Download Amr Ali Esmail _Isoflurane_preconditioning

Isoflurane Attenuates Myocardial Ischemia during Congenital Heart Diseases Correction: A Comparative
Study versus Midazolam Continuous Infusion
Isoflurane Provides Better Myocardial Protection than Midazolam
in Pediatric Patients during Open Heart Surgeries
Amr Keera MD†, Abd El- Hay MD, Doaa M Ghazy MD* & Mohamed Shehata MD*
Departments of Anesthesia and Chemical & Clinical Pathology*, Faulty of Medicine, Cairo &
Benha† Universities
Abstract
Objectives: This study was designed to evaluate the applicability of anesthetic myocardial
protection (pre-conditioning and minimization of reperfusion injury) using two anesthetic
regimens on plasma levels of cardiac troponin T (cTnT), as a marker of myocardial ischemia, in
pediatric patients assigned for surgical correction of congenital heart diseases using
cardiopulmonary bypass (CPB).
Patients & Methods: The study included 60 patients (36 males and 24 females). Patients were
randomly allocated in 2 equal groups: Midazolam group received a continuous infusion of
midazolam (0.2 mg/kg/hour) and Isoflurane group maintained by an end-tidal concentration of
isoflurane of 1-1.5% throughout the operation. Six blood samples were taken for estimation of
plasma cTnT levels immediately after induction of anesthesia, (S1), 8-hours (S2), 16-hours (S3),
24-hours (S4), 36-hours (S5) and 48-hours (S6) after aortic cross-clamping.
Results: Plasma cTnT levels estimated after aortic cross-clamping (S2-S6) showed a significant
(P1<0.001) elevation in both groups compared to levels estimated in S1 sample. Moreover, plasma
cTnT levels showed a progressive increase in all patients irrespective of anesthetic regimen used
reaching a peak levels in S4 sample and started to decline thereafter but still significantly higher
compared to levels estimated in S1 sample. Plasma cTnT levels estimated in S2 sample showed a
non-significant increase in midazolam group compared to levels estimated in isoflurane group. On
contrary, plasma cTnT levels estimated in midazolam group at 16, 24, 36 and 48 hours after aortic
cross-clamping were significantly higher (P6=0.034, 0.01, <0.001 & =0.031, respectively)
compared to levels estimated in isoflurane group. In midazolam group, there was a positive
significant correlation between mechanical ventilation time and plasma cTnT levels estimated at
24-hours (r=0.375, p=0.041), respectively. However, such correlations were non-significant
despite being positive in isoflurane group, (r=0.209, p>0.05).
Conclusion: It could be concluded that the hypothesis of anesthetic myocardial protection
(preconditioning and minimization of reperfusion injury) is applicable for pediatric patients with
congenital heart disease who are assigned for cardiac surgery and isoflurane-based anesthesia
minimized myocardial ischemic and reperfusion injury and provided efficient cardioprotection
irrespective of the type of cardiac lesion.
Introduction
Cardiopulmonary bypass and cardioplegic cardiac arrest with aortic cross-clamping
are used mainly to achieve adequate exposure during various cardiosurgical procedures, but
they carry a risk for local myocardial injury and systemically detrimental inflammatory
effects, (Wan et al., 1996). These harmful effects may be mediated by the generation of free
radicals during reperfusion, (Wu et al., 2000). Many pathophysiological processes in cardiac
ischemia/reperfusion are associated with derangement of cellular ion homeostasis, with
calcium overload likely having a key role in the impairment of ischemic and reperfused tissue,
(Baldwin et al., 2002).
Exposing the adult myocardium to brief periods of ischemia and reperfusion induces greater
tolerance to a subsequent more prolonged ischemic insult, a phenomenon known as ischemic
preconditioning (IP). Ischemic preconditioning is a myocardial endogenous protection against
ischemia, (Chiari et al., 2005). Ischemic stimuli cause the release of stress mediators from the
heart, including adenosine, bradykinin, opioids, noradrenaline and free radicals. They
contribute as initiators, which pass signals to intracellular components, such as inhibitory
guanine nucleotide binding proteins (Gi proteins) and protein kinase C (PKC). Eventually,
ATP-sensitive K+ channels (KATP channels) on the sarcolemma and mitochondria are
activated. Mitochondrial KATP channels play a greater role than sarcolemmal KATP
channels. Halogenated anesthetic agents provide protection via a mechanism similar to that of
ischemic preconditioning, (Rie & Pierre, 2002). Cardioprotection by IP offers higher nitric
oxide production, a lower myocardial ischemia; and better functional recovery of the hearts in
coronary artery surgery patients, (Buyukates et al., 2005).
