4 CONTROLLED CLINICAL STUDIES ON BURN INJURIES

4.1 A New Approach to Local Burn Wound Care: Moist Exposed Therapy. A
Multiphase, Multicenter Study
Atiyeh BS, et al. Journal of Surgical Wound Care 2003; 2(1): 18-27

Summary: MEBO was tested on healing of split thickness skin graft donor sites and
compared to semi-open (Sofra Tulle) and a semi-occlusive (Tegaderm) dressing. Healing
with the ointment was observed within 5-8.9 days versus 10-13 days for the other
dressings. Scar assessment scores demonstrated significantly better scars for MEBO at 1
month (p<0.001) as compared to Tegaderm. The difference was significant (p<0.05) at 2
and 6 months. Subsequently, two clinical trials on burn patients were conducted. MEBO
application resulted in a statistically significant (p<0.001) decrease in overall treatment
costs as compared to other topical treatment modalities. The most significant cost
reduction was observed in the utilization of medical facilities (p<0.0001). The trials
elaborated the practicality of MEBO therapy and its effectiveness in preventing burn
wound sepsis. Initial swab cultures were positive in 29% of the immediately treated
patients and 92% in patients treated on the third post burn day. By the second week,
bacterial colonization dropped to 5% and 23% respectively.

Materials and Methods: All phases of the study have been conducted in accordance with
the indicated guidelines and ethical standards. Signed consent was obtained from all
patients participating in any phase of the study.

Clinical trial 1: A prospective multicenter clinical trial was conducted between December
1999 and November 2000. Fifty-two patients with burn injuries (30 flame burns, 18 scalds
and 4 patients with other causes of thermal injury) with an age range of 12 to 80 years
(mean 40.5 y) were entered in the study according to strict inclusion and exclusion criteria.
The burned areas were cleansed with physiologic saline solution along with debridement
of blisters. The lesions were subsequently dried before the application of a thick layer of
MEBO ointment (1-2 mm). Whenever it was more convenient, dry sterile gauze with an
elastic bandage were applied. Ointment application was performed once or twice daily
after gently removing the previously applied layer. A total of 100 burn sites with a TBSA
of 0.5% to 15% were evaluated by physical examination, recording of patients’
satisfaction, and assessment of pain by the visual analogue scale VAT of Choiniere et al.
Transepidermal water loss and moisture were measured at regular intervals. Swab cultures
were also done regularly. Descriptive statistics and non-parametric ANOVA tests were
used to analyze the changes in VAT pain scores over days 0-12 of MEBO application. The
Dunn's Multiple Comparison Test and the Mann-Whitney Test were used to analyze the
changes in pain scores over two specified days. Changes in TEWL and moisture values on
days 0-12 were analyzed with the one-way ANOVA test. TEWL changes over two
specified tests were analyzed with the Tukey-Kramer Multiple Comparison Test. Since the

1
population analyzed falls under a Gaussian distribution, the unpaired t-test was also used to
confirm the difference between two specified days. Statistical significance was evaluated
using two-tailed probability levels. For all analyses P<0.05 was considered statistically
significant, P<0.001 very significant and P<0.0001 extremely significant.

Clinical trial 2: Forty patients of both sexes between the ages of 5 and 54 years presenting
with superficial partial thickness burns 5-20% TBSA in adults and 5-15% TBSA in
children greater than 5 years of age sustained <24 hrs prior to presentation over a period of
3 months were included in the study. The study was conducted in five different centers in
Egypt where medical care is largely under government control in order to minimize
accounting discrepancies. All patients were admitted to the hospital and assigned
randomly to two comparable study groups. Twenty patients were managed with the moist
exposed method and 20 other patients received the standard local therapy utilized at the
given center. Overall cost of therapy was evaluated by estimating both direct and indirect
costs. Direct cost included actual cost of the topical agent, i.v. fluids, concomitant
antibiotics, analgesics and other pharmaceutical agents and preparations, such as gloves,
catheters and dressing materials. Direct cost also included the cost of hospitalization as
fixed by authorities as well as the cost of all the laboratory tests. Indirect cost was
estimated by computing time spent by the treating physicians and nurses in attending to the
various needs of the patients, such as dressing changes, debridement and bathing. Total
cost of treatment as well as individual components (hospitalizations duration and cost,
physician/nurse time, topical treatment, systemic antibiotics, analgesics, other medications,
laboratory services and medical materials) were recorded, calculated (as per course of
treatment or per day) and analyzed statistically using unpaired t-test or where appropriate
unpaired t-test with Welch correction.

Results: Clinical trial 1: Most burn wounds when first examined were dry. Upon
initiation of topical treatment with the moisture retentive ointment, the wounds became wet
with a red to white base and swollen margins. As treatment progressed in time, the
wounds became red in appearance without an overlying eschar. There was minimal
exudation and the margins looked healthy. At day 6 of treatment, the residual none healed
red and wet surface as compared to the initial surface area decreased significantly in size
(p<0.001). After the application of MEBO, a rapid and progressive reduction of edema
and clinical inflammation was noticed. It was also observed that topical ointment
application contributed to the debridement of the wound facilitating rapid epithelialization
within 2 to 6 days. Prior to MEBO application, the mean value of the pain scores was 6.92
± 5.50. Pain scores decreased gradually following treatment. At day three, with the non-
parametric ANOVA test, the decrease was not statistically significant (p>0.05). However,
it was extremely significant with the Mann-Whitney test (p=0.0001). During the following
assessments at days 6, 9 and 12 the changes in the pain scores became statistically
extremely significant (p<0.001) (non-parametric ANOVA test) and extremely significant
(Mann-Whitney test). During the follow up period, no analgesic drugs were required even
during dressing changes. The measured TEWL values every three days were compared
using the parametric ANOVA test. Immediately after the injury the mean value of TEWL

2
of the wound was high (58.65 ± 22.8 g/m2/h) as compared to that of intact skin (8.12 ±
7.37 g/m2/h). TEWL of partial thickness burns decreased on day 3, but the decrease was
not statistically significant. However, from the 6th day post-treatment, the decrease in
TEWL became very significant (p<0.01 for day 6, p<0.001 for day 9 and p<0.001 for day
12). On the other hand, full thickness burn wounds exhibited no change of TEWL on day
3, but very significant decrease on days 6 and 12, though there were no differences
between these two consecutive measurements. Moisture measurements were significantly
increased during the first five post-burn days as compared to the low values of intact skin.
As re-epithelialization of the wound progressed there was a net decrease in moisture
paralleling TEWL. Swab cultures were regularly taken in all 52 patients. Three patients
were excluded from the statistical analysis because they were treated by systemic
antibiotics. Twenty-one patients were seen immediately following their injury and were
treated with moist exposed therapy. Fifteen patients were started on ointment application
on the first or second post-burn day whereas 13 patients were started on MEBO on the
third post-burn day or later. Positive initial swab cultures were obtained in 6 patients
(29%) of the immediate group (21 patients) and in 12 out of 13 patients (92%) of the late
group. After one week of MEBO treatment, bacterial wound colonization decreased to
10% in the immediate group and to 61% in the late group. By the second week,
colonization dropped to 5% and 23% respectively. All patients with positive swab cultures
progressed to complete healing. Though MEBO exhibited frank antibacterial activity,
persistent bacterial colonization in some patients did not prevent full re-epithelialization.
During the relatively short period of follow-up (2-4 months), the resulting scars in healed
burn wounds appeared normal colored in 68% of patients. The scar was soft in 44 patients
and hypertrophic in one. Scar contracture was observed in three patients, one of whom
ended with a deformity.

Clinical trial 2: Nineteen patients in the MEBO study group and 17 patients in the control
group had adequate data for statistical analysis. A very significant (P <0.01) reduction in
hospital stay for the moist exposed therapy group was demonstrated. The observed
decrease in the average time spent by the treating physicians with patients treated by the
moisture retaining ointment as compared to time spent with patients treated by other
modalities is significant (P <0.05). On the other hand the decrease in average time spent
by nurses between the two groups was very significant (P <0.01) in favor of the moist
exposed therapy. MEBO application resulted in a statistically very significant decrease (P
<0.001) in overall direct treatment costs though this decrease per day of treatment was only
significant (P <0.01). When various parameters responsible for direct costs are examined
separately, the observed differences between the two groups in cost of systemic antibiotics
as well as other medicaments and cost of hematological, biochemical and microbiological
tests were not significant. On the other hand, MEBO-treated patients required less
analgesics (P <0.05). The most extremely significant reduction in cost, however, was
observed with the medical materials utilized (P <0.0001) which reflects the great savings
that can be made by adopting the moist exposed method of burn wound management as
compared to the classical semi-open dressings with topical antimicrobial agents.

