CORRELATION BETWEEN ZINC PLASMA LEVEL TO INFLAMMATION

RESPONSE OF PATIENT WITH VENTILATOR

IN PEDIATRICS INTENSIVE CARE UNIT
Dyah Kanya Wati1, Lanang Sidiartha1, Ketut tunas2, Andrie Setiawan3
1
Pediatric Department, Faculty of Medicine, Udayana University,
Sanglah Hospital, Bali, Indonesia, 2 Public Health Dhyana Pura University, Denpasar, 3Faculty of
Medicine, Udayana University

Correspondence: Dr. Dyah Kanya Wati, MD, Pediatric Consultant of Critical Care Medicine, Udayana
University - Sanglah Hospital, Jalan Pulau Nias, Denpasar 80114, Indonesia. Ph: +62361 246211 Fax:
+62361 244038. Email: dyahpediatric@yahoo.com

ABSTRACT

Objective: Critical conditions arise when there is a threat or ongoing organ failure that disrupts the balance
of the body's oxygen and physiological needs. Patients often require help, such as endotracheal intubation
procedures, mechanical ventilation, and renal or liver replacement therapy, in place of impaired organ
function. Usually, complications are more common in children than in adults. Zinc is one of the
micronutrients that play a vital role as an antioxidant and the role of defense immune modulators against
SIRS. Outcome patient with ventilator depends on systemic inflammatory response syndrome( SIRS) Commented [SN1]: What does SIRS stand for?
response to the disease. Meanwhile the study about Zinc supplementation in Pediatric Intensive Care Unit
(PICU) is limited. The main objective of this study was to look at the correlation of plasma zinc levels Commented [DW2R1]: done
with inflammatory responses on children with ventilator in pediatric intensive care unit. 1-12 years old
children treated at PICU. Commented [SN3]: What does PICU stand for?
Design and Setting: This study was prospective study in Sanglah General Hospital, Denpasar and calculate
by Pearson analysis to determine the correlation of variables plasma zinc with levels of proinflammatory Commented [DW4R3]: Done
cytokines Interleukine-6 (IL-6) and Tumor necrosis factor-alpha (TNF-α) and continued by General
Commented [SN5]: What do IL-6 and TNF-α stand for?
linier Model analysis.
Results: More than 70% sample is insufficiency zinc for the first 24 hours and after 72 hours respectively.
Correlation between plasma zinc and proinflammatory cytokines TNF-α were ; p<0,001 r: -0,91 and IL- Commented [DW6R5]: Done
6; p =0,013, r: -0.48 respectively in 24 hours and IL-6 p>0.05 r: 0,011; p <0.01, r: 0,659 for TNF-α
respectively in 72 hours.
Conclusions: There were significant correlation in TNF-α and IL-6 measurement between zinc plasma
insufficiency with pro inflammatory cytokines in the first 24 and significant correlation in TNF-α in 72
hours patient on PICU. There for supplementation zinc in 72 hours from incharge patient on PICU maybe Commented [SN7]: 72 hours from when?
have important role to reduce morbidity on PICU.
Commented [DW8R7]: Done

Keywords: zinc plasma, inflammation response, children, ,correlations, Pediatric Intensive Care Unit.

1
Background

Critical conditions arise when there is a threat or ongoing organ failure that disrupts the balance

of the body's oxygen and physiological needs.1 If not resolved immediately, the condition will

further aggravate the patient's condition, characterized by ongoing damage or cell death.2 Patients

often require help, such as endotracheal intubation procedures, mechanical ventilation, and renal

or liver replacement therapy, in place of impaired organ function.3 Usually, complications are

more common in children than in adults.4 To date, oxidative and radical stress freedom is widely

known to play a major role as a pathophysiological basis in critically ill patients, especially at the

time of organ failure.5 Thus, to prevent the deterioration of free radical conditions, the increase

in free anti radical systems in the body should also be considered.6

One of the promising alternatives is the physiological function of micronutrients or often called

trace elements.4 Zinc is one of the micronutrients that play a vital role as an antioxidant and the

role of defense immune modulators against Systemic Inflamatory Response Sindrome (SIRS).7

