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Treatment Modalities: Stevens-Johnson syndrome and toxic epidermal necrolysis
2011 Volume 4 No 1Wound Healing Southern Arica
Stevens-Johnson syndrome and toxic epidermal necrolysis:
topical treatment infuencing systemic response
Widgerow AD, MBBCh, FCS(SA) (Plast), MMed(Wits), FACS
Honorary Proessor, Plastic Surgery, University o the Witwatersrand and Irvine, Caliornia
Correspondence to: Alan Widgerow, e-mail: awidgerow@adarscience.com
Keywords: Stevens-Johnson syndrome, toxic epidermal necrolysis
Introduction
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN, Lyells syndrome) can be considered to be among the most
devastating and lie-threatening o the adverse skin reactions.
The two conditions are defned according to severity, based on the
extent o skin involvement. SJS is considered to be a minor orm
o TEN, characterised by less than 10% total body-surace area
(TBSA) o skin detachment, and an average reported mortality o
1-5%, whereas TEN is defned as more than 30% skin detachment,
and an average reported mortality o 25-35%.1 Both conditions
are characterised by keratinocyte apoptosis, and cleavage o the
epidermis rom the dermis, resulting in the exposure o large areas
o dermis akin to superfcial and partial thickness burn injuries. In
this paper, TEN will be used to denote both conditions.
Drugs most commonly associated with TEN are antibiotics such
as sulphonamides, tetracyclines and quinolones; anticonvulsants
such as phenytoin, phenobarbital and carbamazapine; antiretroviral
drugs; nonsteroidal anti-inammatory drugs; and allopurinol.1
TEN is a serious systemic disorder with the potential or severe
morbidity, and even death. Missed diagnosis is common. Although
sepsis is currently accepted as the main cause o mortality, much
o the morbidity and subsequent threat to lie is orchestrated by
an exaggerated inammatory response, with major outpouring
o cytokines and destructive matrix metalloproteinases (MMPs).
These mediators and proteinases cause intense destruction o the
extracellular matrix, major uid shits and a systemic inammatory
response (SIRS) that has lie-threatening consequences.2 Thus
modern therapeutic interventions, aside rom resuscitative eorts,
have sought to control not only the potential sepsis, but also the
marked inammatory response in relation to this pathology.
Nanocrystalline silver (NCS) is one such agent. It has exceptional
antimicrobial efcacy, but is also eective in lowering MMP levels, a
critical part o the disease process.3-5
In the South Arican environment, a number o doctors are using NCS
silver dressings to treat patients with TEN. However, no signifcant
data relating to clinical outcomes and resource utilisation or this
treatment modality are available. Twelve cases o confrmed TEN,
treated with NCS, were analysed with a view to assessing efcacy
and setting logical guidelines or this devastating condition.
Method
Cases were included where details were available and consented to
by patients, sta and amilies. Details were obtained rom medical
records, rom doctors treating the patients, and rom patients and
amilies o patients. Inormation was collated and analysis o this
inormation is presented.
Abstract
Toxic epidermal necrolysis (TEN) and Steven-Johnson syndrome (SJS) are rare, but potentially lie-threatening diseases, which relate to a
variety o medications, and which are characterised by widespread epidermal necrosis. Although sepsis is currently accepted as the main
cause o mortality, much o the morbidity and subsequent threat to lie is orchestrated by an exaggerated inammatory response with major
outpouring o cytokines and destructive matrix metalloproteinases (MMPs). These mediators and proteinases cause intense destruction o
the extracellular matrix, major uid shits, and a systemic inammatory response (SIRS) that has lie-threatening consequences. Modern
therapeutic interventions, aside rom resuscitative eorts, have sought to control not only the potential sepsis, but also the marked inammatory
response in relation to this pathology. Nanocrystalline silver (NCS) is one such agent. It has exceptional antimicrobial efcacy, but is also
eective in lowering MMP levels, a cr itical part o the disease process. Twelve cases o confrmed TEN, treated with NCS, were analysed with
a view to assessing efcacy and setting logical guidelines or this devastating condition. Eleven out o the 12 cases were categorised in the
TEN diagnostic group, with total body-surace area involvement ranging rom 22-100% (mean 64%). Two patients in the series died (16.6%),
but both had a severe co-morbid disease background. Topical application o NCS (Acticoat, Smith and Nephew Hull, UK) dressings, as part
o a comprehensive dressing protocol, proved successul in the management o this devastating disease. Guidelines or the management o
TEN are suggested.
