Risk factor analysis in pediatric heart transplantation.

Abstract

Steady assessment of risk factors will enable identification of patients at higher risk for post-transplant death, and may thus improve organ utilization and outcomes. In this study we aimed to identify the risk factors of mortality in pediatric heart transplantation.
Between November 1989 and February 2004, there were 116 orthotopic heart transplantations performed in patients <18 years of age at our institution.
The 30-day mortality risk was 12% (dilated cardiomyopathy 7%, congenital heart disease 26%; univariate analysis: p = 0.023). The main cause of 30-day mortality was primary graft failure (36%). The late mortality rate was 31 per 1,000 person-years. The main causes of late mortality were acute rejection (44%) and cardiac allograft vasculopathy (26%). The 1-, 5-, 10- and 15-year survival rates were 85%, 77%, 65% and 53%, respectively. Male donor (odds ratio [OR] 6.33, 95% confidence interval [CI] 1.11 to 36.01) and cardiopulmonary bypass >210 minutes (OR 43.05, 95% CI 1.11 to 1,669) were risk factors for 30-day mortality. Risk factors for 1- and 5-year mortality were body weight ratio <0.8 (OR 40.36, 95% CI 3.04 to 536.47) and male donor (OR 3.36, 95% CI 1.05 to 10.75), respectively. Recipient age <1 year (OR 64.65, 95% CI 1.69 to 2,466.77) and donor-recipient body surface area mismatch of <0.9 (OR 10.58, 95% CI 1.03 to 108.25) were risk factors for 10-year mortality.
Pediatric heart transplantation can be performed with an expectation of excellent results. Certain risk factors suggest poorer outcomes.

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Risk Factor Analysis in Pediatric Heart Transplantation
Yanto Sandy Tjang, MD, DSc,a,b Hans Stenlund, PhD,b Gero Tenderich, MD, PhD,a Lech Hornik, MD,a
Andreas Bairaktaris, MD,a Reiner Körfer, MD, PhDa
Background: Steady assessment of risk factors will enable identification of patients at higher risk for post-
transplant death, and may thus improve organ utilization and outcomes. In this study we aimed to
identify the risk factors of mortality in pediatric heart transplantation.
Methods:
Between November 1989 and February 2004, there were 116 orthotopic heart transplantations
performed in patients ?18 years of age at our institution.
Results:
The 30-day mortality risk was 12% (dilated cardiomyopathy 7%, congenital heart disease 26%;
univariate analysis: p ? 0.023). The main cause of 30-day mortality was primary graft failure (36%).
The late mortality rate was 31 per 1,000 person-years. The main causes of late mortality were acute
rejection (44%) and cardiac allograft vasculopathy (26%). The 1-, 5-, 10- and 15-year survival rates
were 85%, 77%, 65% and 53%, respectively. Male donor (odds ratio [OR] 6.33, 95% confidence
interval [CI] 1.11 to 36.01) and cardiopulmonary bypass ?210 minutes (OR 43.05, 95% CI 1.11 to
1,669) were risk factors for 30-day mortality. Risk factors for 1- and 5-year mortality were body
weight ratio ?0.8 (OR 40.36, 95% CI 3.04 to 536.47) and male donor (OR 3.36, 95% CI 1.05 to
10.75), respectively. Recipient age ?1 year (OR 64.65, 95% CI 1.69 to 2,466.77) and donor–
recipient body surface area mismatch of ?0.9 (OR 10.58, 95% CI 1.03 to 108.25) were risk factors
for 10-year mortality.
Conclusions: Pediatric heart transplantation can be performed with an expectation of excellent results. Certain
risk factors suggest poorer outcomes. J Heart Lung Transplant 2008;27:408–15. Copyright © 2008
by the International Society for Heart and Lung Transplantation.
Pediatric heart transplantation has been accepted as the
best therapeutic option for end-stage heart diseases. To
date, nearly 6,500 procedures have been performed
worldwide.1 Despite encouraging long-term survival and
perceived quality of life,2,3 graft half-life after pediatric
heart transplantation has remained at nearly 13 years.4
Deaths are mainly due to acute rejection and early and late
allograft failure.5,6 The shortage of donor hearts, increas-
ing demand, and constraint of financial or medical re-
sources necessitate optimal organ utilization. Steady as-
sessment of risk factors of mortality will enable
identification of patients at higher risk for post-transplant
death, and may thus improve organ utilization and out-
comes. We aimed to identify the risk factors of mortality in
a pediatric heart transplantation population.
