Journal Pre-proofs

Burn-care in Practice

Clinical features and prognosis of toxic epidermal necrolysis requiring inten‐

sive care: A retrospective descriptive single-center study

Yohei Sakai, Yusuke Nagamine, Masashi Yokose, Nobuyuki Yokoyama,

Tasuku Yoshida, Shizuka Kashiwagi, Shunsuke Takaki, Takahisa Goto

PII: S2468-9122(23)00033-0
DOI: https://doi.org/10.1016/j.burnso.2023.09.001
Reference: BURNS 305

To appear in: Burns Open

Received Date: 3 May 2023

Revised Date: 26 August 2023
Accepted Date: 5 September 2023

Please cite this article as: Y. Sakai, Y. Nagamine, M. Yokose, N. Yokoyama, T. Yoshida, S. Kashiwagi, S.
Takaki, T. Goto, Clinical features and prognosis of toxic epidermal necrolysis requiring intensive care: A
retrospective descriptive single-center study, Burns Open (2023), doi: https://doi.org/10.1016/j.burnso.
2023.09.001

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 1

Title:

Clinical features and prognosis of toxic epidermal necrolysis requiring intensive care:

A retrospective descriptive single-center study

Authors:

Yohei Sakai1, Yusuke Nagamine1, Masashi Yokose1, Nobuyuki Yokoyama1,

Tasuku Yoshida1, Shizuka Kashiwagi1, Shunsuke Takaki1, Takahisa Goto1

Affiliations:
1 Department of Anesthesiology and Critical Care Medicine,

Yokohama City University Hospital, Yokohama, Japan

3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Kanagawa, Japan

E-mail address of each author:

Yohei Sakai, sakai.yoh.vo@yokohama-cu.ac.jp

Yusuke Nagamine, ynagamin@yokohama-cu.ac.jp

Masashi Yokose, mayokose@yokohama-cu.ac.jp

Nobuyuki Yokoyama, voth@yokohama-cu.ac.jp

Tasuku Yoshida, ytasuku@yokohama-cu.ac.jp

Shizuka Kashiwagi, kashiwagi.shi.pz@yokohama-cu.ac.jp

Shunsuke Takaki, shun5323@yokohama-cu.ac.jp

Takahisa Goto, takigoto@yokohama-cu.ac.jp

Corresponding Author:
 2

Yusuke Nagamine, MD, PhD, MPH

Department of Anesthesiology and Critical Care Medicine,

Yokohama City University Hospital

3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Kanagawa, Japan

Phone: 045-787-2918

FAX: 045-787-2916

E-mail: ynagamin@yokohama-cu.ac.jp

ORCID:

Yusuke Nagamine, https://orcid.org/0000-0002-0443-5007

 3

Abstract

Background

Toxic epidermal necrolysis (TEN) is the most severe form of drug eruption, necessitating
intensive care management in several cases. Although guidelines have been established
for diagnosing and treating skin symptoms, few studies have reported on the intensive
care management and prognosis of TEN. This study aimed to investigate intensive care
for various types of organ failure associated with TEN and their prognoses.

Methods

This retrospective, descriptive, single-center study included patients admitted to our

intensive care unit (ICU) for treatment of TEN over a 10-year period. We investigated
the participants’ characteristics, organ failure and management, duration of ICU and
hospital stay, and prognosis, through the electronic medical and ICU progress records.

Results

This study enrolled eight patients. Most patients presented with multiple organ failure,
and in-hospital mortality was 50%. The median SOFA score at ICU admission was 9.5,
and the median maximum SOFA score during ICU stay was 16.0. All patients underwent
mechanical ventilation. Renal replacement therapy was administered to five patients. The
median length of stay in the ICU was 31.5 days, and the median duration of
hospitalization was 87 days. Survivors required long-term hospitalization, and only one
patient was discharged home.

Conclusions

Most TEN patients admitted to the ICU had multiple organ failure, and poor short- and
long-term prognoses.