Medpharm Wound Healing Southern Africa 2011;4(1):17-24
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Treatment Modalities: Stevens-Johnson syndrome and toxic epidermal necrolysis
2011 Volume 4 No 1Wound Healing Southern Arica
Twelve cases were included in the study. Eleven out o 12 cases
were categorised in the TEN diagnostic group. One patient (22%
TBSA) was classifed in the intermediate area between SJS and TEN.
No reactions were o the milder SJS orm and TBSA involvement
ranged rom 22-100% (mean 64%). Two patients in the series died
(16.6%). All patients had a clinically confrmed diagnosis o TEN.
The dressing routine was as ollows: wounds were cleansed with
water, saline, or diluted chrlorhexidine and dry skin ragments were
removed. Operating room debridement was undertaken where
deemed necessary by the physician. Intrasitegel (Smith and Nephew
Hull, UK) was applied to wounds and Acticoat (Smith and Nephew
Hull, UK) was applied over the gel. In the majority o cases, classic
Acticoat (a three-layered dressing) was used. The gel created a
moist environment in which to activate the Acticoat dressing, and
to encourage moist wound healing and epithelialisation. A secondary
absorbent dressing, usually oam such as Allevyn oam or Exudry
(Smith and Nephew Hull, UK, or equivalent), was applied i excess
moisture or exudate was anticipated. Most dressings were changed
every three days, unless excess exudate dictated daily dressings
or the frst ew days (three out o 12, 25% o cases). Acticoat
dressings were stopped when epithelialisation was judged to be 90%
complete. I the wound was considered to be deep partial thickness
or deeper, or where scarring or contracture was considered to be
a real possibility, a biological skin substitute was introduced to the
dressing regimen, such as Biobrane (Smith and Nephew Hull, UK).
Operative debridement was carried out using Versajet apparatus
(Smith and Nephew, Hull UK) where deemed necessary.
ResultsThe group comprised seven emale patients and fve male patients.
Age varied rom eight to 52 years (mean 31 years). Background
diseases included diabetes, tuberculosis, immunocompromised state,
epilepsy, varied respiratory problems, head injuries, depression, and
addiction rehabilitation (see Table I). The average number o days
rom the onset o SJS/TENS to diagnosis was 4.6 (+3.8), median 3.0,
range 1-10. In the majority o cases sulphonamides (50%, six out
o 12) or carbamezapine (33.3%, our out o 12) were administered
as causative agents. Epilepsy prophylaxis occurred in 42% o cases
(fve o 12), with epilepsy being diagnosed in only one o these cases.
The mean number o days o exposure to the causative agent was
5.8 days (range one to 24). All cases presented with superfcial-to-
partial thickness (one case, 6% deep partial thickness within 22%
TBSA) wounds. No ull thickness wounds resulted, and no skin
grating was necessary. Two deaths occurred in the series, related to
respiratory ailure (16.6%).
The treatment regimen ollowed routine lines o resuscitation. Nine
out o 12 cases were treated in burn wound acilities, with the
majority o cases (10 out o 12, 86%) having passed through the
intensive care unit (ICU) or high-care acilities. Initial resuscitation
(correct uid loss assessed, as or burn injuries), immediate
withdrawal o the oending agent on recognition and varied pain
control (analgesics to narcotics) was unremarkable. Intravenous
steroids were used in one case, and intravenous immunoglobulins
in two o the 12 cases (16%).
The TBSA o skin disruption varied rom 22-100% (mean 59%). The
most common isolated organisms were Staphylococcus aureus,
Pseudomonas aeruginosa, and Enterobacteriaceae species, with
blood-borne septicaemia disease confrmed in only one case.
Mouthwashes were prescribed where oral mucosal involvement was
evident. A dermatologist or plastic surgeon conducted the diagnosis
and management in seven cases (58%), and an ophthalmologist was
consulted in our cases (33%). Operating room debridement was
undertaken in 33% o cases. Most dressings were changed every
three days, except where copious exudate dictated daily dressings
or the frst ew days in three o the 12 cases (25%).
Only six out o 12 cases were treated in the operating room; two
o these or a tracheotomy procedure, rather than or debridement,
and dressing change (one patient had tracheotomy and dressings
perormed in the operating room). Dressings were carried out in
ICU, high care, or in the ward in eight out o 12 cases. Operative
procedures involved debridement and dressings in our cases, and
three tracheotomy procedures. No dressing application problems
were reported. Only one case reported residual scarring and
pigmentation related to the TEN, but these resolved without sequelae.