METHODS
Study Population
All patients ?18 years of age undergoing heart trans-
plantation at the Department of Thoracic and Cardio-
vascular Surgery, Heart and Diabetes Center North
Rhine Westphalia, Bad Oeynhausen, Germany, between
November 1989 and February 2004 were included in
this study. Our ethics committee approved this study,
and the need for individual informed consent was
waived. The annual transplant distribution data are
presented in Figure 1.
Recipient selection criteria included existing end-
stage heart failure without other feasible medical or
surgical treatment options; absence of systemic dis-
eases, infection, stroke or recent pulmonary infarction;
stable family history; compliance; and evidence of
strong motivation. Currently, we exclude patients with
renal failure who require hemodialysis. Donor hearts
were obtained from beating-heart, brain-dead individu-
als through cooperation with the Eurotransplant orga-
nization. Donor assessment was based on complete
clinical laboratory evaluation and echocardiography.
The generally used criteria to determine a suitable
donor included no active infection or malignancy,
From theaDepartment of Thoracic and Cardiovascular Surgery, Heart
and Diabetes Center North Rhine Westphalia, University Hospital of
Bochum, Bad Oeynhausen, Germany; and
Health and Clinical Medicine, Umeå University, Umeå, Sweden.
Submitted July 24, 2007; revised December 10, 2007; accepted
January 2, 2008.
Reprint requests: Yanto Sandy Tjang, MD, Department of Thoracic
and Cardiovascular Surgery, Heart and Diabetes Center NRW, Georg-
estrasse 11, 32545 Bad Oeynhausen, Germany. Telephone: ?49-5731-
8696921. Fax: ?49-5731-971820. . E-mail: ystjang@hotmail.com
Copyright © 2008 by the International Society for Heart and Lung
Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/
j.healun.2008.01.007
bDepartment of Public
408
PEDIATRIC TRANSPLANTATION

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human immunodeficiency virus (HIV) and hepatitis
negativity, normal cardiac anatomy, and function at
echocardiography after appropriate resuscitation. Both
donor and recipient were matched for ABO blood-type
compatibility and body weight (ratio within ?20%). An
older donor was accepted if coronary artery disease
could be excluded.
Surgical Procedures
Donor hearts were retrieved as part of the multiple-
organ procurement effort. The heart was decom-
pressed during harvesting to avoid coronary air em-
bolization. Just prior to stopping ventilation, both
caval veins were ligated and divided to empty the
right heart. The left atrial appendage was opened to
empty the left heart. After ascending aortic cross-
clamping, 30 to 40 ml/kg cardioplegia solution
(Bretschneider–Custodiol; Kohler Chemie, Alsbach-
Hahnlein, Germany) was administered to arrest and
cool the heart. After dividing the ascending aorta and
pulmonary artery, the heart was explanted by
transecting both caval veins and the four pulmonary
veins preserving the sinus node, its artery and sino-
atrial pathways. For cases in which a reconstructive
procedure was planned, graft harvesting included the
entire aortic arch and descending aorta, pulmonary
artery bifurcation and main pulmonary arteries, supe-
rior vena cava and pulmonary veins. Graft preserva-
tion was achieved through a combination of topical
hypothermia and cold crystalloid cardioplegia solu-
tion. During transportation, temperature was kept
between 4°C and 5°C. Procurement and recipient
surgical teams were in frequent communication to
accurately coordinate the arrival of the donor heart
and explantation of the recipient heart. Implantation
of the donor heart was performed orthotopically,
using the biatrial technique.7
Immunosuppressive Protocol
The initial immunosuppressive regimen included 3 to 4
mg/kg azathioprine (adjusted to renal and hepatic func-
tion), 0.25 mg/kg cyclosporine and 125 mg methylpred-
nisolone (all intravenous). Shortly before releasing the
aortic cross-clamp, 125 mg methylprednisolone was
administered. In the absence of renal failure or severe
circulatory deterioration, 0.1 to 0.2 mg/kg/day cyclo-
sporine (intravenous) was infused to achieve and main-
tain a serum level of 300 to 400 ?g/liter. Administration
of 1 to 4 mg/kg/day azathioprine and 3 ? 125 mg/day
methylprednisolone was also performed. Oral applica-
tion of all drugs was preferred after Day 3 post-
operatively. The long-term immunosuppressive regi-
men consisted of 4 to 6 mg/kg/day cyclosporine and 0
to 2 mg/kg/day azathioprine (dose adjusted to maintain
a white blood cell count of ?4,000 g/liter). Long-term
use of steroid was avoided if possible. In cases of acute
rejection, 15 mg/kg/day prednisolone was administered
or target trough level of cyclosporine was increased. If
acute rejection occurred under normal trough levels,
cyclosporine was switched to tacrolimus. Refractory
rejection was treated with anti-thymocyte globulin or
monoclonal antibody OKT3.
