JOURNAL READING

HYPONATREMIA: A NEW PREDICTOR OF

MORTALITY IN PATIENTS WITH SHIGA
TOXIN-PRODUCING ESCHERICHIA COLI
HEMOLYTIC UREMIC SYNDROME
Laura F. Alconcher1 & Paula A. Coccia2 & Angela del C. Suarez3 & Marta L. Monteverde4 &
María Graciela Perez y Gutiérrez5 ,dkk

M. Farid Huzein
OBJECTIVE

1) Evaluate mortality rate in patients with Shiga toxin-

producing Escherichia coli hemolytic uremic
syndrome
2) Determine the leading causes of death, and
3) Identify predictors of mortality at hospital
admission.
METHODS

We conducted a multicentric, observational, retrospective,

cross-sectional study. It included patients under 18 years old
with Shiga toxin-producing Escherichia coli hemolytic uremic
syndrome hospitalized between January 2005 and June
2016. Clinical and laboratory data were obtained from the
Argentine National Epidemiological Surveillance System of
Hemolytic Uremic Syndrome. Clinical and laboratory variables
were compared between deceased and non-deceased
patients. Univariate and multivariate analyses were
performed. ROC curves and area under the curve were
obtained.
RESULT
Seventeen (3.65%) out of the 466 patients died, being
central nervous system involvement the main cause of
death. Predictors of death were central nervous system
involvement, the number of days since the beginning of
diarrhea to hospitalization, hyponatremia, high hemoglobin,
high leukocyte counts, and low bicarbonate concentration on
admission. In the multivariate analysis, central nervous
system involvement, sodium concentration, and hemoglobin
were independent predictors. The best cut off for sodium
was ≤ 128 meq/l and for hemoglobin ≥ 10.8 g/dl.
CONCLUSION

Mortality was low in children with Shiga toxin-

producing Escherichia coli hemolytic uremic
syndrome, being central nervous system involvement
the main cause of death. The best mortality predictors
found were central nervous system involvement,
hemoglobin, and sodium concentration. Hyponatremia
may be a new Shiga toxin-producing Escherichia coli
hemolytic uremic syndrome mortality predictor.
INTRODUCTION
Hemolytic uremic syndrome (HUS) is characterized by
microangiopathic hemolytic anemia, thrombocytopenia,
and variable degrees of renal compromise

Most of the cases are associated with diarrheal prodrome

induced by a Shiga toxin-producing Escherichia coli (STEC)
infection

Incidence  8.5/100,000 in children under 5 years old

(2011-2015)

HUS  Acute renal failure, responsible for 9% renal

transplants in children and adolescents
 Acute
Renal
Failure

Mortality

Leuko
cytosis Hemoglobin

Hematocrit

Dyalisis

Mortality
Shiga toxin-producing
Escherichia coli (STEC) AIM: (1) evaluate mortality rate, (2)
infection an endemic determine the causes of death, and
(3) identify predictors of death at
disease in Argentina hospital admission in Shiga toxin
producing Escherichia coli hemolytic
uremic syndrome (STEC-HUS)
patients
Methods • This was a multicentric, observational,
retrospective, and crosssectional study.

• Patients under 18 years old with STEC-HUS,

Subject hospitalized from January 2005 to June
2016
 •Gender,
•Age (in months),
•Days since the beginning of diarrhea to hospitalization,
Clinical •Use of antibiotics and/or anticholinergic drugs before
admission

Variables •Anuria (< 1 ml/ kg/day),

•Hemorrhagic colitis,
•Hydration state (dehydration, proper hydration, over hydration),
•Central nervous system (CNS) involvement (normal, irritability,
somnolence, seizures, and coma).

• Leukocytes (cell count per mm3)

• Neutrophils (%)

Laboratory • Hematocrit (%)

• Hemoglobin (g/dl)
• Platelets (count per mm3)

Variables • Sodium and potassium concentration (mEq/l)

• pH
• Bicarbonate (mEq/l)
• Creatinine and urea values (mg/dl).
 • To determine death predictors, we compared
deceased and non-deceased patients

Analysis • The information analyzed was the data at

hospital admission that uploaded in the National
Health Surveillance System

• Epidat-4.2 software
• Quantitative variables between deceased and non-deceased
patients were compared with ANOVA
• Association between categorical variables and the patient
mortality (i.e., presence-absence) was analyzed by X2 test
Statistics • Predictors of mortality, identify by simple logistic regression
• A multivariate logistic regression analysis was performed
• ROC and AUC were also obtained
• Sensitivity (S), specificity (s), and positive and negative
predictive values PPVand NPV, respectively) were obtained
• Significance level considered was P < 0.05
METHODS
HUS Criteria STEC Infection Criteria Ethical Clearance