No unctional problems were reported in this patient. This was the
only contracture that was reported that related to a tracheotomy
procedure. Following discharge, it resolved over a ew months.
Commonly reported TEN complications were noted in this series (see
Table II), with the exception o sepsis and Septicaemia, that were
not commonly observed. Only two cases (both 100% exposure)
experienced signifcant sepsis problems. Two cases o septicaemia
were seen, one o which resolved completely over a ew days.
Long-term ever, or other symptoms and signs o inection, were not
apparent ollowing the application o the dressing regimen, other
than in the one recorded case.
Acticoat dressings were stopped when epithelialisation was judged
to be 90% complete. Time to healing ranged rom 12 days to 65 days
(mean 23 days). A biological skin substitute (Biobrane) was added
to the dressing regime in three o the 12 cases (25%) and Versajet
debridement was carried out in three cases (25%).
Table I: Primary diagnosis, causative actors and co-morbidities (n = 12)
n %
Primary diagnosis/causative factor
Toxic epidermal necrolysis: sulphonamide allergy 6 50
Toxic epidermal necrolysis: carbamazepine allergy/epilepsy 4 33.3
Toxic epidermal necrolysis: lamictin allergy/epilepsy 1 8.3
Toxic epidermal necrolysis: chickenpox/varicella/acute tonsillitis 1 8.3
Co-morbidities
None 2 16.7
Turberculosis and type 2 diabetes 1 8.3
aDiabetes and immunocompromised 1 8.3
aTurberculosis and immunocompromised 1 8.3
Addiction, dependency, depression 1 8.3
a = deaths
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Treatment Modalities: Stevens-Johnson syndrome and toxic epidermal necrolysis
2011 Volume 4 No 1Wound Healing Southern Arica
Discussion
First described in 1922, SJS is an immune-complex-mediated
hypersensitivity disease. TEN and SJS are rare, but potentially lie-
threatening diseases that relate to a variety o medications, and are
characterised by widespread epidermal necrosis.1,2,6 The majority
o cases appear to be related to idiosyncratic drug reactions,
and the drugs most commonly cited include antibiotics such as
sulphonamides, tetracyclines and quinolones; anticonvulsants such
as phenytoin, phenobarbital and carbamazapine; antiretroviraldrugs; nonsteroidal anti-inammatory drugs; and allopurinol.1,2 In
this series, sulphonamide antibiotics (50%) and carbamezapine
drugs (33%) were responsible or the vast majority o cases. Skin
biopsy is the defnitive diagnostic investigation, demonstrating
subepidermal bullae, epidermal cell necrosis, and perivascular areas
infltrated with lymphocytes.1 However, in this series, as in others,
the clinical diagnosis was made relatively easily without impacting
on the prognosis, and without skin biopsy.
Aside rom the devastating consequences o the skin separation,
TEN can involve inammation and subsequent necrosis o mucous
membranes, including oral, nasal, ophthalmic, vaginal, urethral,
gastrointestinal and lower respiratory tract tissues, with severe
internal maniestations o this disease. Three cases in this series
eatured oral mucous membranes, which contributed considerably
to the morbidity seen in these cases (see Figure 1). Enteral eeds
(three patients) were ound to be better tolerated and more eective
than parenteral eeds (one patient, longest recovery).
It is likely that lower respiratory tract involvement was a major
actor in the two deaths in this series. Both these cases died o
respiratory distress, and both were immunocompromised [human
immunodefciency virus (HIV)], one case being compounded by
pulmonary tuberculosis. The TBSA in these cases was 35% and
60%, and the wounds did not appear to present a major problem in
management o these cases.
Presentation
Patients reported a non-specifc upper respiratory tract inection in
most cases. The prodrome o up to 14 days was characterised by
ever, sore throat, headache and malaise. Mucocutaneous lesions
and blistering then began in specifc regions (see Figure 2). The initial
presentation was very similar to an acute burn wound, dependent on
the TBSA exposure: hypotension, ever, tachycardia and dehydration.
In three cases, oral lesions prevented patients rom eating or
drinking. In three cases, ocular involvement was documented.
The SCORTEN scale is a severity-o-illness scale with which
the severity o certain bullous conditions can be systematically
determined (see Table III). It was originally developed or TEN.7 In the
SCORTEN scale, seven independent risk actors or high mortality are
systematically scored, so as to determine the mortality rate or that
particular patient.
