ARTIKEL ASLI
MEDICINA 2017, Volume 48, Number 2: 128-132
P-ISSN.2540-8313, E-ISSN.2540-8321
Department of Child Health,
Medical School, Udayana
University, Sanglah Hospital,
Denpasar
*
Coresspondence to: Ni Luh Putu
Surya Candra Eka Pertiwi, MD
Department of Child Health, Medical
School, Udayana University, Sanglah
Hospital, Jl. Pulau Nias Denpasar Bali
+62-361-244038
dr_niluhputuscep@yahoo.com
Diterima 2 februari 2017
Disetujui 1 maret 2017
Diterbitkan: 1 mei 2017
128
Association between serum cortisol levels and
pediatric logistic organ dysfunction score
in critically ill patients
Ni Luh Putu Surya Candra Eka Pertiwi,* Wayan Bikin Suryawan,
I Made Arimbawa, Ida Bagus Gede Suparyatha
ABSTRACT
Activation of the hypothalamic-pituitary-adrenal axis with the
production of cortisol is a fundamental component of the stress
response and is essential for survival of the host in critical illness.
However, the studies of serum cortisol levels among critically ill
children in association with organ dysfunction are still lacking. The aim
of the study was to investigate the association between serum cortisol
levels and pediatric logistic organ dysfunction (PELOD) score in a group
of pediatric intensive care unit patients. We conducted a cross-sectional
study of pediatric intensive care unit (PICU) patients at Sanglah
Hospital, from February to April 2014. We included children aged 1
to 144 months and subjects were divided into two groups according
Keywords: cortisol, critical ill, children, PELOD score
Cite This Article: Pertiwi, N.S.C.E., Suryawan, W.B., Arimbawa, I.M., Suparyatha, I.B.G. 2017. Association between serum cortisol levels and
pediatric logistic organ dysfunction score in critically ill patients. Medicina 48(2): 128-132. DOI:10.15562/medi.v48i2.41
ABSTRAK
Aksis hipotalamus-hipofisis-adrenal merupakan komponen mendasar
dalam respon stres dan penting untuk kelangsungan hidup penderita
saat sakit kritis. Studi mengenai kadar kortisol pada anak sakit kritis
dan hubungannya dengan gangguan fungsi organ masih sedikit.
Tujuan penelitian ini adalah untuk mengetahui hubungan kadar
kortisol dan skor pediatric logistic organ dysfunction (PELOD) pada
pasien yang dirawat di ruang intensif anak. Penelitian ini merupakan
studi observasional potong lintang yang dilakukan pada pasien
berusia 1 hingga 144 bulan yang dirawat di ruang intensif anak Rumah
Sakit Sanglah sejak Februari hingga April 2014. Subjek dibagi menjadi
2 kelompok berdasarkan skor PELOD. Data dianalisis menggunakan uji t
Kata kunci: kortisol, sakit kritis, anak, skor PELOD
Cite Pasal Ini: Pertiwi, N.S.C.E., Suryawan, W.B., Arimbawa, I.M., Suparyatha, I.B.G. 2017. Association between serum cortisol levels and pediatric
logistic organ dysfunction score in critically ill patients. Medicina 48(2): 128-132. DOI:10.15562/medi.v48i2.41
INTRODUCTION
Critical illness provides major stresses on all body
systems, including those serving important regula-
tory functions. Endocrinologic and metabolic abnor-
malities are common on presentation and during
hospitalization in the intensive care unit (ICU).
Activation of the hypothalamic-pituitary-adrenal
CrossMark
to PELOD score. Data were analyzed using independent sample t-test
and multivariate linear regression analysis. Twenty two children with
low PELOD score less than or equal to 10 (group I) were compared to
20 children with high PELOD score more than 10 (group II). Subjects
in group II had significantly higher serum cortisol levels compare to
group I [mean (SD) 248.8 (172.1) ng/ml versus 138.8 (34.6) ng/ml,
P=0.005]. Multivariate linear regression analysis showed that PELOD
score (P<0.0001) and stress period (P<0.0001) were associated with
serum cortisol levels. In conclusion, high PELOD score was associated
with elevated serum cortisol levels.
sampel bebas dan analisis regresi linear berganda. Dua puluh dua anak
dengan skor PELOD rendah kurang dari sama dengan 10 (kelompok I)
dibandingkan dengan 20 anak dengan skor PELOD tinggi lebih dari 10
(kelompok II). Subjek pada kelompok II secara signifikan menunjukkan
kadar kortisol yang lebih tinggi dari kelompok I [rerata (SB) 248,8
(172,1) ng/ml dibandingkan 138,8 (34,6) ng/ml, P=0,005]. Analisis
regresi linear berganda menunjukkan bahwa skor PELOD (P<0,0001)
dan perjalanan penyakit (P<0,0001) berpengaruh terhadap kadar
kortisol. Disimpulkan bahwa terdapat hubungan antara skor PELOD
tinggi dan peningkatan kadar kortisol.