Keywords:

Multiple organ failure, Prognosis, Toxic epidermal necrolysis, TEN, Drug eruption

Abbreviations:

TEN: toxic epidermal necrosis; SJS: Stevens-Johnsons syndrome; BMI: body mass
index; SOFA: Sequential Organ Failure Assessment; SCORTEN: Severity-of-Illness
Score for Toxic Epidermal Necrolysis; ARDS: acute respiratory distress syndrome;
KDIGO: Kidney Disease Improving Global Outcomes; MRSA: methicillin-resistant
Staphylococcus aureus; CHDF: continuous hemodiafiltration; CMV: cytomegalovirus;
DIC: disseminated intravascular coagulation
4
 5

Introduction

Toxic epidermal necrolysis (TEN), which is the most severe form of drug eruption, is a
serious disease characterized by erythema and erosions over a wide area of the body,
including the lips, mouth, eyes, and vulva. The condition is called Stevens-Johnson
syndrome (SJS) and TEN when epidermal peeling covers less than 10% or more than
30% of the body surface, respectively. The mortality rate is approximately 3-4% for SJS
and is as high as 20-30% for TEN. The most common causative medications are
analgesics, antibacterial drugs, anticonvulsants, and anti-hyperuricemic drugs [1].
Systemic management is necessary in conjunction with the treatment of skin symptoms,
and severe cases require intensive care.

Guidelines have been established for the diagnostic criteria and treatment of the
primary disease [1]. Prior studies have reported complications of organ damage, such as
severe pneumonia [2], gastrointestinal symptoms [3], and renal involvement [4].
However, few studies have reported on the intensive care management and prognosis of
TEN. Moreover, a standard protocol to guide actual systemic management in patients
with TEN is lacking, rendering intensive care management difficult.

This study aimed to conduct a detailed investigation of intensive care for various
types of organ failure and prognoses associated with TEN.
 6

Methods

Design, Setting, and Patients

This single-center, retrospective, descriptive study was conducted at Yokohama City

University Hospital, a 674-bed tertiary care center in Japan. Patients admitted to the
intensive care unit (ICU) for the treatment of TEN between January 2010 and March 2020
were enrolled in this study. The study design did not incorporate any exclusion criteria.

Measurements

Data were extracted from the electronic medical records and ICU progress records. We
investigated the participants’ age, sex, body mass index (BMI), comorbidity and Charlson
Comorbidity Index [5], duration of hospitalization and stay in the ICU, Sequential Organ
Failure Assessment (SOFA) score [6], and outcome. The primary disease was
investigated with respect to the suspected causative drug, maximum epidermal peeling
area during the period, Severity-of-Illness Score for Toxic Epidermal Necrolysis
(SCORTEN), and treatment method. The SCORTEN is a severity grading system for
TEN, which is scored on 7 items: age >40 years, heart rate >120 beats/min, history of
cancer or hematologic malignancy, epidermal peeling area >10%, blood urea nitrogen
>27 mg/dL, HCO3- <20 mmol/L, and blood sugar >233 mg/dL, which have been shown
to have a prognostic association with TEN [7].

We assessed the respiratory system by investigating whether or not tracheal

intubation or tracheostomy was performed, time to ventilator weaning, presence and
severity of acute respiratory distress syndrome (ARDS) [8], adjuvant treatment, and other
complications. The cardiovascular system was investigated with respect to the presence
of septic shock [9], the use of catecholamines, and the development of arrhythmias.
Furthermore, the presence and severity of acute kidney injury and renal replacement
therapy were investigated. The severity of acute kidney injury was staged using the
Kidney Disease Improving Global Outcomes (KDIGO) classification [10]. For the
gastrointestinal tract, the need for enteral nutrition or lack thereof, liver damage,
pancreatic damage, and other complications were investigated. Blood glucose control and
insulin use were investigated for the endocrine system. Blood coagulation was examined
by investigating the presence and type of blood transfusions, minimum platelet counts,
and anticoagulation therapy. The causative bacterial pathogens and the antimicrobials and
antivirals used to treat infection were investigated. The central nervous system was
investigated by assessing the analgesics and sedatives used for treatment and the
presence/absence of delirium.

Statistical analysis
 7

The median and quartile ranges were presented for descriptive statistics. Microsoft Excel
software was used for statistical analysis.
 8

Results

Patient characteristics were shown in Table 1. This study included 8 patients with TEN,
4 of whom were men. The median age at admission was 56 years [interquartile range
(IQR); 47.5-72.5], the median BMI was 20.8 (IQR; 19.6-24.7), and the median Charlson
Comorbidity Index was 1.5 (IQR: 0-5). The minimum length from the onset of TEN to
ICU admission was 2 days (Case 5), whereas the maximum was 158 days (Case 4). One
patient (Case 1) developed TEN 4 days after ICU admission. Three patients were
originally admitted to our hospital, whereas five patients had been transferred from other
centers. Among the transferred cases, only one patient had received treatment for TEN
(steroids, intravenous immunoglobulin, and plasma exchange) prior to being transferred.
The values of the Charlson Comorbidity Index, patient-related parameters, and principal
underlying disease for each participant are presented in Table 1.