3
Conclusion: It is not conceivable to abandon products and methods currently in use for
local burn wound care whose benefits have been well documented unless additional
benefits of the new product can been well elaborated. Our first concern was to
demonstrate that the new moisture retentive ointment has a good antibacterial effect.
Second, it was important to prove its moisture retentive capacity and its positive impact on
wound healing as it applies to burn wounds. Third, it was crucial to determine whether the
use of this ointment could be practical and cost-effective.

Though it is not an antibiotic, adequate local antibacterial action of the ointment has been
demonstrated in a previously reported experimental study. In a parallel study it was shown
that prolonged use of MEBO does not seem to lead to the emergence of resistant strains.
Improved healing potential of the ointment has been demonstrated in previous clinical
studies. The clinical value of the moisture retentive ointment in autolytic debridement and
healing of burn wounds has been elucidated in clinical trial 1. Clinical trial 2, on the other
hand, stressed the practicality and cost-effectiveness of the ointment in local wound care.
Adverse side effects to the ointment was observed in clinical trial 1 in only one female
patient who developed itching and presented with flushing of her face following the second
day of application. All symptoms subsided as soon as application was discontinued.

4.2 MEBO Ointment in the Treatment of Burn Wounds: A Multicenter Study

Dham R, et al. Modern Med Mid East 1999, 16(8):46-50

Abstract: One hundred and thirty-eight (138) patients, with five hundred and sixty-six
(566) different burn sites with different degrees, severity and locations, were enrolled to a
multicenter clinical trial at 25 study centers. The aim of this study was to explore the
therapeutic effectiveness of MEBO and to gain more experience in its use in the Middle
East. Various parameters were studied including: (i) healing time, (ii) need for pain killers,
(iii) consumption of i. v. Fluids, (iv) use of systemic antibiotics and (v) aesthetic
appearance. There was remarkable decrease in the healing time and most patients either
did not need any pain killer or were relieved with only mild analgesics, except in few cases
of deep second degree and third degree burns. A decrease in the volume of i. v. fluids
needed was also reported. Only 19% of cases developed clinical infection, especially in
those who were not treated with MEBO immediately post burn. Even though systemic
antibiotic treatment was prophylactically implemented in most cases as a routine measure,
32 cases did not receive any antibiotic prophylaxis with MEBO and yet did not develop
any infection. The aesthetic appearance reported was very acceptable. This treatment
modality was not associated with any side effects, and patient discomfort during
application and change was negligible. Thus, MEBO treatment was associated with
excellent and relatively faster healing, low incidence of wound infection, and excellent
patient compliance.

Materials and Methods: A total of 138 patients 2 months to 70 years of age having
different degrees of burn injuries with an average total body surface area (TBSA) of 15.1%
were enrolled and completed the study at 25 centers in the Middle East (United Arab
Emirates, Saudi Arabia, Kuwait, Qatar, Egypt and Jordan). The study protocol was

4
prepared in accordance with FDA guidelines and in line with the declaration of Helsinki
and was presented to and approved by the participating doctors before its initiation.
Written informed consent was obtained form participating patients or their guardians. The
study was designed as phase IV post marketing trial to evaluate the efficacy, safety and
cost effectiveness of MEBO in acute burn wounds. Wound management was assessed in
terms of time needed for healing, i. v. fluids consumed, need for analgesics, control of
infection, need for skin grafting, aesthetic appearance, adverse reactions, patient
compliance and overall cost of treatment. Patients were 65% males and 35% females, and
35% of them had dark skin complexion. The source of thermal injury was direct flame in
44% of cases, scald in 45%, and the rest were due to either electric burn, chemical burn or
friction. The number of burn sites treated was 566, as follows: upper arm 21 sites, fore
arm 69 sites, hand 61 sites, thigh 60 sites, leg 66 sites, foot 49 sites, buttocks 21 sites,
genitalia 7 sites, head 63 sites, neck 57 sites, anterior trunk 72 sites, and posterior trunk 20
sites. The range of body surface area treated was 0.5%-40%, with the following
distribution: 65% cases were treated with <15% TBSA, 27% cases were treated with 15%-
30% TBSA, and 8% cases were treated with 30%-40% TBSA. Most of the cases were
deep second degree burns, as follows: 9% were first degree, 71% were second degree (20%
superficial and 51% deep), and 20% were third degree burns. Initiation of treatment was
within the first 8 hours postburn in 75% of first degree burns and 92% of second and third
degree burns, but few reported rather late to the different centers (3-4 days), especially
those with first degree burns.

Results: 1. Analgesia Five to ten minutes after application, MEBO induced a strong
analgesic effect that 58% of first degree, 41% of second degree, and 39% of third degree
patients did not need any pain killer concomitantly with MEBO. The rest who asked for
pain killers were relieved by mild analgesics, mostly paracetamol, and only 14% of second
degree and 21% of third degree patients needed strong analgesics (pethadine). 2. Control
of Infection Although prophylactic use of systemic antibiotics was initiated in most of the
cases as a routine regimen, 35% of second degree burn cases and 11% of third of third
degree did not receive any systemic antibiotic with MEBO and did not develop any
infection, except in one cases of second degree burn which developed local infection at the
beginning, but maintained on MEBO alone which controlled the infection thereafter. 3.
Healing Time First degree burns healed within an average of 6 days, second degree burns
20 days, and third degree burns 35 days. The end point for healing was complete
epithelialization and retain of functions in movable parts (hand, neck). 4. IV Fluids There
was a remarkable reduction in the volume of fluids needed, and 47% of patients with
second degree burns and 18% of those with third degree burns, all with TBSA between 1%
and 19%, did not receive any infusion. 5. Skin Grafting Almost all of second degree
burns, with TBSA ranging between 0.5%-35% epithelialized without grafting, except in 2
cases, one with 6% TBSA and the other with 12.5%, where grafting was initiated. 6 cases
of third degree burn with TBSA range of 16%-28% also did not need grafting. 6.
Complication a. Infection: 112 cases, 32 of them were on MEBO alone without receiving
systemic antibiotic, did not develop any signs of infection during the course of treatment
with MEBO until healing. Local infection was reported only in 15.9% of the cases,
systemic infection in 1.4% and systemic and local in 1.4%. Infected cases were

5
maintained on topical MEBO treatment but their systemic antibiotic treatment was
changed. b. Scar Formation: 84% of the cases of second and third degree burns healed
with acceptable cosmesis and negligible or no scars. Only 14 cases with second degree
burns and 6 cases with third degree burns developed scar, but even in those scars the
quality of sear tissue was acceptable as far as tensile strength, color and retain of function
are concerned. c. Hypopigmentation: Only 4% of second degree burns and 7% of third
degree burns developed hypopigmentation. 7. Safety No adverse events were reported
with the use of MEBO. Two cases developed hypersensitivity reactions and treatment was
discontinued, and two patients complained from the strong odor of the ointment.

