1

VALUE OF PROCALCITONIN AS A PREDICTOR OF NONINFECTIOUS

COMPLICATIONS ASSOCIATED WITH PEDIATRIC LIVER
TRANSPLANTION IN THE CRITICAL CARE UNIT
1 2 3 4
Peña O , Fernández J Gamboa O. Rivera J .
1. Pediatric Intensive Care Fellowship – Universidad de La Sabana
2. Professor, Universidad de la Sabana –Director, Pediatric Intensive Care Unit, Fundación
CárdioInfantil.
3. Universidad de la Sabana Health Research Group, Universidad de la Sabana
4. Pediatric Hepatobiliary and Transplant Surgeon- Fundación CárdioInfantil

ABSTRACT
Introduction/Objectives: Procalcitonin has become an important marker for
infection. However, previous studies of solid organ transplants, including liver,
have related its elevation to non-infectious adverse outcomes. The purpose of
this study is to determine the predictive value of the trend of PCT levels and its
association with non-infectious complications.
Methods: A retrospective observational study of children who underwent liver
transplantation at our center, between August 2009 and December 2015.
Results: 45 patients were included, 40% male. 63% with cholestatic disease .
67% had a moderate to high mortality risk. A declining procalcitonin delta
between the 2nd and 1st day greater than 1 was found to have a 100%
specificity for primary dysfunction of the graft, with an OR of 21.6 (95% CI 1.8-
250.2, p=0.014). Persistently elevated levels were not associated with mortality,
OR 2.57 (95% CI 0.49 - 13.4 p=0.26), or infection, OR 0.18 (95% CI 0.1 – 5.6,
p=0.56).
Conclusion: The procalcitonin trend is a good predictive factor of graft
dysfunction in post-liver transplant pediatric patients, after the second
postoperative day. According to our experience, there is no association between
the trend and mortality. In infected patients, procalcitonin declines in the usual
manner after the second postoperative day.
Key Words: Children, Calcitonin, Liver Transplantation/adverse effects, Liver
Transplantation/mortality, Postoperative Complications/diagnosis, Primary Graft Dysfunction

Pediatric liver transplantation is one of the most successful solid organ transplants
(1), which has consolidated it as an effective strategy for the treatment of
irreversible acute liver failure in children, with a great impact on survival and quality
of life (2)(3). These significant advances have been possible due to the
development of new surgical techniques as well as in the identification of problems
and early intervention (4).
Among the tools that allow this anticipation is procalcitonin (PCT). This is a protein
precursor of the calcitonin hormone, with a molecular weight of approximately 13
kDa, made up of 116 amino acids. It is primarily produced in the thyroid gland and
has a half life close to 26 to 30 hours, with low levels being found in healthy
individuals, < 0.5 mg/dL (5).
Clinically, it is used as an infectious marker in patients with bacterial or fungal
sepsis (6). However, this elevation shows conflicting results when the organ
 2

involved is the liver. Meisner et al. showed that septic shock induced by the
application of endotoxins is not followed by a PCT elevation in anhepatic baboons
(8), which shows the relevance of this organ in the regulation of the production of
this marker.

The usual behavior of PCT levels in postoperative liver transplant patients is an

elevation during the first 24-48 hours, followed by a decline beginning on the
second day, and normalization at 3-4 days (9). However, it has recently been seen
that PCT may be elevated in ischemia-reperfusion lesions, both in liver
transplantation as well as in that of other solid organs. In cardiovascular
postoperative and post-bypass children, it is associated with an increased number
of days on mechanical ventilation, cardio-respiratory arrest, ICU stay, and as a
predictor of graft failure (10)(11)(12).

Taking into account that its main production outside of the thyroid is in the liver, it is
very important to identify its role in determining its prognostic value in pediatric
post-liver transplant patients. The purpose of this research is to evaluate the
prognostic value of the PCT level behavior and its association with non-infectious
complications, such as organ failure, primary graft dysfunction and rejection, during
the postoperative period in the Intensive Care Unit, in children immediately post-
liver transplantation.