The most common suspected causative drug for the primary disease was
acetaminophen in 4 patients (Table 2). The median maximum epidermal peeling area was
55% (IQR: 43.8-76.3), and the median SCORTEN at ICU admission was 4 (IQR: 3.8-
5.3). All patients received treatment with corticosteroids: six patients received
methylprednisolone 500-1000 mg/day for three days (pulse therapy). Plasma exchange
was performed for six patients, and immunoglobulin therapy was administered to all
patients.

Skin treatment was performed daily on TEN patients. The standard protocol
followed at our hospital comprises washing the lesion with warm water and covering the
lesion with gauze coated with dimethyl isopropylazulene. Pain management was
performed at the discretion of the intensive care physician for patients with severe pain.

All patients eventually developed multiple organ failure during the ICU stay (Table
3). The median SOFA score on ICU admission to the ICU was 9.5 (IQR: 8.5-11.3), and
the median maximum SOFA score during admission was 16 (IQR: 14-17.3). The majority
of the patients presented with multiple organ failure at the time of admission to the ICU.
All patients underwent intubation and management with mechanical ventilation for
control of the respiratory symptoms. The median time point of intubation was day 1 of
ICU admission (IQR: 1-3.5) (Table 4). The reasons for intubation were to protect the
airway from oral erosions and/or bleeding, for analgesic sedation management, and for
systemic management of severe circulatory failure. Six of eight patients underwent
tracheostomy during the course of treatment, at a median of day 28 after ICU admission
(IQR: 18-35.8). Five of the six patients who underwent tracheotomy were weaned from
ventilation, with a median duration of ventilation 27 days (IQR: 20-30). Two patients
were diagnosed with severe ARDS. Adjuvant therapy included neuromuscular blockers
and prone position therapy for one patient, but none of the patients were treated with
extracorporeal membrane oxygenation.

Three patients (37.5%) developed cardiovascular complications in the form of

septic shock (Table 5). All patients underwent central venous catheter insertion, and
catecholamine administration, as appropriate. The most commonly used catecholamine
 9

was noradrenaline, which was used in all patients, followed by vasopressin, which was
administered to four patients (50%). Two patients (25%) developed new arrhythmias: one
patient had paroxysmal atrial fibrillation and the other had atrial fibrillation.

All patients tested positive on blood cultures, with methicillin-resistant

Staphylococcus aureus (MRSA) being the most detected pathogen (Table 6). The most
frequently used antibiotics were anti-MRSA agents (vancomycin), which were
administered to seven patients (87.5%). β-lactam cephems, carbapenems,
aminoglycosides, and quinolones as well as antifungal and antiviral drugs were used as
appropriate.

Seven patients (87.5%) were diagnosed with acute kidney injury, which arose
from TEN in six patients, and one patient was originally on hemodialysis. Four patients
(50%) had stage 3 disease according to the KDIGO classification (Table 7). Renal
replacement therapy was administered to five patients (62.5%), four of whom had stage
3 acute kidney injury, and one (above-mentioned) patient was originally on hemodialysis.
All four patients who were newly started on renal replacement therapy died in the hospital
without withdrawal from renal replacement therapy. Four patients were administered
continuous renal replacement therapy, and one patient was administered slow low-
efficiency daily dialysis.

Investigations into gastrointestinal, hepatobiliary, and pancreatic diseases

revealed the following. All patients received post-pyloric nutritional therapy via the
enteral feeding tube. One patient was diagnosed with gastrointestinal perforation on
imaging, but the site of perforation was unknown, and surgery was not indicated. The
median of the highest total bilirubin concentration (an indicator of liver injury) during
ICU admission was 2.3 mg/dL (IQR: 1.6-6.6) (Table 8). The median highest value of
lipase (an indicator of pancreatic injury) was 80 U/L (IQR: 55.5-222). Acute pancreatitis
was not observed in any patient.

Four patients (50%) who were refractory to blood sugar control were
continuously administered insulin (Table 9).

Seven patients (87.5%) required transfusion. Red blood cells were transfused in
seven patients, fresh frozen plasma in five patients (62.5%), and platelets in five patients
(Table 10). Several patients also had low platelet counts, with a median lowest value of
3.75 x 104/µL (IQR: 2.7-4.8) during ICU admission. Anticoagulant therapy was also
administered to six patients (75%) for prophylaxis of deep vein thrombosis.

