Abstract

Background. Ventilator-associated pneumonia (VAP) still remains a common device-associated hospital acquired infection in pediatric and adult intensive care units. The aim of our study was to determine ways of microbial transmission to the lower airways in intubated patients admitted to a single tertiary-care pediatric intensive care unit.

Methods. This was a prospective observational study. A total of 284 sample sets (oropharyngeal swabs, swabs from the lumen of the proximal tip of an endotracheal tube, and bronchoalveolar lavage samples) were collected from 62 consecutive pediatric patients intubated for > 24 hours. Pulsed-field gel electrophoresis was performed on all isolated pathogens, which were later identified by MALDI biotyper (MALDI-TOF mass spectrometry).

Results. Overall colonization rates were high and did not differ significantly at different time points in the oropharynx (75%–100%) and the lower airways (50%–76.5%). The endotracheal tube was colonized at lower rates: on day 1–3 (28.8%), on day 4–6 (52.7%), on day 7–9 (61.8%) and on day 10-12 (52.9%) (P < 0.001). A total of 191 matched sample sets from the lower airways and at least one site above were collected from 46 (74.2%) patients. In the oropharynx-lower airways group, Candida spp. (76.9%) and upper airway bacteria (63.2%); in the endotracheal tube-lower airway group, S. aureus (15.7%) and upper airway bacteria (21.1%); in the oropharynx-endotracheal tube-lower airway group, Enterobacteriaceae (70.8%) prevailed (P < 0.001). The mean survival (entrance) time to lower airways for the Acinetobacter/Pseudomonas/Stenotrophomonas group was 8.28 ± 0.81 days; for the Enterobacteriaceae group, 5.63 ± 0.41; and for Candida spp. group, 3.00 ± 0.82 days (P < 0.005).

Conclusions. Oropharyngeal contamination of the lower airways is the most important route of colonization. Different pathogens enter the lower airways at different time intervals from the insertion of an endotracheal tube.

Key words: colonization, airway, intubation, mechanical ventilation, bronchoalveolar lavage, ventilator-associated pneumonia

Introduction

Ventilator-associated pneumonia (VAP) still remains a common device-associated hospital acquired infection in pediatric and adult intensive care units (ICUs). During the last decade, a remarkable decline in the VAP incidence has been documented in economically developed countries; however, the incidence in developing countries is decreasing as well. (1) Despite significant improvements, there is still a lot of controversy on how to achieve minimal incidence, even knowing the pathogenesis of colonization of the tracheal bronchial tree. (2-4) Sometimes the implementation of VAP prevention bundles in the pediatric population is problematic. Likewise, elevation of the head by 30o–45o angle in an infant is impossible, and deep vein thrombosis prophylaxis in the pediatric population does not work in terms of VAP prevention. Education and training of nursing staff and implementation of adjusted “pediatric” bundles have a significant impact on reduction in VAP incidence. (5) However, despite a minimal incidence, there is still a question of whether we can do something more. Therefore, the aim of our study was to determine ways of bacterial transmission to the lower airways (LA) and associated risk factors in intubated patients after implementation of a VAP prevention bundle in a tertiary-care pediatric intensive care unit (PICU).

Methods

Study population and data collection

This prospective observational study was conducted in a single tertiary-care PICU (8 beds, around 50 patients intubated for > 24 hours annually) at the Hospital of the Lithuanian University of Health Sciences Kauno Klinikos, from February 2012 to June 2013.

All consecutive patients aged from 1 month to 18 years and intubated for >24 hours were eligible for inclusion into the study. Exclusion criteria were multiple congenital abnormalities, chronic infection (e.g. cystic fibrosis), and mental disorders. Patients exited the study at time of extubation, tracheostomy, or death. None refused to participate in the study. The study protocol was approved by Kaunas Regional Biomedical Research Ethics Committee and written informed consent was obtained on January 9, 2012 (registration No. 8/2012).