Experimental evidence has clearly demonstrated that the effects of IP are mimicked
by volatile anaesthetic agents that have direct protective properties against reversible and
irreversible ischemic myocardial damage, (De Hert, 2005). These properties have been
related to a direct preconditioning effect but also to an effect on the extent of reperfusion
injury, (Kato & Foex, 2002). Given the important role of calcium overload, some have
suggested that inhaled anesthetic preconditioning reduces ischemia/reperfusion injury by
activating adenosine triphosphate-sensitive potassium channels, thereby decreasing
intracellular and mitochondrial calcium in adult hearts, (Obal et al., 2005). This is often
referred to as anaesthetic preconditioning; the implementation of these properties during
clinical anesthesia can provide an additional tool in the prevention and/or treatment of
ischemic cardiac dysfunction in the perioperative period, (Guarracino et al., 2006).
Furthermore, Chiari et al., (2005) reported that volatile halogenated anesthetics offer
a myocardial protection both when administrated before a myocardial ischaemia and during
reperfusion after the long ischaemia a phenomenon called postconditioning.
During repair of a congenital heart defect, the child is exposed to myocardial hypoxia.
Pediatric myocardium is more sensitive to hypoxia and cardioplegic arrest than the adult.
Cyanotic patients are exposed to high concentrations of oxygen when bypass starts inducing
an injury similar to reperfusion injury, (Egan et al., 2005). However, the effect of inhaled
anesthetic preconditioning, as well as its efficacy in intact newborn hearts, has not been
addressed. Because the physiology, pharmacology, and metabolic responses of the newborn
heart differ from those of the adult heart extrapolation of results from the adult heart is not
necessarily warranted, (Imura et al., 2001).
Classic IP in rats is not present at birth, and the enhanced recovery of contractile
function develops only at the end of the first postnatal week, (Awad et al., 1998). Baker et al.,
(1999) found that preconditioning can be induced in isolated perfused normoxic immature
rabbit hearts. In an animal study, pregnant rats were exposed chronically to intermittent
periods of hypoxia and their newborn offspring underwent periods of IP immediately after
birth; neither procedure in isolation increased tolerance to subsequent periods of hypoxia,
while the combination increased cardiac tolerance, (Ostadalova et al., 2002). Cheung et al.,
(2006), conducted a randomized controlled trial of the effects of remote IP in children
undergoing repair of congenital heart defects and demonstrated the myocardial protective
effects of remote IP.
All patients undergoing heart surgery experience a certain amount of nonspecific
myocardial injury documented by the release of cardiac biomarkers, (Zangrillo et al., 2005).
The troponin complex consists of TnC, TnI and TnT, and its function is the regulation of
striated and cardiac muscle contraction. Most intracellular cTnI and cTnT are bound to the
myofibrils in the cardiac myocyte; however, a small percentage exists in a cytosolic pool (6–
8% of cTnT and 3–4% of cTnI), (Maynard et al., 2000). The importance of this pool is as the
source of cytosolic troponins released 4–6 h after myocardial injury and continuing
breakdown of the myofibrillary complex in damaged myocytes results in the prolonged
elevation of the concentration of both troponins in blood, (Adamcova & Pelouch, 2001). The
measurement of troponins is sensitive and specific for the detection of perioperative
myocardial ischaemia. Cardiac troponin T has also been reported to be an independent
predictor of early postoperative cardiovascular complications following non-cardiac surgery,
(Jules-Elysee et al., 2001) as well as in that following coronary artery bypass surgery,
(Holmvang et al., 2002). Elevations of blood cTnT in children were found to relate to the
severity of myocardial damage and predict subsequent subclinical and clinical cardiac
morbidity and mortality, (Kanaan & Chiang, 2004).
This study was designed to evaluate the applicability anesthetic myocardial protection
(preconditioning and minimization of reperfusion injury) using two anesthetic regimens. The
plasma levels of cTnT, as a marker of myocardial ischemia was measured in pediatric patients
assigned for correction of congenital heart diseases.
Patients & Methods
This prospective, randomized, comparative study was conducted at Pediatric
Cardiothoracic Anesthesia Unit, Abo El-Reish pediatric Hospital, Cairo University in
conjunction with Anesthesia Department, Benha University Hospital. After obtaining
approval of Ethics and Research Committee and parents consent, 60 pediatric patients were
enrolled in the study through the period from Jan 2005 till October 2006. Patients with
hepatic or renal dysfunction, endocrine or muscle disease were excluded. Also patients with
Fallot tetrallogy, if ventriculotomy is done during correction of the defect and patients with
heart failure were excluded from the study. All operations were performed by the same
surgeon. Patients were fasting 6 hours prior to surgery; 4 hours for breast milk and at least 2
hours for clear fluids. Preoperative intramuscular injections were avoided to prevent skeletal
muscle trauma and release of troponins.