Table 1: Summary of variables and data collected

Study Group
First Degree Second Degree Third Degree
1. No. Of cases 12 98 28
2. TBSA 2%-23% (av. 10.0%) 0.5%-35%(av. 14.5%) 1.5%-40% (av. 21.3%)
3. No Pain Killer 59% 41% 39%
-Only paracetamol 41% 45% 40%
-Pethadine - 14% 21%
4. No Systemic antibiotic 100% 35% 11%
5. Healing Time 6 days 20 days 35 days
6. No I.V. Fluids 100% 47% 18%
7. Skin Grafting Initiated - 2% 79%
8. Infection - 19% 25%
-Systemic - 1% 4%
-Local - 18% 14%
-Systemic and Local - - 7%
9. Scar - 14% 21%
10. Hypopigmentation - 4% 7%

Discussion: This study confirms the results of a vast number of studies conducted in China
that have shown MEBO to be an effective and safe modality in wound management.
MEBO enhanced and expedited healing when applied to the acute burn wound.
Epithelialization was sufficient for epidermal regeneration in almost all second degree
cases which did not require skin grafting. Even some third degree cases, with limited
TBSA, healed without grafting. The analgesic effect of MEBO was fast and strong enough
to relieve most of the patient within 5 to 10 minutes. Even those who asked for pain killers
were mostly satisfied with paracetamol, which usually is not sufficient for severe burn
pain. Another indication of MEBO's analgesic effect was the reported ease of dressing
change especially in children; some slides showed children sleeping or playing while
changing dressing. Thirty-two cases were treated with MEBO alone without systemic
antibiotic and yet, did not develop any signs of infection. This effect is partly due to the
ingredients of MEBO and partly due to the proper method of application. In this study
cases which developed infection, mostly local, were maintained on MEBO as topical
treatment and only the systemic antibiotic was replaced. Knowing the limitations of the
effectiveness of systemically administered antibiotics due to the avascularity of the burned
tissue as a result of thermal thrombosis, the role of MEBO as local anti-infective is to be
considered. Intravenous fluids are an essential measure in the resuscitation of severely

6
burned patients and are routinely maintain due to excessive fluids loss from the burn
wound. With MEBO, it was reported that less volume of fluids is needed to maintain the
balance between fluids intake and urinary output. Furthermore, almost one third of the
patients with second and third of the patients with second and third degree burns (47% of
second degree, 18% of third degree) were maintained without i.v. supplementation.
MEBO isolates the wound and limits fluids loss. As MEBO enhances the natural healing
processes, proper application reduces tremendously the possibility of scar development,
especially when used immediately postburn. In this study, only 15% of the cases
developed scar (20 cases), out of which 5 were on different treatment modality and then
shifted to MEBO. The quality of scar tissue reported was acceptable, and no contractures
have been reported. Almost all cases retained normal skin color after healing with MEBO,
and hypopigmentation was reported only in rare cases. To evaluate the overall cost of
wound management with MEBO, the following parameters were taken into consideration:
(i) the cost of the medicament, (ii) hospitalization time, (iii) use of dressing, (iv) use of
analgesics, (v) use of antibiotics and (vi) i.v. fluids volume needed. Taking into
consideration the reported values and comments on those parameters as discussed earlier,
MEBO was found to be a cost effective modality in wound management.

4.3 The Role of Alternative Therapy in the Management of Partial Thickness

Burns of the Face - Experience with the Use of MEBO Compared with Silver
Sulphadiazine
Ang ES, et al. Ann Acad Med Singapore 2002; 29(1): 7-10

The conservative management of facial burns includes application of Aureomycin cream

and Spenco dressing for superficial partial thickness burns, with silver sulphadiazine cream
for deeper partial thickness burns. Surgical excision and grafting are reserved for full
thickness burns to prevent lid or lip ectropion. This is a single-centre prospective
randomized controlled clinical trial to compare MEBO with silver sulphadiazine in the
management of partial thickness facial burns. Parameters studied included the rate of
wound healing, anti-bacterial effect, analgesic effect, subsequent scar development and the
hospital resource costs.

Patients and Methods: Patients with partial thickness burns of up to 40% body surface
area (BSA) admitted to the Burns Centre were eligible for the trial. The exceptions were
patients in the extremes of ages (<6 years and >80 years) and those with chemical and
electrical burns. The wounds were examined by one of the clinical coordinators to verify
the eligibility of the patient for admission into the trial. The patient's consent to participate
in the trial was obtained after a full explanation was given of the treatment options, and the
manner of treatment allocation. Fluid resuscitation was carried out for patients with burns
involving>15% BSA as per pre-existing Burn Centre protocol, as were analgesic use and
antibiotic prescription.

After the initial assessment, patients were randomly assigned either to the conventional (C)
group or MEBO group either by telephone to the NMRC Clinical Trials and Epidemiology
Research Unit, Singapore during office hours or by sealed envelopes after office hours.

7
Randomly alternating permuted sub-blocks of size 4 and 6, with equal numbers per
treatment within each sub-block, were used to obtain an overall block size of 10. In the C
group, the burn wounds were cleansed with plain chlorhexidine 0.05% and silver
sulphadiazine applied twice daily. In the MEBO group, following cleansing of the
wounds, MEBO was smeared directly onto the wound at 1 mm in thickness at 4 hourly
intervals with a sterile gloved finger. The extent of each facial burn was assessed and
mapped using a Lund and Browder Burn Chart and photographed. The BSA chart and
photographs of the burn area were repeated on the fifth day, thereafter every 3 days and
upon discharge. Healing times are summarized using the Kaplan-Meier estimate and
compared between treatments using the log rank test. The Cox regression model was used
to adjust the difference between treatment for age and gender differences.

Results: Patient Distribution: Between 1 March 1997 and 24 October 1998, 115 patients
with partial thickness burns were enrolled in the trial through the Singapore National Burns
Centre at the Singapore General Hospital. Fifty-eight patients were randomized to the C
group and 57 to the MEBO group. Data were not obtained from 3 patients randomized to
the MEBO group due to various reasons and they were therefore excluded from the trial.
One hundred and twelve patients were therefore available for analysis. Thirty-nine (35%)
out of the 112 patients suffered face-burns with 17 on MEBO and 22 on conventional
treatment (Table 1). Two patients in the MEBO group were discharged early while there
were 1 early discharged and 2 deaths in the conventional group.

Table 1: The Mean BSA Values for Both Treatment Groups

MEBO Conventional
No. of subjects 17 22
Mean BSA(%) 2.16 1.56
Standard error 0.38 0.18
Range 0.13-6 0.5-3.5

Healing Time: There was no difference in the number of days taken for the face-wound to
heal between the two groups. Face-burns in 14 patients in the MEBO group healed by day
10 (range 2 to 35 days) compared to 17 patients in the conventional group. None of the
patients in either group required any reconstructive surgery to correct burn contractures of
the face in the immediate post injury period up to 6 months.

In this study, we found that MEBO resulted in similar healing rates as compared to silver
sulphadiazine dressings in partial thickness burns of the face. Moreover, it was easier to
assess the progress of healing with MEBO as the wound was not obscured by a layer of
slough as is present with silver sulphadiazine-treated wounds. None of our patients in this
series required any reconstructive surgery for burn contractures of the face at 6 months
follow-up so we are unable to comment on the effectiveness of MEBO in obviating the
need for reconstructive surgery for facial contractures beyond 6 months. In addition, the
nurses preferred to use MEBO for facial burns as it is easier to apply than silver
sulphadiazine due to the need to have bulky dressings in the latter technique. MEBO was
less expensive to use though this was offset by the longer dressing time required. This was

8
due to the fact that MEBO was applied every 4 hourly as compared to silver sulphadiazine
that was applied only twice a day. This disadvantage can possibly be minimised by
educating patients or their relatives to apply MEBO themselves once their overall
condition has stabilised.

Conclusion: The use of MEBO for partial thickness burns of the face resulted in similar
healing rates compared to that achieved with silver sulphadiazine dressings. It is a cheaper
alternative, both in terms of hospital costs and consumables, but required increased
manpower time for dressing. It is easier to apply and allows better assessment of the
progress of the underlying wound healing compared to silver sulphadiazine. This suggests
that MEBO is a useful alternative modality in the management of partial thickness burns of
the face.

4.4 Evaluating the Role of Alternative Therapy in Burn Wound Management:

Randomized Trial Comparing MEBO with Conventional Methods in the
Management of Patients with Second-degree Burns
Ang ES, et al. Medscape General Medicine 2001; 3(12):3-18

This study was conducted to compare MEBO with conventional management (C) with
respect to the rate of wound healing, antibacterial and analgesic effect, and hospital costs.
This is a prospective, randomized, controlled clinical trial conducted between 1 March
1997 and 24 October 1998. The trial was conducted in Singapore National Burns Center at
the Singapore General Hospital. One hundred and fifteen consecutive patients between the
ages of 12 and 80 who had partial-thickness thermal burns covering less than 40% of BSA
were assigned to receive either MEBO or C. Fifty-seven patients were assigned to MEBO
and 58 patients to C.