Table II: Complications relating to toxic epidermal necrolysis (n = 12)
Anaemia (as defned by the World Health Organization) requiring packed
cells or blood transusion5
Mucous membrane involvement, e.g. oral, nasal and gastrointestinal
involvement, oesophageal strictures4
Ocular involvement, e.g. symblepharon, keratoconjunctivitis,pseudomembranous conjunctivitis
4
Pneumonia or lower respiratory tract involvement (inormation rom
treating physician)4
Renal ailure (inormation rom treating physician) 3
Septicaemia (positive blood cultures) 2
Genital involvement, e.g. penile scarring, vaginal stenosis (inormation
rom treating physician)2
Ater resolution: scarring, cosmetic deormity, contractures, unctional
problems2
Postinammatory hyperpigmentation 1
Pulmonary embolus 1
Recurrence o inection through slow-healing wounds -
Figure 1: Toxic epidermal necrolysis cases with oral mucous membrane involvement Figure 2: Appearance o mucocutaneous lesions and blistering
Table III: The SCORTEN scale
Risk factor 0 1
Age < 40 years > 40 years
Associated malignancy No Yes
Heart rate (beats/minute) < 120 > 120
Serum blood, urea, nitrogen (BUN) (mg/dl) < 27 > 27
Detached or compromised body surace < 10% > 10%
Serum bicarbonate (mEq/l) > 20 < 20
Serum glucose (mg/dl) < 250 > 250
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Treatment Modalities: Stevens-Johnson syndrome and toxic epidermal necrolysis
2011 Volume 4 No 1Wound Healing Southern Arica
The more risk actors that are present, the higher the SCORTEN
score, and the higher the mortality rate, as shown in Table IV.7
In this series, the SCORTEN system proved to be only partially useul.
Prognostic actors were signifcantly increased in the two cases that
died (scored 3 and 4 respectively), but the chart did not accurately
reect the signifcance o the background diseases that appeared to
play a dominant role in the death o these patients. Although the HIV
status does not necessarily coner added risk (this will be discussed
later), it appears that HIV, combined with another background
illness, severely compromises the prognosis. In this series, the
two patients who died were both HIV positive, one compounded by
severe pulmonary tuberculosis, the other with advanced diabetes.
Had these actors been taken into account by changing the risk
parameter to associated malignancy, or immunocompromised or
co-existent severe chronic disease, both these cases would have
been classifed as 5 or more in the prognostic scale, with a > 90%
mortality. This is even more apparent when one considers that the
patient with severe HIV and pulmonary tuberculosis was a young
adult, had 35% TBSA wounds, but was overwhelmed by respiratory
system ailure.
Intravenous treatment and debridement
Although TEN is a serious systemic disorder with the potential or
severe morbidity and even death, no efcacious pharmaceutical
treatments have been established as standard therapy.1.2 When
easible, admission to a burns or intensive care unit is considered
crucial.1,2,8 Immediate withdrawal o the suspected drug, uid
and electrolyte replacement and topical wound care orms the
cornerstone o frst-line therapy.1,8 Interestingly, corticosteroid usage
has been abandoned (used in one case in this series), and the role
o immunosuppressants in this context is not well understood, and is
not considered standard.1 Having noted this, the role o intravenous
immunoglobulins (IVIG) is worthy o urther discussion.
The largest o the studies involving IVIG was a multicentre study o
48 patients with TEN. Success was concluded based upon an 88%
survival rate, but also the rapid (mean o 2.3 days) cessation o skin
and mucosal detachment in 89.6% o the patients. Mortality was
associated with a lower dose o IVIG, longer time o onset to IVIG use,
co-existing underlying chronic conditions, older age, and greater
body surace area involved.9-13 Brown et al12 reported on 45 patients
with a TBSA epidermal detachment o 45%. Twenty-one were treated
with standard therapy, and 24 were treated with IVIG. Mortality was
42% in the IVIG group, vs 29% in the standard-care group. Mortality
in the IVIG-treated group was also higher than that predicted by
SCORTEN (38%). These surprising results were discussed by French
et al.14 Several eatures o this study were noted as unusual. Wound
debridement, a practice that is no longer routinely recommended,
was perormed on all patients at admission.1 The authors suggest
that the association o IVIG treatment and debridement may have
impacted on the poor outcome in the study. Additionally, the lowdose and late administration o IVIG may have contributed to the
surprising results.1
These are interesting observations. In this series, our cases
underwent debridement in the operating room (18, 30, 30 and 65
days healing time). Two cases had IVIG therapy (18 and 24 days
healing time), one o which underwent operating room debridement.