Moreover, since it was discovered several decades ago, the role of zinc in the physiological body

is not limited only as an antioxidant, but also contributes to linear growth, wound healing,

mucosal barrier function, maintains neurocognitive function, insulin synthesis and glucose

homeostasis, cofactors of more than 300 different enzymes, and controls apoptotic processes.6,8

Free radical production, systemic inflammatory response, and tissue damage as part of the result

of excessive oxidative stress, tend to decrease the body's endogenous antioxidant levels, as well

as zinc.4,6 The phenomenon of decreasing levels to zinc deficiency in critical patients has been

reported by some previous studies.9 Pediatric-CRISIS prevention trial research, Heidemaan et al7,

2
found low zinc levels in 83.9% of pediatric patients treated at Pediatric Intensive Care Unit

(PICU). In fact, Cvijanovich et al10 found that all of the 20 critically significant pediatric patients

had significantly lower zinc levels on the first day until the third day of PICU treatment. Rady et

al11 found that zinc levels in pediatric patients with grade III and IV respiratory distress treated

at PICU were significantly lower than those of grade I and II respiratory distress. In line with the

study, Wang et al4 mentions zinc levels of patients with critical conditions lower than controls.

In addition to the effects of oxidative stress and free radicals, the decrease in zinc levels in critical

conditions is thought to be due to the zinc redistribution of the tissues, increased excretion through

the kidneys, hemodilution, malnutrition and the production of binding proteins zinc.6,12-14 If this

condition is not prevented and left in a long time, this will have a negative effect on the patient's

clinical outcome. Previous studies have suggested an association between a decrease in zinc

levels that is proportional to patients' clinical outcomes.7,10,11,15,16 This is probably due to a

decrease in body immunity secondary to zinc deficiency, in which zinc acts as an immune

modulator in the proliferation of T lymphocytes.17

Inflammatory responses are closely related to oxidative stress in critical patients. In critical

conditions, there is an excessive process of inflammatory responses, characterized by increased

pro inflammatory cytokines, such as interleukine 6 (IL-6), Interleukine 8 (IL-8), Interferon

Gamma (IFN-γ), Intereukine 1-Betha (IL-1β), and TNF-α,16 where IL-6 is known as primary Commented [SN9]: What do these abbreviations stand
for?
interleukin pro inflammatory role in acute phase response.12 Results that previous studies
Commented [DW10R9]: Done
consistently reported zinc were able to describe the patient's inflammatory response to a critical

condition.12,16

Author's knowledge to this day the study about association between inflammatory response to Commented [SN11]: What has not been done? Please
explain it to be clear for the readers
zinc serum level has not been done in developed countries, especially in critically ill patients,
Commented [DW12R11]: done

3
making the study interesting and serve as a preliminary study on which further research is based.

The main objective of this study was to look at the correlation of plasma zinc levels with

inflammatory responses of 1 year- 12 years-old children treated at PICU.

METHODS

Design and Time of Research

This study is a prospective study with a period of January – December 2017 in the PICU Sanglah

Central Hospital, as a tertiary health center. Licensing and informed consent are obtained from

the parent / guardian of each subject before being included in the study.

Sample Research

All children 1-12 years treated in the intensive care unit between January - December 2017 were

screened for inclusion criteria to be included in the study. Exclusion criteria include: Have an

estimated length of stay less than or equal to 48 hours. Children who received any previous zinc

supplementation, children with a history or diarrhea condition at the time of treatment, children

had allergic diseases, children who received blood transfusions less than one month before

plasma zinc measurement, severe malnutrition, severe anemia condition (Hb <8 g / dL ), children

with mechanical ventilators, children with immunodeficiency, parenteral nutrition therapy over

48 hours, children with congenital anomalies and burned children excluded from the study.

The age in question is chronological age at the time of zinc examination. Age is calculated

by the date, month, year of birth and expressed in full in months and years. Research subjects

were selected in the age group 1 to 12 years.. The measurement scale is numerical.

Zinc levels are plasma zinc levels of patients taken in 24 hours and 72 hours of patients after

admission in PICU. Zinc levels are shown in units of μg / mL. Zinc levels are done and worked

4
in Prodia laboratory, Denpasar.. The data of zinc level were then divided into two types of data

ie, the mean of zinc plasma levels and the categories based on the cutoff value to be sufficient

and insufficient. The use of the data is different, depending on the research objectives. The

recommended cutoff value is 65 μg / dL.6,16

Diagnosis of disease is the primary diagnosis that underlays the child to be admitted to the

hospital. The diagnosis is recorded specifically and then classified into several parts: respiration,

cardiovascular, infection, hepato-gastrointestinal, neurological, traumatic, metabolic, and others.

