Age-Dependent and Hypoxia-Related Differences in

Myocardial Protection During Pediatric Open

Heart Surgery
H. Imura, MD; M. Caputo, MD; A. Parry, FRCS; A. Pawade, FRCS;
G.D. Angelini, FRCS; M.-S. Suleiman, PhD
BackgroundCurrent cardioplegic protection techniques used in pediatric cardiac surgery do not take into consideration
age and cyanotic differences. The aim of the present work was to address this question by monitoring clinical outcome,
myocardial metabolism, and reperfusion injury in pediatric patients protected by cold-crystalloid cardioplegia.
Methods and ResultsFifty-eight patients (31 children and 27 infants) with or without hypoxic stress (cyanosis)
undergoing open heart surgery with cold-crystalloid cardioplegia were included in the study. Clinical outcome measures
assessed included inotropic and ventilatory support, intensive care, and hospital stay. Ischemia-induced changes in
metabolism (adenine nucleotides, purines, lactate, and amino acids) were determined in ventricular biopsies collected
at the beginning and end of ischemic time (cross-clamp time). Reperfusion injury was assessed by measuring
postoperative serial release of troponin I. Evidence was observed of ischemic stress during cardioplegic arrest in children
and infants as shown by significant changes in cellular metabolites. Compared with infants, children had significantly
less reperfusion injury and better clinical outcome, and these factors were related to duration of ischemic time. Cyanosis
did not influence outcome in infants, but cyanotic children showed worse reperfusion injury and clinical outcome than
acyanotic children.
ConclusionsExtent of myocardial protection with cold-crystalloid cardioplegia in pediatric open heart surgery is
dependent on age and degree of cyanosis. (Circulation. 2001;103:1551-1556.)
Key Words: pediatrics surgery, pediatric cardioplegia ischemia metabolism

ince the introduction of cardioplegic arrest, major advances have been made in preservation of myocardial
function during open heart surgery. However, despite variation in composition of cardioplegia, myocardial protection
has been based primarily on use of high-potassium coldcardioplegic solutions. Although these solutions originally
were designed to protect adult hearts, they have been adopted
for pediatric cardiac surgery.1 Available laboratory data has
been inconclusive to explain vulnerability of immature myocardium to cardiac surgery. Most reports suggest that developing mammalian hearts are more resistant to damaging
effects of cardiac insults than adult hearts.1 4 This improved
tolerance has been attributed to differences in vascular
resistance, calcium mobilization, and metabolism.5 8 However, others9,10 have reported that immature myocardium is
more vulnerable to injury than adult heart. Experimental
laboratory research that has investigated cardioprotective
action of cardioplegic solutions also has been inconclusive, in
part because of species-dependent and age-related
differences.1113

Current methods of myocardial protection during adult

open heart surgery include a variety of cardioplegic techniques, several of which have been shown to provide good
myocardial preservation.14,15 In contrast, myocardial protection during pediatric open heart surgery remains poor and
associated with relatively more morbidity and mortality.16,17
This is largely because myocardial protection techniques used
in adult hearts are uncritically extended to pediatric hearts.
Furthermore, end points used in myocardial protection studies
in pediatric surgery tend to focus on single aspects (eg,
function or metabolism).16,18 20 No comprehensive studies
have dealt with metabolism, myocardial reperfusion damage,
and clinical outcome or have addressed the question of age
and effect of chronic cyanosis. The aim of the present work
was to investigate whether myocardial protection during
pediatric open heart surgery depends on age and degree of
cyanosis. To achieve this aim, we monitored myocardial
metabolic changes during ischemia, postoperative troponin I
release as a measure of reperfusion injury, and a variety of
parameters of clinical outcome in children and infants with or

Received September 28, 2000; revision received November 17, 2000; accepted November 29, 2000.
From the Bristol Heart Institute (H.I., M.C., G.D.A., M.S.S.), University of Bristol, Bristol Royal Infirmary; and The Royal Hospital for Sick Children
(A. Parry, A. Pawade), Bristol, UK.
Correspondence to M.-S. Suleiman, Bristol Heart Institute, Bristol University, Bristol Royal Infirmary, Bristol BS2 8HW, UK. E-mail
m.s.suleiman@bristol.ac.uk
2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

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TABLE 1.