Propofol, dexmedetomidine, and fentanyl, which act on the central nervous

system, were administered to all patients. Ketamine was used concomitantly, mainly
during the skin procedures, in five patients (62.5%) (Table 11). Two (25%) patients were
diagnosed with overactive delirium and were concurrently referred to the psychiatry
department.

The median length of stay in the ICU was 31.5 days (IQR: 20-39.3), and the
median duration of hospitalization was 87 days (IQR: 52.8-110.3) (Table 12). There
 10

were four (50%) in-hospital deaths, one (12.5%) patient was discharged home, and three
(37.5%) patients were transferred to other hospitals. Among the three patients who were
transferred, two were back transferred to the hospital where they were originally
admitted, and their subsequent outcomes are unknown. Another patient could not be
discharged home and was transferred to a rehabilitation hospital; this patient is alive as
of July 2023. Two of the patients who died in the hospital died of multiple organ failure
due to TEN complications of the original malignancy. Case 1 was a patient with
peripheral T-cell lymphoma who went into septic shock after undergoing a bone
marrow transplant, developed TEN following the administration of antibiotics, and
subsequently died of multiple organ failure. Case 7 was a patient with prostate cancer
with bladder and rectal invasion who developed TEN following the administration of
the drugs used for hormone therapy and died of multiple organ failure, including renal
failure, which developed due to hydronephrosis resulting from the current disease. Case
6 patient had TEN-associated interstitial pneumonia complicated by bacterial
pneumonia, which developed into severe ARDS and resulted in death from hypoxic
respiratory failure. Case 3 patient developed TEN after surgery for infective
endocarditis, and although the skin condition improved, the patient subsequently
became septic and in poor general condition and died of a ruptured infective cerebral
aneurysm. Case 8 patient discharged from the hospital had residual sequelae, such as
skin symptoms and ocular adhesions, and were followed up as outpatients (as of July
2023; followed up for approximately 3 years after discharge).
 11

Discussion

This 10-year analysis of TEN cases treated at our ICU found that all patients presented
with multiple organ failure and a high mortality rate, and even survivors required
prolonged hospitalization and intensive care. Four of the eight patients included in this
study died, three were transferred to another institution, and only one patient was
discharged home.

The guidelines for TEN describe treatment for skin and eye lesions but mention
little about the treatment for complications associated with various organ systems.
Although patients with TEN are treated in accordance with the guidelines for the primary
disease, intensive care physicians refer to guidelines for each organ or ask the opinions
of the respective specialists for organ-related complications.

Most patients with TEN require endotracheal intubation, which may be performed
to protect the airway from oral erosions and/or bleeding, secure the airway for analgesic
sedation management, and for systemic management of severe circulatory failure. Since
the possibility of intubation is very high, it may be necessary to assess the need for
intubation daily and to perform it without delay; previous studies have shown that the in-
hospital mortality rate is high (57%) in patients with SJS/TEN requiring ventilation 2. The
duration of treatment is often prolonged for patients with TEN, and tracheostomies are
performed frequently. In this study, tracheostomy was performed a median of day 28 after
ICU admission, which is long because of coagulopathy and lesions at the tracheostomy
site. However, early tracheostomy has advantages such as reduced analgesia, early
weaning from ventilation, and early rehabilitation. Earlier studies have identified four
indications for tracheostomy within 10 days in patients presenting with oral lesions with
SJS/TEN: (1) epidermal desquamation >70%, (2) increased epidermal desquamation
>15% over 3 days, (3) difficulty in protecting the airway due to neurological
abnormalities, and (4) presence of lesions in the airway [11]. Although few studies have
reported on the association between ARDS and TEN, six of eight patients in the present
study were diagnosed with ARDS. A previous study found that three of 138 patients with
SJS/TEN were diagnosed with ARDS [12]. This difference in the frequency of ARDS
may be due to the fact that the patients in this study were limited to TEN and to patients
with severe disease. All patients in this study were critically ill and required intensive
care, and several were at risk for ARDS, for which sepsis is the most common etiology.
Thus, the management of patients with SJS/TEN should account for the possibility of
ARDS development.