(HPA) axis with enhanced cortisol concentrations
is perhaps the best documented endocrine response
to severe systemic stress.1 The mortality of critically
ill patients in the ICU remains unacceptably high
despite advancements in supportive care over the
last few decades. An appropriate activation of the
 ARTIKEL ASLI

Table 1  Pediatric logistic organ dysfunction (PELOD) score noted high cortisol levels were associated with
mortality. In contrast, Van Woensel et al.4 reported
Points assigned
lower cortisol levels among nonsurvivors group.
Organ system and variables 0 1 10 20 These data support, the conclusions reached by de
Neurologic Kleijn et al.5
Glasgow coma scale 12 to 15 7 to 11 4 to 6 3
Although some researchers have expressed
concern about cortisol levels in severe illness, study
and both or both
on serum cortisol levels among critically ill chil-
Pupillary reaction Positive Negative dren are still lacking. The purpose of this study was
Cardiovascular to investigate the association between serum corti-
Heart rate, beats/minute sol levels and pediatric logistic organ dysfunction
(PELOD) score in a group of pediatric intensive
<12 years <195 >195
care unit patients.
>12 years <150 >150
and or
MATERIALS AND METHODS
Systolic blood pressure, mmHg
<1 month >65 35 to 65 <35 A cross-sectional study was performed in pediatric
intensive care unit (PICU), Sanglah Hospital, from
≥1 month-<1 year >75 35 to 75 <35
February to April 2014. We included children aged
≥1 year-<12 years >85 45 to 85 <45 1 to 144 months. Patients with primary disorder
>12 years >95 55 to 95 <55 of hypothalamus-pituitary-adrenal glands, used
Renal medications that might affect cortisol levels in
the last two weeks, incomplete data, and parents’
Creatinine, mg/dl
refusal to sign the informed consent were excluded
<7 days <1.59 >1.59 from the study.
≥7 days-<1 year <0.62 >0.62 Critically ill patients are defined as those
≥1 year-<12 years <1.13 >1.13 patients who are at high risk for actual or potential
>12 years <1.59 >1.59 life-threatening health problems that can result in
significant morbidity or mortality, thereby requir-
Respiratory
ing an intensive level of care. The PELOD scoring
PaO2:FiO2 ratio, mmHg >70 <70 system consisted of physical and laboratory vari-
and or ables representing 6 organs, namely neurological,
PaCO2 (mmHg) <90 >90 cardiovascular, renal, respiratory, hematological,
and and hepatic systems (Table 1). In all subjects, the
PELOD score were determined during the first
Mechanical ventilation No Yes
48  hours of admission in PICU. Subjects were
Hematologic divided into two groups according to PELOD
Leukocyte count, x109/L >4.5 1.5 to 4.4 <1.5 score, group I consisted of the children with low
and or PELOD score (less than or equal to 10) and group
Platelet count, x109/L >35 <35
II consisted of those with high PELOD score (more
than 10). Blood samples were taken for measure-
Hepatic
ment of serum cortisol at 8 to 10 a.m. and measured
GOT, IU/L <950 and >950 using the ELFA technique (enzyme linked fluores-
or cent assay) with a detection limit was 2 to 650 ng/
PTT (INR) <1.40 >1.40 ml. The intraassay and interassay coefficient of vari-
PTT: partial thromboplastin time; INR: international normalized ratio; ations were 5.6% and 6.4%, respectively.
GOT: glutamic oxaloacetic transaminase Written informed consent was received from
the parents before the study, and the study protocol
hypothalamic-pituitary-adrenal axis and cortisol was approved by the Research Ethics Committee,
response to critical illness is essential for survival Medical School, Udayana University. We took a
because both high and low cortisol levels have detailed history of characteristics of each subject
been associated with increased mortality. Previous including age, gender, main diagnosis, stress
studies have produced mixed results concerning period, and serum albumin levels. The stress period
the correlation of cortisol levels with severity of was treated as binomial variable and classified as
illness. Aydin et al.2 found a positive correlation acute if duration of critical illness was 7 days or less
between cortisol level and mortality. Sam et al.3 and chronic if more than 7 days. Serum albumin

Medicina 2017; 48(2): 128-132 | doi: 10.15562/Medicina.v48i2.41 129

ARTIKEL ASLI
Figure 1  Study enrollment distribution
Figure 2 Comparison of serum cortisol levels based on PELOD score
was considered as low if less than or equal to 2.5 g/
dl and normal if more than 2.5 g/dl.
