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Nikolsky's sign: is it 'dry' or is it 'wet'?

Nikolsky's signs refers to the ability to induce peripheral extension of a blister as a consequence of applying lateral pressure to the border of an intact blister. Although initially used in reference to the pemphigus group of blistering dermatoses, a positive Nikolsky's sign can be seen in other bullous diseases such as toxic epidermal necrolysis and staphylococcus scalded skin syndrome. Appreciating whether the blister is 'wet' or 'dry' at the site of a positive Nikolsky's signs may have both diagnostic and prognostic significance which I illustrate with several clinical cases. Lastly, I review the significance of a positive Nikolsky's sign.

Aged↗

Management of toxic epidermal necrolysis in a pediatric burn center.

Toxic epidermal necrolysis (TEN) is an acute severe exfoliative skin and mucosal membrane disorder with a clinical picture similar to a total-body scald injury. Toxic epidermal necrolysis shares features with severe erythema multiforme seen in Stevens-Johnson syndrome, and is thought by some to be a maximal expression of this syndrome. Drug-related TEN is uncommon in children. Mortalities of 70% have been reported, and death is usually secondary to the bacterial and metabolic consequences of a large open wound. Over the past two years, four children with probable drug-induced TEN were treated successfully. Since the problems of infection, wound care, fluid balance, nutrition, and pain control are similar in TEN and major burn patients, treatment using the principles of burn care may improve survival.

Adolescent↗

Infant deaths due to unintentional injury. An 11-year autopsy review.

OBJECTIVE: The number and causes of unintentional infant deaths were determined to identify common, preventable infant deaths. DESIGN: Retrospective autopsy review. SUBJECTS: Infants aged 1 day to 1 year undergoing complete autopsies. SETTING: Autopsies performed by the Louisville Office of the Kentucky Medical Examiner's Program from 1979 through 1989. METHOD: The manner of death was designated as an "accident" based on review of autopsy findings, scene investigation, and investigation by law enforcement officials. The cases were divided into groups based on the nature of the unintentional injury. RESULTS: Causes of death included asphyxia in mechanically unsafe sleeping environments, overlying, drowning, scald burns, plastic bag suffocation, house fires, motor vehicle collisions, aspiration of foreign bodies, hypothermia, blunt head trauma, and alcohol toxicity. The largest group of deaths in this series resulted from mechanically unsafe sleeping environments. CONCLUSIONS: The majority of deaths in this series could have been prevented by minor changes in the household environment. The causes of fatal unintentional injury to infants are different from those in older children. Pediatricians should be aware of hazards unique to this age group.

Autopsy↗

Age as a risk factor for burn injury requiring hospitalization during early childhood.

OBJECTIVE: To examine the variation by age in the rates and causes of burn injury requiring hospitalization during early childhood. DESIGN AND SETTING: Hospital discharge data and a burn unit admission log were used to identify all children in the Denver (Colo) metropolitan area younger than 5 years who sustained burn injuries and were hospitalized in 1989 and 1990. Patients' medical records were reviewed. RESULTS: One hundred twenty-two children were identified with burn injuries that required hospitalization, an annual incidence of 40.5 per 100,000 children younger than 5 years. Children aged 6 months through 2 years accounted for 88% of all cases and were seven times more likely to be hospitalized for a burn injury than were children outside this age range. Scalding and contact with hot objects accounted for 64% and 20% of cases, respectively, and occurred primarily in the 6-month through 2-year age group. CONCLUSIONS: The findings underscore the importance of developmental stage as a determinant of risk and type of burn injury. Children aged 6 months through 2 years are at increased risk of severe burn injury and should be targeted for prevention efforts.

Age Factors↗

Improvement in survival with peptidyl membrane interactive molecule D4B treatment after burn wound infection.