Patients were pre-medicated by oral atropine sulphate in a dose of 0.02 mg/kg and
midazolam in dose of 0.5 mg/kg 30 min before induction of anesthesia. After ensuring
sedation of the patients, they were transferred to the operating theatre. Noninvasive
monitoring by pulse oximeter, ECG, indirect ABP, was applied. Oxygen was provided using
a facemask. A peripheral venous line was inserted, then anesthesia was induced by fentanyl
in dose of 3µg/kg and pancuronium bromide in a dose of 0.15 mg/kg. Manual ventilation was
applied till tracheal intubation after adequate depth of Anesthesia. Then controlled
mechanical ventilation was instituted using a mixture of oxygen and air to ensure normoxia
and normocapnia. Arterial and central venous catheters were inserted. Monitoring of direct
blood pressure, CVP, nasopharyngeal and skin temperature, urine output was conducted.
Adequate depth of anesthesia was ensured using BIS considering a level of 40-60 was
adequate.
Patients were randomly categorized into 2 equal groups (n=30) according to the type
of anesthetic used for maintenance: Midazolam group received a continuous infusion of
midazolam 0.2 mg/kg/hour and Isoflurane group maintained by an end-tidal concentration of
isoflurane of 1-1.5%throughout the operation. If considerable hypotension exceeding 20% of
the patient base line titration of the inhaled anesthetic to maintain adequate arterial blood
pressure if the possible causes were corrected. Each patient received a continuous infusion of
fentanyl at rate of 2-3 µg/kg/hr throughout the duration of surgery. Additional doses were
given when necessary during skin incision, sternotomy, pericardium opening and aortic
cannulation. Activated clotting time (ACT) and arterial blood gases were estimated after
induction of anesthesia and heparin was administered in a dose of 4 mg/kg so as to keep ACT
value >480 before institution of CPB. CPB was instituted with a Dideco hollow fibre
oxygenator with a blood flow between 200 and 300 ml/kg/min. The priming volume is
calculated according to the patient's weight, containing Ringer's solution, albumin, mannitol,
blood, and heparin. Cooling down during bypass to temperature of 28°C was perforemd.
Hemodynamic monitoring and recording of HR, CVP and systolic (SAP) and
diastolic (DAP) and mean arterial blood pressures (MAP). Cardioplegia was prepared from
blood and crystalloid in a ratio of 1:1 mixture at 4oC. The concentration of the components of
cardioplegia was: K+ 30 mmol/l, NaHCO3 24 mmol/l, Mg+ is 15 mmol/l and lidocaine HCl
120 mg/l. The first dose is 20 ml/kg followed by subsequent doses of 10 ml/kg every 20-30
minutes or with return of electrical activity. Patients underwent modified ultrafiltration at the
end of the bypass. Ischemic time, defined as the time elapsed since aortic clamping till aortic
declamping, duration of bypass and total duration of surgery were recorded. Need for
defibrillation and its frequency was also recordred.
Six blood samples (0.5 ml) were taken immediately after induction of anesthesia,
(S1), 8-hours (S2), 16-hours (S3), 24-hours (S4), 36-hours (S5) and 48-hours (S6) after aortic
clamping. Samples were collected in a Gel-Microtainer tube and immediately analyzed by the
hospital laboratory using the Elecsys Modular E170 immunochemistry analyzer (Cardiac
Troponin T, Roche Diagnostics, Mannheim) for estimation of plasma cardiac troponin T
(cTnT).
Arterial oxygen tension, pH, base excess, bicarbonate, and lactate were measured
immediately after admission to PICU and 24 h later. Ventilator hours and the need to
inotropic support and their doses and duration were recorded. Fluid intake (including
crystalloids, colloids, and blood products), output (urine, blood, serous fluid loss and chest
drain), and fluid balance were recorded hourly over a 36-h period following admission to
PICU.
Statistical analysis
Obtained data were presented as mean±SD, ranges, numbers and ratios. Results were
analyzed using Z-test for unrelated samples and Chi-square (X2) test. Possible relationships
were investigated using Pearson linear regression. Statistical analysis was conducted using the
SPSS (Version 10, 2002) for Windows statistical package. P value <0.05 was considered
statistically significant.
Results
The study included 60 patients; 36 males and 24 females 3-29 months old (mean
14.4±7) and body weight of 3.5-8.1 Kg (mean 6±1.2). There was a non-significant (p>0.05)
difference between groups as regards age, sex and weight of enrolled patients, (Table 1).