MATERIALS AND METHODS
Study design
All pediatric patients undergoing liver transplant, of any type and due to any
etiology, who received complete postoperative care at the Fundación Cardioinfantil
Instituto de Cardiología up to discharge from the Intensive Care Unit or death,
between August 1, 2009 and December 31, 2015, were included. These patients
followed a specific post-operative treatment plan, according to the post-transplant
treatment protocol in the PICU (14). Patients were excluded who had a history of
associated thyroid pathology, transplantation of another solid organ, or who had a
donor history of infection, confirmed clinically, radiologically or by laboratory
exams.

The measurement technique for serum levels of procalcitonin was the same
throughout the sample collection period. It was the LUMI test for quantitative
determination in human plasma or serum (B.R.A.H.M.S., Hennigsdorf, Germany),
with immunoluminometric assay. This test has an analytical sensitivity of
approximately 0.1 ng/mL, and an approximate inter-measurement variability of 0.3
ng/mL, according to the manufacturer, being registered as a continuous variable
during the first seven days of PICU stay, in order to evaluate the trend over time.

Variables related to the demographic characteristics of the patients, surgical and

ischemia times, postoperative lactate levels, liver function tests, culture results and
other variables required for the definitions were also collected.
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Outcomes

The variables to be evaluated were obtained from the included patients by a review
of the electronic patient charts. The non-infectious complication variables were
recorded as dichotomous variables. Organ dysfunction was defined according to
Goldstein´s criteria (15), presenting at any time during the intensive care unit stay.
The graft dysfunction variable was interpreted as poor functioning of the graft
beginning postoperatively, defined by acute liver failure with encephalopathy,
coagulopathy, metabolic acidosis, hemodynamic instability, oliguria, transaminases
>3,000 and persistently prolonged PT without another apparent cause. The
diagnosis of graft rejection was taken from the chart, when clinical suspicion was
confirmed by biopsy.
The presence or absence of infection was recorded, according to the definitions of
the Centers for Disease Control and Prevention (16), and if it presented during the
first 10 days of treatment. Mortality will be followed until hospital discharge.
A non-infectious complication was defined as the presence of one of the previously
mentioned events: organ failure, primary graft dysfunction, or graft rejection.

Statistical analysis

Descriptive statistics were performed using measures of central tendency (mean,

median), location (percentiles) and dispersion (ranges, standard deviation) for the
continuous variables, and absolute and relative frequencies for the categorical
variables. Bivariate analyses were performed to explore the association of
procalcitonin with the outcomes measured in the study. In continuous variables,
the t-student test was used for independent samples if the assumption of normality
was met, which was evaluated using the Shapiro-Wilk test. If the assumption was
not met, Wilcoxon´s non-parametric rank-sum test was applied.
Contingency tables were constructed for the categorical variables, carrying out Chi-
square independence tests, or Fisher´s exact test if the assumption of number of
observations per cell in the two by two tables was not met. Measures of effect
(OR) were calculated with their 95% confidence intervals, using non-conditional
logistic regression. Adjusted ORs were not estimated due to the size of the sample.
Two tailed tests were performed for a type I error level of 5%. The Stata 11
program, licensed to the Universidad de la Sabana, was used for the analyses.

RESULTS

During the study period, a total of 47 liver transplants were carried out, 32 patients
with a cadaver donor, and 15 patients with a living donor. Each of these patients
received the complete post-operative treatment according to the institutional
guideline for liver transplantation (14). However, two of those with a cadaver donor
did not have procalcitonin levels, due to the unavailability of the test on the dates
on which their procedures were performed. Of these two patients, one had a
prolonged stay in intensive care, as a non-infectious complication, and the other
 4

patient did not have non-infectious complications. None of the patients had
infection or mortality.

Among the transplanted patients, the average age was three years, and 50% were
within the range of 1 to 11 years, with a ratio of 1.4 females for every male,
spanning all age ranges, with a minimum of 0.8 and a maximum of 17 years. The
patients also had a varied PELD score, with a median of 14 and a range of 7 to 30.
The majority were eutrophic. The main reason for transplantation was cholestatic
disease, with a third of the patients receiving a transplant from a living donor.
The rest of the demographic characteristics of the patients are expressed in Table
1.

