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CLINICAL STUDY
Bahar Oc1 , Seda B. Akinci2 , Meral Kanbak2 , Eda Satana3 , Bilge Celebioglu2 and Ulku Aypar2
1 Department of Anesthesiology and Reanimation, Selcuklu Faculty of Medicine, Selcuk University, Konya, Turkey;
2 Department of Anesthesiology and Reanimation, Faculty of Medicine, Hacettepe University, Ankara, Turkey;
3 Department of Analytical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey
Abstract
Background: There are few data on the effects of anesthesia and cardiopulmonary bypass (CPB) on perioperative
renal function in children with cyanotic congenital heart disease undergoing open heart surgery. This study aims to
investigate the perioperative renal function in cyanotic versus acyanotic children undergoing sevoflurane anesthesia for
open heart surgery. Methods: After receiving ethical committee approval, 12 acyanotic patients (preoperative oxygen
saturation: SaO2 > 85%) and 12 cyanotic children (SaO2 < 85%) were included. Sevoflurane was administered at
concentration levels of 2% before CPB and 1–2% during CPB after standard anesthesia induction. Inorganic fluoride,
electrolytes, creatinine, urea nitrogen in serum and urine samples, and N-acetyl-β-D-glucosaminidase (NAG) in urine
samples were measured before induction, before CPB, during CPB, after CPB, at the end of surgery, and at 24th h
postoperatively. Results: The levels of serum uric acid levels were higher in the cyanotic group (p < 0.05). There were
no differences in the levels of serum creatinine and urine creatinine, urea nitrogen, and electrolytes between the two
groups. Serum inorganic fluoride levels were always higher in the acyanotic group than in the cyanotic group, but
these differences between the groups reached statistical significance at two measurement times (before CPB and
end of surgery) (p < 0.05). Urinary inorganic fluoride levels increased with time in both groups. Although urinary NAG
increased significantly after the CPB in the cyanotic group, the differences between the two groups did not reach
statistical significance. Conclusions: We have concluded that renal function was not affected during open heart surgery
with sevoflurane anesthesia, in both cyanotic and acyanotic children.
Keywords: renal function, congenital heart disease, children, open heart surgery, sevoflurane
Address correspondence to Bahar Oc, Department of Anesthesiology and Reanimation, Selcuklu Faculty of Medicine, Selcuk University,
Konya 42100, Turkey. Tel.: +90 3322415000/45164; Fax: +90 332 2416065; E-mail: baharoc@selcuk.edu.tr
Received 2 June 2011; Revised 14 September 2011; Accepted 2 October 2011
135
136 B. Oc et al.
fluoromethyl ether (compound A) and plasma fluoride blood cells, fresh frozen plasma, and Isolyte S solution.
ions.9,10 Standard cold cardioplegia was used at a dose of 15
This study was designed to compare the periopera- mL/kg. The hematocrit level in CPB was kept ≥30%
tive renal functions in cyanotic and acyanotic children for patients weighing ≥20 kg or ≥24% for patients
undergoing sevoflurane anesthesia during open heart weighing <20 kg. Mannitol 20%, 1 g/kg, was also
surgery. Renal function was assessed by clinical labo- added to the priming volume.
ratory markers of kidney function, electrolytes, and by a All operations were performed by the same anes-
subclinical, sensitive marker of tubular damage [urinary thesia and surgical team. Aortic cross-clamping time,
N-acetyl-β-D-glucosaminidase (NAG)]. CPB time, duration of operation and anesthesia, and
data regarding hemodynamic parameters, urine out-
put, blood and blood product requirements, and total
METHODS
amount of drainage were recorded.