Management and Assessment: Patients 6-12 years of age with burns greater than 10%
BSA and patients older than 12 years of age with more than 15 % BSA were fluid
resuscitated according to the Muir and Barclay formula. Antibiotics were given only for
clinically septic patients. In the C group, burn wounds were cleansed with plain
chlorhexidine 0.05 % and deblistered where necessary. The burns were dressed with silver
sulfadiazine and changed twice daily. Areas of superficial burns were covered with
paraffin-impregnated gauze (Jelonet, Smith & Nephew Inc, Largo, Florida) or
polyurethane dressing (Opsite, Smith & Nephew). Excision and grafting were carried out
on deep dermal wounds that showed minimal signs of healing after 14 days. In limited
areas not amenable to surgery with slough persisting beyond 14 days, chemical
debridement using Elase (fibrinolysin and desoxyribonuclease) (Warner-Lambert, Parke-
Davis) was used.

In the MEBO group, the wounds were cleansed with normal saline gauze. MEBO was
smeared successively onto the wounds at 1 mm in thickness at 4 hourly intervals with a
sterile gloved finger, without removal in the first 5 days of therapy. On the sixth day, the
accumulated MEBO was removed with a finely serrated metal spatula followed by fresh
application of MEBO renewed at 4 hourly intervals. Excision and skin grafting were

9
carried out on deep dermal wounds that showed minimal signs of healing after 14 days.
The depth and extent of the injury was assessed and mapped using a Lund and Browder
Chart to determine the burns' BSA. The BSA chart and photographs of the burn area were
repeated at day 5, thereafter every 3 days and upon discharge. These photographs were
then assessed by a senior burn surgeon who was not involved in the management of these
cases.

All patients were assessed for pain by a registered burn nurse immediately prior to
randomization. This was carried out using a verbal numerical rating scale (VNRS) similar
to a visual analogue scale (VAS). This verbal assessment was repeated 3 times daily
commencing not later than the morning after the first post-randomization dressing was
applied: once upon awakening, immediately following first dressing of the wound, and
approximately 8 hours later in the day. These assessments continued until the final
dressing before discharge.

The wounds were swabbed once weekly for routine aerobic bacteriology. A clinical
assessment was made daily for the presence of fever and/or reddening of the wound to
indicate infection. If fever of greater than 38.5°C is present and there was evidence of
local burn wound infection (inclusive of but not limited to spreading wound erythema,
black/brown patches of discoloration, rapid eschar separation, conversion of wounds to full
thickness, and/or punctate hemorrhagic subeschar lesions), then blood, urine, and sputum
samples and wound cultures were taken for qualitative bacteriologic examination.
Quantitative assessments of colony-forming units were not performed. Patients were also
screened for methicillin-resistant Staphylococcus aureus (MRSA) colonization by nasal
swabs on admission and once weekly. The wound was classified as free, colonized, or
infected for the named bacterium. To be classified as infected, the wound had to be
colonized together with clinical evidence of fever on the day the swab was taken and had
to exhibit one of the signs of local wound infection. The event/infection was then either
the date of infection or the date of a clinically obvious septic wound -- whichever was
earlier.

The type and dose of any analgesic given were recorded in the inpatient medication record
prior to each dressing. Analgesics were administered on an on-demand basis. Three types
of opiates were available to the patients: pethidine (intramuscular), codeine (oral), and
morphine (intravenous); the nonopiate available was paracetamol administered orally.
Patients generally requested 1 type of opiate together with paracetamol, but there were
some patients who requested more than 1 type of opiate. The nursing time to complete
each dressing and the duration of hospital stay were recorded, as were the costs of all
procedures and medicines for each patient.

End Points: The major end points were defined as time to 75% BSA healing, the
postdressing pain assessment at 14 days postrandomization, and the MRSA infection rates.
Patients were considered for discharge once 75% of the initial total BSA was healed.

10
Results: The median time to 75% healing was 17.0 and 20.0 days with MEBO and C,
respectively (HR = 0.67, 95% CI = 0.41-1.11, P = .11), suggesting similar efficacy
between the 2 modalities. Bacterial infection rates were similar between the 2 groups (HR
= 1.10, 95% CI = 0.59-2.03, P = .76). MEBO imparted a greater analgesic effect in the
first 5 days of therapy and reduced hospital costs by 8%.

Conclusion: This trial demonstrates similar outcomes when partial-thickness burns

covering less than 40 % BSA are treated with C or MEBO. Time taken for 75 % of the
original BSA to epithelialize was taken as the end point for in-hospital healing in our
study. Patients treated with MEBO took 17 days on average to heal vs 20 days when on C.
The rate of MRSA presence in MEBO wounds was similar to that in C wounds. In
addition, Acinetobacter baumannii and Pseudomonas aeruginosa, 2 gram-negative
organisms that pose a particular problem in our Burns Center, continued to persist in the
MEBO-treated wounds as compared with the relative absence of these organisms by the
second week postburn in C wounds. This shows that MEBO is not bactericidal against
potentially pathogenic microorganisms as previously claimed.

With regard to pain control, MEBO imparts a greater analgesic effect than that afforded by
C, especially in the first 5 days following injury. Effective pain relief during this period is
advantageous to modulate the acute immune response. This is reflected by the increased
number of patients requesting opiate analgesics in the C group and the more than double
mean dose of Pethidine administered in the first week to this group. The analgesic effect is
attributable to the presence of the layer of ointment that shields the burn wound from the
external environment. Notably, as therapy progressed, this analgesic advantage was
reduced, possibly due to the daily removal of accumulated MEBO at this stage.

From a practical standpoint, a straw poll of the nurses indicated that they found it easier to
manage facial and neck burns with MEBO, as it did not require the elaborate bandaging
that is required with silver sulfadiazine. Additionally, occupational therapy in MEBO-
managed hand burns was instituted earlier as there was no hindrance from bulky dressings,
thus improving rehabilitation prospects in these cases.

11
From the results of this prospective randomized, controlled trial, it is concluded that
MEBO is as effective as the conventional approach in the management of second-degree
burns, though it is not the panacea for all burn wounds as claimed. It may be useful
alternative in burn injuries involving certain anatomical sites such as the face, neck, and
hands. MEBO is less expensive than conventional treatment and provides better pain relief
in the first 5 days after burns. In addition, as MEBO is conveniently stored in large
quantities, portable, easily dispensable, and applied even by semiskilled personnel, its use
may be advantageous in mass casualty situations before evacuation to definitive burn care
facilities.

4.5 Benefit-Cost Analysis of Moist Exposed Burn Ointment

Atiyeh BS, et al. Burns 2002; 28:659-663

Burn injury is one of the most devastating injuries that may affect a patient. Even in
economically deprived areas, burn care is largely driven by relatively plentiful resources
equating quality of care with generous monitoring and clinical attention with little concern
to management cost. Burn care costs have been the subject of very few investigations and
are among the least studied by health services researchers. Nevertheless, it can be stated
that local care of burn wounds accounts for a large proportion of the cost per day for
treating patients. As economic times are changing and as market penetration of managed
care contracts and stiff competition in the health care industry gains momentum, ways to
reduce expenditures without adversely affecting the quality of care have become of
primary importance. We report a randomized prospective comparative study analyzing the
benefit-cost value of moist exposed burn ointment (MEBO) application, an exposed
method for burn wound care without the need for a secondary covering dressing, as
compared to conventional closed methods.