Patient Characteristics and Clinical Outcome

Assessment of Clinical Outcome

Infants
(n27)

Children
(n31)

Mean

4.70.6

46.85.9*

Range

111

12120

Body wt, kg

5.20.4

15.91.4*

20/7

21/10

Ventricular septal defect

Tetralogy of Fallot

Atrioventricular septal defect

Pulmonary atresia or stenosis

Total anomalous pulmonary vein drainage

Atrial septal defect/partial defect

Mitral or aortic valve

Age, mo

Sex, M/F
Pathology, n

Other

Cardiopulmonary bypass time, min

61.03.9

54.74.8

Aortic cross-clamp time, min

28.22.3

25.31.7

Inotropic support duration, h

619

287*

Ventilatory support duration, h

477

163*

Intensive Care Unit stay, d

4.90.7

2.90.5*

13.71.7

9.60.9*

Hospital stay, d
*P0.05 vs infants.

without evidence of cyanosis who were undergoing open

heart surgery with St. Thomas Hospital cardioplegic solution 1.

Methods
Fifty-eight patients (27 infants 12 months and 31 children 12
months of age) who underwent elective open heart surgery for
congenital heart disease between March 1998 and November 1999 at
the Bristol Royal Hospital for Sick Children were recruited prospectively into the present study. The 2 groups were divided into cyanotic
and acyanotic patients according to arterial blood oxygen saturation
(oxygen saturation acyanotic, 90% to 100%; cyanotic, 90%).
Preoperative characteristics are summarized in Table 1. All cyanotic
patients were stable and none was acutely hypoxic. No emergency
operations had occurred, and no patients were on preoperative
respiratory or inotropic support. Ethical approval from the local
authority and informed consent were obtained for all patients.

Operative Procedure
All operations were performed by use of cardiopulmonary bypass
with ascending aortic and bicaval venous cannulation. Anesthetic
technique was standardized for all patients. Slow induction with
sevoflurane and 50% air-50% O2 followed by fentanyl 25 to 50
mg/Kg was used. Morphine 0.5 mg/Kg was infused during cardiopulmonary bypass, and neuromuscular blockade was achieved by 0.1
to 0.15 mg/Kg pancuronium bromide. Heparin 3 mg/Kg body wt was
initially added and supplemented as required to maintain active
clotting time of 480 seconds. Alpha-stat acid-base management
was adopted.
Cold-crystalloid St. Thomas Hospital cardioplegic solution 1
(4C to 6C) was used for myocardial protection (Martindale
Pharmaceuticals). Cardioplegic arrest was achieved by an antegrade
infusion of 25 mL kg1 min1 for 4 minutes. No additional
cardioplegia was administered. Topical cooling with ice slush was
used to maintain myocardial cooling.

Intraoperative and postoperative clinical parameters were used to

determine level of clinical outcome. These parameters included
intraoperative requirement of inotropes for weaning patients from
cardiopulmonary bypass and postoperative inotropic support. The
latter was considered to be either minimal (6 g kg1 min1 of
dopamine) or significant (6 to 10 g kg1 min1 of dopamine
with or without other inotropic agents such as adrenaline or noradrenaline). Other clinical parameters included length of inotropic
and ventilatory support, intensive care, and hospital stay.

Collection of Ventricular Biopsies and Extraction

of Metabolites
Myocardial biopsies (5.50.5 mg) were collected from right ventricle (free wall of trabecular portion) through tricuspid valve by direct
resection with surgical scissors. Biopsies were collected from only
42 patients. First biopsy was taken immediately after cross-clamping
the aorta (control biopsy), whereas second biopsy was taken before
releasing the aortic cross-clamp (ischemic biopsy). Each specimen
was immediately frozen in liquid nitrogen until processing for
analysis of cellular metabolites.