Nutritional status is determined based on anthropometric status i.e. weightto the length or

height (PB / TB). Research subjects aged ≤ 5 years using BB / TB z-score score based on World

Health Organization (WHO) Anthropometry Chart with interpretation as follows: (1) BB / TB z- Commented [SN13]: What does WHO stand for?
Commented [DW14R13]: done
score> 3 SD: obese, (2) BB / TB z-score> 2 SD : overweight, (3) BB / TB z-score> 1 SD: potential

risk of overweight, (4) BB / TB z-score <-2 SD: wasted, (5) BB / TB z-score <-3 SD : severely

wasted. In patients aged ≤ 5 years with severely wasted nutritional status, not included in the

study.18 While in patients aged> 5 years, BB / TB was used according to The Centers for Disease

Control and Prevention (CDC) in 2000 and subsequently classified according to Waterlow's18

criteria (BB / ideal body weight) as follows: (1) Obesity:> 120%, (2) More nutrition:> 110-120%,

(3) Good nutrition: 90-110%, (4) Undernutrition : 70% to <90%, (5) Malnutrition: <70%. Patients Commented [SN15]: What was the status of number 4?
Commented [DW16R15]: Done
with malnutrition were excluded from the study.

The severity of illness in critically ill children in PICU was determined by scoring the

prognosis of mortality and organ dysfunction of PICU patients ie Pediatric Logistic Organ

Dysfunction (PELOD)-2score. The PELOD-2 score is a measurement of organ dysfunction and Commented [SN17]: What does PELOD stand for?
Commented [DW18R17]: Done
has been validated and developed to identify the severity of the disease each day. This score

consists of 10 variables for 5 key organs, namely cardiovascular (mean arterial pressure and

5
lactatemia), respiration (use of mechanical ventilation, PaO2 / FiO2 ratio, PaCO2), hematology

(leukocytes and platelets), neurology (Glasgow Coma Scale/GCS and pupil reflex), kidney Commented [SN19]: What does GCS stand for?

(creatinine).19 All points in each variable are summed up. Higher scores represent a poor Commented [DW20R19]: Done

prognosis. An increase in scores indicates a deterioration. The length of stay is the number of

days the patient receives treatment in the intensive care unit of the child from the patient entering

to out from PICU.

The outcome of the patient is the state of the patient when out of the intensive care unit

treatment room, then divided into recover and death. Commented [SN21]: Should be “recovered and dead”
Commented [DW22R21]: Done
The immunity status of each sample is also evaluated, this is because the immune status of

the body is associated with zinc levels. The immune status is then divided into immunocompetent

and immunocompromised. Immunocompromised status in children is defined as the presence of

a state or suspicion of damage to the body's normal immune system, be it primary immune

deficiency or secondary immune deficiency due to underlying factors (post splenectomy, Human

Immunodeficiency Virus (HIV) / Aquired immunodeficiency syndrome (AIDS), severe Commented [SN23]: What do HIV and AIDS stand for?
Commented [DW24R23]: Done
malnutrition, malignancy / leukemia, immunosuppressive drug use ).17

The history of exclusive breastfeeding is a history of breastfeeding in the first six months of

life without providing other foods, as determined by WHO. The history of exclusive

breastfeeding is divided into two nominal variables, yes and no.

The timing of nutrition is the time of initiation of enteral nutrition in patients during PICU

treatment. The time of enteral nutrition is divided into two, i.e. <48 hours and ≥ 48 hours.

The patient's origin is divided into rural and urban areas. Rural areas are areas where the

population density is less than 400 persons / km2 or with a population of less than 10,000 people.

6
While the urban area is a density of more than 400 people / km2 or with population of more than

10,000 people.20

The patient's inflammatory response to a critical condition is determined by pro

inflammatory cytokine examination, IL-6 and TNF-α, as one of the major pro inflammatory

cytokines. Both cytokine examinations were performed and tested in Prodia laboratory,

Denpasar. The cytokine examination sample was taken from the venous blood sample.. The

concentration of cytokines is shown in units of pg / mL.16

Each admitted patient to PICU will be screened according to the previously mentioned

inclusion and exclusion criteria. Patients who meet the criteria will be included in the study.