Table 1. Frequency distribution of the clinical characteristics of patients prior

to liver transplant
Variable Category n %
Male 19 40.4
Sex
Female 28 59.6
Eutrophic 29 62.2
Nutritional state. Acute Malnutrition 7 15.6
Chronic Malnutrition 11 22.2
Variable Category n %
Cholestatic Disease 30 63.8
Acute Liver Failure 7 14.8
Reason for Transplant
Metabolic Disease 7 14.8
Neoplasms (others) 3 6.38
Live Donor 15 33.3
Type of Transplant
Cadaver Donor 32 66.7
Yes 5 10.6
Additional extra-hepatic procedures
No 42 89.4
Methylprednisolone 44 93.6
Administered immunosuppression
Adjunct basiliximab 3 6.4
Normal 44 93.6
Graft duplex
Increased Index 3 6.4
< 20 15 33.3
PRISM III Score 21 - 30 21 46.7
> 31 9 20.0

During surgery, the intervention time had a mean of 6.5 hours, in 50% of patients
the time was 5.3 to 7.6 hours.
Less than 10% of patients required an additional extra-hepatic procedure. All
patients received immunosuppression with methylprednisolone, and three required
an additional medication.
 5

In the postoperative period, the PRISM III score showed intermediate risk in 46%
and high risk of mortality in 20%, which is a reflection of the complexity of these
patients. Following surgery, the patients had a mean lactate of 2.2. Half of the
patients had an intensive care stay of less than seven days, with ventilated time
less than three days. The rest of the characteristics of the postoperative variables
are found in Table 2.

Table 2. Descriptions of the clinical and paraclinical characteristics of liver

transplant patients
Interquartile
Variable Median Min. Max.
Range
Surgery Time (minutes) 360 315 460 219 695
Cold Ischemia Time (minutes) 449 350 530 122 759
Anhepatic Phase Time (minutes) 59 48 67 27 94
Post-reperfusion Lactate
2.26 1.80 2.88 .77 8.10
(mmol/L)
AST day 1(uI/L) 1080 610 1825 113 5232
ALT day 1(uI/L) 937 483 1306 116 4574
Interquartile
Variable Median Min. Max.
Range
GGT day 1(uI/L) 101 37 157 16 4202
AST day 2(uI/L) 942 370 1586 110 4202
ALT day 2(uI/L) 967 409 1275 78 5965
GGT day 2(uI/L) 76 34 154 8 584
Admission Procalcitonin (ng/mL) 3.80 1.79 7.30 .05 38.89
Procalcitonin day 1 (ng/mL) 13.96 5.80 28.41 .69 125.21
Procalcitonin day 2 (ng/mL) 11.87 3.60 32.63 .54 80.84
Procalcitonin day 3 (ng/mL) 5.46 2.49 21.77 .54 162.07
Procalcitonin day 4 (ng/mL) 3.23 1.03 13.49 .30 69.37
Procalcitonin day 5 (ng/mL) 1.17 .60 7.03 .17 15.43
Procalcitonin day 6 (ng/mL) .80 .48 2.91 .05 106.68
Procalcitonin day 7 (ng/mL) .75 .33 1.66 .10 83.20
Days in ICU 7 4 11 2 38
Ventilated Days 3 1 6 1 24

With regard to infection, eight children out of the total number of patients (17.7%)
met one of the criteria, pulmonary infection being the most common with 37.5% of
the cases, and blood stream infections with 25%. Of these eight patients, seven
developed sepsis criteria.
 6

Furthermore, non-infectious complications, defined as organ dysfunction, and

acute or hyper-acute graft rejection, presented singly or multiply in 30 patients,
among which organ dysfunction was the most prevalent, being diagnosed in 83.3%
of these patients, followed by rejection, which presented in 23.3% of patients, and
primary dysfunction in 13.3% of those who had complications. Mortality was 24%,
with 11 patients.
Among the complications related to the graft, the most common one was biliary
with 77.8%, followed by graft rejection.