Determination of Adenine Nucleotides, Purines,

Lactate, and Amino Acids in Biopsy Specimens
Adenine nucleotides, purines, lactate, and free amino acids were
measured in all biopsies collected. Adenine nucleotides and purines
in neutralized extract were separated and quantified by use of a
high-performance liquid chromatography method based on previous
reports.21 Lactate was determined by use of a diagnostic kit from
Sigma Chemical Co. Amino acids were determined according to the
Pico-Tag method of Water as reported earlier.22

Measurements of Myocardial Troponin I and

Characteristics of Exclusion
Serum concentration of myocardial troponin I was determined before
surgery and at 4, 12, 24, and 48 hours postoperatively with ACCESS
system (Beckman, Inc). Corrective congenital heart surgery can
involve significant ventricular incision or myocardial resection. In
such patients, postoperative release of troponin I is likely to be due
to reperfusion injury as well as damage from incision and resection.
We found that postoperative release of troponin I in patients who had
significant right ventricular incision was markedly higher than
patients who had minimum or no incision or resection of ventricular
muscle (data not shown). Eight patients with significant incision and
resection therefore were excluded from troponin I analysis.

Data Collection and Analysis

Clinical outcome data were collected prospectively and analyzed for
all 58 patients recruited. Ventricular biopsies were collected from 42
patients, all of which were used in the analysis. Postoperative release
of troponin I was measured in all 58 patients, but results from only
50 were used for analysis (see exclusion criteria above). The 50
patients for whom troponin I analysis was completed included 26
children (6 with cyanosis) and 24 infants (10 with cyanosis). Clinical
and biochemical data were expressed as meanSEM. Statistical
intragroup analysis was performed by use of paired t test or repeated
measures ANOVA with Bonferroni post hoc test as appropriate.
Intergroup analysis was performed by use of unpaired t test.
Correlation coefficient was calculated and significance determined
by use of Fishers r to z. Statistical analysis was performed with a
StatView personal computing package (SAS Institute Inc).

Results
Clinical Outcome
No in hospital deaths occurred, and no differences were found
between children and infants with regard to cardiopulmonary
bypass and aortic cross-clamp time (Table 1). Significant

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Imura et al

Age and Hypoxia in Pediatric Heart Surgery

1553

Figure 1. Effect of cross-clamp time on

clinical outcome. Different clinical outcome parameters in children (F; n31)
and infants (; n27) measured as a
function of ischemic duration (20 minutes). *P0.05 vs 20-minute crossclamp time; P0.05 vs children.

present study. However, 2 pathologies were examined that

included relatively more patients (Table 1); children with
tetralogy of Fallot (n7) and infants with ventricular septal
defect (n9). As a result of narrow range of cross-clamp time
in children with tetralogy of Fallot (25 to 35 minutes), no
correlation existed between cross-clamp time and clinical
outcome. However, significant (P0.05) negative correlation
was seen between increased degree of hypoxia and clinical
parameters. As for infants with ventricular septal defect
pathology, positive correlation was seen between cross-clamp
time and inotropic duration (P0.05).

postoperative inotropic support was required for 67% of

infants and 39% of children, and amount of dopamine needed
for weaning patients from cardiopulmonary bypass was
significantly higher in infants than children (6.90.7 versus
4.60.6 g kg1 min1, respectively; P0.05). All clinical
outcome parameters were significantly better for children
(Table 1) and were dependent on ischemic cross-clamp time
(Figure 1).
Clinical outcome in infants was not dependent on presence
of cyanosis. However, despite similar cross-clamp times,
cyanotic children had worse outcome compared with acyanotic children (Table 2).
Given the small number of patients in each pathology
(Table 1), firm conclusions on the effect of different pathologies on clinical outcome are difficult to make from the