Clinical Protocol The pH was kept within normal range. At the end of
After ethics committee approval and parental consent, surgery, patients were transported to the intensive care
59 patients 1–6 years of age with cyanotic and acyanotic unit. All patients received mechanical ventilation for at
congenital cardiac anomalies scheduled for cardiac least 6 h. Data regarding urine output were recorded.
surgery at the Hacettepe University Hospital were First blood samples were collected before anesthe-
included in this study. Patients with renal or hepatic sia induction. First urine samples were collected after
failure, diabetes mellitus, heart failure, acute or chronic urinary catheter was placed just after induction. Fur-
pulmonary disease, pulmonary artery hypertension, ther blood and urine samples were collected before
previous cardiac surgery, or anomalies of other organ onset of CPB (5 min after heparin administration),
systems were excluded. Patients requiring surgical at 15th min of CPB, after CPB (5 min after pro-
revision for any reason; patients receiving mechanical tamine administration), at the end of surgery, and 24 h
ventilation for more than 24 h and those who required after surgery. Sodium (Na+ ), potassium (K+ ), calcium
peritoneal dialysis, hemodialysis, or ultrafiltration (Ca++ ), chloride (Cl− ), creatinine (Cr), urea nitro-
intraoperatively or postoperatively; and patients with gen, uric acid, and inorganic fluoride were measured
preoperative or postoperative inotropic support and in blood samples and urine specimen using standard
those who died in an early period were also excluded laboratory techniques. Urinary NAG concentrations
from this study. were determined by spectrophotometric assay using
The patients were divided into two groups according sodium cresolsulphonphtalein NAG (HITACHI 7150
to the oxygen saturation measured by pulse oximetry: type automatic analyzer; Hitachi Co., Tokyo, Japan).5
the acyanotic group (O2 sat ≥ 85%) and the cyanotic Plasma inorganic fluoride concentrations were analyzed
group (O2 sat < 85%). Patients were premedicated using an ion-selective electrode.6 The potential values
with midazolam (0.5 mg/kg intranasal) 30 min before of the solutions were measured using ORION Model
surgery. 720-A mV/pH meter (Thermo Electron Co., New
Anesthesia was induced with thiopental sodium 5 York, USA) with ORION 9409 BN fluoride electrode
mg/kg, morphine HCl 0.1 mg/kg, and vecuronium (Thermo Electron Co.) and ORION Double Junction
bromide 0.1 mg/kg and maintained with morphine, reference electrode (Ag–AgCl) (Thermo Electron Co.).
vecuronium, and sevoflurane 2% together with 3 L/min Values less than 0.05 μmol/L could not be measured.
nitrous oxide and 3 L/min oxygen using a semiclosed
circle system with a soda lime canister before CPB and Statistical Analysis
sevoflurane 1–2% during CPB. The depth of anesthesia All data were expressed as mean and standard devia-
was monitored with bispectral index (BISTM ) (Aspect tion (mean ± SD) or median (95% confidence intervals)
Medical Systems, Newton, MA, USA), and acceptable unless otherwise indicated. All categorical variables were
anesthetic depth (between 30 and 50) was achieved. tested by chi-square test. All normally distributed data
Heparin sulfate (300 U/kg) was given prior to (tested by Kolmogorov–Smirnov test) were analyzed
cannulation. Activated clotting time (Hemochron 80, using the unpaired t-test. One-way and two-way anal-
International Technidyne Corp., Edison, NJ, USA) was ysis of variance with repeated measures and post hoc
kept at ≥400 s during extracorporeal circulation. At Scheffe test were used to determine the effect of group,
the end of CPB circulating heparin was antagonized by time, and group–time interaction. The Mann–Whitney
protamine (3 mg/kg), and additional doses of protamine U-test or Kruskal–Wallis test and Friedman tests were
were given if needed. used when appropriate (for the analysis of non-normal
DeBakey roller pump, membrane oxygenator distribution data). Pearson correlation analysis was
[Dideco Membrane 901, 902, or 705 (Sorin Group, used for the determination of correlation coefficients.
Mirandola, Italy) according to the weight of the A p-value less than 0.05 was considered significant.
patient], nonpulsatile flow (200 mL/kg/min), and mild All data were entered and processed by SPSS 11.0
hypothermia (26–28◦ C) were used for CPB. Priming (SPSS Inc., Chicago, IL, USA) for Windows statistical
fluid of the CPB pump consisted of fresh packed red package.