•We defined HUS as the • STEC infection was •This study was
triad: identify by at least one of approved by the
these three laboratory
criteria: Review Boards and
•Thrombocytopenia (< Ethics Committees of
150,000/mm3) • Screening by polymerase the hospitals.
•Microangiopathic chain reaction (PCR) •The requirement to
hemolytic • Isolation of STEC, obtain informed
anemia(esquistocytes detection of free Shiga consent was waived
in blood smear), and toxin (Stx) in stool by the institutional
•Renal dysfunction • and in the last years, by review boards.
(increase of serum the detection of anti-
lipopolysaccharide
creatinine antibodies O157, O145,
concentration and/or O121 (anti-LPS).
proteinuria and/or
hematuria)
RESULTS
Tabel 2

Terdapat perbedaan bermakna pada kedua grup

Terdapat perbedaan bermakna pada kedua grup
Tabel 3

Terdapat perbedaan bermakna pada kedua grup

Terdapat perbedaan bermakna pada kedua grup
Tabel 4

 The best cut off for hemoglobin was ≥ 10.8 g/dl (S = 68.75%, s
= 79.56%, PPV = 11.6%, NPV = 98.5%).
 The best cut off for sodium concentration was ≤ 128 mEq/l (S
= 70.59%, s = 79.03%, PPV = 11.7%, NPV = 98.6%)
DISCUSSION
Previous studies identified
leukocytosis, greater hematocrit
or hemoglobin, CNS
complications, hemorrhagic
colitis, and recent respiratory
tract infection as death predictors
in children with post diarrhea HUS
In this study, Patients with CNS
involvement, hyponatremia (sodium
≤ 128 mEq/L), and hemoglobin ≥
10.8 g/dl had a higher probability of
in-hospital death
DISCUSSION
CNS involvement is the most
threatening complication
associated with increased
morbidity and mortality in
children with STEC-HUS
(Occurs 17–50%)
The mechanisms of damage in In this study,
the CNS are frequently mortality was
considered to be due to multiple
specially associated
factors, including local
microangiopathy, hypertension, with coma and
and hyponatremia seizures
DISCUSSION

Acute hyponatremia results in

Hyponatremia was
brain swelling and intracranial
Hyponatremia has not been
and can progress to life- identified as a death
previously established as a
threatening neurologic predictor at hospital
death predictor at hospital
complications, which can lead
admission admission in this
to permanent brain damage or
study
death
DISCUSSION

This association between high
The majority of studies,
hematocrit and the severity of
including our own, conclude
STEC-HUS likely reflects
that greater hemoglobin or
dehydration and
hematocrit upon admission
hemoconcentration (meta-
are major death predictors
analysis by Grisaru et al)
Two predictors of
poor outcomes
among STEC-infected
children who
progressed to HUS is
the lack of
intravenous fluid and
a higher hematocrit
value at admission.
DISCUSSION

An increase leukocyte count on

In this study, leukocyte counts were
peripheral blood at diagnosis is
higher in patients who died, but the
one of the most consistent
multivariate analysis did not identify
parameters associated with poor
this factor as being related to death.
prognosis and death

This unexpected finding can be explained because in our study, we

only analyzed laboratory variables at hospital admission
DISCUSSION
Recently, a shorter period of time
between the onset of diarrhea and a
diagnosis of diarrhea-associated
HUS as a risk factor for more severe
clinical course (Ninchoji et al)
In this study, also found that the number
of days since the beginning of diarrhea
to hospitalization was significantly
shorter in the group of deceased
patients
 1) Design is
retrospective
2) The number of
deaths was low.

First study to provide

clinical and laboratory
predictors of in-
hospital death in
patients with
confirmed STEC-HUS
CONCLUSION

Hyponatremia showed a
The mortality rate was The best mortality predictors strong association with
low in STEC-HUS patients were CNS involvement, high mortality rate and may
and CNS involvement was hemoglobin, and sodium be a new STEC-HUS
the main cause of death concentration predictor of poor outcome
and death.
TELAAH KRITIS JURNAL