Most patients with TEN develop complications due to infections, often culminating
in septic shock. The skin barrier function is disrupted, and the immune system is
suppressed by corticosteroid use. Notably, in the evaluation of infection in TEN, it is
difficult to distinguish between infection through the skin and bloodstream infection. In
this study, three of eight patients went into septic shock. Previous studies have shown that
13% of patients with SJS/TEN developed sepsis [13]; however, no study has reported the
percentage of patients who developed septic shock. In this study, MRSA was the most
common pathogen detected in blood cultures. In a previous study focusing on infection
 12

in SJS/TEN, Staphylococcal species was the most common pathogen, and Pseudomonas
aeruginosa was the most common gram-negative rod [14]. The most commonly used
antimicrobials in this study were anti-MRSA drugs. Previous studies reported that
vancomycin was used frequently [14], similar to the present study. The guideline of
SJS/TEN does not clearly state the use of antimicrobials but states that they should follow
the guideline of sepsis. In practice, on-site judgment is required, and infection treatment
should target MRSA and Gram-negative rods, so consultation with infectious disease
specialists is necessary. MRSA and methicillin-resistant Staphylococcus epidermidis
were detected in blood cultures in five of eight cases in this study, for which prophylactic
anti-MRSA drugs were used. Antivirals against cytomegalovirus (CMV) were used in
three of eight cases in this study. Notably, according to previous studies, reactivation of
CMV and Epstein-Barr virus often occurs in SJS/TEN [15].

Renal dysfunction is a frequent complication in patients with TEN and often

requires renal replacement therapy. In patients with TEN, particular attention should be
paid to the site of placement and method of securing the blood access catheter. Previous
studies have reported that renal dysfunction was observed in 14.9% of patients with
SJS/TEN [16]. Renal replacement therapy was used in 37.5% of patients with only TEN
[17]. Risk factors for renal dysfunction in patients with TEN include fluid loss due to
cutaneous symptoms, infection-induced complications, and gastrointestinal symptoms
such as diarrhea [4]. Previous studies have reported that the frequency of complications
such as shock was higher and the duration of hospitalization was longer in patients with
SJS/TEN diagnosed with acute kidney injury; the mortality rate was higher in patients
with KDIGO stage 2 and 3 than that in stage 0 and 1 [4], concordant with the present
study. Furthermore, all patients with KDIGO 3 or higher died, which may be a marker of
poor prognosis.

Patients with TEN often have severe oral mucosal symptoms that make oral intake
impossible, necessitating early nutritional therapy; relatively few patients with SJS/TEN
have gastrointestinal tract involvement besides the oral cavity (approximately 10%) [1],
suggesting that enteral nutrition can be started early. Contrastingly, it is generally
believed that corticosteroid administration increases the risk of gastrointestinal bleeding
and perforation [18]; thus, caution should be exercised while administering nutritional
therapy. In this study, some patients were diagnosed with liver or pancreatic injury due
to elevation in total bilirubin and lipase levels, which was considered to be symptomatic
of multiorgan failure. None of the patients developed liver failure or acute pancreatitis,
which should be differentiated from drug-induced liver injury caused by the drug
responsible for TEN.

Control of the blood glucose level is often difficult in patients with TEN because
of increased insulin resistance, owing to systemic inflammation and corticosteroid
administration. The control of blood glucose is associated with the prognosis of patients
with TEN; thus, the blood sugar level was adopted as a criterion in the SCORTEN system
[7]. It should also be noted that subcutaneous injection of hypoglycemics for blood
glucose control is difficult in the presence of skin symptoms.
 13

Patients with TEN present with anemia and coagulopathy due to persistent
inflammation and infection. Several participants in this study also presented with anemia
and coagulopathy characterized by thrombocytopenia. A previous study reported that 25
of 32 patients with SJS/TEN with disseminated intravascular coagulation (DIC) had
platelet counts of less than 8.0×104/µL or greater than 50% reduction [19], suggesting
that thrombocytopenia is an important consideration in this patient population. Previous
studies have reported that the frequency of DIC ranged from 1.3% [20] to 21% [19]
among patients with SJS/TEN. The mortality rate was reportedly 78.1% in patients with
SJS/TEN complicated with DIC compared to 6.8% in patients without DIC [19]. There is
no clear recommendation for drugs to DIC; anticoagulants may be difficult to use with
skin bleeding associated with TEN.