Informed consent and signature are obtained from the parent / guardian of each patient who is

included. Each sample is then given an identity number and recorded as initials in accordance

with applicable codes of ethics.

From each patient included in the study, demographic data such as identity, age, address,

weight, height, gender, nutritional status, PICU admission date and other supporting data such as

referral, admission diagnosis, were taken from the medical record. History of administration of

zinc supplementation, presence of allergic disease, history of diarrhea during treatment, blood

transfusion before zinc examination was taken from the parent / guardian of the patient by

interview method based on questionnaire.

Each patient who is included and has been taken an identity, will be examined levels of zinc

and pro inflammatory cytokines (IL-6 and TNF-α) in the first 24 hours and after 72 hours

treatment PICU. Blood samples were taken from venous blood and analyzed in Prodia laboratory,

Denpasar. In addition, during the first 24 hours and 72 hours, an evaluation of PELOD-2 scores,

both clinically and laboratory, was performed according to the criteria. All subject of this study

7
will be treated equally and evaluated daily in accordance with the procedures and standards Commented [SN25]: What did you mean?
Commented [DW26R25]: Done
applicable at PICU, Sanglah Hospital Denpasar. During the treatment the patient is noted about

the type of nutrients and when the nutrients are administered. Patients will be followed until out

from PICU, for final assessment of duration of PICU treatment and clinical outcome of the patient

(dead or not). The results that have been collected are then recorded by the research staff to be

processed and published.

The sample size was calculated using the sample formula for the correlation test in one

sample,21 taking into account the type I error (alpha) of 5%, the value of type II error (beta) of

20%, and the correlation considered significant in the previous study is -0.53, then the required

number of samples is 26 patients.

Data obtained from the sample, then collected and processed into software of Microsoft Excel

2007, then analyzed using program of SPSS 16.0. The results are then presented in the form of

mean ± standard deviations for continuous data with normal distribution or median (interquartile

range) for continuous data with not normal distribution. Absolute numbers (percentages) are

selected to show categorical or nominal data. Demographic and clinical data are presented

descriptively and in the form of tables or graphs.

Bivariate analysis to determine the correlation of variables plasma zinc levels with levels of

pro inflammatory cytokines (IL-6 and TNF-α) using Pearson correlation test. The zinc levels are

then divided into sufficient and insufficient based on the previously mentioned cut-off point

value. Analysis data continued by General Linier Model (GLM) analysis. Commented [SN27]: What did you mean?
Commented [DW28R27]: Done
All parent / guardian of patients who participated in the study were given an oral and written

explanation of the objectives and procedures of the study, if willing to participate in the study

8
will be asked for written approval after explanation. The research will be conducted after the

approval of the Ethics Committee of Medical Faculty of Udayana / Sanglah Hospital Denpasar.

RESULT

The study had run 1 years and the process of obtaining samples according to inclusion and

exclusion criteria run slowly because patients that entering PICU are generally severe and

required long hospitalization so that the rotation of patients with 9 bed capacity goes slow. All

samples had been checked for zinc status and we got the data according to table 1. The mean age

of the samples is 5.55 years in the insufficient group. The mortality rate is 26.9% with mean value

of PELOD 4.

Mayority of subject has insufficiency Zinc (76.92%) in the first take and the number was

increase in the second take (84.61%), whereas enteral nutrition ≤ 48 hours was found in 46.2%

of subjects research. Patients were entered into the PICU then using ventilator, mostly with major

diagmosis, from respiratory system (61.54%) and the rest with a primary diagnosis of

cardiovascular system (25%), followed by other causes such as neurological system (25%).

Proinflammatory cytokine levels in each group of zinc plasma is generally decreased after

72 hours observation. In the insufficiency group, IL-6 decreased the most with the average of

6.09.