Interestingly this case involved a TBSA o only 22%, the smallest
surace area in this series, but the deepest recorded wounds (18
days healing time). The size o this series precludes us rom making
any defnite decisions in this regard. However, some observations
are appropriate. IVIG did not seem to have an impact on prognosisin these cases. Debridement did not seem to aect healing time or
prognosis, but numbers are small or defnitive statements. One may
argue that cases reerred to plastic surgeons may have been more
severe, and thus may have warranted debridement in the operating
room. However, the other parameters o these cases (TBSA, systemic
symptoms and signs) do not confrm this supposition. Thereore,
debridement and IVIG therapy do not appear to be constants in a
TEN therapeutic regimen. This is especially complicated in HIV-
positive patients. These patients are more prone to TEN when their
CD4 counts are high (able to mount a response). Administration o
IVIG may help to douse the immune response, and theoretically haltthe process o skin separation. However, it is unknown whether
debridement and exposure o large areas o wounds in patients who
have decreased CD4 counts now, makes them more susceptible to
inective complications. An alternative therapeutic agent that halts
the skin separation process, without systemic immune modulation,
would be preerable. This may be possible with the right choice o
dressing, an important ocus o this paper.
Additionally, a total o six blood transusions were administered.
Three o our patients were debrided, and three o eight were
not debrided. The trend appears to demonstrate a likelihood o
debridement being ollowed by blood replacement, although othervariables may be possible. Thus, aggressive debridement should be
restricted unless absolutely necessary. In most cases, a controlled
gentle washing or debridement should sufce.
The use o systemic steroids remains controversial.1 Treatment with
systemic steroids has been associated with an increased prevalence
o complications. The ophthalmology literature contains several
papers that advocate systemic and topical steroids to minimise
ocular morbidity.15-19 Treatment with steroids appears to be limited
to that directed against ocular complications.
Causative drugs and human immunodeciency virusUse o therapeutic drugs is reported in over 95% o patients with
TEN. A strong association between drug ingestion and development
Table IV: Risk actors in relation to mortality ra te
Risk factors Mortality rate
0-1 3.2%
2 12.1%
3 35.3%
4 58.3%
5 or more > 90%
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Treatment Modalities: Stevens-Johnson syndrome and toxic epidermal necrolysis
2011 Volume 4 No 1Wound Healing Southern Arica
o the cutaneous eruption is observed in 80% o cases.1-3 Many
drugs have been identifed as causative agents, and the drugs in
this series appear to be typical o those reported previously. 1,8,20.21
However, with the advent o greater numbers o HIV-positive cases,
antiretrovirals have come into ocus. More particularly, nevirapine
has been reported as a cause o TEN in some reports.22,23 Metry etal reported Stevens-Johnson syndrome in two HIV patients treated
with nevirapine, and mentioned one other in the literature.24Although
sulphonamide drugs have been the most common cause o adverse
skin reactions in HIV-inected patients or many years, nevirapine
has become the leading cause o severe skin reactions in these
patients in the past decade.23 Although the incidence o nevirapine-
related rash is reported to be as high as 36.0%, the requency o
TEN described in HIV patients on ART is relative low, between 0.3-
1.5%.22-26 Risk actors or nevirapine-related rash include the emale
sex, a high baseline CD4 cell count, a history o drug allergy, lower
body weight, a high nevirapine plasma level, and probably certain
human leukocyte antigen types.22-26
Allied to this, many patients are treated or complications o HIV
inection, particularly respiratory complications and pneumonia
[(Pneumocystis carinii pneumonia (PCP)] with sulphonamide
antibiotics. This increases the risk o TEN considerably, particularly
in cases with high CD4 counts. The overlap o sulphonamide and
nevirapine therapy in these patients may make identifcation o
the causative agent more difcult. It is important that physicians
are aware o the potential problems associated with these drugs
in this group o patients. Sulphonamide antibiotics appear to be
particularly troublesome in this regard, and it may be time to seek
alternatives, or to strictly control the time o exposure to these
drugs when dealing with respiratory complications o HIV disease.
Physicians should consider the risk o the lie-threatening cutaneous
reactions when prescribing a change to a nevirapine-based regimen
in patients with a high CD4 count. In this series, it is important to
note that the HIV status o many o the patients on sulphonamide
antibiotics was not known, or disclosed. In keeping with South
Arican laws o confdentiality, this inormation was not orthcoming.
