Myofibroblasts and apoptosis in human hypertrophic scars: the effect of interferon-alpha2b.

BACKGROUND: Hypertrophic scars (HSc) are a dermal fibroproliferative disorder that leads to considerable morbidity. Preliminary evidence suggests that interferon (IFN) may improve HSc clinically. The aims of this study were (1) to compare the cell density in HSc and in wounds that heal without the development of HSc (normotrophic scars), (2) to examine the presence of myofibroblasts and apoptosis in normotrophic and HSc scars over time, and (3) to determine if the systemic administration of IFN-alpha2b can induce apoptosis. METHODS: Two groups of patients underwent serial tissue biopsies. Six burn patients were studied prospectively by obtaining biopsy specimens from wound granulation tissue, normal skin, post-burn HSc, and normotrophic scars (healed donor sites). A second patient group with HSc was treated with systemic IFN-alpha2b and had biopsy material taken before, during, and after IFN therapy. The tissue was analyzed by immunohistochemical staining for alpha-smooth muscle actin (alpha-SMA) and in situ DNA fragmentation terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay for apoptosis. RESULTS: The total numbers of fibroblasts in HSc were found to be similar to granulation tissue and twice that of normal skin and normotrophic scar. Over time the numbers of cells in HSc tissue decreased toward normal skin levels. There was a significantly higher percentage of fibroblasts staining for alpha-SMA in HSc as compared with normotrophic scar or normal skin obtained from the same patient (P >.05). Serial biopsy specimens of resolving HSc tissue obtained from the patients who received systemic IFN-alpha2b showed a general reduction in total number of fibroblasts and myofibroblasts associated with a significant increase in the percentage of apoptotic cells compared with normal dermis from the same patient. CONCLUSIONS: HSc tissues have greater numbers of fibroblasts and myofibroblasts than normal skin and normotrophic scars. As HSc remodels, the numbers of fibroblasts and myofibroblasts reduces, possibly by the induction of apoptosis. Systemic IFN-alpha2b may contribute to the resolution of HSc in part by the enhanced induction of apoptosis.

Rating the resolving hypertrophic scar: comparison of the Vancouver Scar Scale and scar volume.

The increased focus of research interests and clinical documentation on outcomes demands that evaluation tools provide reliable and valid data. The Vancouver Scar Scale (VSS) was developed to provide a more objective measurement of burn scars; however, the validity (a test's ability to measure the phenomenon for which it was designed) of the VSS has not been tested. To examine the construct validity of the VSS, we compared it with scar volume, which has established face validity. Burn scars were evaluated monthly for a minimum of 7 months. Three scar volume measurements were performed on each scar. In addition, 3 independent examiners completed the VSS for the same scar. The data generated by these 2 measurements were used to establish the following: (1) the interrater agreement estimated by interclass correlation coefficient, (2) convergence validity, (3) the sensitivity of the assessments to discriminate changes in the scar over time, and (4) the prevalence of related parameters that are not currently being captured by the VSS. In an attempt to address some of the deficiencies of the VSS, we propose several modifications. We anticipate that these changes will increase the reliability and validity of the VSS through an increase in the awareness that training in the use of this scale is required, through improvement in the quality of the subscales, and through the documentation of additional pertinent information.

Electrical injuries in Canadian burn care. Identification of unsolved problems.