9
Table 1. Data Characteristic
No Characteristic Sufficient Insufficient Commented [SN29]: What number is this? Is it the
1. Gender ordinal number? If yes, better you omit these numbers since
 Male 0 (0%) 10 (50%) they are not necessary.
 Female 6 (100%) 10 (50%) Commented [DW30R29]: Done
2. Age (years), Mean (SD) 2,4 (0,548) 5,55 (5,83)
3 Body weight, Mean (SD) 3,3 (0,1) 5,32 (1,31)
4 Body Height, Mean(SD) 49,6 (0,548) 60,13 (8,5)
5 Nutritional Status
 Over nutrition 0 (0%) 0 (0%)
 Normal 6 (100%) 10 (50%)
 Malnutrition 0 (0%) 10 (50%)
6 Origin of Patient
 Rural 6 (100%) 10 (50%)
 Urban 0 (0%) 10 (50%)
7. History of exclusive Breast feeding
 Yes 6 (100%) 15 (75%)
 No 0 (0%) 5 (25%)
8. Diagnose in PICU
 Respiration 6 (100%) 10 (50%)
 Cardiovascular 0 (0%) 5 (25%)
 Infection 0 (0%) 0 (0%)
 Hepatic/Gastrointestinal 0 (0%) 0 (0%)
 Neurological 0 (0%) 5 (25%)
 Hematology/Oncology 0 (0%) 0 (0%)
0 (0%) 0 (0%)
 Post Surgery
0 (0%) 0 (0%)
 Trauma
0 (0%) 0 (0%)
 Metabolic
0 (0%) 0 (0%)
 Other
13. PELOD Score, Mean (SD) 4 (0,0) 4 (2,17)
17. Length of stay in PICU, Mean (SD) 5 (0,0) 6 (1,9)
18. Time of enteral nutrition
 ≤ 48 h 6 (100%) 5 (25%)
 > 48 h 0 (0%) 10 (75%)
19. Mortality 0 7 (26.9%)
20. Zinc Plasma, Mean(SD)
24 hour 70 (0.0) 45 (6,19)
72 hour 57.8 (9.75) 39.5 (3.68)

20. IL-6, Mean (SD)

24 hour 16,54 (0,0) 25.47 (7.73)

10
 72 hour 14.51 (2.4) 19,38 (8,35)

21. TNF-α, Mean (SD)

24 hour 35,3 (0,0) 17,55 (1,70)
72 hour 25.08 (8.20) 16.15 (1.00)

There was a negative correlation of 24 hours zinc (p = 0.013) but no correlation was obtained

on 72 hours (p> 0.05) (table 2). While Table 3 shows there was a positive correlation between

zinc levels with TNF-α at 24 h (p <0.001) and on the second taking at 72 hours p <0.01

Table 2. Correlation of Zinc Plasma and IL-6

IL-6 IL-6
24 hour 72 hour
Concentration of zinc r = -0,48 r = 0.011
p = 0,013 p > 0.05
n = 26 n = 26

Table 3. Correlation of Zinc Plasma and IL-6TNF-α

TNF-α TNF-α
24 hour 72 hour
Concentration of zinc r = 0,911 r =0.659
p < 0.001 p <0.01
n = 26 n = 26

Table 4, 5, 6, showing the association between zinc and exclusive breastfeeding history,

length of stay, and time of enteral nutrition. A significant association was found only in length of

stay and zinc status (p = 0.03) while the other variables did not show significant association.

11
Table 4. Bivariate analysis between history of exclusive breastfeeding and zinc status

Zinc Status
Variable p value*
Sufficient Insufficient
History Of Exclusive
Breastfeeding
Yes 6 (28,6%) 15 (71,4%) 0,236
No 0 (0%) 5 (100%)
* Chi square test

Table 5. Bivariate analysis between length of stay and zinc status

P* Value
Variable Mean Difference
Zinc Status (95% CI)
Sufficient -1.00
0.03
(-1.898 - -0.102)
Insufficient
*Independent T test Commented [SN31]: Did you mean this was the legend
for p value?
Table 6. Bivariate analysis between time of enteral feeding and zinc status Commented [DW32R31]: Yes

Time Of Enteral Feeding

Variable p* value
≤48 h >48 h
Zinc Status
Sufficient 6 (0%) 0 (100%) 0,298
Insufficient 5 (33,3%) 10 (66,7%)
* Chi square test

First figure shows the pattern of changes that occur in pro inflammatory cytokines within

72 hours. There are significant differences in IL-6 changes between the sufficient and

insufficiency groups (p <001). The sufficient group had a tendency to increase pro-inflammatory