According to the protocol, microbiological specimens were collected from three sites: oropharynx (OPX) (swabs), lumen of the proximal tip of an endotracheal tube (ETT) (swabs), and LA (bronchoalveolar lavage [BAL] aspirate). The blind BAL sample was taken by inserting a single-lumen regular endotracheal suction catheter of appropriate size through an orally inserted endotracheal tube. Patients were preoxygenated with 100% oxygen. Then a suction catheter was inserted to a wedge position, instilling 1 mL/kg saline for <20 kg and 20 mL saline for >20 kg patient, and then immediately withdrawing the fluid. (6-8) Any count of pathogens (cfu/mL) in LA was considered as positive, and BAL aspirate with ≥105 cfu/mL was defined as heavy colonization. (9) The oropharynx was chosen because it is a crossroad for the nasopharynx, oral cavity, and hypopharynx and potential endogenous source, and proximal tip of the ETT because of its potential exogenous source of contamination and colonization of the tracheal bronchial tree (1;3;4;10). Sets of three microbiological samples were collected on the first day and every third consecutive day until day 18 and later every fifth day until day 28. Extra sample sets were taken in the following seven circumstances: 1) before extubation, 2) after bronchoscopy, 3) gastrointestinal endoscopy and after patient transportation for investigations such as 4) computed tomography (CT), 5) magnetic resonance imaging (MRI), and 6) other or 7) surgery outside the PICU area. A total of 284 sample sets (284 × 3 samples) were collected for 62 patients.

Microbiologic methods

Study samples were coded and sent to the microbiology laboratory for identification. The samples were inoculated directly onto 5% sheep blood agar (BBL, USA), chocolate agar (BBL, USA), and MacConkey agar plates (Oxoid, UK). Sheep blood and chocolate agar plates were incubated at 35°C in an atmosphere containing 5% CO2 and MacConkey agar plates, at 35°C for 18–24 hours. If a culture was negative on the first observation, sheep blood and chocolate agar plates were re-examined after the second 24-hour incubation. Pulsed-field gel electrophoresis (PFGE) was performed on all isolated pathogens by using the modified procedures published by Barth and Pitt as well as Grothues and Tümmler. (10,11) Isolated pathogens, potentially causing VAP, and others (S. pneumoniae, H. influenzae, S. aureus, E. coli, K. pneumoniae, Enterobacter cloacae, Enterococcus spp., P. aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia, Candida spp., beta-hemolytic streptococci) were identified using matrix-assisted laser desorption ionization-time of flight (MALDI-TOF, Bruker) mass spectrometry (MS). Disk diffusion susceptibility testing was performed, and zone diameters of inhibition were interpreted according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations.

VAP definition and prevention in the PICU

VAP was identified during routine surveillance procedures by using a combination of imaging, clinical, and laboratory criteria (pathogen concentration of ≥104 cfu/mL in a blind BAL aspirate). A diagnosis of Ventilator-associated tracheobronchitis (VAT) was based on the absence of clinical and radiographic evidence of pneumonia and the following criteria: positive culture obtained by deep tracheal aspirate and 2 signs or symptoms with no recognizable cause (fever [>38.5°C], cough, new or increased sputum production, rhonchi, or wheezing). (12,13)

Between 2006 and 2007, when the multimodal intervention was designed (education of PICU staff about VAP prevention and correction of daily patient care according to evidence-based recommendations, feedback communication with PICU staff in the postintervention period and implementation of new daily care protocols), there was a sharp decrease in VAP incidence (21.8 versus 8.8 per 1000 ventilator-days). (14) Later, the implementation of a VAP prevention bundle (semi-recumbent 30°–45° position of the head, daily evaluation of readiness to wean, comprehensive oral care protocol, periodical check for gastric overdistention, ETT cuff pressure between 20 and 30 cm of water, stress ulcer prophylaxis, periodic drainage and absence of tubing condensate and annual reporting of surveillance results in the PICU) led to a further decline in the VAP incidence curve (2.0 per 1000 ventilator-days in 2012; surveillance data were submitted to the INICC registry). (1)

Statistical analysis

First of all, all microbiological samples were analyzed and later, matched sample sets. A matched sample set was defined if there was a growth of matching pathogens from the LA and at least one of the other upper airway sites (OPX or ETT) at the moment of sample collection. For statistical analysis, all pathogens were divided into five groups: Acinetobacter, Pseudomonas and Stenotrophomonas (APS); Candida spp.; Enterobacteriaceae; S. aureus; and bacteria of the upper airway (UA) with the oral cavity.