The required sample size was determined by a
formula of mean difference of two independent
groups, with α=5% and power of 80%. Therefore,
20 patients per study group, or a total of 40 patients,
were needed for this study.
Independent sample t-test was used to assess
possible differences between two groups. The asso-
ciation between serum cortisol levels and PELOD
score was analyzed by a multivariate linear regres-
sion analysis. In this analysis, stress period was
entered as a 2-category dummy variable. Statistical
analyses were performed using SPSS 18.0 for
Windows software package, with P<0.05 consid-
ered as statistically significant.
130
RESULTS
During the study period, 79 patients were investi-
gated. Thirty seven patients were excluded (33 due
to the used of medications that affect cortisol levels
and 4 had incomplete data). At the end of the study
period, 42 subjects were eligible for further analy-
sis, consisting of 22 children with low PELOD score
less than or equal to 10 (group I) and 20 children
with high PELOD score more than 10 (group II)
(Figure 1).
The clinical characteristics of the patients are
listed in Table 2. Majority of the subjects in both
groups were male gender and in acute stress period.
The most common diagnosis leading to PICU
admission was sepsis. Both subjects with low and
high PELOD score had normal albumin level.
Bivariate analysis was performed to analyze the
differences between the two groups in terms of
the  cortisol levels. Children in group II (PELOD
score >10) had significantly higher serum corti-
sol levels compare to group I (PELOD score ≤10)
[mean (SD) 248.8 (172.1) ng/ml versus 138.8 (34.6)
ng/ml, P=0.005] (Figure 2).
Multivariate linear regression analysis revealed
a significant association between PELOD score
(P<0.0001) and stress period (P<0.0001) with
serum cortisol levels (Table 3).
DISCUSSION
Our study noted a clear association between PELOD
score and cortisol levels in critically ill children.
The result is similar to a report from Aydin et al.2
They showed a positive correlation between cortisol
levels and the PRISM (pediatric risk of mortality)
score. Animal and human studies have demon-
strated increasing serum levels of cortisol with
increasing severity of stress, with hypotension and
sepsis being two of the most intense stressors. Sam
et al.3 reported serum cortisol levels ≥1242 nmol/l
(≥449.6 ng/ml) were associated with significantly
higher mortality in septic shock. Dalegrave et al.6
reported mean serum baseline cortisol concentra-
tions in survivors was 190 ng/ml versus 240 ng/
ml in nonsurvivors (P=0.047). In a prospective
cohort study involving 30 adults with septic shock
conducted by Maqbool et al.7, mean serum baseline
cortisol concentrations in survivors and nonsurvi-
vors was 280 ng/ml and 386.6 ng/ml, respectively
(P=0.014). Our data clearly demonstrates that the
degree serum cortisol level is related to the severity
of the stressor.
In severely ill children paradoxically lower
cortisol levels have been reported. A study of
pediatric meningococcal disease by Van Woensel
Medicina; 48(2): 128-132 | doi: 10.15562/Medicina.v48i2.41
 ARTIKEL ASLI

Table 2  Subject characteristics according to PELOD score in survivors were 339±9 ng/ml and 197±18 ng/ml
in nonsurvivors (P<0.01).
PELOD score ≤10 PELOD score >10
Characteristics (N=22) (N=20)
An appropriate activation of the hypothalam-
ic-pituitary-adrenal axis during critical illness is
Age (months), mean (SD) 63.1 (46.0) 47.6 (38.9) essential for survival. This could explain the mixed
Male gender, n (%) 15 (68.2) 15 (75.0) results concerning the association of cortisol levels
Stress period with severity of illness. Cortisol prevent immu-
notoxicity, provide metabolic substrate, promote
Acute, n (%) 21 (95.5) 14 (70.0)
catecholaminergic cardiovascular action, optimize
Chronic, n (%) 1 (4.5) 6 (30.0) vascular tone and integrity. Circulating cortisol
Diagnosis concentrations elevated during acute period of
Sepsis, n (%) 10 (45.5) 4 (20.0) stress or serious illness in patients with normal
Respiratory, n (%) 0 (0) 4 (20.0) hypothalamic-pituitary-adrenal axis function.