Surgical procedures performed were presented in table (2) showed a non-significant (p>0.05)
difference between the three groups as regards patients' distribution according to surgical
procedure performed.
There was a non-significant (p>0.05) difference between the studied groups as
regards surgery, bypass or clamping times. During the stay in PICU, the mean duration of
mechanical ventilation showed a non-significant (p>0.05) difference between the studied
groups, (Table 3).
Plasma cTnT levels estimated after aortic cross-clamping (S2-S6) showed a
significant (P1<0.001) elevation in both groups compared to levels estimated immediately
after induction of anesthesia. Moreover, plasma cTnT levels showed a progressive increase in
all patients irrespective of anesthetic regimen used reaching a peak levels at 24-hours after
aortic cross-clamping (S4) and started to decline thereafter but still significantly higher
compared to levels estimated immediately after induction of anesthesia. Plasma cTnT levels
estimated 8-hrs after aortic cross-clamping (S2) showed a non-significant increase in
midazolam group compared to levels estimated in isoflurane group. On contrary, plasma
cTnT levels estimated in midazolam group at 16, 24, 36 and 48 hours after aortic crossclamping were significantly higher (P6=0.034, 0.01, <0.001 & =0.031, respectively) compared
to levels estimated in isoflurane groups, (Table 4, Fig. 1).
In medazolam group, there was a positive significant correlation between mechanical
ventilation time and plasma cTnT levels estimated at 24-hours after clamping (r=0.375,
p=0.041), respectively, (Fig. 2a). However, such correlations were non-significant despite
being positive in isoflurane group, (r=0.209, p>0.05), respectively, (Fig. 2b).
There were no significant differences in arterial oxygen tension, pH, base excess,
bicarbonate, or lactate between the groups. The differences in hemodynamic variable, fluid
balance, ratios and duration of mechanical ventilation in the 36 hours following admission to
the PICU were not significantly (p>0.05) different between both groups. Moreover, there
were no differences between the groups in the use of inotropic drugs on admission to the
intensive care or 24 h later.
Table (1): Patients' distribution according to their demographic data
Data
Age (months)
Sex; M:F
Weight (kg)
Midazolam group
14.3±7.8 (3-24)
20:10
6±1.3 (3.5-7.8)
Isoflurane group
14.4±7.4 (6-29)
16:14
5.9±1.1 (3.8-8.1)
Data are presented as mean±SD, ratios and numbers; ranges are in parenthesis
Total
14.4±7 (3-29)
36:24
6±1.2 (3.5-8.1)
Table (2): Patients' distribution according to surgical procedures performed
Ventricular septal defect
Atrial septal defect
Arterial switch
Partial Atrioventricular canal
defect
Total anomalous pulmonary
venous drainage.
Total
Midazolam group
15 (50%)
5 (16.7%)
4 (13.3%)
4 (13.3%)
Isoflurane group
16 (53.4%)
6 (20%)
2 (6.6%)
5 (16.7%)
Total
31 (51.7%)
11 (18.3%)
6 (10%)
9 (15%)
2 (6.7%)
1 (3.3%)
3 (5%)
30
30
60
Data are presented as numbers; percentages are in parenthesis
Table (3): Operative & PICU data of studied patients.
Ischemic time (min)
CPB time (min)
Duration of surgery( min)
Duration of mechanical ventillation (hours)
Midazolam group
56.7±35.5 (20-155)
116.3±14 (90-140)
186±21.1 (150-210)
92.7±17.4 (60-125)
Isoflurane group
46.7±30 (20-145)
119.2±12.4 (95-140)
193±13.5 (165-210)
88.7±15.3 (60-120)
Data are presented as mean±SD and numbers; ranges are in parenthesis
Table (4): Plasma cTnT (ng/ml) levels estimated in the studied groups
S1
S2
S3
S4
S5
S6
0.65±0.1
(0.38-0.79)
2±0.22
(1.51-2.33)
<0.001
2.25±0.32
(1.69-2.65)
<0.001
<0.001
2.67±0.5
(1.82-3.58)
<0.001
<0.001
<0.001
2.38±0.31
(1.94-2.95)
<0.001
<0.001
=0.031
=0.001
2.08±0.22
(1.69-2.5)
<0.001
>0.05
=0.005
<0.001
<0.001
0.67±0.11
(0.35-0.88)
1.93±0.29
(1.46-2.51)
<0.001
2.06±0.28
(1.62-2.65)
<0.001
=0.004
2.39±0.45
(1.85-3.95)
<0.001
<0.001
<0.001
2.01±0.25
(1.63-2.4)
<0.001
0.014
=0.032
<0.001
>0.05
>0.05
=0.034
=0.010
<0.001
1.94±0.26
(1.54-2.4)
<0.001
>0.05
=0.006
<0.001
=0.034
=0.031
Midazolam group
Mean±SD
(range)
Statistical
analysis
P1
P2
P3
P4
P5
Isoflurane group
Mean±SD
(range)
Statistical
analysis
P1
P2
P3
P4
P5
P6
P1: significance of difference compared to S1 value
P3: significance of difference compared to S3 value
P5: significance of difference compared to S5 value
P2: significance of difference compared to S2 value
P4: significance of difference compared to S4 value