Changes in Cellular Metabolites During Ischemia

During ischemia, a significant fall in myocardial concentration of ATP was seen in both groups: from 45.23.5 to

TABLE 2. Patient Characteristics and Clinical Outcome in Children and Infants

With or Without Evidence of Cyanosis
Infants

Cardiopulmonary bypass time, min

Aortic cross-clamp time, min

Children

Cyanotic
(n12)

Acyanotic
(n15)

Cyanotic
(n11)

Acyanotic
(n20)

65.46.7

57.54.7

75.69.0

43.23.7*

294

283

292

242

Hemoglobin, g/L

14.00.6

11.30.3*

14.90.4

12.10.3*

Blood O2 saturation, %

84.21.0

95.30.7*

83.51.5

97.90.5*

Postoperative inotropic support, n

Minimum
Significant

17

11

Dopamine, g kg1 min1

7.70.8

6.20.9

6.61.2

3.30.6*

Inotropic duration, h

6112

6114

5617

143*

Intubation time, h

4310

5012

296

92*
1.70.2*

ICU stay, d
Hospital stay, d

3.90.7

5.61.3

5.21.2

10.31.1

16.42.7

11.11.0

8.81.3

*P0.05 vs cyanotic patients in the same group; P0.05 vs acyanotic infants; P0.05 vs
cyanotic infants.

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March 20, 2001

TABLE 3. Myocardial Concentration of Metabolites Before and
After Ischemia in Cyanotic and Acyanotic Children and Infants
Infants (n22)
Cyanotic
(n9)

Acyanotic
(n13)

Children (n20)
Cyanotic
(n10)

Acyanotic
(n10)

ATP
Control

42.25.2

47.34.7

41.73.5

42.82.4

Ischemia

19.82.9*

23.43.2*

22.13.2*

27.25.8*

Control

29.85.1

23.53.1

21.52.1

18.02.0

Ischemia

18.74.0*.

18.62.1

15.00.56*

16.21.6

Control

7.01.1

6.91.9

5.10.8

3.20.8

Ischemia

6.00.7

7.61.1

4.70.5

4.40.8

Control

1.00.2

1.40.3

1.20.3

1.20.4

Ischemia

4.61.0*

3.81.2*

3.90.9*

3.41.1

Control

0.70.1

0.60.1

0.60.2

0.80.3

Ischemia

1.70.4*

1.40.3*

0.90.2

1.40.3

Control

0.080.06

0.140.09

0.090.05

0.080.05

Ischemia

0.810.22*

0.910.32*

0.750.20*

0.730.30*

Control

68.89.5

86.18.0

72.76.6

76.13.5

Ischemia

39.45.1*

61.06.6*

42.85.0*.

56.27.5*

ADP

AMP

Inosine

Adenosine

Hypoxanthine

Glutamate
Figure 2. Effect of cross-clamp time on ischemic stress and
reperfusion injury in children (F, n20) and infants (E, n20).
Scattergrams show correlation between ischemic stress (% fall
in ATP) and cross-clamp time (A) and between reperfusion injury
(peak troponin I release) and cross-clamp time (B). Strong positive correlation existed (coefficients were 0.73 for both children
and infants in A and 0.68 for children and 0.69 for infants in B;
P0.0001).

21.92.2 nmol/mg protein for infants and from 42.22.1 to

24.63.3 nmol/mg protein for children (P0.05). Changes in
ATP were strongly dependent on duration of ischemia (Figure 2A). Furthermore, fall in ATP was significantly greater in
patients who needed a higher amount of inotropic support
versus patients who had minimum postoperative inotropic
requirement (P0.05). A significant rise in lactate during
ischemia was seen only in children (from 16432 to 30871
nmol/mg protein for children, P0.05, versus 25955 to
26345 nmol/mg protein for infants). Although resting levels
of lactate in children tended to be lower than in infants, this
did not reach statistical significance.
Table 3 shows concentration of all metabolites before and
after ischemia in children and infants, with each group further
divided into cyanotic and acyanotic patients. A significant
ischemia-induced fall in ATP was evident in cyanotic and
acyanotic hearts in both children and infants. A significant
fall in ADP occurred after ischemia only in cyanotic hearts of
infants and children. The concentrations of inosine, adenosine, and hypoxanthine in control biopsies were similar in
acyanotic and cyanotic children and infants and increased in
a similar fashion at end of ischemia (Table 3). A significant
fall in concentration of glutamate during ischemia was seen in