Descriptive analysis methods were used (mean, standard deviation, median, interquartile range (IQR), proportion). Pediatric index of mortality (PIM2) was used as an independent descriptive variable for the assessment of the status of a patient at the time of admission to PICU or the first face-to-face contact with a PICU physician. (15) The cross-tabulation method and the chi-square test with an estimate of adjusted residual (≥ |2.0|) were used to compare categorical variables among different subgroups. In addition, matched samples were tested using Kaplan-Meier survival analysis and the Breslow test for pairwise comparisons. Survival time was defined as the time period between ETT placement and entry of a matching pathogen from the OPX or the ETT to the LA. For all analyses, P < 0.05 (2-tailed) was considered statistically significant.

Results

Among 62 orally intubated patients, there were 40 (64.5%) males with a mean age of 7.3 years (SD=6.5) and 22 (35.5%) females with a mean age of 8.6 years (SD=7.2). The mean PIM2 was 10.8% (median, 4.8; IQR, 7.63). (1,15) Most of the patients’ clinical characteristics are presented in Table 1.

The overall colonization rate was high and distributed homogeneously in the OPX (75%–100%; (χ2 = 5.35, df = 6, > 0.05) and the LA (50%–76.5%; χ2 = 6.85, df = 6, > 0.05). However, the ETT was colonized at lower rates and the colonization rates differed significantly (22.2%–80%; χ2 = 25.02, df = 6,< 0.001). The lowest rate was observed on days 1–3 (28.8%, AR=-4.2) and the highest, on days 4–6 (52.7%, AR=2.2), days 7–9 (61.8%, AR=2.8) and days 10-12 (52.9%, AR=1.2) (Table 2). A total of 166 (58.5%) BAL aspirates were positive, and in 94 (56.6%) of them, heavy colonization (≥105 cfu/mL) was observed.

A total of 191 matched samples were collected from 46 (74.2%) of the 62 patients. A triple OPX-ETT-LA sample set was seen in 112 (58.6%) of all cases; double OPX-LA, in 62 (32.5%); and double ETT-LA, in 17 (8.9%). The overall picture of colonizing pathogens and their antimicrobial susceptibility are presented in Table 3. S. aureus (26.7%), Klebsiella spp. (16.2%), Enterobacter spp. (10.0%), Acinetobacter spp. (9.4%), E. coli (8.4%), and Candida spp. (6.8%) prevailed in matched sample sets. Antimicrobial susceptibility rates of the majority of pathogens was high and ranged from 83.9% to 100% with the exception of Acinetobacter spp. susceptibility to ceftazidime (63.6%), S. maltophilia susceptibility to ceftazidime (0%) and trimethoprim/sulfonamide (40%), and H. influenzae susceptibility to ampicillin (50%).

The colonization rates by pathogen groups and matched sample groups were differently distributed (χ2 = 42.22, df = 8, < 0.001). In the OPX-LA group, Candida spp. (76.9%) and UA bacteria (63.2%); in the ETT-LA group, S. aureus (15.7%) and UA bacteria (21.1%); and in the OPX-ETT-LA group, Enterobacteriaceae (70.8%) were most frequently observed (Table 4). Analysis of colonization rates by different pathogens showed a very similar pattern: Candida spp. (76.9%) prevailed in the OPX-LA group; S. aureus (15.7%), in the ETT-LA group; and Klebsiella spp. (77.4%), in the OPX-ETT-LA group (χ2 = 59.01, df = 30, < 0.001). A total of 106 (55.5%) BAL aspirates were heavily colonized (≥ 105 cfu/mL). There was a monomicrobial growth in the OPX and the ETT in almost two-thirds of the matched sample sets (n = 123, 64.4%), but a polymicrobial growth was also observed (n = 68, 35.6%). Mono and polymicrobial growth was steady over time (χ2 = 3.39, df = 5, > 0.05).

There were one VAP (OPX-ETT-LA) and five VAT (OPX-ETT-LA – 4, OPX- LA – 1) cases in the matched sample group. A single case of VAP was caused by P. aeruginosa, and VAT, by S. aureus (n = 2), Acinetobacter spp. (n = 1), C. freundii (n = 1) and Klebsiella spp. (n = 1).

The colonization rates by time groups and matched sample groups significantly differed (χ2 = 35.20, df = 10, < 0.001). The occurrence of OPX-LA matched cases (48.2%) was significant on days 1–3. However, OPX-ETT-LA cases were frequently observed throughout almost all the periods (≥25%), and on days 1–3 and 7–9 (40.2% and 91.4%, respectively) its occurrence was significant. There were no matched samples on days 16–18 (Table 5).