Renal Failure
Renal Function in Cyanotic versus Acyanotic Children 137
RESULTS level was lower in the acyanotic group than in the cyan-
otic group, 24 h after surgery (p < 0.05). Urinary urea
There were no differences between the groups regarding
nitrogen levels were higher in the acyanotic group than
gender, age, body weight, duration of operation, aortic
in the cyanotic group before induction and before the
cross-clamping time, CPB time, duration of the anes-
onset of CPB, but the urea nitrogen levels were similar
thesia, and surgery (Table 1). Preoperatively, the cyan-
between the two groups later on (p < 0.05). The urine
otic patients had lower oxygen saturation and higher
output was higher in the acyanotic group than in the
hemoglobin and hematocrit values than the acyanotic
cyanotic group during CPB (p < 0.05).
patients (p < 0.05). Four patients of the acyanotic
Serum inorganic fluoride levels were always higher
group had atrial septal defect, whereas eight had ven-
in the acyanotic group than in the cyanotic group,
tricular septal defect. In the cyanotic group, all patients
but these differences in between the groups reached
had Tetralogy of Fallot. A total of 42 cyanotic and 17
statistical significance only at two measurement times
acyanotic patients were eligible for the study. Three
(pre-CPB and at the end of surgery) (Figure 1)
cyanotic patients and 1 acyanotic patient underwent
(p < 0.05). Urinary inorganic fluoride levels increased
revision for bleeding, 6 cyanotic and 2 acyanotic chil-
in time in both groups, but the measured values
dren required ventilatory support more than 24 h,
were not statistically different between the groups
7 cyanotic and 3 acyanotic patients required dialysis,
(Figure 2).
30 cyanotic and 5 acyanotic patients required inotropic
In the cyanotic group, urine NAG excretion was
support and were excluded from the study. After those
increased at the end of surgery when compared with the
exclusions, the study was continued with 12 cyanotic
levels before the induction (Figure 3). Although urinary
and 12 acyanotic patients. They all underwent total cor-
NAG increased significantly after the CPB in the cyan-
rective interventions. No diuretic other than mannitol
otic group, the differences between the two groups did
was used in the bypass priming solution.
not reach statistical significance.
There were no differences in plasma Na+ , K+ , Ca++ ,
and Cl− levels between the two groups (Table 2).
In both groups, serum electrolytes showed generally
similar trends; the levels gradually decreased start- DISCUSSION
ing before the onset of CPB, during CPB, until the
We were interested in the clinical and subclinical renal
end of CPB, and gradually returned to preinduction
function changes in routine pediatric cardiac cases
levels.
exposed to sevoflurane anesthesia. We compared cyan-
There were no differences in serum Cr and blood
otic patients with acyanotic patients. The two groups
urea nitrogen (BUN) levels between the two groups
were similar regarding serum and urine biochemistry
(Table 2). The serum uric acid levels were significantly
from the beginning of anesthesia until the 24 h after
higher in the cyanotic group than in the acyanotic group
surgery. The two groups did not differ regarding clin-
(p < 0.05).
ical and subclinical renal function tests on the day after
Urinary Na+ , K+ , Cl− , Cr, and uric acid levels did
the operation.
not differ between the groups (Table 3). Urinary Ca++
Nephropathy is recognized as a potential compli-
cation of cyanotic congenital heart disease, and the
risk rises sharply during the second decade of life.7
Glomerular and tubular dysfunction in longstanding
Table 1. Comparison of acyanotic and cyanotic groups (values
cyanotic heart disease is related to the duration and
are mean ± SD).
degree of cyanosis and the extent to which the hema-
Acyanotic Cyanotic tocrit is elevated.7,11 Our cyanotic group consisted of
(n = 12) (n = 12)
young patients (mean age 40.3 months) so we did not
Gender (F/M) 8/4 6/6 detect any baseline overt clinical renal insufficiency.