Over the past decade, the Firefighters' Burn Treatment Unit of the University of Alberta Hospital in Edmonton, Alberta, Canada, has treated 1399 inpatients suffering from thermal injury. Regional burn care is provided in a 10-bed intensive care unit with 18 plastic surgery reconstructive beds for a large referral region of central and northern Alberta, portions of the Northwest Territories, and neighboring provinces of British Columbia and Saskatchewan. Of the total burn inpatients during this period, 74 electrical injuries were treated (5.3% of all admissions): 71 were males (95.9%) and 3 females (4.1%). The mean age of all patients was 33.9 +/- 12.6 years (range 1-67). Compared to our general population of thermally injured patients, those with electrical injuries had smaller injuries [9.9 +/- 12.9% TBSA (range 1-65) versus 15.1 +/- 10.1], shorter length of hospitalization [18.6 +/- 7.3 days (range 1-80) versus 26.2 +/- 0.8], and substantially lower mortality once reaching the hospital (0% versus 4%). Electrical injuries were classified as flash in 30 cases, contact in 42 cases, and lightning in 2 cases; 74.3% of injuries occurred during work-related activities. A total of 118 operative procedures were performed during the acute admission (1.6 procedures per patient), including 19 amputations: 12 in the upper and 7 in the lower extremity. The mean time of amputation was 9.3 +/- 5.3 days after admission. In contact injuries of the upper extremity, 14 patients suffered amputations or neurologic injury that required reconstruction with free tissue transfers and nerve grafts. Long-term functional outcome of these patients using sensory testing, the Jebsen-Taylor hand function test, and wound coverage has revealed that these patients have substantial persistent sensory impairment of their upper extremities postinjury despite reconstruction, although many remain active and functional with acceptable wound coverage. Based on our analysis of electrical injury as it presents to one typical Canadian burn unit, our patients suffer limb loss on a delayed basis, which leads to substantial morbidity. Reconstruction of the upper extremity with microsurgical techniques after profound electrical injury has provided acceptable coverage, but in many instances is associated with poor or marginal sensory recovery limiting reemployment options for patients with upper extremity electrical burns. Further understanding of the cellular biology of delayed tissue loss after electric injury would offer the potential for reduction in amputation rate and improvement in functional outcome and overall morbidity.

A matched-pair, randomized study evaluating the efficacy and safety of Acticoat silver-coated dressing for the treatment of burn wounds.

A new silver-coating technology was developed to prevent wound adhesion, limit nosocomial infection, control bacterial growth, and facilitate burn wound care through a silver-coated dressing material. For the purposes of this article, Acticoat (Westaim Biomedical Inc, Fort Saskatchawan, Alberta, Canada) silver-coated dressing was used. After in vitro and in vivo studies, a randomized, prospective clinical study was performed to assess the efficacy and ease of use of Acticoat dressing as compared with the efficacy and ease of our institution's standard burn wound care. Thirty burn patients with symmetric wounds were randomized to be treated with either 0.5% silver nitrate solution or Acticoat silver-coated dressing. The dressing was evaluated on the basis of overall patient comfort, ease of use for the wound care provider, and level of antimicrobial effectiveness. Wound pain was rated by the patient using a visual analog scale during dressing removal, application, and 2 hours after application. Ease of use was rated by the nurse providing wound care. Antimicrobial effectiveness was evaluated by quantitative burn wound biopsies performed before and at the end of treatment. Patients found dressing removal less painful with Acticoat than with silver nitrate, but they found the pain to be comparable during application and 2 hours after application. According to the nurses, there was no statistically significant difference in the ease of use. The frequency of burn wound sepsis (> 10(5) organisms per gram of tissue) was less in Acticoat-treated wounds than in those treated with silver nitrate (5 vs 16). Secondary bacteremias arising from infected burn wounds were also less frequent with Acticoat than with silver nitrate-treated wounds (1 vs 5). Acticoat dressing offers a new form of dressing for the burn wound, but it requires further investigation with greater numbers of patients in a larger number of centers and in different phases of burn wound care.

Transforming growth factor-beta in thermally injured patients with hypertrophic scars: effects of interferon alpha-2b.