Materials and methods: In order to minimize accounting discrepancies and variations, the
study was conducted in five different centers in Egypt where medical care is largely under
government control and accounting is rather uniform. Forty patients of both sexes between
5 and 54 years of age presenting with superficial partial thickness burns sustained <24 h
prior to presentation over a period of 3 months (maximum duration of treatment was 29
days, minimum duration of treatment was 6 days) were included in the study. Inclusion
criteria included healthy patients with no visual, mental or physical disabilities and thermal
burns 5-20% TBSA in adults and 5-15% TBSA in children. Children less than 5 years of
age were excluded as were pregnant or lactating women as well as females at risk of
pregnancy. Patients with burns over 20% in adults and 15% in children were also
excluded from the study as for patients with diabetes, renal insufficiency, hepatic
insufficiency, primary immunosuppressive disease or documented malignancies as well as
patients presenting with old infected burn injuries or associated injuries serious enough to
require surgery or specific therapy. All patients entered in the study have been admitted to
hospital and were assigned randomly to two comparable study groups (Table 1). Twenty
patients were managed with MEBO application and 20 other control patients received the
standard local therapy utilized at the given center. Agents and preparations used other than
MEBO are summarized in Table 2. Patients were discharged from hospital only after

12
healing of burn wounds as determined by the primary treating physician. Overall cost of
therapy was evaluated by estimating both direct and indirect costs. Direct cost included
actual cost of the topical agent used, i.v. fluids, concomitant antibiotics, analgesics and
other pharmaceutical agents and preparations, such as gloves, catheters and dressing
materials. Direct cost included also cost of hospitalization as fixed by authorities as well
as the cost of all performed laboratory tests. Indirect cost was estimated by computing
time spent by the treating physicians and nurses in attending to the various needs of the
patients, such as dressing changes, debridement and bathing. Total cost of treatment as
well as individual components (hospitalizations duration and cost, physician/nurse time,
topical treatment, systemic antibiotics, analgesics, other medications, laboratory services
and medical materials) were recorded, calculated (as per course of treatment or per day)
and analyzed statistically using unpaired t-test or where appropriate unpaired t-test with
Welch correction if standard deviations were found to be not similar. Differences between
MEBO and control treatments were considered to be statistically significant if P < 0.05,
very significant if P <0.01 and extremely significant if P <0.001.

Table 1. Epidemiologic data of the two study groups

Patients Etiology Age TBSA (%)
Range Average ± S.D. Average S.D.
Male Female Total Scald Flame Range (%)
(years) (years) (%)
MEBO 13 6 19 11 8 5–45 17.1 ±13.68 5–17 11.53 ±3.55
Control 11 6 17 8 10 5–54 21.79± 15.48 7–20 11.43 ±5.58

Table 2. Other topical preparations utilized for local burn wound treatment
Silversulphadiazine
Sofratulle
Chlorhexidinetulle
Nitrofurazone
Quadriderm (betamethasone + chlorocresol + clioquinol +gentamicin+ tolnaftate)
Dexpanthenol
Nitrofurazone
Savlon (cetrimide + chlorhexidine)
Hydrogen peroxide
Povidone–iodine

Results: Two patients were excluded from the study because of non-compliance and
protocol violation. Two patients in the control group have required skin grafting, thus they
were excluded from the analysis while all the MEBO-treated patients healed without the
need of surgical intervention. Nineteen patients in the MEBO study group and 17 patients
in the control group were available for analysis. Mean hospitalization for both study
groups is shown in Table 3. The reduction in hospital stay for the MEBO-treated group
was statistically very significant (P < 0.01). The observed decrease in the average time
spent by the treating physicians with patients treated by MEBO as compared to time spent
with patients treated by other modalities is significant (P < 0.05). On the other hand the
decrease in average time spent by nurses between the two groups was very significant (P <
0.01) in favor of MEBO application (Table 4). Direct costs expressed by currency unit are

13
shown in Table 5 and Figure 1. MEBO application resulted in a statistically very
significant decrease (P < 0.001) in overall direct treatment costs though this decrease per
day of treatment was only significant (P < 0.01). When various parameters responsible for
direct costs are examined separately, the observed differences between the two groups in
cost of systemic antibiotics as well as other medicaments and cost of hematological,
biochemical and microbiological tests were not significant. Cost per day of treatment
calculations showed that the cost of topical ointment per day was higher for MEBO though
the overall topical agent cost was higher for the other ointments used. These observed
differences, however, were statistically not significant. On the other hand, MEBO-treated
patients required less analgesics (P < 0.05). The most extremely significant reduction in
cost, however, was observed with the medical materials utilized (P < 0.0001) which
reflects the great savings that can be made by adopting the moist exposed method of
MEBO ointment as compared to the classical semi-open dressings.

Table 3. Hospitalization time (days)

Minimum number of days Maximum number of days Median Mean ± S.E.M.
MEBO 6 23 11 12.84 ±1.23 (P< 0.01)
Control 7 29 18 18.35± 1.64

Table 4. Time spent by physicians and nurses (h) for local burn wound care (mean ±S.E.M.)
Physician Nurse
MEBO
Per day 0.21 ± 0.05 0.51 ± 0.05
Per course 2.58 ± 0.68 (P< 0.05) 6.73 ± 1.01 (P < 0.01)
Control
Per day 0.29 ± 0.05 0.61 ± 0.04
Per course 4.82 ± 0.79 10.95 ± 1.10

Table 5. Direct cost expressed by currency unit (mean ± S.E.M.)

MEBO Control
Per day Per course Per day Per course
Topical burn
34.06 ± 5.38 491.45 ± 100.24 28.20 ± 4.99 546.02 ± 121.44
ointment
Systemic antibiotics 11.49 ± 2.96 125.30 ± 29.31 16.16 ± 3.98 255.04 ± 56.81
Analgesics 0.98 ± 0.40 8.7 ± 2.61 3.87 ± 1.41 52.25 ± 17.71
(P< 0.05) (P 0.05)
Other medicaments 1.26 ± 0.42 12.31 ± 4.14 0.56 ± 0.27 8.06 ± 3.17
a 16.14 ± 1.70 212.64 ± 35.25
Medical material 39.98 ± 4.22 771.38 ± 117.05
(P< 0.001) (P< 0.001)
Laboratory tests 7.4 ± 1.2 92.83 ± 12.91 8.49 ±1.41 143.38 ± 22.06
72.49 ± 7.52 951.94 ± 137.94
Total 100.42 ± 8.70 1,840.7 ± 231.97
(P< 0.05) (P< 0.01)
Total + 123 ± 7.5 1,610.1 ± 188.38 152 ± 8.76 2,785.9 ± 293.31
hospitalization (P< 0.05) (P< 0.01)
a
Medical material includes gloves, dressing material, syringes, canulae, i.v. fluids, cleansing
solutions, etc.

14
 Figure 1. Costs per course of treatment

Conclusion: The study has shown that patients not treated with MEBO application
required statistically significant longer hospitalization. It has shown also that the increased
daily cost of MEBO ointment, though statistically not significant, is largely offset by the
60% increase in cost of dressing and medical materials required by other topical therapy
modalities which is extremely significant. The combination of longer hospitalization and
increased cost of conventional dressings clearly demonstrate the positive benefit of MEBO
application in the topical treatment of minor to moderate second degree burns over
conventional standard methods of local treatment whenever early surgical tangential
excision and skin grafting is not feasible or warranted. The present study does not allow,
however, extrapolation of these positive results to more extensive or deeper burns.
Moreover, the limitation of computation of cost of management to the period necessary for
healing and re-epithelialization alone without considering the future cost of rehabilitation
after actual wound healing and the cost of secondary corrective procedures may not give a
realistic idea about the total actual cost of the local therapeutic modalities under study,
particularly since different scar qualities may be expected. Though scarring was not
evaluated in the present study and its impact on the need of secondary corrective therapies
with their obvious effect on total cost was not assessed, it has been previously shown that
better scar quality may be expected following treatment of partial thickness wounds with
MEBO. This may mean that resultant scars following MEBO application may require less
scar related treatment modalities and perhaps less secondary corrective procedures that by
itself may make MEBO application even more cost beneficial. Within the limits of the
study, MEBO has been shown to be a cost beneficial alternative in the local management
of minor to moderate second degree burns. Benefit-cost analysis evaluating only the
financial elements of a program is based on the assumption that the goal of a health care
program is to save money. This raises serious philosophical and ethical concerns. The
goals of health care must be to add years to life and life to years, in other words, to
increase the quantity and quality of life that is practically impossible and even
inappropriate to price tag. From that particular perspective, the positive effects of MEBO
expressed in terms of analgesia, psychological comfort, ease of application and better

15
healing and scarring as demonstrated by previous studies adds tremendously to the benefit-
cost analysis.