Age (months) 55.8 ± 36.4 40.3 ± 23.1 The deranged intrarenal hemodynamics in patients
Body weight (kg) 15.9 ± 6.7 14.4 ± 5.7
Oxygen saturation (%) 96 ± 1∗ 69 ± 14∗
with cyanotic heart disease are associated with pro-
Preoperative hemoglobin (g/dL) 11.8 ± 1.3∗ 15.5 ± 1.6∗ teinuria, increased renal blood flow, increased renal
Preoperative hematocrit (%) 35.3 ± 4.1∗ 46.2 ± 5.1∗ vascular resistance, decreased renal plasma flow, normal
Duration of anesthesia (min) 215 ± 48 228 ± 33 or reduced glomerular filtration rates, and histologic
Duration of surgery (min) 167 ± 40 185 ± 28 changes on biopsy or at autopsy.5,12 Cyanotic glomeru-
CPB time (min) 74 ± 16 76 ± 15
Aortic cross-clamping time (min) 54 ± 15 60 ± 14
lopathy has been shown to be associated with elevated
Intraoperative blood 16.1 ± 5.3 15.8 ± 6.9 hematocrit. Perfusion of the tubular apparatus, which is
products (mL/kg) most vulnerable to ischemic damage, is provided by the
Postoperative blood 13.4 ± 4.5 17.2 ± 8.9 capillaries of the peritubular plexus. To maintain nor-
products (mL/kg) mal blood flow in the peritubular capillaries, as there is
Total amount of drainage (mL/kg) 14.6 ± 4.2 19.1 ± 5.5
increased resistance to flow of viscous blood in patients
Note: ∗ p < 0.05 between the two groups. with elevated hematocrit, a high intravascular pressure
0.3
** ** *
* **
**
0.25
**
**
0.2
**
Acyanotic
0.15
Cyanotic
0.1
0.05
0
Preinduction Pre-CPB CPB 15th min End of CPB End of surgery 24 h after
surgery
Renal Failure
Renal Function in Cyanotic versus Acyanotic Children 139
5
* *
*
4
*
*
3
*
2
* Acyanotic
Cyanotic
1
0
Preinduction Pre-CPB CPB 15th min End of CPB End of surgery 24 h after
surgery
16
*
12
8 Acyanotic
Cyanotic
0
Preinduction Pre-CPB CPB 15th min End of CPB End of surgery 24 h after
surgery
is needed, which makes these patients easily susceptible in electrolyte levels from the baseline, which may be
to renal injury during CPB.1 due to the dilution as a result of fluid replacement
We measured NAG as a sensitive marker of proximal and the priming solution of the CPB. In another study
lysosomal tubular damage because standard markers of in 34 patients weighting less than 10 kg, repeated
renal damage such as creatinine and creatinine clear- analysis of urine, blood, and plasma viscosity were per-
ance are not sensitive enough to detect discrete changes formed only during CPB.13 Polyuria and proteinuria
in renal function.8 The transient increase observed in that appeared during CPB indicated an elevated trans-
NAG excretion at the end of surgery was indicative of glomerular filtration gradient, which recovered within
some mild tubular renal damage. Despite these data, the 24 h. Similar to our results, the appearance of NAG
urine output and other biochemical markers remained in the urine was additionally indicative of mild tubu-
within normal limits after surgery with a declining trend lar damage.13 The increase in urinary NAG excretion
was not indicative of clinically significant renal damage The introduction of sevoflurane into clinical anesthe-
in our patients. sia has been clouded by concerns about the potential
The plasma creatinine concentration has been val- risk for nephrotoxicity after its use. Theoretical sources
idated as clinically important for renal function.14 for the nephrotoxicity would be hemodynamic insta-
However, the urinary creatinine concentrations showed bility and the metabolites of sevoflurane (fluoride and
similar trends in both groups; the urinary creatinine compound A). Most of the in vivo and in vitro stud-
levels decreased during and after CPB compared with ies revealed no major harmful effects of sevoflurane
the baseline. Although plasma urea concentration is less anesthesia on kidneys. Lee et al.22 demonstrated the
reliable than creatinine, along with creatinine, urea is anti-inflammatory and anti-necrotic effects of sevoflu-
frequently used in routine chemistry.14 The blood and rane in cultured kidney proximal tubule cells and
urine nitrogen concentrations were similar between the probed the mechanism of sevoflurane-induced renal
two groups, and this finding associated with sevoflurane cell protection. Similarly, Şekeroğlu et al.23 found
anesthesia also accords with the findings associated with out that although there is an acute altering in renal
halothane anesthesia.15 glomerular function with sevoflurane, this does not have
Acute changes in hematocrit affect renal plasma flow a significant effect on biochemical markers of renal