Figure 1 shows the median of procalcitonin levels for each of the first seven days,
according to each type of complication and in patients without complications,
evidencing, as described in the literature, an initial increase, followed by a
decrease in the first days. However, in patients with non-infectious complications,
the increase continues, or there is no decrease following the second day.
Grouping the patients with non-infectious complications and comparing them with
patients who did not develop this complication (Figure 2), a variation in the time of
descent of the levels can be seen in the first patients, towards the second day, with
a lack of descent or a lower speed of descent, similar to what was seen previously.

FIG 1. The different bars express the median and distribution of values for each day, beginning
after surgery, or on day 0. A similar behavior is observed in the four groups, with an initial
elevation and a progressive descent which begins on the second day for patients with infection
(n=7) and without complications (n=7), while in those with non-infectious complications (n=30), the
elevation persists until the second day. Only one patient had both types of complications.
 7

FIG 2. The different bars express the median and distribution of values for each day, beginning
postoperatively, or at day 0, between patients with non-infectious complications and the rest of
the patients. It shows more clearly a persistent elevation or a much lower delta between 24 and 48
hours postoperatively.

According to the previously described findings, the procalcitonin delta was

calculated as the difference in its value between day 2 and day 1. In order to
determine the delta value of the change in procalcitonin between these days, an
ROC curve was constructed, selecting the delta value beginning at which
specificity was 100%, since the sensitivity was poor (area under the curve 0.68
with a 95% CI of 0.516 to 0.843). Within the different delta values of decreasing
procalcitonin, it was found that the best discriminating threshold is a delta >1 as
positive.

Table 3 shows the results of the bivariate analysis in relation to the presence of
non-infectious complications, within which, the variables that were seen to be
related were: increased resistance in the graft duplex, with an OR of 0.19 (95% CI
0.1-0.03, p0.03), chronic malnutrition, OR of 0.14 (0.28-0.7 p0.017), and a
procalcitonin delta between days 2 and 1 >1 for primary graft dysfunction, with an
OR of 21.6 (95% CI 1.8-250.2 p0.014).
For the other variables, no association was found with the development of the
outcome of non-infectious complications, including isolated procalcitonin values on
the different days. OR was not calculated for the whole set of non-infectious
complications, since one of the values in the table is zero.
 8

Table3. Estimate of the association of pre- and post-operative variables with

the presence of non-infectious complications

Variable Compli- No OR (95% CI) p

cation complication Value

Age (years) 5.6 6.0 0.98 (0.87- 0.81

1.10)

Sex 0.57 (0.15-

Male 14 5 2.07) 0.39
Female 16 10

Nutritional State
Eutrophic 21 7
Acute malnutrition 6 1 2 (0.2-19.6) 0.55
Chronic malnutrition 3 7 0.14 (0.28-0.7) 0.017

Etiology
Cholestasis 19 11 1.44(0.24-8.75)
Acute Liver Failure 5 2 2.31(0.23-23.4) 0.68
Metabolic 4 1 1.15(0.93-14.2) 0.47
Others 2 1 0.90

PELD 14.1 15.7 1.01(0.92- 0.68

1.12)

Type of transplant
Living Donor 9 6
Cadaver Donor 21 9 0.68(0.16-2.93) 0.61

Surgical Time (Minutes) 397.1 375.1 1 (0.99-1.01) 0.50

Cold Ischemia Time 440.5 465.3 0.98 (0.99- 0.59

(Minutes) 1.01)

Anhepatic phase time 60.8 56.4 1.02 (0.99- 0.57

(Minutes) 1.06)

Extra-hepatic procedure

Yes 3 1
No 27 14 0.6 (0.18-2.0) 0.71
 9

Variable Compli- No OR (95% CI) p

cation complication Value

Immunosuppression
Methylprednisolone (MTP) 28 14 0.71
MTP+Basiliximab 2 1 0.75 (0.17-3.1)