Aspartate
Control

9.01.7

10.61.5

9.61.3

9.11.0

Ischemia

5.30.9*

7.31.0

5.40.7*

9.11.4

Control

353104

18246

25355

9319

Ischemia

29359

23967

282104

330102*

Lactate

Values are nmol/mg of protein.

*P0.05 vs corresponding control biopsy; P0.05 vs control biopsy in
cyanotic infants; P0.05 vs control biopsies in cyanotic children and infants;
and P0.05 vs corresponding ischemic biopsy in cyanotic infants for
glutamate and vs acyanotic children for aspartate.

all groups, although this was more marked in cyanotic

compared with acyanotic patients. Furthermore, fall in concentration of aspartate was significant only in cyanotic
patients. No difference in concentration of lactate was observed in biopsies collected at the beginning of ischemia in
cyanotic or acyanotic infants. However, acyanotic hearts in
children had significantly lower concentration of lactate
compared with cyanotic children or infants. No significant
change occurred in lactate concentration at end of ischemia in
infant hearts (cyanotic or acyanotic) or cyanotic hearts of
children. A significant increase in myocardial lactate during
ischemia was seen only in acyanotic children.

Reperfusion Injury (Postoperative

Troponin I Release)
Troponin I values 4 and 12 hours after operation were
significantly higher for infants compared with children

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Imura et al

Figure 3. Effect of cyanosis on reperfusion injury. A, Timedependent postoperative troponin I release in acyanotic children
(F; n20) and acyanotic infants (; n14). B, Time-dependent
postoperative troponin I release in cyanotic children (F; n6)
and cyanotic infants (; n10). *P0.05 vs troponin I levels at
corresponding cross-clamp time in acyanotic children.

(5.50.6 versus 3.20.3 ng/mL at 4 hours and 4.00.4

versus 2.50.3 ng/mL at 12 hours after operation; P0.05).
Peak troponin I release correlated positively with cross-clamp
time in both infants and children (Figure 2B). Total and peak
troponin I release in infants but not in children correlated
positively with intensive care unit stay, hospital stay, and
duration of inotropic support (all P0.01; data not shown).
Time-dependent postoperative release of troponin I was
significantly lower in acyanotic children compared with
acyanotic infants (Figure 3A) but was similar for both
cyanotic infants and children (Figure 3B).

Discussion
The present work shows for the first time that myocardial
protection with cold-crystalloid cardioplegia in pediatric open
heart surgery is dependent on age and cyanosis. This conclusion was reached by use of markers of myocardial ischemic
stress, reperfusion injury, and clinical outcome.

Myocardial Protection in Pediatric Surgery is Age

and Cyanosis Dependent
In the present study, we found that clinical outcome after
pediatric open heart surgery is age dependent; children
showed more resistance to reperfusion injury than infants.
However, cyanotic children had worse outcome and more
reperfusion injury compared with acyanotic children. Cyanosis did not influence outcome and injury in infants. The
finding that cyanosis predisposes heart to more damage