12
cytokine IL-6 whereas in the insufficient group had a tendency decrease pro-inflammatory

cytokineIL-6

Second figure shows the pattern of changes that occur in pro inflammatory cytokines

within 72 hours. There are significant differences in TNF-α changes between the sufficient and

insufficiency groups (p <001). The sufficient group had a tendency to decrease pro inflammatory

cytokine TNF-α while in the insufficient group of insufficiency had a tendency to increase pro Commented [SN33]: Insufficiency of what? Please clarify
it.
inflammatory cytokine TNF-α. Commented [DW34R33]: Done

P<0,001

24 hour 72 hour

Figure 1. The pattern of pro-inflammatory IL-6 cytokine changes in both zinc groups in a
72-hour observation

13
 P<0,001

24 hour 72 hour

Figure 2. The pattern of proinflammatory cytokine TNF-α changes in both zinc groups in
a 72-hour observation

DISCUSSION
The data previously mentioned, together, gave rise to a paradigm of zinc use as a predictor

that was able to describe the patient's condition and the inflammatory response. Then, the

assessment of zinc levels and an understanding of their association with inflammatory responses

and severity degrees have been very useful in determining prognosis, outcome prediction of

patients, and ultimately the choice of management strategies.16 A management strategy that has

finally been developed is the concept of zinc supplementation as a low-cost, easy to get, and

effective for the patient's critical condition. Better patient handling of infants will improve the

child's condition in childhood and adulthood. 22

14
Most researchers linked zinc levels to the patient's inflammatory response in PICU. 10,11,12,16 This

study further investigated the inflammatory response of patients by looking at 2 parameters of

pro inflammatory cytokine i.e. IL-6 and TNF-α. Blood sampling was done in 2 periods, the first

24 hours in PICU and 72 hours. Those time are very important because the first 24 hours is the

base line of the data from the research subject and 72 hours is the minimum time patient to stable

in PICU so that the value is the patient's body response that unaffected by early resuscitation and

it is the patient's acute phase response in PICU. IL-6 is a pro inflammatory cytokine that appears

after stimulation by IL-1. 5 Il-6 in general can be seen in 4-6 hours of acute phase patient and

finally settled levels in the blood. The results of this study showed there was a negative correlation

between Zinc levels with IL-6 (r = -0.48, p = 0.013) but showed no significantly correlations on

the second take or after 72 hours (Table 2). While TNF-α showed significant results on both time

of taking although the indicated were positive correlations (Table 3). Negative correlations

between IL-6 and zinc levels were also found in the study of Liuzzi et al12 at the in vitro and in

vivo levels even though it has not been corrected up to 72 hours later. No significant correlation

of IL-6 and Zinc levels did not affect the change in pattern of IL-6 pro inflammatory cytokines

on the GLM curve. Subject with insufficiency showed significant decrease in IL-6 function

(Figure 1. While on the TNF-α GLM curve actually increased in Zinc insufficiency group

(Figure 2). No similar study has examined the relationship between zinc and TNF-α levels, since

TNF-α is unstable in circulation and will bind to the ligand sTNFR-1 within hours23, there for Commented [SN35]: Did you mean that TNF-a will bind
to sTNFR-1 within hours?
the result in 24 hours and 72 hours later probably different than IL-6 pattern. The different pattern Commented [DW36R35]: yes

of inflammations response in 72 hours especially in IL-6 (Figure 1) between 2 group, means that

15
cytokines worked properly in sufficient zinc than group insufficient zinc and there for associates

with the length of stay in both group (Table 5)

The child is in a stage of rapid physical growth, and the period of development of adaptive

immunity. Thus, children are in need of macro and micronutrients in considerable amounts,

especially zinc.24 Children at this time will be more susceptible to decreased levels of zinc in the

body.4 Nutrition in infancy less than two years depends heavily on breast milk consumption,

where breast milk contains various types of nutrients, both macronutrients and micronutrients,

which provide the right foods for babies. Various sources have recommended exclusive

breastfeeding for six months, and with complementary feeding to age 1 to 2 years, to meet the

nutritional needs of infants, not least zinc.25,26 Exclusive breastfeeding provides the total zinc

requirement of infants during the first six months of life, and breast milk remains the main source

of zinc to 24-month-old children. Zinc deficiency in childhood due to lack of zinc intake. This is

mainly due to partial breastfeeding during early life and the use of a formula with zinc

bioavailability is lower than breastmilk.24 Thus in the age range of children < 2 years, zinc intake

is a factor affecting body zinc levels, especially in breast-fed children. However, exclusive

breastfeeding history there is not have significant association with zinc level in this study. This

is quite relevant considering the average age of patients who include in that period is the age of

