaya, et al. Igakunoay MI ( Japan) Proceeding of

Fourth International Congress on HBO Treatment. 1965;5:53.

( n8.) Waisbren V, Schutz D, Colentine G, et al. Hyperbaric oxygen for severeburns. Burns Including Therm Inj 1982;8:176-9.

( n9.) Cianci P, Lueders H, Lee H, et al. Adjunctive hyperbaric oxygen therapy reduces length of hospitalization in thermal burns. J Burn Care & Rehab,1989;10:432-500.

( n10.) Cianci P, William C, Lueders H, et al. Adjunctive hyperbaric oxygen intreatment of thermal burns: An economic analysis. J Burn Care & Rehab,1990;11:140-3.

( n11.) Hammarlund C, Svedman C, Svedman P. Hyperbaric oxygen treatment of healthy volunteers with UV-radiated blister wounds. Burns 1991;17:296-300.



( n12.) Grossman A. Hyperbaric oxygen in the treatment of burns. Ann Plast Surg 1978;1:163-7.

( n13.) Grube BJ, Marvin JA, Heimbach DM. Therapeutic Hyperbaric oxygen:Help or hindrance in burn patients with carbon monoxide poisoning. J BurnCare and Rehab 1988;9:249-52.

Presented at the 64th Annual Scientific Meeting and Postgraduate CourseProgram, Southeastern Surgical Congress, Tampa, Florida, February 4-7, 1996.

Address correspondence and reprint requests to Edward J. Law, M.D., 1120George C. Wilson Drive, Augusta, GA 30909.

~~~~~~~~

By A. LYNNE BRANNEN, M.D.,(*) JOSEPH STILL, M.D.,(*) MICHAEL HAYNES,M.D.,(*) HERMANN ORLET, M.D., (*) FRED ROSENBLUM, M.D.,(*) EDWARD

LAW, M.D.,(*) WILLIAM O. THOMPSON, PH.D.(A), From the (*)AugustaRegional Medical Center and (A)Department of Biostatistics, Medical College of Georgia, Augusta, Georgia

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a randomized prospective trial of hyperbaric oxygen in a referral burn center population

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