The occurrences of matched samples were not associated with eight circumstances (one planned and seven extra) for sample collection (χ2 = 22.11, df = 14, > 0.05). The overall distribution of the first matched cases in matched sample groups by eight reasons was also homogeneous (χ2 = 20.77, df = 12, = 0.05), however, the occurrence of the first OPX-LA case was significantly associated with transportation for a CT scan outside the PICU area (n = 6, 100%, AR = 2.1).

Overall survival analysis of matched samples showed that the mean survival time was the longest for APS (8.28 days, 95% CI 6.69–9.86) in pairwise comparisons between five pathogen groups. It was shorter for Enterobacteriaceae (5.63 days, 95% CI 4.82–6.43), S. aureus (4.31 days, 95% CI 3.08–5.55) and UA bacteria (3.42 days, 95% CI 2.00–4.85); and the shortest for Candida spp. (3.00 days, 95% CI 1.38–4.62) (P = 0.001–0.005) (Figure 1).

Subgroup analysis also showed that the mean survival time in the OPX-LA subgroup was longest for APS (10.44 days, 95% CI 5.25–15.64) when five pathogen groups were compared (P = 0.01–0.029). The mean survival time for Enterobacteriaceae (3.50 days, 95% CI 2.25–4.75) and Candida spp. (2.90 days, 95% CI 0.83–4.98) was shorter (P = 0.01–0.029); and for S. aureus, the shortest (1.64 days, 95% CI 0.88–2.40) (P = 0.001–0.01). In the ETT-LA subgroup, there were no significant differences in the mean survival times comparing the groups by pathogens. In the OPX-ETT-LA subgroup, the mean survival time for APS was the longest (7.52 days, 95% CI 6.2–8.81); for Enterobacteriaceae (6.51 days, 95% CI 5.5–7.43) and S. aureus (4.75 days, 95% CI 3.16–6.34) shorter; and for UA bacteria, the shortest (2.67 days, 95% CI 0.94–4.40) (P = 0.001–0.009).

Table 1. Clinical characteristics of patients

N %
Pathology and syndromes:

Trauma

Neurologic diseases

Sepsis

Pneumonia and bronchiolitis

Burns (skin and/or airways)

Myocarditis

Poisoning

Respiratory failure

Coma

Shock

Seizures

Dehydration

Multiple organ failure

Disseminated intravascular coagulation

Acute renal failure

Acute hepatic failure

Heart arrest

20

18

10

7

5

1

1

43

32

19

10

9

4

2

2

2

2

32.3

29.0

16.1

11.3

8.1

1.6

1.6

69.4

51.6

30.6

16.1

14.5

6.5

3.2

3.2

3.2

3.2

Invasive and noninvasive procedures:

Urinary catheter

Central venous catheter

Head CT

Arterial catheter

Lumbar puncture

Gastrointestinal endoscopy

Therapeutic hypothermia (33°C–34°C)

Head MRI

Bronchoscopy

EEG

Surgical operation:

clean

clean-contaminated or contaminated

ICP probe

55

39

31

23

16

9

7

5

3

2

23

16

7

6

88.7

62.9

50.0

37.1

25.8

14.5

11.3

8.1

4.8

3.2

37.1

25.8

11.3

9.7

Inotropic and vasoactive drugs:

Dopamine

Norepinephrine

Epinephrine

Dobutamine

Levosimendan

18

5

4

3

1

29.0

8.1

6.5

4.8

1.6

CT, computed tomography; EEG, electroencephalography; ICP, intracranial pressure MRI, magnetic resonance imaging.

Table 2. Colonization rates by site and time period

All samples Planned

Samples

Extra samples OPX ETT LA
Days N N N Positive % Positive % Positive %
1–3 160 114 46 85.0 28.8 53.5
4–6 55 29 26 81.8 52.7 60.7
7–9 34 18 16 88.2 61.8 76.5
10–12 17 9 8 94.1 52.9 52.9
13–15 9 6 3 66.7 22.2 66.7
16–18 4 4 0 75.0 25.0 50.0
19–28 5 4 1 100 80.0 60.0

ETT, proximal tip of an endotracheal tube site; LA, lower airways site; OPX, oropharynx site.