Analgesia, sedation, and the presence of delirium are also important aspects of
intensive care for TEN. Opioid analgesics are frequently used because cutaneous pain is
severe, and acetaminophen and other non-steroidal anti-inflammatory drugs are often
avoided since they may be suspected of causing TEN. The use of ketamine during wound
care was another characteristic feature of patient management in this study. Originally,
ketamine was commonly used for analgesia in burn patients and has been reported to
provide effective analgesia, in addition to reducing opioid use [21], and may be equally
effective in severe skin conditions such as TEN. Two patients in this study were
diagnosed with hyperactive delirium, but hypoactive delirium may not have been
diagnosed accurately. Patients with TEN are at a high risk of delirium due to prolonged
pain, long duration of sedation, sepsis, etc.

Patients with SJS/TEN have a very poor short-term prognosis, and survivors often
suffer from residual skin symptoms and complications. Although previous studies have
reported mortality rates of 31% at 6 months and 34% at 1 year after SJS/TEN [22], the 6-
month mortality rate in this study was as high as 50%. The prognosis of our study cohort
may be poorer than that reported by previous studies because our study only included
patients who were admitted to the ICU. Two of the four patients who died had been
diagnosed with malignancy (Cases 1 and 6). Patients with concomitant malignancy tend
to have a poorer prognosis due in part to the symptoms of the original malignancy, which
is consistent with the inclusion of the presence of malignancy in SCORTEN. Three
patients died of TEN-related organ failure (Cases 1, 6, and 7). Although the cause of death
in patients with TEN has not been reported in detail previously, it is likely that deaths due
to TEN-related multiple organ failure are common. Large epidemiological studies
focusing on organ damage and intensive care may be a starting point in improving the
prognosis of patients with severe TEN.

In the long-term prognosis, only one patient in this study was discharged home and
returned to society, albeit with some sequelae. Previous studies have shown that patients
with SJS/TEN have residual complications, such as skin manifestations and renal
dysfunction [23]. Future studies are needed to evaluate the quality of life of patients with
SJS/TEN after discharge.
 14

This study has several limitations. First, it incorporated a single-center design. Our
institution is a university hospital to which severe cases are referred, which may have led
to selection bias and poor prognosis. Intensive care management policies may be unitary
and lack generalizability. Second, the sample size was small. Multicenter studies are
needed in the future, owing to the rarity of cases of TEN requiring intensive care.

Conclusion

Patients with TEN admitted to the ICU were severely ill, and multiple organ failure was
inevitable. In addition to local skin management, multidisciplinary intensive care was
required for organ damage, sedation, and analgesia. Especially, all patients required
mechanical ventilation, and those requiring renal replacement therapy had a poor
prognosis. They had poor short-term prognoses with an in-hospital mortality rate of 50%
and a long-term prognosis with only one patient (12.5%) discharged home.
 15

Funding

This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Yokohama City University
(approval number: B200600008; chairperson: Dr. Shin Maeda; approval date: July 6,
2020). The need to obtain patient consent was waived, and patients were given the
opportunity to opt out on the Yokohama City University Hospital website.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the
corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Not applicable
 16

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18. Narum S, Westergren T, Klemp M. Corticosteroids and risk of gastrointestinal

bleeding: a systematic review and meta-analysis. BMJ Open 2014;4(5):e004587.

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Disseminated intravascular coagulation in Stevens-Johnson syndrome and toxic
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intravascular coagulopathy: a complication of Stevens-Johnson syndrome/toxic
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administration of injectable ketamine during burn wound dressing changes. J
Pharm Pract 2021;34(3):423–7.

22. Sekula P, Dunant A, Mockenhaupt M, Naldi L, Bouwes Bavinck JN, Halevy S, et

al. Comprehensive survival analysis of a cohort of patients with Stevens-Johnson
syndrome and toxic epidermal necrolysis. J Invest Dermatol 2013;133(5):1197–
204.

23. Lee HY, Walsh SA, Creamer D. Long-term complications of Stevens-Johnson

syndrome/toxic epidermal necrolysis (SJS/TEN): the spectrum of chronic
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multidisciplinary follow-up. Br J Dermatol 2017;177(4):924–35.
 19

Tables

Table 1 Patient characteristics (N=8)

 20

Patient 1 2 3 4 5 6 7 8

Age at 53 72 74 41 49 59 76 43
onset of
illness
(years)

Sex Female Male Male Female Female Male Male Female

BMI 20.6 18.6 20.8 Missing 17.8 31.4 24.3 25.2

(kg/m2)

Body 45.2 55.6 50.4 57 39 82.4 62.3 72.7

weight at
ICU
admission
(kg)

Principal Autoimm Af, Infectious Follicular Cerebral Hypertens Progressi None

underlyin une CRF endocardi lymphom palsy ion ve
g disease hepatitis, (dialysis) tis a prostate
(after cancer
Peripheral surgery)
T-cell
lymphom
a