UMUM
 TELAAH KRITIS JURNAL
No HAL YANG CHECK LIST PENILAIAN YA TIDAK
DINILAI
1 Judul a. Apakah judul tidak terlalu panjang atau
Makalah pendek? 
b. Apakah judul menggambarkan isi utama
penilaian? 
c. Apakah judul cukup menarik? 
d. Apakah judul menggunakan singkatan
selain yang baku? 
2 Abstrak a. Apakah merupakan abstrak satu paragraf, 
atau abstrak terstruktur Terstruktur

b. Apakah sudah tercakup komponen IMRAC 

(Introduction, methods, Results,
Discussion?)
c. Apakah secara keseluruhan abstrak 
informatif?
d. Apakah abstrak lebih dari 250 
kata? 237 kata
 No HAL YANG CHECK LIST PENILAIAN YA TIDAK
DINILAI
3 Pendahuluan a. Apakah mengemukakan alasan
dilakukannya penelitian? 
b. Apakah menyatakan hipotesis atau
tujuan penelitian? 
c. Apakah pendahuluan didukung oleh
pustaka yang kuat dan relevan? 

4 Metode a. Apakah disebutkan desain, tempat & 

waktu penelitian?
b. Apakah disebutkan populasi sumber 
(populasi terjangkau)?
c. Apakah kriteria pemilihan (inklusi & 
eksklusi) dijelaskan?
d. Apakah cara pemilihan subjek (teknik 
sampling) disebutkan?
e. Apakah perkiraan besar sampel 
disebutkan & disebut pula alasannya?
f. Apakah perkiraan besar sampel dihitung 
dengan meggunakan rumus yang
sesuai?
N HAL YANG CHECK LIST PENILAIAN YA TIDAK
o DINILAI

g. Apakah observasi, pengukuran, serta intervensi

dirinci sehingga orang lain dapat 
mengulanginya?
h. Bila teknik pengukuran tidak dirinci, apakah _
disebutkan rujukannya?
i. Apakah definisi istilah & variabel penting 
dikemukakan?
j. Apakah ethical clearance diperoleh? 
k. Apakah disebutkan rencana analisis, batas
kemaknaan & power penelitian? 

5 Hasil a. Apakah disertakan tabel deskripsi subjek 

penelitian?
b. Apakah karakteristik subjek yang penting (data 
awal) dibandingkan kesetaraannya?
c. Apakah dilakukan uji hipotesis untuk kesetaraan
ini? 
d. Apakah disebutkan jumlah subjek yang diteliti? 
No HAL YANG CHECK LIST PENILAIAN YA TIDAK
DINILAI

e. Apakah dijelaskan subyek yang drop out 

dengan alasannya?
f. Apakah semua hasil di dalam tabel
disebutkan dalam naskah? 
g. Apakah semua outcome yang penting
disebutkan dalam hasil? 
h. Apakah subyek yang drop out diikutkan -
dalam analisis?
i. Apakah disertakan hasil uji statistik (x2,t) 
derajat kebebasan (degree of freedom),
dan nilai p?
j. Apakah dalam hasil disertakan komentar 
& pendapat?

6 Diskusi a. Apakah semua hal yang relevan 

dibahas?
b. Apakah dibahas keterbatasan penelitian,
dan kemungkinan dampaknya terhadap 
hasil?
No HAL YANG CHECK LIST PENILAIAN YA TIDAK
DINILAI

c. Apakah disebutkan kesulitan penelitian, 

penyimpangan dari protokol, dan
kemungkinan dampaknya terhadap hasil?
d. Apakah pembahasan dilakukan dengan
meghubungkannya dengan teori dan hasil 
penelitian terdahulu?
e. Apakah dibahas hubungan hasil dengan 
praktek klinis?
f. Apakah disertakan kesimpulan utama 
penelitian?
g. Apakah kesimpulan didasarkan pada data 
penelitian?
h. Apakah efek samping dikemukakan dan
dibahas? 
i. Apakah disebutkan hasil tambahan selama
diobservasi? 
j. Apakah disebutkan generalisasi hasil
penelitian? 
k. Apakah disertakan saran penelitian
selanjutnya, dengan anjuran metodologis 
yang tepat?
TELAAH KRITIS JURNAL

KHUSUS
 VALIDITY

1. Apakah awal penelitian didefinisikan dengan jelas ? (pertanyaan

penelitian / tujuan penelitian)
 Ya, penelitian ini bertujuan untuk :
1) menilai angka mortalitas,
2) menentukan penyebab utama, dan
3) mengidentifikasi prediksi kematian pada perawatan pasien
STEC-HUS

2. Apakah menyatakan desain penelitian dengan jelas ?

 Ya, Desain penelitiannya adalah multisenter, observational,
retrospektif dan cross-sectional