5.55 years old, which is generally over the age of applying the benefits of exclusive breastfeeding

optimally, that is 2 years old. and the main source of nutrition not only from breast feeding or

formula but mainly from adult diet (Table 4).

As a result of the many metabolic functions that depend on zinc, the morbidity due to zinc

deficiency should be noted. Infants with zinc deficiency in general will have higher morbidity,

more susceptibility to disease, and gastrointestinal hypertrophy, and other chronic disorders.24 In

16
addition, the state of zinc deficiency in children will worsen the condition of the illness suffered

as a result of immune dysfunction.

Pediatric patients with severe critical illness are increasing in line with the increasing of

population and social. Critical illness can be caused by one or more organ failure. Children with

severe disease require assistance so that their organs can function properly. Ventilator use in the

PICU will lead to an inflammatory process and is most likely caused by severe infections

especially in the respiratory organs. At the beginning of the inflammatory process and infection

zinc levels will decrease. The investigation of Wang et al3 showed that zinc has a negative

correlation with Pediatric Risk of Mortality (PRISM ) Score (r = -0.36, p = <0.05). The negative Commented [SN37]: What does PRISM stand for?
Commented [DW38R37]: Done
correlation between PELOD score and zinc level was also found in study by Faridha F Negm et

all9 (p = 0,026). Table 1 shows the mean of PELOD 2 score in both group is the equal i.e 4,

there for time to enteral feeding in both group is not significantly different because the severity

of disease is comparable (Table 6). There for this study did not evaluation further association

between zinc and severity of disease by PELOD 2 score. Commented [SN39]: Do you mean that your study did
not evaluate further association between zinc and the
severity of the disease by PELOD-2 score?
CONCLUSIONS
Commented [DW40R39]: yes
There were significant correlation between plasma zinc insufficiency with pro inflammatory

cytokines (TNF-α and IL-6) in the first 24 hours and with TNF-α in 72 hours of the patients

treated in PICU?

SUGGESTION
 A follow-up study with a larger sample size is needed to demonstrate the association

between pro inflammatory cytokines with zinc levels and related factors.

 Zinc supplementation in children treated in PICU is an indispensable follow-up study

in the future?

17
DISCLOSURE

I certify that there is no conflict of interest in relation to this study

REFFERENCE
1. Frost P. dan Wise MP. Recognition and Early Management of the Critically Ill Ward Patient.
British Journal of Hospital Medicine 2007;68:180-183.
2. Frankel LR, DiCarlo JV. Pediatric intensive care. In: Bernstein D, Shelov SP, editors.
Pediatrics for Medical Students. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins;
2003:541.
3. Wang G, Feng X, Yu X, Xu X, Wang D, Yang H, et al. Prognostic Value of Blood Zinc, Iron,
and Copper levels in critically ill children with pediatric risk of mortality score III. Biol Trace
Elem Res 2013;152(3):300-4.
4. Hazinski MF. Children are Different. Hazinski, M.F. editor. Nursing Care of the Critically Ill
Child. Third edition. 2013. United State: Elsevier. h.1-18.
5. Heyland DK, Jones N, Cvijanovich NZ, Wong H. Zinc Supplementation in Critically Ill
Patients: A Key Pharmaconutrient? (JPEN J Parenter Enteral Nutr 2008;32:509-519.
6. Suresh K and Singhi S. Zinc and Selenium in critically ill childre: where do they stand? IPP
2014;2:297-306.
7. Heidemann SM, Holubkov R, Meert KL, Dean JM, Berger J, Bell M et al. Baseline Serum
Concentrations of Zinc, Selenium, and Prolactin in Critically ill children. Pediatr Crit Care
Med 2013;4:e202–e206.
8. Prasad AS. Discovery of human zinc deficiency: 50 years later. J Trace Elem Med Bio
2012;26:66-9.
9. Negm FF, Soliman DR, Ahmed ES, Elmasry RA. Assessment of serum zinc, selenium, and
prolactin concentrations in critically ill children. Pediatric Health, Medicine and Therapeutics
2016;7:17–23.
10. Cvijanovich NZ, King JC, Flori HR, Gildengorin G, Wong HR. Zinc homeostasis in pediatric
critical illness. Pediatr Crit Care Med 2009;10:29-34.