P6: significance of difference compared to Ketamine group
3.25
Midazolam
Isoflurane
3
2.75
2.5
Plasma cTnT (ng/ml)
2.25
2
1.75
1.5
1.25
1
0.75
0.5
0.25
0
S1
S2
S3
S4
S5
Fig. (1): Mean (+SD) plasma cTnT levels estimated in the
studied groups throughout the study period
130
Ventilation time (hours)-Isoflurane group
130
S6
120
110
100
90
80
70
60
50
1.6
1.7
120
110
100
90
80
70
60
1.8
1.9
2.0
2.1
2.2
2.3
2.4
2.5
a) Plasma cTnT (mg/ml) estimated at 48-hrs after clamping
2.6
50
1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8
b) Plasma cTnT (ng/ml) estimated at 48-hrs after clamping
Fig. (2): Correlation between mechanical ventilation time and plasma cTnT levels estimated at
24-hours after aortic cross-clamping in both groups
Discussion
There was a significant increase of plasma cTnT in all samples examined after aortic
cross-clamping (S2-S6), with a progressive increase in all patients irrespective of anesthetic
regimen used reaching a peak levels at 24-hours after aortic cross-clamping (S4). This rise
started to decline thereafter but still significantly higher compared to levels estimated
immediately after induction of anesthesia (S1). This result illustrates the effect of ischemia
resulting from aortic cross clamping on the myocardium and hence the production of ischemia
markers. These data agreed with previous studies reporting increased plasma levels of cardiac
troponins after cardiac surgery; Immer et al., (1999), reported that cardiac troponin serum
levels after open heart surgery in children and infants 4 h after admission to the ICU allowed
anticipation of the postoperative course and correlated with the incidence of significant
postoperative complications. Zhang et al., (2000) found that the elevation of troponin T is
closely related to cardiopulmonary bypass, especially the duration of aortic cross clamping,
insufficiency of cardioplegia, and metabolic acidosis. Moreover, Checchia et al., (2003) and
Cheung et al., (2006) reported significant increases of cTnT in children undergoing repair
of congenital heart defects especially in samples obtained immediately after release of
aortic clamping. Also, Malagon et al., (2005) reported significant increases of plasma cTnT
after cardiac surgery in pediatric patients in all samples taken at 8, 15 and 24 hours after
admission to PICU
Plasma cTnT levels at (S2) despite were significantly higher compared to (S1) and
lower in isoflurane group than in midazolam group but the difference between groups was not
significant. These data point to the applicability of isoflurane for preconditioning and agreed
with Belhomme et al., (1999), who found that isoflurane preconditioning significantly
reduced the release of cardiac troponins and concluded that the obtained data support a
cardioprotective effect of isoflurane and, more generally, demonstrate the feasibility of
pharmacologically preconditioning the human heart during cardiac surgery. Similarly,
Haroun-Bizri et al., (2001), reported that administration of isoflurane before aortic crossclamping in patients undergoing coronary artery bypass graft surgery may optimize the
myocardial protective effect of cardioplegia and may be particularly advantageous whenever
prolonged periods of aortic cross-clamping or inadequate delivery of cardioplegia is expected.
On contrary, Wang et al., (2004), compared isoflurane preconditioning versus nonconditioned patients and found isoflurane patients released slightly less creatine kinase
cardiac isoenzyme (CK-MB) and troponin than the controls postoperatively, but the
difference was not significant. However, results obtained by Lee et al., (2006), support the
preconditioning effect of isoflurane in patients undergoing coronary artery bypass graft
surgery as clinically feasible and providing optimal cardiac protection.
On the other hand, plasma cTnT levels estimated in patients received midazolam in
(S3), (S4), (S5), and (S6) were significantly higher (P6=0.034, 0.01, <0.001 & =0.031,
respectively) compared to levels estimated in patients received by isoflurane. Furthermore,
isoflurane cardioprotective effect extended after release of aortic clamp till 24-hours after
clamping manifested as shorter duration of postoperative mechanical ventilation with a
positive non-significant correlation between mechanical ventilation time at PICU and plasma
cTnT estimated at 24-hr in isoflurane group, but the correlation was positive significant in
midazolam group.
