Tissue Oxygenation During Treatment of Infant Congenital Heart Defects
Conditions: Acute Kidney Injury, Hypoxia-Ischemia, Brain, Mesenteric Ischemia
Sponsor: Beijing Anzhen Hospital

NCT03941015 
Document Date: November 1, 2018 
Tissue Oxygenation During Treatment of Infant Congenital Heart Defects 
Study design 
This prospective observational study was approved by the Internal Review Board of 
Beijing Anzhen Hospital, Capital Medical University, Beijing, China (#2018009), 
registered at ClinicalTrials.gov (Identifier: NCT03941015), and performed from 
December 2018 to August 2020 at Beijing Anzhen Hospital, Capital Medical 
University, Beijing, China. 
Participants 
Infants between 1 and 12 months old and scheduled to undergo surgical repair of an 
isolated VSD involving CPB were eligible. The exclusion criteria were any of the 
following: 1) refusal to participate; 2) emergent or urgent surgery; 3) weight >10 kg; 4) 
preoperative renal dysfunction; 5) pulmonary failure requiring respiratory support; 6) 
digestive system failure requiring total parenteral nutrition; 7) chromosomal 
abnormalities; and 8) skin abnormalities precluding the application of the tissue 
oximetry probe. We excluded infants with a body weight > 10 kg because tissue 
oximetry may not be able to interrogate the renal tissue bed in heavier infants due to 
the limited penetrating capacity of near-infrared light.18 Written informed consent was 
obtained from the infants’ parents. 
Anesthetic care 
The anesthetic care was provided by the same team, comprising one attending 
anesthesiologist and four residents. The infants were allowed formula milk feeding until 
six hours before surgery, milk feeding until four hours before surgery, and water 
drinking until two hours before surgery. In the operating room, all infants received 
electrocardiography, pulse oximetry, noninvasive blood pressure, and temperature 
monitoring. Anesthesia was induced using 3-5% sevoflurane delivered over a fit face 

NCT03941015 
Document Date: November 1, 2018 
mask. Midazolam (0.2 mg/kg), pipecuronium (0.2 mg/kg), and sufentanil (10 mcg/kg) 
were administered intravenously following the establishment of the peripheral access. 
All infants were endotracheally intubated and mechanically ventilated with a tidal 
volume of 8 mL/kg, a respiratory rate of 18-30 breaths/min, an inspiratory to expiratory 
time ratio of 1:1-1.5, and an inspired oxygen fraction of 50%. The end-tidal carbon 
dioxide was maintained at 35-45 mmHg. All infants received a radial or femoral arterial 
catheter for continuous arterial blood pressure monitoring and an internal jugular or 
femoral venous catheter for central venous pressure monitoring and intravenous access. 
Hemodynamics was monitored using a hemodynamic monitoring system based on 
arterial pressure waveform analysis (MostCare, Vytech, Padova, Italy). Anesthesia was 
maintained using a midazolam (0.2-0.4 mg/kg/h), pipecuronium (0.08-0.16 mg/kg/h), 
and sufentanil (2-4 mcg/kg/h) continuous infusion. Hemoglobin was maintained at ≥8 
g/dL during CPB and ≥10g/dL before and after CPB. The CPB flow was maintained at 
150-200 mL/kg/min and the mean arterial pressure was maintained at 30-50 mmHg. 
Hemodynamics was managed using crystalloid, dopamine, epinephrine, and/or 
milrinone before and after CPB. The core temperature was maintained at about 32-34°C 
during CPB; otherwise, it was maintained above 36°C before and after CPB. All infants 
received modified ultrafiltration following the weaning from CPB. 
Ventricular septal defect repair  
The procedure was performed through either an anterolateral fourth intercostal incision 
or a median sternotomy per the infant’s condition and surgeon’s preference. The VSD 
was closed using a patch through either a right atrium or right ventricle incision, 
depending on the location of the defect. All infants were admitted to the pediatric 
intensive care unit after surgery. 
Renal tissue oxygen saturation monitoring 