Table 3. Antimicrobial susceptibility of isolates in matched sample sets

 

Table 4. Colonization rates by pathogen groups and matched sample groups

Pathogen groups n, %, AR OPX-LA ETT-LA OPX-ETT-LA Total
APS 

 

n 9 2 25 36
proc. 25.0 5.6 69.4 100
AR –1.1 –0.8 1.5
Candida spp. 

 

n 10 2 1 13
proc. 76.9 15.4 7.7 100
AR 3.5 0.9 –3.9
Enterobacteriaceae 

 

n 20 1 51 72
proc. 27.8 1.4 70.8 100
AR –1.1 –2.8 2.7
S. aureus 

 

n 11 8 32 51
proc. 21.6 15.7 62.7 100
AR –1.9 2.0 0.7
UA bacteria n 12 4 3 19
proc. 63.2 21.1 15.8 100
AR 3.0 2.0 –4.0
Total n 62 17 112 191
% 32.5 8.9 58.6 100

AR, adjusted residual; APS, Acinetobacter, Pseudomonas and Stenotrophomonas; OPX-LA, oropharynx and lower airways sites; ETT-LA, proximal tip of an endotracheal tube and lower airways sites; OPX-ETT-LA, oropharynx, proximal tip of endotracheal tube and lower airways sites; UA, upper airway.

Table 5. Colonization rates by time period and matched sample groups

Days n, %, AR OPX-LA ETT-LA OPX-ETT-LA Total
1–3

 

 

N 42 10 35 87
% 48.3 11.5 40.2 100
AR 4.3 1.2 –4.7
4–6

 

 

N 11 3 31 45
% 24.4 6.7 68.9 100
AR –1.3 –0.6 1.6
7–9

 

 

N 1 2 32 35
% 2.9 5.7 91.4 100
AR –4.1 –0.7 4.4
10–12

 

 

N 2 1 8 11
% 18.2 9.1 72.7 100
AR –1.0 0.02 1.0
13–15

 

 

N 4 0 5 9
% 44.4 0 55.6 100
AR 0.8 –1.0 –0.2
16–18 N 0 0 0 0
% 0 0 0 0
19–28

 

 

n 2 1 1 4
% 50 25 25 100
AR 0.8 1.1 –1.4
Total n 62 17 112 191
% 32.5 8.9 58.6 100

AR, adjusted residual; OPX-LA, oropharynx and lower airways sites; ETT-LA, proximal tip of an endotracheal tube and lower airways sites; OPX-ETT-LA, oropharynx, proximal tip of endotracheal tube and lower airways sites; UA, upper airway.

Figure 1. Survival analysis of matched samples by pathogen groups

Pathogen groups All matches

(n = 191)

OPX-LA

(n = 62)

ETT-LA

(n = 17)

OPX-ETT-LA

(n = 112)

Mean SE Mean SE Mean SE Mean SE
Enterobacteriaceae 5.63 0.41 3.50 0.64 3.00 0 6.51 0.47
S. aureus  4.31 0.63 1.64 0.39 6.25 2.01 4.75 0.81
APS 8.28 0.81 10.44 2.65 8.00 1.00 7.52 0.66
Upper airway bacteria 3.42 0.73 3.75 1.12 3.00 0.82 2.67 0.88
Candida spp.  3.00 0.82 2.90 1.06 2.50 0.50 5.00 0
Overall 5.38 0.31 4.13 0.61 5.06 1.05 6.12 0.36

APS, Acinetobacter, Pseudomonas and Stenotrophomonas; OPX-LA, oropharynx and lower airways sites; ETT-LA, proximal tip of an endotracheal tube and lower airways sites; OPX-ETT-LA, oropharynx, proximal tip of endotracheal tube and lower airways sites; UA, upper airway.

Discussion

The strength of this study is that it was conducted in the PICU and exclusively patients with ETTs were enrolled. An overall LA colonization rate varied from 50% to 76.6%, and in more than 50% of cases, a bacterial count exceeded the threshold of heavy colonization. In most (74.2%) participants, matching microorganisms were detected in the LA and the OPX or/and the ETT. Interestingly, Enterobacteriaceae were most frequently observed in the OPX-ETT-LA group, leading us to conclude that colonization in the OPX leads to LA colonization and secondary contamination of the ETT. The proximal tip of the ETT was less frequently colonized, and there were no nonfermenting gram-negative bacteria (Pseudomonas spp., Acinetobacter spp., S. maltophilia) in the ETT-LA matching pathogen group. The presence of S. aureus and UA bacteria in the tube most likely shows its secondary contamination from the LA, given that UA bacteria and Candida spp. (at high rates) and S. aureus (at lower rates) were most frequently seen in the OPX-LA group. Associations between a high colonization rate in the OPX and its significance in matching group formation suggest that the OPX was the most important initial site before LA colonization.