These data agreed with the results of previous studied compared the cardioprotective
effect of total intravenous and inhalational anesthetics; De Hert et al., (2004), found the use
of inhalational anesthetics resulted in lower postoperative troponin concentrations and
lower need for prolonged inotropic support with a shorter ICU and length of hospital stay
and attributed this to a better preservation of early postoperative myocardial function. Also,
Guarracino et al., (2006), compared cardiac troponin release in patients receiving either
volatile anesthetics or total intravenous anesthesia for cardiac surgery on the beating heart and
found myocardial damage measured by cardiac troponin release, could be reduced by volatile
anesthetics. Moreover, Xia et al., (2006), evaluated the cardioprotective effect of isoflurane
compared to small and large dose propofol and found the cardioprotective effect of propofol
is dose-dependent and only higher dose propofol is advantageous compared to isoflurane.
The significant reduction of plasma cTnT levels estimated in S3-S6 samples in
isoflurane group compared to midazolam group that extended for 48 hours after time of aortic
clamping illustrated the beneficial cardioprotection effect of isoflurane and could be attributed
to the ability of isoflurane to combat the injurious effects of ischemia and reperfusion after
aortic decalmping. Various experimental studies tried to investigate the metabolic pathway of
myocardial preconditioning effect of isoflurane; Raphael et al., (2005) and Krolikowski et al.,
(2006), reported that administration of isoflurane during early reperfusion after prolonged
coronary artery occlusion decreases myocardial infarct size by activating
phosphatidylinositol-3-kinase (PI3K) signal transduction and the extracellular signal-related
kinases represent a redundant mechanism by which signaling elements downstream from
PI3K, including 70-kDA ribosomal protein s6 kinase and endothelial nitric oxide synthase
may be activated to reduce reperfusion injury.
Krolikowski et al., (2005), found inhibition of the mitochondrial permeability
transition pore (mPTP) enhances, whereas opening abolishes isoflurane-induced
postconditioning and isoflurane-induced inhibition of mitochondrial permeability transition is
dependent on activation of mitochondrial KATP channels in vivo. Wang et al., (2006),
suggested that enhanced expression of the antiapoptotic protein B cell lymphoma-2 (Bcl-2)
mediates isoflurane-induced postconditioning by indirectly modulating the mPTP activity in
vivo. Pagel et al., (2006), reported that glycogen synthase kinase (GSK)-beta inhibition
enhances isoflurane-induced protection against infarction during early reperfusion via an
mPTP-dependent mechanism.
Feng et al., (2006), reported that isoflurane postconditioning retains its marked
protection in diseased myocardium and the infarct-remodeled myocardium is receptive to
protection by isoflurane postconditioning via protein kinase B/Akt signaling. Kalenka et al.,
(2006), evaluated post-anesthetic myocardial protein expression profiles associated with the
anesthesia with isoflurane, sevoflurane or desflurane and found that these volatile anesthetics
promote a distinct change in the myocardial protein expression profile, whereby changes in
the expression pattern still exist 72 h after anesthesia and these changes are closely related to
cardioprotection.
Tessier-Vetzel et al., (2006), found isoflurane potentiates postconditioning at
reperfusion through a NO-dependent mechanism. Bains et al., (2006), reported that isoflurane
and sevoflurane may act as metabolic inhibitors by depolarizing pre-synaptic mitochondria
through inhibition of the electron transport chain, although isoflurane seems to inhibit
mitochondrial function more significantly than sevoflurane and both agents inhibit the
respiratory chain sufficiently to cause ATP synthase reversal.
It could be concluded that the hypothesis of anesthetic myocardial protection is
applicable for pediatric patients with congenital heart disease who are assigned for cardiac
surgery and isoflurane-based anesthesia minimized myocardial ischemic and ischemiareperfusion injury and provided efficient cardioprotection irrespective of the type of cardiac
lesion, duration of intraoperative aortic cross clamping time.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Adamcova M & Pelouch V (2001): Myocardial regulatory proteins in children with
congenital heart defects. Acta Medica.; 44(1):13-7.
Awad WI, Shattock MJ & Chambers DJ (1998): Ischemic preconditioning in immature
myocardium. Circulation; 98: 206–13.
Bains R, Moe MC, Larsen GA, Berg-Johnsen J, Vinje ML (2006): Volatile anaesthetics
depolarize neural mitochondria by inhibiton of the electron transport chain. Acta Anaesthesiol
Scand.; 50(5):572-9.
Baker JE, Holman P & Gross GJ (1999): Preconditioning in immature rabbit hearts. Role of
KATP channels. Circulation; 99: 1249–54.