OBJECTIVE: To examine the effects of peptidyl membrane interactive molecule D4B in a murine model of lethal burn wound infection. EXPERIMENTAL DESIGN: Four experiments were performed: (1) growth inhibition assays of Pseudomonas aeruginosa treated with D4B, 0 to 100 micromol/L; (2) in vitro coculture of bone marrow cells with D4B, 0 to 100 micromol/L; (3) D4B treatment survival studies after burn injury only or burn wound infection in mice; and (4) peripheral white blood cell count, burn wound tissue bacterial culture, and burn wound morphological analysis at days 1, 2, and 3 after injury. SETTING: University medical center laboratory. SUBJECTS: Groups of B6D2F1 male mice (20 each) were studied. INTERVENTIONS: Full-thickness scald burn, 15% of total body surface area, with P aeruginosa topical infection, and subeschar injections of D4B at 200 microg or 0.25 mL of placebo per mouse at 2 and 24 hours after injury. MAIN OUTCOME MEASURES: Animal survival after thermal burn wound bacterial infection, circulating leukocyte numbers, in vitro clonal cell culture of granulocyte-macrophage progenitor cells, and wound histopathological analysis. RESULTS: The survival rate in the D4B-treated group was nearly 2-fold greater than that in controls (P<.01) during 14 days of study. Bacterial quantitative wound cultures disclosed significant reductions in bacterial numbers at days 1, 2, and 3 in D4B-treated animals as compared with controls (P<.05 to <.01). D4B induced a dose-dependent inhibition of bacterial cell growth when added to in vitro P aeruginosa cultures (P<.01). Granulocyte-macrophage progenitor cell growth in culture was not altered by D4B treatment. D4B-treated animals displayed no signs of toxic effects or impairment in wound healing. CONCLUSIONS: The peptidyl membrane interactive molecule D4B had the ability to improve survival after gram-negative burn wound sepsis via direct antimicrobial effects. Peptidyl membrane interactive molecules may offer the potential of alternative treatments to standard topical agents or in patients with drug-resistant microbes.

Animals↗

Attenuation of the acute-phase response in thermally injured rats by cholesterol-containing cationic liposomes used as a delivery system for gene therapy.

HYPOTHESIS: Cholesterol-containing cationic liposomes alone modulate the acute-phase response and cytokine expression in thermally injured rats and are an effective delivery system for gene therapy in trauma. SETTING: Laboratory. INTERVENTION: Fifty-six adult male Sprague-Dawley rats with a full-thickness scald burn covering 60% of total body surface area were randomly divided into 2 groups to receive either intravenous injections of cholesterol-containing cationic liposomes or saline (control). MAIN OUTCOME MEASURES: Body weights, muscle and liver dry-wet weights, serum levels of constitutive hepatic proteins, acute-phase protein levels, and cytokine levels were determined at 1, 2, 5, and 7 days after thermal injury. RESULTS: Rats receiving cholesterol-containing cationic liposomes had less body weight loss, increased serum transferrin levels, and decreased serum alpha1-acid glycoprotein levels when compared with controls (P<.05). Serum interleukin 1beta and tumor necrosis factor alpha levels were decreased in rats receiving liposomes at 1 and 2 days after burn compared with controls (P<.05). CONCLUSIONS: These results suggest that cholesterol-containing cationic liposomes alone may have a beneficial effect in modulating the hypermetabolic response after burn injury by decreasing type 1 acute-phase proteins and the expression of the proinflammatory cytokines interleukin 1beta and tumor necrosis factor alpha. Therefore, cholesterol-containing cationic liposomes appear to be suitable as a delivery system for gene therapy in trauma.

Acute-Phase Reaction↗

Effect of multiple gene transfers of insulinlike growth factor I complementary DNA gene constructs in rats after thermal injury.