Thus, it is possible that more o these cases were HIV positive. It is
noteworthy that o the two cases who died, both were HIV positive,
one with advanced HIV disease and pulmonary tuberculosis, and the
other, with advanced diabetic disease. The signifcance o severe co-
morbidities is stressed.
In dealing with HIV patients in many situations, the current regimen
advocates using sulphonamide antibiotics as prophylaxis against
PCP when CD4 counts are low. Once antiretrovirals are started, and
the CD4 counts rise to an acceptable level, the sulphonamides are
stopped. Although difcult to ascertain rom this study, it is likely that
as CD4 counts increase, patients are probably going to be susceptible
to TEN i they are on sulphonamide antibiotics. It would be worthwhile
considering withdrawing the sulphonamides as soon as the CD4
count starts responding and rising, rather than waiting or it to reach
high levels, especially i they are being used prophylactically. This
is worthy o urther discussion with physicians. O course, this will
help i the TEN is a result o sulphonamide exposure. I nevirapine
is the cause, the problem will persist. It would appear that in cases
o immunosupression, patients appear to be more susceptible to
TEN outbreaks as their immune status improves. It is during this
transition o immunity that careul drug choices and usage, or
limitations, should be borne in mind by managing physicians.
An additional observation that warrants discussion concerns the use
o antiepileptic prophylaxis, or the use o these drugs in patients
without documented epilepsy. In this series, only one patient was
reported to have diagnosed epilepsy. The other our cases were
prescribed antiepileptic drugs or head injury, meningitis and
depression, as part o a rehabilitative programme. Circumspection
is needed when choosing drugs, especially when they are selected
prophylactically.
Infection
With cleavage o the epidermal rom the dermal plane, impaired
barrier unction o the skin results, with inevitable bacterial
colonisation. Inection is generally considered to be the major
actor associated with morbidity and mortality in TEN.1,7-10 However,
although ever was present in many cases periodically, sepsis and
Septicaemia were not the major components o morbidity in 10 o
12 cases in this series. It would appear that the efcacy o NCS
against bacterial burden and gross sepsis had the desired eect o
controlling any overwhelming septic incidents. The one exception to
this was the case involving 100% o the TBSA. This was a severely
ill patient, with a delayed transer to the surgeon, and where
healing took 65 days, the longest in the series. In this case, multiple
organisms were isolated, including Candida albicans. Interestingly,this was the frst case, dating back eight years, in which NCS was
used. Excluding this case, mean healing time in this series would
have been 15 days.
Additionally, when sta were questioned on the tipping point to
wound healing (when skin separation appeared to stop, and the toxic
symptoms and signs began to subside), 11 o the 12 related this
to the start o the NCS dressing regimen. The single case where
extended healing and septic episodes occurred is described above.
The two cases that died were not reported to have signifcant wound
healing problems. Sepsis did not appear to play a role in their
deaths, which were due to respiratory ailure, against a background
o severe chronic disease and compromised immunity. Overall
isolated organisms included Staphylococcus aureus, Pseudomonas
aeruginosa, Enterobacteriaceaeand in one case, Candida albicans
organisms. It is also important to note that prophylactic antibiotics
were prescribed in 90% o cases.
Nanocrystalline silver
Pathologically, cellular cleavage o the epidermis rom the dermis
occurs. The death receptor, Fas, and its ligand, FasL, have been
linked to the process, as has tumour necrosis actor-alpha (TNF-
alpha). Researchers have ound increased soluble FasL levels in the
sera o patients with SJS and TEN beore skin detachment, or the
inset o mucosal lesions.1,27 Others have also linked inammatory
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Treatment Modalities: Stevens-Johnson syndrome and toxic epidermal necrolysis
2011 Volume 4 No 1Wound Healing Southern Arica
cytokines to the pathogenesis.28 The process o epidermal basal cell
separation, with detachment o this layer, is very suggestive o a
proteolytic process thought to involve MMPs.28 Keratinocytes have
also been shown to express metalloproteinases such as gelatinase
A (MMP-2) and gelatinase B (MMP-9), which are able to degrade
components o the basement membrane.28 Increased gelatinaseactivity in theculture medium o skin rom TEN and SJS patients,
maintained in organ culture and in blister uid, may be responsible
or the detachment o the epidermis in this drug-induced necrolysis.28
As with many other inammatory conditions, the control o MMPs
and their destructive eects, appears to be critical. Additionally, the
two processes described above are likely to be interrelated. Recent
papers have suggested that the apoptosis o cells (endothelial and
neural) in varying disease processes may be as a direct result
o MMP-9 release, that, in turn, causes a release o extracellular
soluble FasL.43,44 I this is the case, the control o MMP-9 should
aect the entire cleavage and apoptotic process that is seen in TEN.