Primary graft failure was defined as a severe impair-
ment of systolic graft function affecting the right, left or
both ventricles, accompanied by hypotension, low car-
diac output and high filling pressures.8Acute rejection
episodes were diagnosed by clinical findings, electro-
cardiography, echocardiography and cytoimmunologic
monitoring (if necessary, endomyocardial biopsy), and
defined as any event leading to the acute augmentation
of immunosuppressive therapy, which basically corre-
sponds to ISHLT Grade ?3A.9Cardiac allograft vascu-
lopathy was defined either angiographically or at au-
topsy as a narrowing of ?50% in one primary vessel or
?50% in two branch vessels. Routine coronary angiog-
Figure 1. Annual distribution data for pediatric heart transplantation.
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Volume 27, Number 4
Tjang et al.
409

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raphy was performed at 1, 5 and 10 years, unless
coronary artery disease outside that schedule was sus-
pected.
Data Collection and Follow-up
Pre- and intra-operative data have been recorded ad hoc
in a computerized database. Donor, recipient and intra-
operative characteristics were retrieved for analyses.
Autopsies were obtained in the majority of death cases.
Follow-up information was obtained through outpatient
clinic reports or by telephone interview with patients,
their relatives and (or) the referring physician, and was
100% complete.
Study Variables
Dependent variables were mortality at 30 days, 1 year,
5 years and 10 years, respectively, after transplantation.
Independent variables were recipient characteristics
(age, gender, body height and weight, body surface area
and blood group, transplant indication, previous car-
diac surgery, transplant status, waiting time, need for
ventricular assist device), donor characteristics (age,
gender, body height and weight, body surface area,
blood group, cause of death, natrium concentration,
cardiopulmonary resuscitation), donor–recipient mis-
match (age, gender, body weight ratio, body surface
area, blood type) and operative characteristics (isch-
emic time, cardiopulmonary bypass, transplant period).
Statistical Analysis
All analyses were done using SPSS software, version
13.0 (SPSS, Inc., Chicago, IL). Results are expressed as
mean ? standard deviation or median (interquartile
range, IQR) for continuous variables, and as count
(percentage) for categorical variables. Univariate logis-
tic regression analysis was performed to show the
association between dependent variable (mortality) and
independent variable (recipient, donor, operative char-
acteristics). To control confounding effects, variables
with p ? 0.05 were entered into a multivariate logistic
regression analysis to determine the independent risk
factors for mortality. p ? 0.05 was considered statisti-
cally significant.
RESULTS
Baseline Characteristics
One hundred sixteen consecutive pediatric heart trans-
plantations have been performed. Baseline characteris-
tics are presented in Table 1. Median recipient age was
6 years (IQR 1.6 to 13.9 years). Of the 116 patients, 59%
(n ? 68) were male and 41% (n ? 48) were female.
Recipient mean body height was 116.3 ? 42.9 cm, and
median body weight was 16.2 kg (IQR 9 to 43.6 kg).
Recipient median body surface area was 0.7 m2(IQR
0.5 to 1.4 m2). Indications for transplantation were
Table 1. Baseline Characteristics (N ? 116)
Characteristics
Recipient age (years)
?1
1–10
?10
Male recipient
Recipient body height (cm)a
Recipient body weight (kg)b
Recipient body surface area (m2)b
Indication for heart transplantation
Dilated cardiomyopathy
Congenital heart disease
Recipient blood group
A
B
O
AB
Previous cardiac surgery
High-urgency status
Waiting time (days)b
Ventricular assist device
Donor age (years)
?1
1–10
?10
Male donor
Donor body height (cm)b
Donor body weight (kg)b
Donor body surface area (m2)b
Donor blood group
A
B
O
AB
Donor cause of death
Head trauma
Spontaneous bleeding
Others
Donor natrium concentration (mEq/liter)a
Cardiopulmonary resuscitation in donor
Age mismatch
Gender mismatch
Body weight ratio mismatch
?0.8
0.8–1.2
?1.2
Body surface area ratio mismatch
?0.9
0.9–1.1
?1.1
Blood type non-identical
Ischemic time ?240 minutes
Cardiopulmonary bypass (minutes)
?90
90–149
150–209
?210
19 (16)
53 (46)
44 (38)
68 (59)
116.3 ? 42.9
16.2 (9–43.6)