HYPOTHESIS: Multiple subcutaneous injections of cholesterol-containing cationic liposomes encapsulating the complementary DNA (cDNA) gene for insulinlike growth factor I (IGF-I) increase the rate of transfected skin cells and result in increased IGF-I protein levels in the skin with subsequent improvement in wound healing when compared with a single injection. SETTING: Laboratory. INTERVENTION: Twenty-four adult male Sprague-Dawley rats (350-375 g) received a full-thickness scald burn on 60% of their body surface. These rats were randomly divided to receive either 1 injection of liposomes containing 2.2 microg-cytomegalovirus-driven cDNA coding for IGF-I and 0.2 microg of the Lac Z gene cDNA construct, or 2 injections of liposomes containing 2.2 microg cytomegalovirus-driven cDNA coding for IGF-I and 0.2 microg of the Lac Z gene cDNA construct. MAIN OUTCOME MEASURES: Transfection rates and IGF-I protein levels in the skin and physiological responses to the IGF-I gene therapy, evaluated from changes in body weight, protein content in serum and liver, and the rate of burn wound healing. RESULTS: There was a significant decrease in transfection rate and IGF-I protein expression distal from the injection site in animals receiving 1 injection, as compared with a consistent increase in rats receiving multiple injections. Multiple injections improved the response to thermal trauma by increasing the extent of the healed burn wound 33 days after thermal injury (single injection, 31% +/- 1% vs multiple injections, 38% +/- 2%), total serum protein (single injection, 52 +/- 0.5 g/L vs multiple injections, 55 +/- 0.6 g/L), and total liver protein (single injection, 82.0 +/- 0.3 mg/mL vs multiple injections, 91.0 +/- 3.8 mg/mL), P<.05. CONCLUSIONS: Gene transfer rates can be increased by multiple injections of liposomes encapsulating IGF-I cDNA constructs. Increased transfer results in greater IGF-I protein skin concentrations, accelerated wound healing, and increased serum and liver protein concentrations. The clinical relevance of these findings is that liposomal gene constructs should be applied in well-defined distances to improve gene transfer in the skin, and thus clinical outcome after thermal injury.

Animals↗

Outcome for older burn patients.

BACKGROUND: Physicians will be increasingly responsible for an aging society whose members demonstrate a notable striving for independence. HYPOTHESIS: With standard treatment of burns, older patients will have a survival rate of more than 70%, with at least 60% of patients becoming fully functional 6 months after hospital discharge. METHODS: A 7-year retrospective medical review of burn unit patients was performed, and 221 ( 11%) of 1957 patients who were at least 59 years old were identified. RESULTS: Of 97 women (44%) and 124 men (56%), 64 (29%) had an associated smoke inhalation injury; 146 (66%), flame injury; and 44 (20%), scald injury. The bedroom and/or living room were the most common areas of injury (90 [41%]), followed by outdoors and the workplace (62 [28%]), the kitchen (40 [18%]), the bathroom ( 18 [8%]), and the garage or basement (11 [5%]) (P<.005). One hundred twenty-six injuries (57%) were associated with impaired judgment, mobility, or both. On hospital admission, 74 patients (36%) were intubated, 60 (30%) required intubation postoperatively, and 34 (18%) required both. The survival rate was 159 patients (72%) overall. Findings from an ethanol screening and a drug toxicology screening were positive in 22 and 32 patients (10% and 29%) on admission, respectively. Of the survivors, most were discharged to home with (87 [64%) or without visiting nurse supervision, and at 6 months after discharge, 16 patients (50%) in transitional care facilities were able to return to an independent level of functioning. Of the 59- to 69-year-old age group, 83 (86%) survived compared with 59 (69%) in the 70- to 79-year-old age group and 18 (47%) in the 80 years and older age group. CONCLUSIONS: In contrast to the usual male preponderance in patients with thermal injury, older women, many of whom are widowed, constituted almost half of the older patients admitted to the hospital. Modalities for injury prevention are necessary to provide optimal and safe household environments for a growing population of older persons.

Age Factors↗

Pharmacology of sulfadiazine silver. Its attachment to burned human and rat skin and studies of gastrointestinal absorption and extension.

The attachment of Ag110-labeled sulfadiazine silver (AgSU) to the burn wound of humans and full and partial thickness scald burns of rats was studied over time. The duration of Ag adherence to burned skin and the absorption and organ distribution of ingested AgSU was studied. Peak attachment to human burns was 1% of the administered dose in 24 hours. Rat wounds showed greater attachment. Dissections of the wounds showed 81% to 98.7% of this attachment to be in the most superficial layers of cells and no silver was observed in organs of surface-treated animals. Duration of attachment after one application was until wound slough with percent attachment dropping from 5% to 1.7% over that time. Oral ingestion resulted in substantial silver deposition, particularly in liver and lungs. Clearance occurs in three weeks. The basic function of AgSU may be through the slow release of silver into the superficial wound environment.

Animals↗

Experimental Proteus mirabilis burn surface infection.