LA colonization starts from the time of intubation and continues over time. (16,17) In our study, the LA were already colonized at a rate of >50% during the first period (days 1–3) and the colonization rate was stable through all periods. In almost two-thirds of the matched cases, there was a monomicrobial growth in the OPX and the ETT, and it was steady over time. Therefore, we partially agree with Berdal et al., who proposed to use oropharyngeal swab surveillance data to guide empirical antimicrobial therapy for VAP cases in the ICU. (17) However, in one-third of cases, in the presence of polymicrobial growth and different combinations of pathogens in OPX, a clinician can be mistaken.

Survival analysis revealed that Candida spp. reached the LA from the OPX during 1.38–4.62 days on average; Enterobacteriaceae, during 4.82–6.43 days; and; nonfermenting gram-negative bacteria during 6.69–9.86 days. Most likely, in the absolute majority of cases, insertion of the ETT allowed Candida spp. direct access to the LA from the OPX, because the mean survival time was the shortest. We cannot confirm entry of other pathogens to the LA at the moment of oral endotracheal intubation. We suggest their later entry to the LA, even entry of UA and S. aureus, based on the results of survival analysis in latter subgroups.

Analysis of the reasons for sample collection or risk factors for LA colonization has showed that occurrence of the first matching OPX-LA case was associated with transportation for a CT scan outside the PICU. This could be explained by increased leakage near the cuff due to slight movements of the ETT during transportation, suggesting better preventive oropharyngeal and deep hypopharyngeal suctioning of secretions and cuff pressure monitoring before transportation of patients in the future.

In the literature, there is an ongoing debate about the importance of LA colonization while an intubated patient stays in the ICU. (4,9,18) Colonization, VAT, and VAP seem to be integral parts of one process. (9,19) In our study, only a few cases of VAT and VAP were diagnosed. A single VAP case met the criteria; however, only one VAT case met the criteria described by Craven et al. because we did not use the quantitative criteria defining VAT in our surveillance system. (4,12,18) Risk factors for VAP are well described and preventive bundles have been proposed based on these data. (20-22) However, leakage near the endotracheal cuff remains the main bridge between the OPX and the LA, causing colonization, VAT, and VAP. Prevention of leakage still remains a big challenge in the care of a critically ill patient. (5) In the PICU, cuff pressure measurements are crucial, (5,23,24) because an application of subglotic secretion drainage (SSD) is limited due to smaller tube sizes used (ETT tubes <5 mm in diameter with a SSD port are not produced), despite evidence about SSD benefit in VAP prevention. The clinical benefit of ETT with taper-shaped cuffs and silver-coated ETT still needs to be proved. (5,25)

Interestingly, in our study we did not detect highly resistant or multidrug-resistant pathogens in the LA, and an overall antimicrobial susceptibility picture was even better than we expected. A limitation of our study is that we did not investigate the influence of antimicrobials on the colonization of OPX, ETT, and LA. However, we are sure that our colonization data cannot be biased by antimicrobials, because OPX and LA colonization rates remained steady over time and antimicrobial susceptibility rates were high and mortality rate was low, indicating efficacy of the antimicrobial stewardship program in the PICU.

In conclusion, oropharyngeal contamination of the lower airways is the most important route of colonization. Different pathogens enter the lower airways at different time intervals from the moment of endotracheal tube placement. Reduction of leakage near the endotracheal cuff remains challenging in the PICU, and meticulous care of the oropharynx and endotracheal cuff pressure monitoring are advised before transportation of an intubated patient.

Acknowledgments

We highly appreciate the PICU nurses and laboratory technicians for their kindness and considerable contribution to this study.

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Corresponding author:
Tomas Kondratas
Pediatric Intensive Care Unit
Department of Pediatrics
Lithuanian University of Health Sciences
Eiveniu str. 2, LT-50009 Kaunas, Lithuania
Phone: +370 37 326038
Fax: +370 37 327160,
E-mail: tomaskondratas@gmail.com

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