0.7 (0.5–1.4)
84 (72)
32 (28)
56 (48)
8 (7)
44 (38)
8 (7)
25 (22)
13 (11)
36.5 (14.3–89)
11 (10)
24 (21)
56 (48)
36 (31)
64 (55)
111 (82–157.5)
17.5 (10–45)
0.7 (0.5–1.4)
46 (40)
7 (6)
58 (50)
5 (4)
64 (55)
11 (10)
41 (35)
147.7 (11.6)
33 (28)
22 (19)
55 (47)
12 (10)
61 (53)
43 (37)
25 (22)
42 (36)
49 (42)
16 (14)
28 (24)
37 (32)
57 (49)
18 (16)
4 (3)
410
Tjang et al.The Journal of Heart and Lung Transplantation
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Page 4

dilated cardiomyopathy in 72% (84 of 116) of patients
and congenital heart disease in 28% (32 of 116). Twen-
ty-two percent (25 of 116) of recipients had prior
cardiac surgery, 5 of whom had more than one. Eighty-
nine percent (103 of 116) of recipients were electively
transplanted. Median waiting time was 36.5 days (IQR
14.3 to 89 days). Ten percent (11 of 116) of recipients
required ventricular assist device support as a bridge to
transplantation. The median age of donors was 5 years
(IQR 1.1 to 12 years). Donor gender was equally
distributed. Donor median body weight was 17.5 kg
(IQR 10 to 45 kg). Donor median body surface area was
0.7 m2(IQR 0.5 to 1.4 m2). Donor cause of death was
mainly head trauma (55%). Donor mean natrium con-
centration was 147.7 ? 11.6 mEq/liter; 26% (30 of 116)
of donors had natrium concentrations of ?155 mEq/
liter. Cardiopulmonary resuscitation was required in
28% (33 of 116) of donors.
Donor–recipient mismatch was associated with age
(19%), gender (47%), body weight ratio (47%) and body
surface area ratio (64%). Most of the transplantations
were performed with an identical blood type (86%).
Mean ischemic time was 212.1 ? 47.6 minutes; 24% (28
of 116) of patients had an ischemic time of ?240
minutes. Median cardiopulmonary bypass was 100.5
minutes (IQR 85 to 128.8 minutes).
Outcomes
There were 14 deaths within 30 days after transplanta-
tion, resulting in a 30-day mortality risk of 12% (dilated
cardiomyopathy 7%, congenital heart disease 26%; uni-
variate analysis: p ? 0.023). The main cause of 30-day
mortality was primary graft failure (36%) (Table 2).
Excluding all 30-day mortality, the total follow-up time
was 745 person-years (mean 77.1 ? 54.6 months).
Another 23 patients died during the follow-up period,
resulting in a late mortality rate of 31 per 1,000
person-years. The main causes of late mortality were
acute rejection (44%) and cardiac allograft vasculopathy
(26%). The 1-, 5-, 10- and 15-year survival rates were
85%, 77%, 65% and 53%, respectively (Figure 2).
Risk Factors for Mortality
Table 3 summarizes the significant risk factors for
mortality according to univariate analyses. Recipient
age ?1 year, recipient body height and body surface
area, congenital heart disease, male donor, donor body
height and body surface area, and cardiopulmonary
bypass ?210 minutes were associated with 30-day
mortality. Recipient age ?1 year, recipient body height
and body surface area, congenital heart disease, donor
body height, donor–recipient body weight ratio ?0.8
and cardiopulmonary bypass ?210 minutes were asso-
ciated with 1-year mortality. Recipient age ?1 year and
congenital heart disease, male donor, ischemic time
?240 minutes and cardiopulmonary bypass between
150 and 209 minutes were associated with 5-year
mortality. Recipient age between 1 and 10 years, high-
urgency status, donor age between 1 and 10 years, and
donor–recipient body surface area ratio mismatch ?0.9
were associated with 10-year mortality. Multivariate
analyses identified male donor (odds ratio [OR] 6.33;
95% confidence interval [CI] 1.11 to 36.01) and cardio-
pulmonary bypass ?210 minutes (OR 43.05, 95% CI
Table 1. (continued)
Characteristics
Transplant period
1989–1993
1994–1998
1999–2004
41 (35)
45 (39)
30 (26)
Values are count (percentage) unless otherwise indicated.
aMean (? standard deviation).
bMedian (interquartile range).
Table 2. Causes of Death
Cause of death
Primary graft failure
Acute rejection
Infection
Right ventricular failure
Multi-organ failure
Pulmonary complication
Technical issues
Neurologic complication
Abdominal complication
Non-specific graft failure
Cardiac allograft vasculopathy
Tumor
Unknown
Early
(N ? 14)
Late
(N ? 23)
Total
(N ? 37)
n
5
%
36
n%n%
14
27
11
3
3
5
5
3
3
3
16
3
5
5
10
2
44
9
10
4
1
1
2
2
1
1
1
2
1
1
2
2
1
14
7
7
14
14
7
1
1
6
1
2
4
4
26
4
9
6
1
2
Because of rounding, not all percentages add to 100.