4.6 Cost-Effectiveness of Moist Exposed Burn Therapy

Atiyeh BS, et al. J Burns & Surg Wound Care, 2004; 3(1): 3-12

In light of the increasingly limited health care resources, and as funding for health care is
becoming a critical national concern, current reimbursement policies for burn care
underscores the importance of cost containment in the management of these injuries. By
taking into account both economic and clinical performance, ways to reduce expenditures
without adversely affecting the quality of care are becoming of primary importance. Cost-
effective burn wound management could indeed be developed without impairing the
quality or delivery of health care. Use of Topical ointments and associated dressing
materials are the highest expenditure items in a burn unit. Thoughtful assessment of these
items with modification of unnecessary practices could result in great savings. Moist
exposed burn therapy (MEBT) consists of frequent application of a moisture retentive
ointment (MEBO) without the need of an overlying reinforcing dressing. This treatment
modality is claimed to possess the advantages of both the open treatment method and the
occlusive dressings without their disadvantages. In a prospective clinical study, cost-
effectiveness of MEBT was assessed as compared to standard local burn care modalities.
A very significant earlier spontaneous healing of second degree burns with significant
reduction in overall total treatment cost was observed with MEBT.

Material and Methods: A prospective clinical study was conducted from September 2003
to December 2003 in 14 different hospitals in the Kingdom of Saudi Arabia (KSA). Fifty-
two patients with second degree TBSA burns of 5 to 35% (average 12.55 ± 5.77) were
included in the study after obtaining a signed informed consent from the patients or from
their legal guardians. The procedures followed in the study were in accordance with the
recognized ethical standards and with the Helsinki Declaration. Twenty-nine patients had
flame burns (55.76%). Scald burns were observed in 19 patients (35.25%). Miscellaneous
other causative factors were encountered in 3 patients (5.76%). 76.4% were males.
Patients’ age range was 2-58 years (average 27.33 ±14.8 years). All patients were
admitted to the hospital and assigned randomly into two groups. One study group was
treated with MEBT using the MEBO under investigation, and a second control group
received the standard burn treatment for the given hospital. Agents used for local burn
wound care are summarized in table 1. They were discharged only after full re-
epithelialization was observed. Seven patients were excluded from the analysis due to
protocol violations for age range (5-50 years) or for extent of burn (>15% TBSA for
children and >20% for adults). Forty-four patients (22 in each group) were available for
final analysis. The 2 groups were comparable for age, sex, etiology of burn, and % TBSA
burned (table 2). As for the previously reported similar study, overall cost of therapy was
evaluated by estimating both direct and indirect costs. Direct cost included actual cost of
the topical agent used, intra-venous fluids, concomitant antibiotics, analgesics and other
pharmaceutical agents and preparations, such as gloves, catheters and dressing materials.
Direct cost included also cost of hospitalization as well as the cost of all performed

16
laboratory tests. Indirect cost was estimated by computing time spent by the treating
physicians and nurses in attending to the various needs of the patients, such as dressing
changes, debridement and bathing. Total cost of treatment as well as individual
components (hospitalizations duration and cost, physician/nurse time, topical treatment,
systemic antibiotics, analgesics, other medications, laboratory services and medical
materials) were recorded, calculated (as per course of treatment or per day) and statistically
analyzed with the Mann-Whitney test or the Welch correction test.

Table 1. Topical agents used in the control group

Silver Sulfadiazine
Extract cepae 10%, heparin sodium 5000 iu and allantion
Panothenic acid
Chlorohexidine
Fucidic acid
Bacitracin zinc and neomycin sulphate
Povidone iodine
Sofratulle

Table 2. Epidemiology of the study (MEBO) and Control groups

PATIENTS ETIOLOGY AGE (years) TBSA%
Average+Sd
Male Female Total Scald Flame Range Average+Sd Range%
%
MEBO 16 6 22 8 13 5-49y 27.27+13.27 5%-20% 12.45+4.8
Control 16 6 22 9 11 5-50y 27.18+13.2 6%-17% 10.77+3.5

Results: A reduction of 20.24% in hospitalization time was observed for the study group
as compared to the control group (very significant two-sided p=0.0056) (fig. 1). The
overall reduction in treatment cost for the MEBO study group was significant (p=0.025)
per course of treatment (fig. 2), but not significant (p=0.5653) per day though a 9.41%
reduction in daily cost was observed. Difference between the 2 groups in treatment cost
excluding hospitalization was not significant per course (p=0.1381), and per day
(p=0.2700) despite a 25% reduction in daily cost achieved with moisture retentive
ointment application. On the other hand difference in hospitalization cost including
accommodation and physicians and nurses cost was very significant in favor of the study
group (p=0.0051) per course of treatment (fig. 3) but not significant (p=0.4317) per day.
The reduction in total time spent by physicians attending patients was significant
(p=0.0216) per course (39.43% reduction achieved with MBT), but not significant per day
of treatment (p=0.1546) despite a 23.14% reduction with MEBO application. The
reduction in total time spent by nurses, however, was very significant (p=0.0095) per
course of treatment yet not significant (p=0.2223) per day despite a 16.43% reduction (fig.
4). Cost of topical agent was 9% lower with MEBO per course of treatment and 2.4% per
day of treatment. This difference was not significant. Similarly, the decrease in material
cost including gloves, catheters, canulae, syringes, IV fluids, dressings, and cleansing
solutions observed with MEBO per course or per day was not significant despite 36.43%
and 28.05% reduction respectively. Reduction in systemic antibiotic cost achieved with
MBT was 50.42% per course and 47.72% per day. These differences statistically were not
significant. The same was observed for the cost of other medications cost. Analgesic cost

17
per day was reduced by 60.8% with MEBO per course (significant p=0.0135) and 55.88%
per day (significant=0.0271). Cost of laboratory tests (hematological, biochemical, and
microbiological) was reduced by moisture retentive ointment application, however, this
reduction is not statistically different per course nor per day of treatment. On the other
hand, without including the cost of associated dressings, no significant difference was
observed in the cost of MEBO ointment as compared to that of other topical materials
applied even though the cost of MEBO was 9% less per day and 2.4% less per course of
treatment (fig. 5).

All patients included in the statistical analysis had burns <15% TBSA for children and
<20% for adults and had no underlying medical disease likely to affect healing. All
patients in both study groups had a smooth hospitalization course till full healing and
discharge. Though routine burn wound cultures were not part of the study protocol, none
of the patients, in both groups, developed clinical burn wound sepsis or any other medical
complication due to the burn injury itself or to the prescribed therapy. Although the pain
during treatment was not directly assessed, it seems, however, that patients in the MEBO
group had less pain judging by the significant reduction in required analgesia as compared
to the control group and experienced less discomfort during local burn wound care.

Surgical debridement was required in 4.54% (n=1) of the MEBO treatment group, and in
18.18% (n=4) of the conventional treatment group (P >0.05). However, split thickness
skin graft grafting was performed for only 2 patients (9.09%) from the second group (P
>0.05). Physiotherapy for the range of motion was performed during the hospitalization
course for 6 ±0.81 days (ranging between 5 to 7 days) in 22.72% (n=5) of the MEBO
group. The same number of patients from the conventional treatment group required
physiotherapy for an average duration of 14 ±5.7 days (ranging between 7 to 21 days).
The observed difference in duration of physiotherapy between the two groups was, by the
unpaired t-test, statistically significant (P =0.032). Immediately following healing,
hyperemic scars were noticed in 54.54% (n= 12) of the MEBO group and in 68.18%
(n=15) of the standard treatment group (P >0.05). However, pigmentation changes were
noticed in 4.54% (n=1) and 31.81% (n=7) respectively. Fisher’s exact test revealed that
this observed difference was statistically significant (P =0.0459). Scar hypertrophy, on the
other hand, was detected in only 2 patients in the conventional treatment group (9.09%).
This observation was not significant (p>0.05). Mild scar contracture was observed in
27.27% of patients from each group (n=6). However, deformity was noticed in only 2
patients (9.09%) from the standard treatment group, producing mild dysfunction in one
patient (4.54%). This observation, however, was not statistically significant (P >0.05).
Scar evolution with time, however, was beyond the scope of this present study.

18
Figure 1. Duration of hospitalization of the two groups. 20.2% reduction in hospitalization with the MEBO
group as compared to the control group.

Figure 2. Total treatment cost. MEBO application resulted in a reduction of 25.7% as compared to the
control group.

Figure 3. Total hospitalization cost (accommodation, physicians and nurses cost). MEBO application
resulted in 20% reduction as compared to the control group.

Figure 4. Time spent by physicians and nurses per course of treatment. MEBO application resulted in
39.43% reduction in physicians’ time and 28.67% nurse’s time.