Age and Hypoxia in Pediatric Heart Surgery

1555

during open heart surgery has been confirmed indirectly in 2

recent studies,18,23 although neither addressed the question of
age. However, these observations are in contrast to work on
chronically hypoxic immature rabbit hearts, which were
found to be more tolerant to ischemia compared with normoxic hearts.24 This difference probably occurred because
hearts from animal models are different from wellcompensated hypoxemic pediatric human hearts. Underlying
mechanisms responsible for hearts of infants and cyanotic
children being more susceptible to ischemia and reperfusion
injury than hearts of acyanotic children are not readily
apparent. These mechanisms may include differences in
myocardial calcium handling and in metabolic properties.
Calcium handling properties have been used to explain
differences between adult and immature animal hearts.25
Whether these properties also change during development of
human heart is presently unknown.
Low myocardial lactate levels and their significant increase
during ischemia seem to be the only metabolic change that
distinguishes acyanotic children from both infants and cyanotic children. The observation that hearts of infants and
cyanotic children do not accumulate lactate during ischemia
is not consistent with known changes during myocardial
anaerobic metabolism and suggests that anaerobic metabolism in these hearts is different from that of hearts of
acyanotic children. Hypothermia has been shown to reduce
significantly buildup of lactate during ischemia in newborn
pig heart.26 However, given that all hearts were equally
hypothermic in the present study, the difference clearly is not
due to temperature. One can argue that the increase in lactate
concentration in hearts of acyanotic children during ischemia
can protect myocardium by lowering intracellular pH. In fact,
mild acidification of cardioplegia was found to improve
myocardial protection of immature rabbit heart.27 Intracellular acidosis early after reperfusion can protect myocardium
by influencing several pathways implicated in myocardial
protection (eg, inhibition of mitochondrial pore).28 One also
can argue that, in contrast to hearts of infants and cyanotic
children, hearts of acyanotic children develop the ability to
use lactate as a substrate for energy production, particularly
given that concentration of ATP at the end of ischemia tended
to be higher in acyanotic children. Another possibility as to
why lactate may protect the heart could be due to an increase
in KATP channel activity.29
In our assessment of children and infants, we avoided the
question of pathologies. Pathologies can be different for
different age groups, and study would require a large sample
size. However, in 2 pathologies with relatively more patients,
we found correlation between clinical outcome and crossclamp time in ventricular septal defect and between clinical
outcome and degree of cyanosis in tetralogy of Fallot.

Clinical Implications for Use of

Cold-Crystalloid Cardioplegia
Current cardioplegic techniques have contributed to decrease
in mortality in pediatric patients during open heart surgery.
However, as shown in this work and by others16,17,19 use of
cold St. Thomas Hospital solutions 1 and 2 is still associated
with significant reperfusion injury. Experimental studies have

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March 20, 2001

shown that St. Thomas Hospital solution 2 provides better

protection than solution 1.30 However, to the best of our
knowledge, no clinical evidence has demonstrated superiority
of St Thomas solution 2 over solution 1. In recent years,
many surgeons, particularly in North America, have begun to
use cold-blood cardioplegia in pediatric surgery, although
little evidence suggests that cold-blood cardioplegia is superior to crystalloid cardioplegia.1,18
Limitations of the present study include absence of neonatal patients and patients with acute high degree of cyanosis.
The former was due to technical difficulties of obtaining
biopsies and the latter because ethical approval was granted
to study only patients undergoing elective surgery. Finally,
range of cross-clamp time was relatively narrow and in most
patients did not exceed 70 minutes.

Summary
In the present study, we present novel data that show that
cold-crystalloid cardioplegia in pediatric cardiac surgery is
associated with significant ischemic stress and myocardial
injury. Reperfusion injury and clinical outcome were dependent on age and cyanosis.

Acknowledgments
We acknowledge Anne Moffat for technical assistance and Prof A.C.
Newby for helpful comments. The present study was supported by
the British Heart Foundation, the Garfield Western Trust, and the
National Heart Research Fund.

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Age-Dependent and Hypoxia-Related Differences in Myocardial Protection During Pediatric Open

Heart Surgery
H. Imura, M. Caputo, A. Parry, A. Pawade, G. D. Angelini and M.-S. Suleiman
Circulation. 2001;103:1551-1556
doi: 10.1161/01.CIR.103.11.1551
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