We established a human burn isolate of Proteus mirabilis as an experimental pathogen. Infliction of a nonfatal scald injury (30%) rendered rats highly susceptible to lethal surface infection with this isolate. Dose-response experiments indicated that the lethal inoculation dose (50%) was less than 10(3) organisms per square centimeter. Histopathologically, surface colonization was followed by progressive growth with subsequent invasion of viable tissue. The invasion was not characterized by the perivascular or perineural lesions observed in experimental Pseudomonas burn sepsis. Bacteriologic examinations showed moribund animals to be bacteremic with the test strain and to have wound biopsy counts exceeding 10(6) organisms per gram of tissue. The role of bacterial motility as a virulence factor in this surface infection was investigated. Substrains selected for loss of subsurface spreading in soft agar lost virulence. This model of burn infection with a member of the Enterobacteriaceae should be used to evaluate topical and parenteral antimicrobial agents needed for the control of wound infections caused by such agents.

Animals↗

Topical chlorhexidine diphosphanilate (WP-973) in burn wound sepsis.

We studied the diphosphanilate salt of chlorhexidine (WP-973), as a 2% cream, for therapeutic activity in two rat models of fatal burn wound infection. Control treatments were infection and placebo cream; infection only; infection and 1% sulfadiazine silver; and burning only. Activity against Pseudomonas aeruginosa or Proteus mirabilis was tested in surface-inoculated rats with 20% scalds. Treatments were initiated 24 hours or four hours, respectively, after inoculation. Pseudomonas-infected rats were treated once a day for ten days. Proteus-infected rats were treated once a day for five days. In these experimental models, chlorhexidine diphosphanilate was equal to silver sulfadiazine, an established topical chemotherapeutic agent. In vitro activity was examined using bacteremia isolates from 65 burned patients. Using agar diffusion trench plates, chlorhexidine diphosphanilate was active against all strains. No evidence of cross-resistance between sulfonamide and chlorhexidine diphosphanilate or its components was observed.

Administration, Topical↗

Susceptibility to bacterial sepsis. Accurate measurement by the delayed-type hypersensitivity skin test score.

To test the hypothesis that any alteration in the delayed-type hypersensitivity (DTH) skin test response (not necessarily total anergy) reflects increased susceptibility to bacterial sepsis, male Sprague-Dawley rats presensitized to keyhole-limpet hemocyanin were subjected to a 30% full-thickness scald burn. Susceptibility to bacteria was assessed by the intradermal injection of Staphylococcus aureus 502A. The DTH response decreased following burn injury from 6.6 to 3.9 mm on days 2 and 8. Skin abscess size increased from 5.8 to 9.3 mm on day 2 and 8.9 mm on day 8. There was a significant inverse correlation between DTH skin test score and abscess size. Histologically there was no difference in the overall leukocyte accumulation in the abscess or the DTH reaction between the two groups, yet the overall size of the abscess was greater and the swelling of the dermis in the DTH response was less in the burned rats.

Abscess↗

Suppression of interleukin 2 production in an animal model of thermal injury is related to prostaglandin synthesis.

We performed studies using an animal model of thermal injury to confirm the observed decrease in interleukin 2 (IL-2) production in burned patients and to explore the underlying mechanisms. Ten mice subjected to a 25% scald were compared with ten anesthetized littermates (controls) and six untreated mice (normal mice) 1, 3, 5, 7, 10, 14, and 21 days after burn. Production of IL-2 by splenocytes was stimulated by concanavalin A alone, or in the presence of the cyclooxygenase inhibitor indomethacin or flurbiprofen. The IL-2 content of the resulting supernatant was determined by the response of the IL-2-dependent cell line CTLL-2. The IL-2 production was significantly suppressed in the burned mice at three days (mean +/- SEM, 30.9% +/- 5.2%), five days (19% +/- 5.5%), seven days (41.6% +/- 6.4%), and 21 days (20% +/- 4.5%). Significant enhancement of IL-2 production by indomethacin was seen in the burned group (mean, 95%), but not in controls (mean, 23.8%) or normal mice (mean, 17.2%), and similar effects were seen with flurbiprofen. In separate experiments the effects of exogenous prostaglandin E2 on lymphocyte blastogenesis and IL-2 production were studied, and an increased susceptibility to the inhibitory effects of prostaglandin E2 was observed following thermal injury.