Hypertrophic scarring is a common dermal fibroproliferative disorder that leads to poor quality wound healing, prolongs rehabilitation, and increases morbidity following major thermal and other injuries to the deep dermis. Local and systemic transforming growth factor (TGF)-beta has been implicated as a fibrogenic cytokine in the pathogenesis of many fibrotic disorders, whereas interferon (IFN) alpha-2b may improve the pathologic features of dermal fibrosis directly or by antagonizing the effects of TGF-beta and histamine. Nine patients with severe hypertrophic scarring were evaluated for 8 weeks before treatment with subcutaneous recombinant IFN alpha-2b, 2 x 10(6) IU three times per week for 24 weeks. Clinical assessment was performed using standardized photography, a burn scar assessment tool, and serial scar volume measurements. Monthly measurements of serum TGF-beta and plasma Ntau-methylhistamine were made prior to, during, and after IFN alpha-2b therapy and compared with 27 age-matched controls. Serial biopsies of the hypertrophic scars and normal skin were performed for evaluation of mast cell numbers. Significant improvement in scar assessment occurred in 7 of 9 patients, and 3 of 9 demonstrated significant reductions in scar volume with interferon therapy beyond that occurring during the 8-week control period. For the entire group, mean rates of improvement were significantly better during interferon therapy with no recurrence following treatment. Before interferon therapy, serum TGF-beta was significantly higher in the burn patients with hypertrophic scarring than in a control population (123.04 +/- 36.48 vs. 56.85 +/- 8.38 ng/ml, p < 0.05). Within 3 months of IFN alpha-2b therapy, serum TGF-beta levels fell significantly and remained within the normal range during therapy and after interferon therapy was stopped. Plasma Ntau-methylhistamine levels were also significantly elevated in the hypertrophic scar patients as compared with age and sex-matched controls (153.6 +/- 92.07 vs. 48.3 +/- 28.9 pg/ml, p < 0.05), and significant reductions were achieved with interferon therapy and maintained after interferon was discontinued. Paired biopsies of hypertrophic scarring and normal tissue demonstrated increased numbers of mast cells in hypertrophic scars compared with normal uninjured skin from the same patients (2.65 +/- 1.63 vs. 1.04 +/- 0.62 cells/high power field, p < 0.001); however, no significant change in mast cell content of the hypertrophic scars accompanied interferon therapy. Patients with severe hypertrophic scarring demonstrate increased levels of serum TGF-beta and plasma Ntau-methylhistamine following thermal injury. A significant clinical improvement in scar quality and volume occurred during IFN alpha-2b therapy, which was associated with normalization of serum TGF-beta and plasma Ntau-methylhistamine levels. A double-blind, placebo-controlled trial will be required to further assess the usefulness of subcutaneous treatment with IFN alpha-2b for the treatment of hypertrophic scarring.

Differential effects of thermal injury on circulating insulin-like growth factor binding proteins in burn patients.

The results of this report provide evidence that insulin-like growth factor-1 binding proteins (IGFBPs) in human sera are differentially regulated as a result of severe burn injury. Using the ligand binding technique, 125I-IGF-1 visualizes 5 different protein bands corresponding to those previously reported for IGFBP-1 to 4 with apparent sizes of 23-42 kd in serum samples prepared from severely burned patients and healthy individuals. The level of IGFBP-3 was significantly decreased within 3-5 days of injury and remained depressed for up to 20 days post injury. The average level of this binding protein reached its lowest value within 3-5 days of the injury (3.8 +/- 1.48% relative to day 0-1 value, n = 4, p < 0.01). Serum samples from 3 of 4 patients showed no recovery within 20 days post injury and the level of IGFBP-3 remained significantly depressed (p < 0.01). In contrast, the levels of IGFBP-2 and IGFBP-4 increased 2 and 3 fold in the same serum samples within 3-5 days of the burn injury, respectively. This increase returns to normal (day 0-1 value) within 7-10 days for IGFBP-2, but the level of IGFBP-4 remained elevated 4 fold relative to the day 0-1 (p < 0.01). However, the abundance of IGFBP-1 in these serum samples was not significantly altered by the burn injury. By controlling for protein loading, these apparent alterations of IGFBPs in the sera of burned patients were not due to hemodilution. Similarly, significant reductions in IGFBP-3 were not likely due to IGFBP-3 specific protease activity in the sera of burn patients since incubation of sera from burn patients and normal individuals at 37 degrees C did not alter the pattern of IGFBPs in sera obtained from normal individuals. Of interest, the level of IGF-1 protein in these samples was also markedly reduced following severe burn injury similar to IGFBP-3. The results of this study suggest that a marked reduction of serum IGF-1 seen in burn patients is associated with a significant reduction of IGFBP-3, a major IGF-1 binding protein in human serum.