This is where NCS has become a very exciting therapeutic modality
or control o these conditions. Acticoat NSC dressings exert rapid
(within 30 minutes) and potent (releasing active silver at a level
o 70-80 g/ml) antibacterial action that is sustained or a period
o three days.31 Not only does NCS have a broad, eective, well-
accepted potency against bacterial and ungal organisms, but the
Ag0 ion appears to oer signifcant anti-inammatory eects.3-5,32-34
This is particularly evident against MMP-9, the destructive gelatinase
responsible or much o the destruction in the wound milieu o
chronic non-healing wounds, chronic wound uid corrosive eects,
and in some acute (dermatitic) conditions.35-37
MMP-9 coordinates and eects multiple events that are involved
in the process o epithelial regeneration.35,38 In an acute surgical
wound, MMP-9 is transiently expressed.38 In contrast, MMP-9 is
persistently elevated in chronic wounds. Increased MMP-9 is seen
in decubitus ulcers, venous stasis ulcers and non-healed burn
wounds. As these wounds heal, MMP-9 disappears.35-37 MMP-9
is not expressed in normal, uninjured skin.38 Reis et al speculate
that the excess MMP-9 ound in the centre o burn wounds, or in
the chronic wound milieu, prevents reconstitution o the normal
dermal and epidermal structures.38 According to these authors, the
complicated interplay between the matrix attachment molecules,cytokines, inhibitors and activators in the wound environment
becomes disjointed and unbalanced in the wound that ails to heal.38
The TEN epidermal cleavage eect appears to ft well into this model
o MMP-9 excess.3-5,35
Most o the research that unearthed the anti-MMP-9 eect o NCS
started with studies that were carried out in a contact dermatitis
porcine model. Contact dermatitis is associated with potent
inammation and raised MMP-9 levels. NCS was shown to be
more eective than traditional anti-inammatory agents, such
as silver nitrate, in lowering inammatory mediators. 3-5,35 The
decreased inammation in the NCS-treated group was associated
with increased inammatory cell apoptosis, a decreased expression
o proinammatory cytokines, and decreased gelatinase (MMP-9)
activity. These data oer support that a species o silver (Ag 0) that
is uniquely associated with NCS may be responsible or the anti-
protease activity and improvement in healing.4 Results suggest
that at higher pHs, more o the total silver in solution is actively
anti-inammatory, likely to be related to Ag0 clusters.4,35 The Ag+
released into the solution reacts with hydroxyl ions, orming calciumhydroxide in the solution, and causing precipitation, resulting in
a greater amount o Ag0 species being available to aect its anti-
inammatory properties.39
Considering these acts related to the disease entity and the
therapeutic eects o NCS, it would appear that this is an ideal agent
or topical application to acute TEN wounds. The anti-inammatory
eects and efcacious bioburden-diminishing abilities appear to halt
the destructive process and decrease complications. Although this is
a small series, the use o NCS appears to have been very eective
in achieving these goals. This report echoes similar fndings in other
reported series or case reports.8,40
Recommended treatment
Although this series involved Smith and Nephew dressings, the
real ocus is on the use o NCS in a unique spectrum o pathology.
From the authors perspective, it is important that this study is not
misconstrued as one that recommends the products mentioned here
only. Many orms o oams, exudate absorbent dressings and other
hydrogels may well be acceptable to use in these cases. In act, it
is believed that the use o Versajet is not indicated in most TEN
cases. However, NCS (and to an extent, Biobrane) appear to be real
advances in the management o TENS.
Based on the fndings o 12 cases in this series, a provisional
guideline can be suggested or the management o TEN. This is
aimed at limiting disease progression and preventing inection.
An acute awareness o the condition is important, particularly in the
light o increased disease prevalence o specifc diseases, where
the disease process and the therapy put the patient at increased
risk o TEN occurrence. This will prevent unnecessary delays in
diagnosis. Consideration should be given to stopping prophylactic
sulphonamide antibiotics in HIV patients on antiretrovirals as soon as
CD4 counts are seen to be rising.