Animals↗

Flow cytometric measurement of rat lymphocyte subpopulations after burn injury and burn injury with infection.

Increased infection rates in burned patients may result from a disproportionate increase in the suppressor subpopulations. Measurement of lymphocyte subpopulations is difficult in burned patients because gradient-purified cells are contaminated by nonlymphoid cells. The accuracy of flow cytometric subpopulation analysis was improved by restricting (gating) the analysis to cells with light-scatter intensity typical of lymphocytes. Blood was obtained 48 hours after burn from rats receiving no burns, 30% scald burns, or burns seeded with Pseudomonas aeruginosa to induce infection. Subpopulations were identified by monoclonal antibodies to T-lymphocyte antigens. Gating increased the values obtained for most subpopulations, but the relative differences between groups were unchanged. Burned and infected animals, but not animals burned only, had a decreased ratio of helper to suppressor lymphocytes (HSR) relative to control. A decreased HSR correlated with sepsis, but not with infection susceptibility. This suggests that a decrease in HSR may be a result of infection rather than a cause of susceptibility to infection.

Animals↗

Early burn wound excision and skin grafting postburn trauma restores in vivo neutrophil delivery to inflammatory lesions.

This study assessed the effect of early vs delayed postburn wound excision and skin grafting on the in vivo neutrophil delivery to a delayed-type hypersensitivity (DTH) reaction and a bacterial skin lesion (BSL). Male Lewis rats were presensitized to keyhole-limpet hemocyanin. Group 1 comprised sham controls. Groups 2 through 4 were given a 30% 3 degrees scald burn, but the burn wounds were excised, and skin was grafted on days 1, 3, and 7, respectively, after the burn. Group 5 comprised burn controls. Twelve days after burn trauma, all rats were injected at different intervals (during a 24-hour period) with a trio of intradermal injections of keyhole-limpet hemocyanin, Staphylococcus aureus 502A, and saline at different sites. In vivo neutrophil delivery to these dermal lesions was determined by injecting indium in 111 oxyquinoline-labeled neutrophils isolated from similarly treated groups of rats. Neutrophil delivery to DTH and BSL lesions was restored to normal by excision and skin grafting of the burn wound one day after burn trauma. Waiting three days after burn trauma to excise and skin graft the wound partially, but not completely, restored the in vivo neutrophil delivery to DTH and BSL lesions. Waiting one week to excise and skin graft a burn wound resulted in no improvement in neutrophil delivery to DTH and BSL dermal lesions. It was concluded that burn wound excision and skin grafting immediately after burn trauma restored in vivo neutrophil delivery to a BSL and DTH dermal lesion. This may, in part, explain the beneficial effect of early aggressive burn wound debridement in patients with burn injuries.

Animals↗

Additive effects of thermal injury and infection on gut permeability.

OBJECTIVE: To determine the effects of burn size and burn wound infection on gut permeability to the macromolecule polyethylene glycol 3350 (PEG 3350; molecular weight, 3350 d). DESIGN: Randomized, controlled study using 36 male Sprague-Dawley rats. SETTING: Hospital research laboratory. INTERVENTIONS: Animals received scald burns to 0%, 20%, or 35% of their total body surface area. Half of the animals in each group were infected with Pseudomonas aeruginosa. MAIN OUTCOME MEASURES: Gut permeability was measured using the intestinal absorption and renal excretion of enterally administered PEG 3350 and mannitol (molecular weight, 182 d). RESULTS: There were dramatic increases in PEG 3350 excretion and in the PEG 3350/mannitol ratios (P = .0001 in both instances) that were seen in relation to burn size. Significant increases in PEG 3350 excretion and in the PEG 3350/mannitol ratios (P = .017 and P = .045, respectively) were also seen in animals in which infection was present. This was in addition to the effects of burn size already noted. CONCLUSIONS: A direct relationship between gut permeability and the extent of burn injury was found, which is consistent with the results from a previous study in humans. In addition, this study found that further separate increases in gut permeability occur in the presence of P aeruginosa in burn wound infections.

Animals↗

Augmented tumor necrosis factor response to lipopolysaccharide after thermal injury is regulated posttranscriptionally.