Typically, serum cortisol levels can increase 5 to
Cardiology, n (%) 2 (9.1) 0 (0)
10 fold in close proximity to the insult, and there is a
Neurology, n (%) 4 (18.2) 3 (15.0) loss of diurnal variation.9 In contrast to the changes
Gastroenterology, n (%) 0 (0.0) 1 (5.0) seen in the acute phase of critical illness, prolonged
Hematooncology, n (%) 1 (4.5) 0 (0) critical illness is characterized by reduced pulsatile
Renal, n (%) 0 (0) 3 (15.0) secretion of anterior pituitary hormones, which
correlate positively with reduced activity of target
Surgical, n (%) 5 (22.7) 5 (25.0)
tissues. Vanhorebeek et al.10 demonstrated that,
Serum albumin unlike the situation during the acute phase of
≤2.5 g/dl, n (%) 2 (9.1) 1 (5.0) critical illness, hormonal changes seen during the
>2.5 g/dl, n (%) 20 (90.9) 19 (95.0) prolonged phase of adult critical illness have been
assumed not to be adaptive. Our results confirm
SD: standard of deviation
the association of stress period with serum cortisol
levels.
Table 3  M
 ultiple linear regression analysis of variables associated More recently, American College of Critical Care
with serum cortisol Medicine published a recommendation for the use
of “critical illness-related corticosteroid insuffi-
Variables Coefficients regression β P
ciency (CIRCI)” to described an inadequate cellular
PELOD score 0.636 <0.0001 corticosteroid activity for the severity of the patient’s
Stress period -0.631 <0.0001 illness.11 The major impact of CIRCI is on the
β: beta
systemic inflammatory response. Glucocorticoids
(cortisol) play a central role in modulating the
et al.4 showed that cortisol levels on admission were activation of NF-kB (nuclear factor-kappa beta),
inversely related to disease severity. Accordingly, the major nuclear transcription factor responsible
serum cortisol levels of 457±51 ng/ml, 369±15 ng/ for the production of proinflammatory mediators.
ml, and 225±30 ng/ml were recorded for children Diminished glucocorticoid activity results in exces-
with meningococcal meningitis, meningococcal sive production of these mediators.12 This occurs
sepsis, and fulminant meningococcal sepsis. Yet as a result of a decrease in adrenal steroid produc-
another study of severe pediatric meningococ- tion (adrenal insufficiency) or tissue resistance to
cal disease by de Kleijn et al.5 confirmed that low glucocorticoids (with or without adrenal insuf-
serum cortisol levels were associated with poor ficiency). Adrenal insufficiency may arise due to
outcome as median serum cortisol levels of 417 ng/ dysfunction at any point in the HPA axis. Necrosis
ml, 359 ng/ml, and 235 ng/ml were recorded for of the hypothalamus or the pituitary gland has been
children with sepsis survival, septic shock survival, reported by Arlt and Allolio in patients with sepsis
and septic shock nonsurvival, respectively. More with resultant decreased synthesis of corticotro-
recently, an investigation by Önenli-Mungan et pin-releasing hormone (CRH) and ACTH (adre-
al.8 also found a relationship between lower serum nocorticotropic hormone).13 This necrosis often
cortisol levels and more severe disease. In this develops as a result of insufficient oxygen supply
study, serum cortisol levels of 294±15 ng/ml, 308±8 due to prolonged hypotension or severe coagula-
ng/ml, and 104±15 ng/ml were characteristic of tion disorders. Furthermore, patients with critical
nonseptic control children, children with sepsis illness such as sepsis may develop adrenal insuf-
(mortality 26%), and children with septic shock ficiency due to bilateral necrosis or haemorrhage
(mortality 71%), respectively. Serum cortisol levels of the adrenals. This phenomenon is well-known

Medicina 2017; 48(2): 128-132 | doi: 10.15562/Medicina.v48i2.41 131

ARTIKEL ASLI
in the Waterhouse-Friderichsen syndrome char-
acterised by meningococcal infection, although
other pathogens have also been associated with
adrenal haemorrhage and insufficiency in dissem-
inated infection.14 A study by Xia et al.15 showed
that TNF-α (tumor necrosis factor-alpha) impairs
CRH-stimulated ACTH-release and inhibits the
stimulatory actions of ACTH on the adrenals in
cortisol synthesis. Proinflammatory cytokines and
sepsis have also been demonstrated to modulate
numbers, expression and function of the glucocor-
ticoid receptor.16
Two practical implications of these results
should be emphasized. The routine measurement of
baseline cortisol could help identify subgroups of
patients at high risk and stratify them accordingly.
It could also help rule out critical illness-related
corticosteroid insufficiency and better delineate
which patients could benefit more from steroid
replacement.
There are several limitations to our study. First,
this study had not been prospectively designed to
use cortisol concentrations and patient’s outcome
as a primary endpoint, and only single presentation
cortisol levels were measured. A second limitation
includes a possibility of recall bias as we included
stress period variable.
CONCLUSIONS
Pediatric logistic organ dysfunction (PELOD) score
was associated with serum cortisol levels. Children
with high PELOD score have significantly higher
serum cortisol levels compare to those with low
PELOD score.
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Medicina; 48(2): 128-132 | doi: 10.15562/Medicina.v48i2.41