Post-operative Lactate 2.55 2.84 0.89 (0.6 – 0.62

(mmol/L) 1.31)

AST day 1(uI/L) 1311.3 1590.6 1 (0.99-1) 0.73

GGT day 1(uI/L) 242.5 202.4 1 (0.99-1.01) 0.11

ALT day 1(uI/L) 1132.5 1146.5 0.99 (0.99-1) 0.32

Graft duplex
Normal 30 12
Increased index 0 3 0.19 (0.1-0.03) 0.03

PRISM III SCORE

Less than 20 8 7
From 21 to 30 15 6 1.35 (0.56-3.2) 0.46
Greater than or equal to 31 7 2 3.3 (1.15-9.43)
PCT Delta day 2-1
Delta ≤ 1 22 15 - -
Delta >1 8 0
PCT Delta >1
Graft Rejection
Yes 4 3 .
No 33 5 4.95(0.84-29.0) 0.94
PCT Delta >1
Primary graft dysfunction
Yes .
No 1 3 .
36 5 21.6(1.8-250.2) 0.014
PCT Delta >1
Organ failure
Yes 19 6
No 18 2 2.84 (0.5-15.9) 0.23

For each of the etiologies or non-infectious complications, a bivariate analysis was

performed in order to determine which of the other pre- and post-operative
variables could be related to each of these non-infectious outcomes. In patients
who presented organ failure, dysfunction or graft rejection, no statistically
 10

significant association was found with the other variables, except having a PRISM
score higher than 20, for organ dysfunction, with an OR of 7.69 (95% CI 1.2 -
41.2 p 0.042)

Likewise, in the group which developed infectious complications, whether or not a

procalcitonin delta value >1 was a predictive factor for this outcome was analyzed,
finding an OR of 0.18 (95% CI 0.1 – 5.6, p 0.56), which is not significant.

The possible relationships of the mortality variable with the different pre- and post-
operative variables were also explored, finding an association with a PRISM III
mortality prediction score greater than 30, with an OR of 28 (95% CI 2.4 -
326.7 p0.008). Graphically, a decrease in procalcitonin delta was also found
between days 1 and 2. However, when the delta greater than 1 between these
days was analyzed, an OR of 2.57 was obtained (95% CI 0.49 - 13.4 p0.26),
which was not statistically significant.

We attempted to determine if perfusion indicators, such as postoperative serum

lactate, surgical times, and cold ischemia and anhepatic phase times were
asociated with a PCT level delta greater than 1, or an elevation in absolute levels
during follow-up. However, no statistically significant association was found.

DISCUSSION

Pediatric post-liver transplant patients make up a population which is especially

vulnerable to complications, given the multiple conditions, risk factors and
comorbidities they entail. Therefore, it is very important to have strategies for the
early identification of patients with a greater risk of morbidity and mortality (18).

Recently, PCT has been described not just as an important marker for infection,
but also as a predictive factor for non-infectious complications in patients at risk for
presenting reperfusion ischemia injuries, such as patients with extensive burns
(19), severe trauma (20), and in cardiovascular surgery (21)(10). In this last group
of patients, it has proven to be a predictor of systemic inflammation associated with
organ failure, including ARDS, kidney, and cardiovascular failure. Likewise, a
prospective study carried out on this same group of patients found that high levels
in the first two days postoperatively had a greater risk of complications unrelated to
infection, such as cardio-respiratory arrest, length of stay in intensive care, duration
of mechanical ventilation, and requirement of inotropic support (11). These
patients also had higher lactate levels, and underwent a longer time on
cardiopulmonary bypass, a longer aortic clamp time, and longer surgery time.

In this retrospective study, we evaluated the descending trend of procalcitonin,

more than an absolute value. We found that an increase greater than 1 ng/mL of
procalcitonin levels between day 1 and 2 is associated with primary graft
dysfunction, OR of 21.6 (95% CI 1.8-250.2 p=0.014), observing a similar tendency
in graft rejection and organ failure.
 11

In these patients with a decrease in the decline of PCT, a postoperative elevation

of lactate was not seen, possibly due to the fact that lactate was drawn on exiting
the operating room, and those levels could have been purged by the new organ.
Therefore, we consider that lactate drawn at that time is not a good marker for
predicting lack of perfusion.