19
 Figure 5. Cost per course of topical agents, medical materials, systemic antibiotics, analgesics, other
medicines, and laboratory expenses for the two study groups.

Conclusions: In the present study, a very significant earlier spontaneous healing of second
degree burns was achieved with the moist exposed therapy at a lesser cost of most of the
measured parameters, even though some differences were not statistically significant
probably due to the small size of the study and control groups. Overall total treatment cost
was also significantly reduced by MEBO with a significant reduction of the physicians’
work load, and a very significant reduction of the nurses’ work load. The exact benefit of
the reduction in work load and time spent with the burned patients by the concerned health
personnel cannot be evaluated by the present study which only estimates the cost of labor
affected. Measures to estimate the added benefits that may be derived from investing the
health personnel during the saved time in other beneficial actions with other patients might
only add to the cost-effectiveness of the moist exposed therapy and is an important
parameter that must be considered in future cost-benefit studies. Even though no
significant difference between the cost of MEBO and that of the other topical agents was
observed, when the cost of dressings is added to the cost of topical materials, the extent of
savings realized by moist exposed therapy without an overlying dressing become clearly
evident. Moreover, better scar quality following primary and secondary healing with
moisture retentive ointment application has already been reported. This may mean that
resultant scars following MEBO application may require fewer scars related treatment
modalities and perhaps less secondary corrective procedures that by itself may make
MEBO application a more cost beneficial local burn wound care modality. MEBT is a
valid alternative to local care of second degree burn wounds. In a previously published
study, MEBO has been found to be a cost-beneficial alternative in the local management of
minor to moderate second degree burns. Results of the present study confirm these earlier
observations. Moreover, in addition to being less labor intensive, MEBT results in actual
direct savings appreciated by all health care systems. Its real value, however, can be
appreciated better if the reduction in estimated losses due to poor healing and scarring are
accounted for. Positive investment of the saved physicians’ and nurses’ time adds further
to the cost-effectiveness of this new local burn wound care modality.

20
 4.7 Clinical Trial Report of Burns Regenerative Medicine and Therapy – a
Multicenter Phase III Study
Xu RX. Burns Regenerative Medicine and Therapy, 1st ed., Basel: Karger; 2004. p. 119-128

In order to further examine and evaluate the therapeutic effects, main indications, and
possible side effects of MEBO in burn treatment, this multi-center study was conducted as
a phase III clinical trial. In this trial, MEBO was used for treating vast numbers of burn
patients of both sexes in varied ages, all suffering burns from different causes, occurring at
different sites, encompassing varied areas, and injured to varied depths. From January 1,
1996 to June 30, 1999, this phase III clinical trial was carried out at five burn centers of the
China National Science and Technology Center for Burns, Wounds and Ulcers, located in
Changsha, Taishan, Dalian, and Nanyang, China.

Materials and Methods

Clinical Data - General Information: Five hundred and eight hospitalized burn patients
were enrolled. They were divided randomly into two groups: treatment group (MEBO
group) and control group (silver sulfadiazine (SD-Ag) group). There were 363 patients in
MEBO group, 282 males and 81 females, ages from 10 days to 73 years (average 28.4 ±
15.5 years). There were 145 patients in the SD-Ag group, 122 males and 23 females, ages
from 8 months to 72 years (average 29.2 ± 12.1 years). Causes of Burns: The most
frequent causes of burns injury in this trial were flame and hot liquid - 211 cases (41.5%)
and 202 cases (39.8%), respectively. Fifty-eight burns were caused by chemicals (11.4%),
and among these chemical burns, 28, 26, and 4 cases were injured by acid (5.5%), alkali
(5.1%), and phosphorus (0.8%), respectively. Twenty-two (4.3%) cases had electric burns.
The remaining 15 cases (3.0%) were accidental scalding by hot solid metal. The burn
causes of both the MEBO and the control groups were comparable. Anatomical Regions
of Burns: The anatomical regions of burns are shown in table 1. In both groups, the burns
often involved the extremities, head, and neck. Patient Assessment: Extent and depth of
burns were showed in table 2. The largest burns area was 94% TBSA, and the largest
third-degree wound was 82% TBSA. One hundred and six (20.9%) out of 508 cases in this
trial were extensive burns patients with TBSA>50%, 75 cases in the MEBO group and 31
cases in the control group. The wounds showed no significant differences between the two
groups (p >0.05). According to the Chinese national standard classification of burn
severity, there was no obvious differences between the two groups (p > 0.05) (table 3).

21
 Table 1. Frequency of anatomical regions burned in 508 patients of this trial
Head/ Neck Left Right Left Right Left Right Left Right Trunk Perineum/
face arm arm leg Leg Hand hand foot foot genital
MEBO group
n 304 293 310 317 243 263 360 373 127 130 135 57
% 59.8 57.8 61.0 62.2 47.2 52.7 70.8 73.4 25.0 25.6 26.6 11.2
SD-Ag group
n 92 83 97 84 96 98 90 81 62 54 98 22
% 63.4 57.2 66.9 57.3 66.2 67.6 62.1 55.9 42.8 37.2 67.6 15.1

Table 2. Extent and depth of burns wounds

Superficial Deep
Group (n) TBSA % (n) Third-degree % (n)
second-degree % (n) second-degree % (n)
MEBO group 29.9±18.1 9.2±8.2 17.7±13.7 11.9±11.7
(363) (363) (310) (285) (150)
SD-Ag group 31.3±16.4 10.4±7.3 16.9±1.8 12.8±7.4
(145) (145) (135) (128) (56)

Table 3. Classification of burns severity

Mild Moderate Severe Extraordinarily severe
Group (n)
n % n % n % n %
MEBO group (363) 96 26.4 110 30.3 83 22.6 75 20.7
SD-Ag group (145) 48 33.1 42 29.0 24 16.6 31 21.3

Burn Management - Local Wound Treatment: Generally, exposure therapy was adopted in
both groups. The occlusive method was used unless the individual requirement
contraindicated it. In both groups, the superficial and deep partial-thickness wounds were
permitted to heal spontaneously. Skin grafting could be performed in order to repair full-
thickness burns wounds at the appropriate time. In the MEBO group, patients received
standard MEBT throughout the treatment period with MEBO applied to the wounds at a
thickness of 0.5-1 mm every 4-6 h. No conventional debridement was performed. In the
control group, the wounds were treated with 1% silver sulfadiazine (SD-Ag) cream or
paste according to the typical SD-Ag protocols after debridement. Systemic Treatment:
Systemic treatment was delivered as required by the patients’ conditions. These systemic
treatments included anti-shock, anti-infection, and nutritional support. In the control
group, the anti-shock regime followed the standard resuscitation protocol of burn surgery.
In MEBO group, the following formula was recommended as a guideline for estimating
daily fluid requirements during 48-72 h after injury: Total amount of fluid infusion
(ml/day) = [physiological water needs (2000-2500 ml) + 1 ml/kg x % TBSA of second and
third degree x kg body weight] / [hourly urine output (ml) per kg body weight x 1 ml/kg].
In both adults and children, the desirable denominator should be monitored, adjusted and
maintained at a value of 1 ml.

Standard of Wound Healing - Complete re-epithelialization in patients with TBSA < 50%
and residual wound less than 5% in patients with TBSA > 50% were considered as healed.

22
Assessment of Pain during Treatment and Changing Dressing - Pain during treatment was
classified by the following four levels: 0- No pain, infant and young patients remaining
quiet; I- Mild pain, infant and young patients remaining quiet; II- Moderate pain but
bearable in adults, infant and young patients crying, wounds bleeding; III- Unbearable
severe pain, wounds bleeding, analgesic required.

Evaluation of the Analgesic Effect - The analgesic effect was classified as the following
five levels: Excellent- Relief of wound pain within 10 min after application; Good-
Alleviation of wound pain within 10 min and relief within 30 min after application; Fair-
Alleviation of wound pain within 30 min after application and no analgesic was required;
Poor- Wound pain not alleviated within 30 min after application and analgesic was
required; Very poor- Aggravation of wound pain after application and analgesic was
required.