Charlson 5 6 1 2 0 0 5 0
Comorbid
ity Index

Days -4 (Onset 6 8 158 2 7 14 4

from 4 days
onset to after ICU
ICU admission
admission )
 21

In- In- In- In- Transfer Transfer Transfer Transfer Transfer

hospital hospital hospital hospital
onset or onset onset onset
transfer

Outcome Death Transfer Death Transfer Transfer Death Death Discharge

to another to another to another
hospital hospital hospital

BMI: body mass index, ICU: intensive care unit, Af: atrial fibrillation, CRF: chronic renal failure
 22

Table 2 Information about the primary disease and its treatment

 23

Patient 1 2 3 4 5 6 7 8

Suspected Doripene Vancomy Ampicilli Sulfa+ Acetamin Acetamin Apalutam Acetamin

causative m, cin, n, Trimetho ophen ophen, ide ophen
drug Meropen Proton Acetamin prim, Tranexa
em pump ophen, Acyclovir mic acid,
inhibitor, Lansopra Losartan
Doripene zole potassiu
m m

Maximum
skin peeling 70 40 95 40 45 50 95 60
area (%)

SCORTEN 4 5 4 6 3 4 6 1

Corticosteroid
Yes No Yes Yes Yes Yes Yes No
pulse therapy

Maintenance Betameth Prednisol Betameth Prednisol Prednisol Betameth Betameth Betameth

corticosteroid asone one asone one one asone asone asone

Maximum
6 mg 40 mg 8 mg 50 mg 40 mg 12 mg 8 mg 8 mg
usage (/day)

IVIG therapy

Maximum 20 g 20 g 5g 2g 15 g 35 g 25 g 25 g
 24

usage (/day)

Number of
1 1 2 3 1 1 2 1
sets

Plasmapheres
Yes Yes Yes Yes No No Yes Yes
is

Number of
1 1 6 4 - - 4 2
sets

SCORTEN: Severity-of-Illness Score for Toxic Epidermal Necrolysis, IVIG: intravenous

immunoglobulin
 25

Table 3 Organ failure

Case 1 2 3 4 5 6 7 8

Respiratory failure ○ ○ ○ ○ ○ ○ ○ ○

Circulatory failure ○ ○ ○ ○ ○ ○ ○ ○

Renal dysfunction ○ Hemodialysis ○ ○ ○ ○ ○ ×

Gastrointestinal disorder ○ × × × × × × ×

Liver failure ○ ○ × × ○ ○ ○ ×

Pancreatic disorder × × ○ × ○ ○ ○ ○

Coagulopathy ○ ○ ○ ○ ○ ○ ○ ×

Infection ○ ○ ○ ○ ○ ○ ○ ○

SOFA score

At ICU admission 9 10 9 16 15 5 7 10

Maximum 17 11 18 16 16 20 15 10

Respiratory failure requiring mechanical ventilation, Circulatory failure requiring catecholamines,

Renal dysfunction that falls under the definition of KDIGO, Gastrointestinal disorder that have
developed as a result of toxic epidermal necrolysis such as perforation of the gastrointestinal tract,
Liver failure was indicated by total bilirubin > 2 mg/dL, and Pancreatic disorder was indicated by
lipase > 60 U/L, Infection was positive blood culture, SOFA: Sequential Organ Failure Assessment,
ICU: Intensive Care Unit
 26

Table 4 Respiratory system

Patient 1 2 3 4 5 6 7 8

Mechanical Ventilation ○ ○ ○ ○ ○ ○ ○ ○

Intubation ○ ○ ○ ○ ○ ○ ○ ○

Number of days from Before ICU

1 5 6 1 1 1 3
ICU admission to intubation admission

Tracheotomy × ○ ○ ○ ○ × ○ ○

Number of days from

1 3
ICU admission to 35 69 21 17
0 5
tracheotomy

Weaning from MV × ○ ○ ○ × × ○ ○

3
Duration of MV 9 42 27 20
0

ARDS × × × × ○ ○ × ×

Sever Sever
Severity
e e

Muscle-relaxant × ○

Prone position × ○

ICU: Intensive Care Unit, ARDS: acute respiratory distress syndrome, MV: mechanical ventilation
 27