Once the diagnosis is made, this syndrome should be treated as
an acute burn, with admission to a burn wound centre i possible.
Full burn resuscitative measures are instituted. Anticoagulation with
low-dose heparin should be considered in all cases, as one would do
when treating comparable burn injuries.
Initial and continued debridement is controversial, and i considered
necessary by the surgeon, debridement with Versajet should be
gentle, at a very low setting, removing blisters and involved epidermis
without damaging the underlying dermis. This is an aspiration,
vacuum mode, rather than an excisional mode.41 (see Figure 3). This
is extremely important: i over-aggressive debridement is carried out,
the patient has a good chance o experiencing the added morbidities
o bleeding, sepsis, delayed healing and scarring. In most cases,
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2011 Volume 4 No 1Wound Healing Southern Arica
the nature o the injury appears to suit a mechanical gentle wash,
rather than an aggressive debridement. Thus Versajet is probably
not indicated in most cases.
Many cases can be dressed directly without debridement, ollowing
a gentle cleansing in the ICU/high-care environment. The NCS
dressing should applied as soon as possible. Initial application o
an hydrogel may acilitate the application o the Acticoat (NCS)
dressing. Choices are available, o Acticoat or Acticoat Flex,
making it easier to choose an appropriate dressing suited to the
wound circumstance. The amount o exudate, anatomical areas
involved, and nature o the wound, will determine which Acticoat
dressing would be used. Ideally, the dressing should be changed
every third day, or longer, i possible. This has the distinct advantage
o encouraging healing with minimum exposure o the wounds. It is
also advantageous in terms o pain control, an exceedingly important
component o the healing process. I deemed necessary, a secondary
absorptive dressing can be applied.
Should the wound be assessed to be deeper (deep partial thickness),
or in contracture-prone anatomical areas, a biological skin
substitute is an excellent addition to the process. This aids in dermal
regeneration and can prevent potential scarring and contractures in
anatomically prone areas.42 Additionally, a biological skin substitute
also reduces exudate loss and reduces pain, and decreases the
number o dressings, so it may be chosen as a primary dressing in
combination with Acticoat in many cases, even where depth is not
in question, but where anatomical areas are prone to contractures
(the neck, hands, eet and elbows). (See Figure 4.) In this series,
Biobrane was successully used in appropriate cases. The skin
substitute is placed on the wound frst, ollowed by the NCS dressing.
The combination dressings are changed when they appear saturated
with wound exudate, or i the wound appears to have dried. The
regimen is continued until 90% healing is achieved. Most o these
areas may then be let exposed with moisturising agents that are
used to prevent desiccation.
Systemic therapeutic interventions are applied on an individual
basis, according to circumstances. This includes intravenous
antibiotics, blood replacement and systemic respiratory or cardiac
support agents (inotropes, volume expanders and diuretics).
Enteral eeds are preerred to parenteral eeds.
Conclusion
TEN is a devastating disease, with signifcant mortality i not
diagnosed and managed early and aggressively. It is likely that therewill be increasing numbers o TEN due to more immunocompromised
patients, as a result o disease or treatment modalities.
In keeping with newer strategies to inuence systemic outcome
by targeting the local wound interace, newer dressings are being
used to aid healing and to control sepsis, and now to decrease the
destructive inammatory component o the disease. NCS is one such
agent that has an impressive antibacterial spectrum, but also has
the potential o dousing the excessive inammatory component o
the disease. As in previous reports, the dressing appears to have
been eective in this series o patients in terms o sepsis control and
Figure 3: Gentle debridement with Versajet. This is only when deemed
necessary. A gentle wash is preerable.
Figure 4: Application o a biological skin substitute (Biobrane) prior to the
Acticoat application
Figure 5: Surviving cases in the series underwent eective non-scarring
epithelialisation
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2011 Volume 4 No 1Wound Healing Southern Arica
initiating the tipping point o a halt to epidermal cleavage and the
start o re-epithelialisation (see Figure 5).8,40 Together with biological
skin substitutes, NCS can serve as an eective means to promote
healing, control pain and prevent contractures in a potentially
devastating disease process. I this can be achieved by local dressing
application, rather than systemic immune-modulating agents whichhave inherent problems or host and disease, the choice would be a
very logical one.
Acknowledgements
Acknowledgement is given to the ollowing clinicians or help with
clinical details relating to the cases discussed above: Drs Struwig,
Steyn, Schroder, Altena, Mokgosi, Moledi, Hartslie, French, Naude
and Sacoor.
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