and renal vascular resistance. Palliative surgery has a tubular damage. In another randomized study com-
significant improving effect on hematocrit and oxy- paring sevoflurane and halothane anesthesia in infants
gen saturation level as well as renal glomerular and and children with congenital heart disease, sevoflurane
tubular integrity.11 We believe that the beneficial effect had hemodynamic advantages over halothane.24 The
of corrective surgery in cyanotic patients reverses the plasma concentration of inorganic fluoride, an in vivo
detrimental effects of CPB on renal function. This metabolite of sevoflurane, was found to be low [less
may explain the improvement of the perioperative renal than 50 μmol/L (1.02 ppm) theoretical threshold for
dysfunction on the first postoperative day. nephrotoxicity] in children after sevoflurane anesthesia
Reduced uric acid clearances in infants, young and was eliminated rapidly, and the children sched-
children with congenital heart disease, and in late uled for elective surgery were unlikely to be at risk for
survivors with cyanotic congenital heart disease have nephrotoxicity from high fluoride levels.25 In our study,
been reported to be secondary to inappropriately the serum inorganic fluoride levels were also low (less
low fractional uric acid excretion.12,16 In our study, than the theoretical threshold for nephrotoxicity). Sim-
urinary uric acid excretions were also lower in the ilar to our results, the serum inorganic fluoride levels
cyanotic patients than in the acyanotic patients, were even lower in the cyanotic group than in the acyan-
although these differences did not reach statistical otic group. The plasma fluoride concentrations were
significance. Enhanced urate reabsorption appears to consistent with other reported values in children.26 The
result from renal hypoperfusion reinforced by high urinary fluoride levels were always higher in the acyan-
filtration fraction.12 The serum uric acid levels have otic group than in the cyanotic group until the end
been found previously to be higher in the cyanotic of the operation, although these differences between
children compared with the acyanotic children under- the two groups did not reach statistical significance.
going cardiac operations.17 Hyperuricemia serves as It is difficult to explain the relatively higher fluoride
a marker of abnormal intrarenal hemodynamics.12 In levels and fluoride excretion in the acyanotic children.
our patient cohort, serum uric acid levels at all times The concentration of compound A, an in vitro metabo-
were higher in the cyanotic patients compared with the lite of sevoflurane, during sevoflurane anesthesia, using
acyanotic patients. Classifications such as acute kidney approximately 2 L fresh gas flow in a circle absorption
injury network (AKIN) and risk, injury, failure, loss, system, has been found to be low in pediatric patients.26
end-stage (RIFLE) are used for evaluating the severity Although we did not measure compound A levels, we
of postoperative renal dysfunction in adults.18 Although think our patients were exposed to even lower com-
pediatric RIFLE (pRIFLE) classification has been pound A levels because we used high fresh gas flow
proposed for children, it has not been used for patients rates (6 L/min) and a semiclosed circle system. Exclu-
undergoing congenital cardiac surgery.19 Therefore, we sion of children with congenital heart disease at high
did not use pRIFLE or AKIN for assessment. risk for acute renal injury may have also affected our
Numerous factors have been postulated to cause results.
renal dysfunction after anesthesia and cardiac surgery. The relatively small number of patients and
Besides the anesthesia technique, these factors include younger patient age in the cyanotic group are lim-
but not limited to antibiotics, surgical stress, preop- itations of this study. According to the observed
erative renal dysfunction, intraoperative hemodynamic, data, we have concluded that sevoflurane anesthe-
use of dopamine, diuretics, type of the surgery, and sia and CBP do not adversely affect renal functions
patient positioning.2,20,21 In our study, we tried to in both cyanotic and acyanotic children undergo-
standardize the prophylactic antibiotics, intraoperative ing open heart surgery. Further studies should also
hemodynamic, CBP method, type, and dosage of anes- include children with high risk for acute renal
thetics in all patients. failure.
Renal Failure
Renal Function in Cyanotic versus Acyanotic Children 141