Table 5 Circulatory system

Case 1 2 3 4 5 6 7 8

Septic shock × × ○ ○ ○ × × ×

Catecholamines

Noradrenaline ○ ○ ○ ○ ○ ○ ○ ○

Dopamine ○

Dobutamine ○ ○

Adrenaline ○ ○

Vasopressin ○ ○ ○ ○

Milrinone ○

New onset of arrhythmia pAf Af

Af: atrial fibrillation, pAf: paroxysmal atrial fibrillation

 28

Table 6 Infection

Patient 1 2 3 4 5 6 7 8

Blood culture ○ ○ ○ ○ ○ ○ ○ ○
positivity

Bacteria causing Candida MRS MRS MRS E. MR Corynebacteriu MRS

infection famata A A A coli SE m sp. A

CRE Serrat
ia

Antibacterial
drugs, etc.

β-lactam ○ × × ○ ○ × ○ ○
cephems

Carbapenem × × ○ × × ○ × ×

Anti-MRSA ○ ○ ○ ○ × ○ ○ ○

× × ○ ○ × × × ×
Aminoglycoside

Quinolone × ○ ○ × × ○ × ×

Antifungal ○ × ○ ○ ○ ○ ○ ×

Antiviral ○ × ○ × × × ○ ×

CRE: carbapenem-resistant Enterobacteriaceae, MRSA: methicillin-resistant Staphylococcus Aureus,

MRSE: methicillin-resistant Staphylococcus Epidermidis
29
 30

Table 7 Kidney

Patient 1 2 3 4 5 6 7 8

Acute kidney injury ○ Dialys ○ ○ ○ ○ ○ ×

is

KDIGO Stage 3 3 1 1 3 3

Renal replacement therapy ○ ○ ○ × × ○ ○ ×

Number of days from ICU admission to 1 1 Before ICU 17 29

renal replacement therapy admission

Details CH CHDF CHDF→HD CH SLE

DF → DF DD
SLED
D→
HD

KDIGO: Kidney Disease Improving Global Outcomes, ICU: Intensive Care Unit, CHDF: continuous
hemodiafiltration, HD: hemodialysis, SLEDD: slow low-efficiency daily dialysis
 31

Table 8 Gastrointestinal tract and hepatobiliary/pancreatic diseases

Patient 1 2 3 4 5 6 7 8

Maximum T-Bil (mg/dL) 9.4 2.1 1.4 1.7 8.2 6.1 2.5 1.3

Maximum lipase (U/L) 26 Missing 80 38 262 73 278 182

Gastrointestinal complications perforation

T-Bil: total bilirubin

 32

Table 9 Insulin use

Patient 1 2 3 4 5 6 7 8

Continuous intravenous insulin administration × × ○ ○ × ○ ○ ×

 33

Table 10 Transfusion and Coagulopathy

Case 1 2 3 4 5 6 7 8

Red blood cell ○ ○ ○ ○ ○ ○ ○ ×

Fresh frozen plasma ○ ○ ○ ○ × × ○ ×

Platelets ○ × ○ ○ × ○ ○ ×

Minimum platelets (10×4/µL) 1.1 8.3 3.2 0.3 4.6 3.7 3.8 5.2

Anticoagulant use × × ○ ○ ○ ○ ○ ○
 34

Table 11 Analgesics, sedatives, and delirium

Case 1 2 3 4 5 6 7 8

Analgesic

Fentanyl ○ ○ ○ ○ ○ ○ ○ ○

Ketamine × ○ ○ × × ○ ○ ○

Morphine × × × × × × × ×

Sedative

Propofol ○ ○ ○ ○ ○ ○ ○ ○

Dexmedetomidine ○ ○ ○ ○ ○ ○ ○ ○

Midazolam × × ○ ○ × × × ×

Delirium ○ ○
 35

Table 12 Length of stay in the ICU and hospital, and outcome

Patient 1 2 3 4 5 6 7 8

Length of stay in
33 9 45 43 30 21 38 17
ICU (days)

Length of stay in
76 98 141 100 147 21 52 53
hospital (days)

Outcome D Transfer to Death Transfer to Transfer to De D Disc

ea another another another ath ea harg
th hospital hospital hospital th e

Cause of death M Cerebral A M

O hemorrha R O
F ge D F
S

Days from ICU

admission to 33 120 21 51
death

ICU: intensive care unit, MOF: multiple organ failure, ARDS: acute respiratory distress syndrome
 36

Highlights:

 Most toxic epidermal necrolysis ICU patients admitted had multiple organ failure

 Patients had poor short- prognosis (in-hospital mortality 50%)

 Survivors required long-term hospitalization