3. Apakah pembanding dinyatakan jelas?

 Ya, Variabel yang diteliti ( klinis dan laboratorium) dibandingkan
antara penderita STEC-HUS yang meninggal dan tidak meninggal
4. Apakah pemantauan (follow up) pasien dilakukan cukup
panjang dan lengkap?
Tidak dilakukan follow up, penelitian bersifat retrospektif,
mengambil data pasien STEC-HUS dari Sistem Informasi
Surveilens Kesehatan Nasional Argentina
5. Apakah ada identifikasi dengan jelas kelompok dengan
prognostik yang berbeda?
Ya, hasil penelitian ini menyatakan bahwa prediktor
mortalitas yang terbaik pada pasien STEC-HUS adalah
adanya gangguan SSP, kadar Hemoglobin, konsentrasi
Natrium serum
6. Apakah outcome dinilai dengan kriteria objectif?
Ya, pada penelitian ini nilai prediksi kematian tertinggi
apabila hiponatremia (Na< 128 mEq/l) dan hemoglobin (>
10,8 gr/dl)
IMPORTANT

1. Apakah outcome / hasil dipaparkan secara jelas ?

 Ya, hasil penelitian dipaparkan secara jelas.

2. Seberapa besarkah ketepatan estimasi outcome yang

didapat dengan nilai p, or,rr dengan nilai korelasi
95% CI?
APLICABILITY

1. Apakah karakteristik pasien kita mirip dengan

subjek yang diteliti?
Tidak, pasien yang kita rawat dengan penyakit
STEC-HUS masih jarang
2. Apakah bukti ini akan mempunyai pengaruh yang
penting secara klinis terhadap kesembuhan
pasien kita tentang apa yang telah
ditawarkan/diberikan kepada pasien kita?
 Hasil penelitian ini bisa dijadikan rujukan dalam
prediksi kematian pasien STEC-HUS.
“TERIMA KASIH….”
 As a cause of enteric infections, 6 different mechanisms of action of
6 different varieties of E coli :
1. Enterotoxigenic E coli (ETEC) is a cause of traveler's diarrhea.
2. Enteropathogenic E coli (EPEC) is a cause of childhood diarrhea.
3. Enteroinvasive E coli (EIEC) causes a Shigella -like dysentery.
4. Enterohemorrhagic E coli (EHEC) causes hemorrhagic colitis
or hemolytic-uremic syndrome (HUS)
5. Enteroaggregative E coli (EAggEC) is primarily associated with
persistent diarrhea in children in developing countries
6. and enteroadherent E coli (EAEC) is a cause of childhood diarrhea
and traveler's diarrhea in Mexico and North Africa.
 ETEC, EPEC, EAggEC, and EAEC colonize the small bowel, and EIEC
and EHEC preferentially colonize the large bowel prior to causing
diarrhea
 Shiga toxin–producing E coli (STEC) is among
the most common causes of foodborne
diseases. This organism is responsible for
several GI illnesses, including nonbloody and
bloody diarrhea. Patients with these diseases,
especially children, may be affected by
neurologic and renal complications, including
HUS. Strains of STEC serotype O157-H7 have
caused numerous outbreaks and sporadic
cases of bloody diarrhea and HUS
 Patients with E coli HUS (caused by EHEC) have
fever, bloody diarrhea, dehydration, hemolysis,
thrombocytopenia, and uremia requiring dialysis.
Symptoms of E coli HUS range from asymptomatic
to nonbloody diarrhea to bloody diarrhea, renal
failure, microangiopathic hemolytic anemia,
thrombocytopenia, and CNS manifestations. The
differential diagnoses of E coli HUS
include Shigellainfections, Clostridium
difficile enterocolitis, ulcerative colitis/Crohn
disease, ischemic colitis, diverticulosis, and
appendicitis
 Infection with EHEC strains of the serotype
0157:H7 begin as watery diarrhea followed by
grossly bloody stool without inflammatory PMN
cells and results in HUS in 10% of cases,
characterized by hemolysis, thrombocytopenia,
uremia (possibly requiring dialysis), and death
in some cases.
 Medical care of E coli infection is based on the
site and severity of infection. In addition to
antibiotics, provide supportive care, such as
hydration, adequate oxygenation, and blood
pressure support, if indicated
 E coli enteric infections require fluid replacement
with solutions containing appropriate electrolytes.
Antimicrobials known to be useful in cases of
traveler's diarrhea include doxycycline,
trimethoprim/sulfamethoxazole (TMP/SMZ),
fluoroquinolones, and rifaximin. They shorten the
duration of diarrhea by 24-36 h. Antibiotics are not
useful in enterohemorrhagic E coli (EHEC)
infection and may predispose to development of
HUS. Antimotility agents are contraindicated in
children and in persons with enteroinvasive E
coli (EIEC) infection