North American survey of hydrotherapy in modern burn care.

To investigate the role of hydrotherapy in the treatment of patients with burns, a survey was conducted of the use of hydrotherapy in Canada and the United States as part of an intensive investigation into the causes of Pseudomonas aeruginosa infections in burn injury. Results of the survey conducted indicate that hydrotherapy continues to be an important part of burn wound care in most (94.8%) burn centers in North America. Of the burn centers that use hydrotherapy, 81.4% continue to immerse patients, 82.8% perform hydrotherapy on all patients with burns regardless of total body surface area, and 86.9% continue with hydrotherapy throughout the entire phase of the patient's hospitalization. Routine culturing of the hydrotherapy equipment is standard procedure in 49.7% of the units surveyed, and culturing of the water supply to the equipment on a regular basis is done in only 18.6% of those burn units regularly using hydrotherapy. Pseudomonas aeruginosa was identified as the most common, major cause of sepsis in 52.9% of the burn units surveyed, Staphylococcus aureus in 25.5%, and Candida albicans in 5.2%. This survey demonstrates the extensive use of hydrotherapy in North American burn units and the concern for serious infections in patients with burns from gram-negative organisms such as Pseudomonas species. With the increasing number of reports of Pseudomonas infections related to the use of hydrotherapy equipment, the importance for further investigation into burn wound care with and without hydrotherapy, infection rates, and cost analysis appears to be indicated.

Epidemiology of infections with Pseudomonas aeruginosa in burn patients: the role of hydrotherapy.

Pseudomonas aeruginosa remains a cause of serious wound infection and mortality in burn patients. By means of restriction fragment length polymorphism analysis and a DNA probe for the pilin gene of Pseudomonas, a lethal strain of nosocomial P. aeruginosa was identified as the cause of an outbreak of wound infections among burn patients. Environmental surveys suggested an association of the outbreak with hydrotherapy provided to many patients in a common facility. In a trial of burn wound care without hydrotherapy, overall mortality was reduced significantly, mortality associated with pseudomonas sepsis was eliminated, and the strain of P. aeruginosa associated with earlier mortality was eradicated. Moreover, fewer nosocomial pseudomonas infections, lower levels of pseudomonas resistance to aminoglycoside antibiotics, significantly fewer pseudomonas infections of skin graft donor sites, and later appearance of Pseodomonas species in burn patients were found during the period when hydrotherapy was not used.

Profile of the paediatric burn patient in a Canadian burn centre.

Five hundred and eighty-three children (0-18 years old), consisting of 33.4 per cent of all burn inpatients, were admitted to the University of Alberta Hospitals over an 11-year period (January 1978 to December 1988). Demographic and outcome variables, in addition to aetiological factors, were examined. 48.4 per cent of burns occurred in children less than 4 years of age, with males predominating in every age group (P less than 0.001). Children had smaller burns, a higher incidence of scalds, less inhalation injuries and a lower mortality compared to adult burn patients admitted over the same time period (P less than 0.05). There was a low incidence of confirmed child abuse by burns (1.4 per cent). High-risk environments identified were the home (74.6 per cent of burns) and recreational settings (12.4 per cent of burns), mainly occurring around campfires. Native children were overrepresented in the burn population compared to the general population by a factor of approximately 10:1. Scald prevention, high-risk environments (home and recreational), high-risk populations (male and natives) and unsafe practices with flammable liquids (petrol in particular) should be emphasized in paediatric burn prevention programmes.

The role of inhalation injury in burn trauma. A Canadian experience.