Complications - Local Complications: Carefully observed if wound infection occurred

during treatment, such as serious inflammation of normal tissue surrounding a wound,
wound cellulitis, sub-crustal/subeschar empyema, bleeding and necrosis of newly
regeneration tissues resulting in inactive growth, etc. Systemic Complications: These were
observed with the incidence of any systemic complication such as hypovolemic shock,
cardiac failure, renal failure, respiratory failure and adult respiratory distress syndrome,
hemorrhage of upper digestive tract, sepsis or septicemia, etc.

Toxicity and Side Effects - Hematological, biochemical and serological tests were carried
out to ascertain the degree of toxicity and side effects of the topical medicines. The
potential for localized skin or systemic allergic reactions to the topical medicines used in
this trial was also monitored.

Results

Wound Healing Mode

1. Superficial Second-Degree Burn Wounds: The average healing time in MEBO group
was determined to be significantly shorter than that of the SD-Ag group. Remarkably,
whereas no scarring occurred in MEBO group, by comparison, scar formation of
superficial second-degree wounds did occur in the SD-Ag group, which was treated with
SD-Ag (table 4).

Table 4. Comparison of healing mode in superficial second-degree wound

Scar formation
Group (n) TBSA % Spontaneous healing time days
n %
MEBO group (310) 9.7±8.2 9.1±3.6 0 0
SD-Ag group (135) 10.4±7.3 13.5±2.7 * 5 3.7 **
* t = 9.582, p < 0.01; ** χ2 = 11.612, p < 0.01.

23
2. Deep Second-Degree Burn Wounds: Most deep second-degree wounds in the MEBO
group healed spontaneously, with a significant shorter healing time. (table 5). These
results indicate that MEBO provides better quality of wound healing.

Table 5. Comparison of healing mode in deep second-degree wounds

Spontaneous Skin grafting Scar formation
Group (n) TBSA %
healing time days n % n %
MEBO group (285) 17.7±13.7 20.3±3.1 2 0.7 38 20.4
SD-Ag group (128) 16.9±11.8 27.2±3.4* 11 8.5** 81 63.3***
* t = 11.977, p < 0.01; ** χ2= 17.609, p < 0.01;*** χ2 = 72.906, p < 0.01.

3. Third-Degree Burn Wounds: The majority of third-degree burns wounds in the SD-Ag
group required skin grafting, in contrast to 43.3% in MEBO group. The rate of scar
formation in the SD-Ag group was markedly higher than that in MEBO group (table 6).

Table 6. Comparison of healing mode of third-degree wounds

Spontaneous Skin grafting Scar formation
Group (n) TBSA %
healing time days n % n %
MEBO group (150) 11.9±11.7 38.1±7.1 65 43.3 72 48.0
SD-Ag group (56) 12.8±7.4 42.9±5.5 47 83.9* 51 91.1**
* χ2= 27.086, p < 0.01;** χ2 = 31.440, p < 0.01.

Analgesic Effect and Alleviation of Pain Sensation during Treatment

Regarding both the analgesic effect and severity of pain sensation during treatment and
changing dressing, patients in the MEBO group were all dramatically superior to one in the
SD-Ag group (tables 7, 8).

Table 7. Comparison of analgesic effect after application of topical medicines

Excellent Good Fair Poor Very poor
Group (n)
n % n % n % n % n %
MEBO group (363) 204 56.2 142 39.1 17 4.7 0 0 0 0
SD-Ag group (145) 10 6.9* 29 20.0* 65 44.8* 31 21.4* 10 6.9*
* χ2 > 50, p < 0.01.

Table 8. Comparison of pain sensation during the treatment and dressing changes
0 I II III
Group (n)
n % n % n % n %
MEBO group (363) 176 48.5 165 45.5 22 6.0 0 0
SD-Ag group (145) 5 7.4* 31 21.4* 70 48.3* 39 26.9*
* χ2 > 50, p < 0.01.

Wound Infection
The incidence rate of wound infection in the SD-Ag group was significantly higher than
that of MEBO group (table 9). This finding confirmed that MEBO effectively prevented
wounds from infections.

Table 9. Comparison of wound infection between the two groups

24
 Wound infection
Group (n)
n %
MEBO group (363) 28 15.98
SD-Ag group (145) 57 39.31**
* χ2 > 50, p < 0.01.

Toxicity and Side Effects

In this trial, no side effects, local or systemic allergic reactions were found in either group.

Effects on Extensive Burns Patients

In both groups, the patients suffering TBSA < 50% burns were discharged with complete
healing. All 75 extensive burn patients (TBSA > 50%) in MEBO group was healed. The
healing rate for extensive burns in MEBO group was 100% with no obvious side effects
noted. On the other hand, 2 of 31 extensive burn patients in the SD-Ag group died and 18
patients were discharged with unhealed residual wounds. The healing rate for the SD-Ag
group was 73.7% with improvement rate of 24% and mortality rate of 2.3%. We
concluded from these results that it was safe to use MEBT/MEBO for the treatment of
patients with extensive burns.

Discussion

Effects of MEBO on Burns Wounds Management: According to the results of this trial,
MEBO promotes burn wounds healing in each depth of wound. Remarkably, 99% of deep
partial-thickness burn wounds healed spontaneously without skin grafting, at a very low
scarring rate of 20.4% compared to 63.3% in the SD-Ag group. Furthermore, in this trial,
more than half of the clinically diagnosed full-thickness burns wounds could be healed
spontaneously by MEBO without skin grafting. MEBO provided burn wounds an
optimum physiological environment for tissue regeneration and repair without further
damage to viable tissue, subsequently, the wound would heal spontaneously with limited
scarring, deformity, and disability. Meanwhile, it was found that in the MEBO group, the
incidence rate of wound infection was significantly reduced compared to that in the SD-Ag
group, indicating that MEBO was capable of preventing wound infection.

Analgesic Effect of MEBO: It was determined in this trial that throughout the treatment
and during dressing changes, the analgesic effect and alleviation of pain in the MEBO
group was dramatically superior to that of in the SD-Ag group. Unlike SD-Ag which
required painful peeling away of crusted and dried dressing from fragile tissue, MEBO
neither aggravated the suffering and pain during the treatment and changing of dressing,
nor did it fail to offer a satisfactory analgesic effect. The need for an analgesic agent was
rare in MEBO group.

Feasibility of Using MEBO for Treating Extensive Burns: In this trial, 75 extensive burn
patients with TBSA >50% were treated with MEBO which resulted in a 100% healing rate
whereby all patients were completely healed when discharged from the hospital. No side
effects and local or systemic allergic reactions were found. In contrast, 2 of 31 extensive

25
burn patients in the SD-Ag group died and 18 patients were discharged with unhealed
residual wounds. Meanwhile, almost half of the extensive burns patients in the SD-Ag
group were failing the treatment due to complications of wound infection, bleeding, severe
painful or delayed healing, and had to switch into the MEBO group for ethical reasons,
and, despite the relatively late access to MEBO, these patients achieved the same
satisfactory results. Therefore, it was concluded that treatment with MEBO for extensive
burn patients was practical and safe. In addition, it indicated that when the treatment with
SD-Ag for extensive burn patients appeared to be unsatisfactory, switching them to MEBO
was appropriate. MEBO seemed to promote spontaneous healing in delayed-healing
wounds and was able to free or decrease the needs of grafting.

26
Clinical Demonstration of MEBO Treatment
- in Extensive Full Thickness Burns -

a. TBSA 95%.
Before treatment.

b. On the 55th day

after treatment with
MEBO, the skin
tissue was
regenerated and
wounds healed
completely.

27
Pictures showed
recovered skin in
three years later.

a. The wound healed

spontaneously from
deep second-degree
burns (dorsal surface
of right wrist) with a
full structural and
functional recovery.

b. Most wounds
healed
spontaneously from
mixed deep second-
and superficial third-
degree burns (inside
of right forearm and
wrist). Recovered in
normal skin with
little hypo-
pigmentation.

c. The wounds
healed
spontaneously from
superficial third
degree burns (right
cheek) with almost
normal function
(hair growth, and
secretion of sweat
glands).

28
d. The wounds
healed
spontaneously from
superficial third-
degree burns (chest
and abdomen)
appearing normal in
structure without
obvious scars.

e. Few scars upon

deep third-degree
wounds (right
shoulder) appeared
smooth and soft
without contracture
or dysfunction.

29