Figure 2. Survival curve for pediatric heart transplantation.
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Tjang et al.
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1.11 to 1,669) as independent risk factors for 30-day
mortality. Independent risk factors for 1- and 5-year
mortality were body weight ratio ?0.8 (OR ?40.36,
95% CI 3.04 to 536.47) and male donor (OR 3.36, 95%
CI 1.05 to 10.75), respectively. Recipient age ?1 year
(OR 64.65, 95% CI 1.69 to 2,466.77) and donor–
recipient body surface area mismatch ?0.9 (OR 10.58,
95% CI 1.03 to 108.25) were independent risk factors
for 10-year mortality (Table 4).
DISCUSSION
Only a few investigators have identified risk factors for
mortality in pediatric heart transplantation. Canter et
al10reported that previous sternotomy and donor cause
of death other than closed-head trauma were the risk
factors of 30-day mortality. Morales et al11revealed
prolonged post-operative intubation (?5 days) and
longer cardiopulmonary bypass time as risk factors for
overall mortality. Another multicenter study12demon-
strated that younger age, pre-transplant mechanical
assistance and non-identical ABO blood-type match
were independent risk factors of early mortality.
Boucek et al1showed that being on extracorporeal
membrane oxygenation at the time of transplantation,
congenital diagnosis leading to transplantation, re-trans-
plantation, the need for a ventilator or hospitalization,
year of transplantation, donor age, creatinine, weight
ratio, transplant volume and bilirubin increased the risk
of 1-year mortality, whereas congenital diagnosis with
or without extracorporeal membrane oxygenation, re-
transplant, being on a ventilator or hospitalized, year of
transplant, female recipient, receiving a heart from a
female donor, recipient age, bilirubin and transplant
volume increased the risk of 5-year mortality.
Our study has presented the largest number of pedi-
atric heart transplantations from a single European
center, and clearly provides additional comparative
information to the current data of the ISHLT (pediatric
Table 3. Risk Factors For Mortality (Univariate Analyses)
Variable
Recipient age (years)
? 1
1–10
?10
Recipient body height (cm)
Recipient BSA (m2)
High-urgency status
Transplant indication
DCM
CHD
Donor age (years)
?10
1–10
?1
Male donor
Donor body height (cm)
Donor BSA (m2)
BWR mismatch
? 0.8
0.8–1.2
?1.2
BSA mismatch
? 0.9
0.9–1.1
? 1.1
IT ?240 minutes
CPB (minutes)
?90
90–149
150–209
?210
Mortality
30-day1-year5-year 10-year
7.97 (1.78–35.64)
1.12 (0.24–5.27)
1 [reference]
0.98 (0.96–0.99)
0.21 (0.05–0.89)
5.69 (1.42–22.80)
1.27 (0.34–4.83)
1 [reference]
0.98 (0.97–0.99)
0.29 (0.09–0.99)
3.86 (1.08–13.75)
0.83 (0.27–2.54)
1 [reference]
1.5 (0.31–7.36)
0.25 (0.08–0.832)
1 [reference]
7.8 (0.90–67.62)
1 [reference]
4.52 (1.42–14.37)
1 [reference]
3.78 (1.31–10.97)
1 [reference]
2.77 (1.06–7.22)
1 [reference]
0.26 (0.07–0.91)
0.44 (0.1–1.87)
5.77 (1.23–7.34)
0.98 (0.96–0.99)
0.21 (0.05–0.89)
3.45 (1.23–9.69)
0.98 (0.97–0.99)
4.33 (1.01–18.62)
1 [reference]
1.23 (0.38–3.95)
4.03 (0.87–18.76)
1 [reference]
0.83 (0.27–2.57)
2.6 (0.99–6.85)
1 [reference]
2.06 (0.39–10.78)
3.5 (0.53–23.10)
52.45 (3.62–760.42)
1 [reference]
1.62 (0.39–6.71)
3.49 (0.69–17.76)
34 (2.65–436.51)
1 [reference]
1.82 (0.56–5.93)
7 (1.65–29.67)
8,050.39 (0–8.4E ? 21)
Values are expressed as odds ratios with 95% confidence interval in parentheses. BSA, body surface area; BWR, body weight ratio; CHD, congenital heart disease;
CPB, cardiopulmonary bypass; DCM, dilated cardiomyopathy; IT, ischemic time.
412
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April 2008