From 1977 to 1987, 1705 thermally injured patients were admitted to the Firefighters' Burn Center at the University of Alberta Hospitals. Thirteen hundred forty-four were male (78.8%) and 361 were female (21.2%), with a mean total burn surface area (TBSA) of 15.1 (SEM +/- 0.4%) and a range of 1% to 99% TBSA. Sixteen hundred thirty-five patients survived to be discharged from hospital, with an overall survival rate of 95.9%. One hundred twenty-four burn patients (7.3%) suffered concomitant inhalation injury diagnosed by bronchoscopy. Patients with inhalation injury suffered from larger TBSA (39.7% +/- 2.8% versus 12.2% +/- 0.3%; p less than 0.01) than those without inhalation injury. Inhalation injury increased the number of deaths from burn injury (34.7% versus 1.7%; p less than 0.01) independent of age and TBSA. Inhalation injury was associated with a threefold prolongation of hospital stay (23.7 +/- 0.7 versus 74.4 +/- 6.2 days; p less than 0.01) and was independent of age and TBSA. Multifactorial probit analysis was performed for both inhalation- and noninhalation-injured burned patients to allow TBSA and age adjusted rates of mortality for the burn population presented. The maximum detrimental effects of inhalation injury in burn patient outcome occurred when it coexisted with moderate (15% to 29% TBSA) to large (30% to 69% TBSA) thermal injuries. These data demonstrate that inhalation injury is an important comorbid factor in burn injury that increases the number of deaths substantially. Most importantly such injuries also independently prolong the duration of hospitalization in a highly unpredictable fashion as compared to patients with cutaneous burns only. As such our data illustrate the extreme importance of inhalation injury as a comorbid factor following thermal injury and reveal the present limitations for accurate quantification of the magnitude of respiratory tract injury accompanying thermal trauma.

Burn injuries in native Canadians: a 10-year experience.

Between 1977 and 1986, 1598 patients were admitted to the Firefighters' Burn Unit of the University of Alberta Hospital in Edmonton, Alberta. One hundred and twenty-five (7.8 per cent) of these patients were Treaty Indians or Metis compared to 4.2 per cent of the general population in the same given area. The data show native people suffered larger total body surface area (TBSA) burns, were hospitalized on average 16.9 days longer and required 0.7 more operations than their non-native counterparts. Natives are also three times more likely to remain within the health care system as inpatients for rehabilitation after acute burn management has been completed. Mortality rates as a result of these burns were similar for natives (4.8 per cent) and non-natives (4.3 per cent). This review indicates that the native population is at higher risk of suffering burn injury even after adjusting for certain demographic variables, consequently impacting the utilization of the health care system.

Canadian Association of Radiologists: treatment results in 2719 patients with carcinoma of the endometrium 1973-1977.

A retrospective analysis of treatment results in 2719 patients with endometrial cancer registered at 14 Canadian cancer centres in the 5-year period 1973-1977 was performed. The patients had a median age of 61.5 years and an overall 5-year survival of 78.5% (relative survival rate 86.0%). After preoperative radiotherapy the number of poorly differentiated and deeply invasive lesions seen at hysterectomy was reduced. The 1063 patients with stage I cancer treated with preoperative radiotherapy had a 5-year survival rate of 85.9% and a 5-year actuarial complication rate of 3.8%. The 359 patients with stage I cancer who had a hysterectomy followed by radiotherapy had a survival rate of 81.6% and a complication rate of 11.9%. Both differences are statistically significant (p less than 0.05 and p less than 0.0001 respectively). External beam radiotherapy was associated with the majority of severe complications. The actuarial complication rate in patients treated with postoperative radiotherapy was 9.8%, but when radiotherapy had been given before hysterectomy, it was 4.4% (p less than 0.001). We conclude from this study that when adjuvant radiotherapy is indicated, in the (generally elderly) patient with endometrial cancer it is safer to give preoperative rather than postoperative treatment. This largely avoids administering external beam radiotherapy with its potential high complication rate and no benefit in extended survival.