Baldwin D, Chandrashekhar Y, McFalls E, Anand I, Liu D, Jaimes D, Marx D & Ward H
(2002): Ischemic preconditioning prior to aortic cross-clamping protects high-energy
phosphate levels, glucose uptake, and myocyte contractility. J Surg Res.; 105(2):153-9.
Belhomme D, Peynet J, Louzy M, Launay JM, Kitakaze M & Menasche P (1999): Evidence
for preconditioning by isoflurane in coronary artery bypass graft surgery. Circulation.; 100(19
Suppl): II340-4.
Buyukates M, Kalaycioglu S, Oz E & Soncul H (2005): Effects of ischemic preconditioning
in human heart. J Card Surg.; 20(3): 241-5.
Checchia PA, Backer CL, Bronicki RA, Baden HP, Crawford SE, Green TP & Mavroudis
C (2003): Dexamethasone reduces postoperative troponin levels in children undergoing
cardiopulmonary bypass. Crit Care Med.; 31(6): 1742-5.
Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, Holtby HM,
Cox PN, Smallhorn JF, Van Arsdell GS & Redington AN (2006): Randomized controlled
trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery:
first clinical application in humans. J Am Coll Cardiol.; 47(11):2277-82.
Chiari P, Bouvet F & Piriou V (2005): Anaesthetic-induced myocardial preconditioning:
fundamental basis and clinical implications. Ann Fr Anesth Reanim.; 24(4):383-96.
De Hert SG, Van der Linden PJ, Cromheecke S, Meeus R, ten Broecke PW, De Blier IG,
Stockman BA & Rodrigus IE (2004): Choice of primary anesthetic regimen can influence
intensive care unit length of stay after coronary surgery with cardiopulmonary bypass.
Anesthesiology; 101(1):9-20.
12. De Hert SG (2005): The concept of anaesthetic-induced cardioprotection: clinical relevance.
Best Pract Res Clin Anaesthesiol.; 19(3):445-59.
13. Egan JR, Festa M, Cole AD, Nunn GR, Gillis J & Winlaw DS (2005): Clinical assessment
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
of cardiac performance in infants and children following cardiac surgery. Intensive Care
Med.; 31(4):568-73.
Feng J, Fischer G, Lucchinetti E, Zhu M, Bestmann L, Jegger D, Arras M, Pasch T,
Perriard JC, Schaub MC & Zaugg M (2006): Infarct-remodeled myocardium is receptive to
protection by isoflurane postconditioning: role of protein kinase B/Akt signaling.
Anesthesiology.; 104(5):1004-14.
Guarracino F, Landoni G, Tritapepe L, Pompei F, Leoni A, Aletti G, Scandroglio AM,
Maselli D, De Luca M, Marchetti C, Crescenzi G & Zangrillo A (2006): Myocardial damage
prevented by volatile anesthetics: a multicenter randomized controlled study. J Cardiothorac
Vasc Anesth.;20(4):477-83.
Haroun-Bizri S, Khoury SS, Chehab IR, Kassas CM & Baraka A (2001): Does isoflurane
optimize myocardial protection during cardiopulmonary bypass? J Cardiothorac Vasc
Anesth.; 15(4):418-21.
Holmvang L, Jurlander B, Rasmussen C, Thiis JJ, Grande P & Clemmensen P (2002): Use
of biochemical markers of infarction for diagnosis perioperative myocardial infarction and
early graft occlusion after coronary artery bypass surgery. Chest; 121: 103–11
Immer FF, Stocker F, Seiler AM, Pfammatter JP, Bachmann D, Printzen G & Carrel T
(1999): Troponin-I for prediction of early postoperative course after pediatric cardiac surgery.
J Am Coll Cardiol.; 33(6):1719-23.
Imura H, Caputo M, Parry A (2001): Age-dependent and hypoxia-related differences in
myocardial protection during pediatric open heart surgery. Circulation;103:1551–6.
Jules-Elysee K, Urban MK, Urquhart B & Milman S (2001): Troponin I as a diagnostic
marker of perioperative myocardial infarction in the orthopedic population. J Clin Anesth; 13:
556–9
Kalenka A, Maurer MH, Feldmann RE, Kuschinsky W & Waschke KF (2006): Volatile
anesthetics evoke prolonged changes in the proteome of the left ventricule myocardium:
defining a molecular basis of cardioprotection? Acta Anaesthesiol Scand.; 50(4):414-27.
Kanaan UB & Chiang VW (2004): Cardiac troponins in pediatrics. Pediatr Emerg Care.;
20(5):323-9.
Kato R & Foex P (2002): Myocardial protection by anesthetic agents against ischemiareperfusion injury: an update for anesthesiologists. Can J Anaesth; 49: 777–91.