BACKGROUND AND OBJECTIVE: Thermal injury has been shown to enhance macrophage sensitivity to lipopolysaccharide (LPS), resulting in augmented tumor necrosis factor alpha (TNF-alpha) production. This study was designed to examine whether enhanced TNF-alpha response after thermal injury and LPS stimulation is regulated at the level of transcription. DESIGN: Tumor necrosis factor alpha release in alveolar macrophages harvested from sham- or thermal-injured Wistar rats was determined using an L929 cytotoxicity bioassay on days 1, 3, and 5 following 40% scald burn and incubation for 24 hours with LPS (0 or 10 micrograms/mL). Separate groups of rats underwent intraperitoneal injection of LPS (5 mg/kg) 3 days following sham or thermal injury. Lung tissue RNA was isolated and probed for TNF-alpha messenger RNA (mRNA), using nuclease protection analysis. Finally, pooled alveolar macrophages were harvested 3 days following sham or thermal injury and cultured in the presence or absence of LPS (10 micrograms/mL) for 4 hours. The RNA from the pooled alveolar macrophages was extracted and probed for TNF-alpha mRNA levels. RESULTS: Thermal injury alone did not significantly increase alveolar macrophage TNF-alpha bioactivity, whole-lung TNF-alpha mRNA levels, or pooled alveolar macrophages TNF-alpha mRNA levels when compared with levels in sham-injured rats. However, alveolar macrophages from postburn day 3 (PBD 3) demonstrated increased sensitivity to LPS (10 micrograms/mL) compared with alveolar macrophages from sham-injured animals undergoing similar LPS treatment (2365 +/- 1011 vs 169 +/- 79 ng/mL; P < .05). Whole-lung mRNA levels in both sham-injured and PBD-3 rats receiving intraperitoneal LPS, while elevated approximately 2.5-fold from those of non-LPS treated rats, were not different from each other. Finally, pooled alveolar macrophages from sham-injured and PBD-3 rats cultured in the presence of LPS had approximately 1.7-fold and threefold increased TNF-alpha mRNA levels, respectively, compared with alveolar macrophages not cultured with LPS. CONCLUSIONS: Thermal injury induces priming of alveolar macrophages, resulting in significant increases in macrophage TNF-alpha production after exposure to LPS. The majority of this effect appears to be regulated at a posttranscriptional level, since there were only moderate increases in TNF-alpha mRNA levels after LPS stimulation, which did not coincide with large differences in bioactivity.

Animals↗

The role of cyclic adenosine monophosphate in the suppression of cellular immunity after thermal injury.

BACKGROUND AND OBJECTIVE: Cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is known to convey inhibitory signals for T-cell proliferation and function. We investigated the association between this molecule and the profound immunosuppression that accompanies thermal injury. DESIGN: Mice were randomized into two groups: one group was subjected to a 20% full-thickness scald burn; the second to a sham burn (control). The mice were killed on days 4, 7, or 10 after the burn injury and splenocytes were pooled and cultured for 15 minutes in the presence or absence of prostaglandin E2 (PGE2). RESULTS: Levels of cAMP in splenocytes were significantly elevated on day 7 after burn in the burn group compared with the sham controls (P < .05, Wilcoxon Rank Sum Test). Incubation of splenocytes with PGE2 resulted in significantly greater levels of intracellular cAMP in cells from the burn group compared with controls on days 4, 7, and 10. Incubation of normal splenocytes with dibutyryl cAMP in the presence of concanavalin A significantly decreased cell proliferation and the production of interleukin-2. The decrease in interleukin-2 production was evident at the level of messenger RNA expression. Stimulation of splenocytes with a combination of phorbol ester and calcium ionophore, bypassing all membrane-associated events prior to protein kinase C activation, reversed the inhibitory effects of dibutyryl cAMP. Incubation of splenocytes from burned animals with H-8, a selective inhibitor of cAMP-dependent protein kinases, restored the proliferative response to that of sham controls on days 4, 7, and 10 after thermal injury. CONCLUSIONS: These data indicate that elevated levels of intracellular cAMP, combined with an increased production of cAMP in response to circulating PGE2, may play a fundamental role in suppression of the immune response following thermal injury and that cAMP exerts its immunomodulatory effects prior to protein kinase C activation.

Animals↗