No difference was found between the absolute values or the procalcitonin descent
delta in patients who had a diagnosed infection, probably due to the use of broad
spectrum antibiotics in these patients, which, as they controlled the infection led to
a decrease in the microbiological triggers which generally increase the production
of PCT. Likewise, although there was a similar tendency, there was no statistically
significant association to establish the procalcitonin delta as a predictor of
mortality.

As a hypothesis or explanation of the findings regarding the relationship between

the decreased speed of descent or the decreasing PCT delta in this group of
patients, it could be caused by a non-specific release of cytokines from the injured
tissue, mainly due to reperfusion ischemia injury (22). This is mainly explained by
the fact that following direct cellular damage, or damage due to ischemia-
reperfusion, such as burns, pancreatitis, or major surgery, among others, an
inflammatory response of cytokine synthesis is generated, due to the synthesis of
trigger factors known as ¨damage associated molecular patterns¨ (DAMPs),
released mainly from the mitochondria of damaged cells, and which generate a
response similar to that of the same patterns associated with pathogens (PAMPs)
or bacterial lipopolysaccharides (LPS). This inflammatory response includes the
release of PCT (23).

These findings of the association of the elevation of this marker as a prognostic

factor of non-infectious adverse outcomes are concordant with associations found
in liver transplant studies both in adults (22)(20)(24) as well as in children. In
children, Zant et al. found an association in children between high levels of
procalcitonin and a greater morbidity and primary graft dysfunction, without finding
an association between these levels and the presence of systemic inflammatory
response signs (SIRS) or sepsis (12).

Coelho et al. demonstrated the usefulness in children of the elevation of

procalcitonin to differentiate between infection and rejection. However, other non-
infectious complications are not taken into account that could aggravate an
infectious complication, or concomitantly elevate the PCT (25).

In clinical practice, procalcitonin is used as a tool or coadjuvant for arriving at a

diagnosis of sepsis in transplanted patients. A recent meta-analysis (26) of seven
studies, including one pediatric study, concludes that the sensitivity and specificity
of procalcitonin for detecting infection is 85% and 81%, respectively, with a positive
LR of 4.41 and a negative LR of 0.18, which mainly confers a strong value as a
prognostic factor in the event of being negative.
 12

These findings agree with what we found in our study, in the sense that a delta
between the second and first day greater than 1 ng/mL is correlated with non-
infectious complications which should be investigated, given that a decrease in
levels in infected patients may be produced due to the favorable progress of the
infection after beginning antibiotic therapy.

The other variables that showed an association were nutritional status, with a
negative OR for patients with chronic malnutrition, which could be explained by the
diminished immunological response and capacity for production of PCT in these
patients. Likewise, an increased resistance index in the graft duplex showed a
negative OR, which could be an incidental finding, due to the small number of
patients who had it.

The main limitations of our research are that due to the small number of patients
who presented primary dysfunction, the results must be interpreted cautiously, and
prospective studies are needed to corroborate these findings. Being a
retrospective cohort analysis, it could have an information bias. However, the
analysis and data collection from the electronic chart is the same for all the cases,
and the same technique and sample processing time was used for all processed
test samples. Moreover, being a surgical event with a relatively low frequency, the
sample size is greater than in other pediatric liver transplant studies.

CONCLUSIONS

The procalcitonin trend is a good predictive factor of graft dysfunction in pediatric

post-liver transplant patients, after the second postoperative day. According to our
experience, there is no association between the trend and mortality. In patients
with documented infection, procalcitonin has a usual decline after the second
postoperative day.

ACKNOWLEDGEMENTS
- Pediatric Liver Transplant Group, Fundación Cárdio Infantil
- Team of nurses and residents of the Pediatric Intensive Care Unit, Fundación
CárdioInfantil

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