Krolikowski JG, Bienengraeber M, Weihrauch D, Warltier DC, Kersten JR & Pagel PS
(2005): Inhibition of mitochondrial permeability transition enhances isoflurane-induced
cardioprotection during early reperfusion: the role of mitochondrial KATP channels. Anesth
Analg.; 101(6):1590-6.
Krolikowski JG, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC & Pagel PS
(2006): Role of Erk1/2, p70s6K, and eNOS in isoflurane-induced cardioprotection during
early reperfusion in vivo. Can J Anaesth.; 53(2):174-82.
Lee MC, Chen CH, Kuo MC, Kang PL, Lo A & Liu K (2006): Isoflurane preconditioninginduced cardio-protection in patients undergoing coronary artery bypass grafting. Eur J
Anaesthesiol.; 23(10):841-7.
Malagon I, Hogenbirk K, van Pelt J, Hazekamp MG & Bovill JG (2005): Effect of
dexamethasone on postoperative cardiac troponin T production in pediatric cardiac surgery.
Intensive Care Med.; 31(10):1420-6.
Maynard SJ, Mentown IBA & Adgey AA (2000): Troponin T or troponin I as cardiac
markers in ischemic heart disease. Heart; 83: 371–3.
Obal D, Dettwiler S, Favoccia C, Scharbatke H, Preckel B & Schlack W (2005): The
influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and
postconditioning by sevoflurane in the rat in vivo. Anesth Analg.; 101(5):1252-60
Ostadalova I, Ostadal B, Jarkovska D & Kolar F (2002): Ischemic preconditioning in
chronically hypoxic neonatal rat heart. Pediatr Res; 52: 561–7.
Pagel PS, Krolikowski JG, Neff DA, Weihrauch D, Bienengraeber M, Kersten JR &
Warltier DC (2006): Inhibition of glycogen synthase kinase enhances isoflurane-induced
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
protection against myocardial infarction during early reperfusion in vivo. Anesth Analg.;
102(5):1348-54.
Raphael J, Rivo J & Gozal Y (2005): Isoflurane-induced myocardial preconditioning is
dependent on phosphatidylinositol-3-kinase/Akt signalling. Br J Anaesth.; 95(6):756-63.
Rie K & Pierre F (2002): Myocardial protection by anesthetic agents against ischemiareperfusion injury: an update for anesthesiologists. Can J Anesth.; 49(8): 777-791
Tessier-Vetzel D, Tissier R, Waintraub X, Ghaleh B & Berdeaux A (2006): Isoflurane
inhaled at the onset of reperfusion potentiates the cardioprotective effect of ischemic
postconditioning through a NO-dependent mechanism. J Cardiovasc Pharmacol.; 47(3):48792.
Wan S DeSmet JM & Barvais L (1996): Myocardium is a major source of proinflammatory
cytokines in patients undergoing cardiopulmonary bypass. Thorac Cardiovasc Surg.; 112:
806-11.
Wang X, Jarvinen O, Kuukasjarvi P, Laurikka J, Wei M, Rinne T, Honkonen EL & Tarkka
M (2004): Isoflurane produces only minor preconditioning in coronary artery bypass grafting.
Scand Cardiovasc J.; 38(5):287-92.
Wang C, Neff DA, Krolikowski JG, Weihrauch D, Bienengraeber M, Warltier DC, Kersten
JR & Pagel PS (2006): The influence of B-cell lymphoma 2 protein, an antiapoptotic
regulator of mitochondrial permeability transition, on isoflurane-induced and ischemic
postconditioning in rabbits. Anesth Analg.; 102(5):1355-60.
Wu ZK, Tarkka MR & Eloranta J (2000): Effect of ischemic preconditioning (IP) on
myocardial protection in CABG patients: can the free radicals act as a trigger for IP? Chest;
119: 1061-8.
Xia Z, Huang Z & Ansley DM (2006): Large-dose propofol during cardiopulmonary bypass
decreases biochemical markers of myocardial injury in coronary surgery patients: a
comparison with isoflurane. Anesth Analg.; 103(3):527-32.
Zangrillo A, Crescenzi G, Landoni G, Benussi S, Crivellari M, Pappalardo F, Dorigo E,
Pappone C & Alfieri O (2005): The effect of concomitant radiofrequency ablation and
surgical technique (repair versus replacement) on release of cardiac biomarkers during mitral
valve surgery. Anesth Analg.; 101(1):24-9
Zhang D, Jin S, Wei S, Wang X & Sun B (2000): Troponin T during cardiopulmonary
bypass. Zhonghua Wai Ke Za Zhi.;38(5):372-4 (English abstract).