18
11. Rady HI, Rabie WA, Rasslan HA, El Ayadi AA. Blood Zinc Levels in children hospitalized
with pneumonia: a cross sectional study. Egyptian Journal of Chest Diseases and Tuberculosis
2013;62:697-700.
12. Liuzzi JP, Lichten LA, Rivera S, et al. Interleukin-6 regulates the zinctransporter Zip14 in
liver and contributes to the hypozincemia of theacute-phase response. Proc Natl Acad Sci
USA 2005;102:6843-8.
13. Sukhani VK. Biology of Acute Phase Proteins and their response to inflammation. The
Intensivist 2012.Jan-March:11-16. Commented [SN41]: This ref could not be found. Please
send us the copy.
14. Berger MM and Chiolero RL. Antioxidant supplementation in sepsis and systemic
inflammatory response syndrome. Crit Care Med 2007;35[9 Suppl]:S584-90.
15. Schneider ACR, Pinto RB, Froehlich PE, Hammes TO, da Silveira TR. Low Plasma Zinc
Concentrations in Pediatric patients with Cirrhosis. J Pediatr (Rio J) 2009;85(4):359-364.
16. Besecker BY, Exline MC, Hollyfield J, Phillips G, diSilvestro RA, Wewers MD et al.
Acomparison of zinc metabolism, inflammation, and disease severityin critically ill infected
and noninfected adults early after intensive careunit admission. Am J Clin Nutr
2011;93:1356–64.
17. Fraker PJ, King LE, Laakko T, dan Vollmer TL. The Dynamic Link between theIntegrity of
the Immune Systemand Zinc Status. J Nutr 2000 May;130(5S Suppl):1399S-406S.
18. Preiser JC, van Zanten ARH, Berger MM, Biolo G, Casaer MP, Doig GS. Metabolic and
nutritional support of critically ill patients : concenssus and controversies. Crit Care
2015;195:35.
19. Leteurtre S, Duhamel A, Salleron J, Grandbastien B, Lacroix J, Leclerc F. PELOD-2: an
update of the PEdiatric Logistic Organ Dysfunction Score. Crit Care Med 2013;41(7):1761–
1773
20. du Plessis V, Beshiri R and Bollman RD. Definitions of rural. Rural and Small Town Canada
Analysis Bulletin 2001;3:1-17. Commented [SN42]: Please send us the copy of this ref.

21. Sastroasmoro S and Ismael S. Pemilihan Subyek penelitian. dalam : Sastroasmoro S,

Ismael S (eds). Dasar-Dasar Metodologi Penelitian Klinis. Jakarta : Sagung Seto. 2008. Commented [SN43]: Please send us the copy of this ref.

22. Wong HR. Genome-wide expression profiling in pediatric septic shock. Pediatr Res.
2013;73:564-9.

19
23. Wati D.K., Sastroasmoro S, Madjid A, Boedina S, Djer MM, Santoso H. Superior cava
vein saturation and cardiac lactate as cardiac output predictor after cardio-pulmonary
bypass on children. Crit Care Shock. 2016:19:14-20.
24. Nriagu J. Zinc deficiency in human health. In Nriagu J (ed). Encyclopedia of
Environmental Health. Elsevier B.V. 2007:1-8. Commented [SN44]: Please send us the copy of this ref.

25. Hannan MA, Faraji B, Tanguma J, Longoria N, Rodriguez RC. Maternal milk
concentration of zinc, iron, selenium, and iodine and its relationship to dietary intakes.
Biol Trace Elem Res 2009:127:6–15.
26. Mahdavi R, Nikniaz L, Gayemmagami SJ. Association between zinc, copper, and iron
concentrations in breast milk and growth of healthy infants in Tabriz, Iran. Biol Trace
Elem Res 2010:135:174–181.

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