NCT03941015 
Document Date: November 1, 2018 
SrtO2 was monitored using a tissue near-infrared spectroscopy oximeter (FORE-SIGHT 
ELITE, CASMED, Branford, Connecticut, USA; now acquired by Edwards 
Lifesciences, Irvine, California, USA). A biophotonic sensor was placed on the left 
flank at the level of T10-L2 to monitor SrtO2.3, 6, 18 A dedicated research personnel 
stayed in the operating room to ensure the proper function of the tissue oximeter. The 
patient care team was blinded to the monitoring because the SrtO2 data were intended 
solely for research, not for clinical decision making, per the research protocol. The 
SrtO2 data, generated by the tissue oximeter every 2 seconds, were extracted from the 
monitor at the end of the surgery. 
Data collection 
Demographic data including age, sex, height, weight, and body mass index (BMI) were 
recorded. Data based on the last echocardiography and laboratory results before surgery 
were collected. Intraoperative data including SrtO2, systolic blood pressure, diastolic 
blood pressure, mean arterial pressure, heart rate, cardiac index, stroke volume index, 
stroke volume variation, body temperature, surgery time, CPB duration, aortic 
clamping time, urine output, estimated blood loss, and intravascular fluid repleted were 
recorded. Serum creatinine was recorded within one week before surgery and on 
postoperative days 1-3. The infant was dropped from the study if the SrtO2 monitoring 
was interrupted for more than 5 minutes during surgery. 
The baseline SrtO2 and hemodynamics 
The baseline SrtO2 was defined as the median value of the data recorded over a 5-
minute epoch when the infant was induced and mechanically ventilated and had a 
cardiac index ≥2.5 L/min/m2, but before skin incision. The average cardiac index in 
infants weighing ≥4 kg is about 2.76 ± 0.41 L/min/m2 (mean ± SD).22 A previous study 
suggested an association between SrtO2 and cardiac output.23 In order to adopt a 

NCT03941015 
Document Date: November 1, 2018 
baseline SrtO2 that was not misleading due to an abnormally low cardiac output, we 
chose to use an SrtO2 value that was measured when the infant’s cardiac index was in 
the normal range. Blood pressure typically decreases following anesthesia induction 
and may or may not be accompanied by a reduction in cardiac output.24 Therefore, we 
chose to consider cardiac output, instead of blood pressure, during the determination of 
the baseline level of SrtO2. Similar to the determination of the baseline SrtO2, the 
baseline systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart 
rate, cardiac index, stroke volume index, and stroke volume variation were defined as 
the median value of the data recorded during a 5-minute epoch when the infant was 
anesthetized and mechanically ventilated and had a cardiac index ≥ 2.5 L/min/m2, but 
before skin incision. 
Renal desaturation and outcome measures 
The exposure of this study was renal desaturation, defined as an at least 20% decrease 
in SrtO2 from the baseline level for at least 60 consecutive seconds. The primary 
outcome was the incidence of AKI arising within postoperative days 1-3. AKI was 
diagnosed per the Kidney Disease: Improving Global Outcomes (KDIGO) criteria.25 
The secondary outcomes were the incidences of stages 1, 2, and 3 AKI per the KDIGO 
criteria. 
Statistical analysis 
The power analysis was based on the preliminary results of the first 50 infants. The 
ratio of infants with and without renal desaturation was about 1:6, and the incidences 
of AKI in infants with and without renal desaturation were about 50% and 25%, 
respectively. Hence, a total of 217 infants (i.e., 31:186) were needed to detect a 25% 
difference (i.e., 50% minus 25%) with a power of 80% using a two-side proportion test 
at an alpha level of 0.05. We aimed to recruit 242 infants, with the anticipation of a 

NCT03941015 
Document Date: November 1, 2018 
drop-off rate of 10%. 
The continuous variables that followed a normal distribution were presented as 
mean and standard deviation (SD); otherwise, they were presented as median and 
interquartile range (IQR). The normality of distribution was assessed using histograms 
and the Shapiro-Wilk test. The categorical variables were presented as frequency and 
percentage. 
The primary analysis was the comparison of the incidences of AKI in infants with 
and without renal desaturation based on the propensity score-matched cohort. The 
matched pairs were identified using a one-to-three nearest neighbor caliper with a width 
of 0.1, accounting for demographics, echocardiography and laboratory data, baseline 
hemodynamics, and surgical information. The balance between the matched pairs was 
assessed using the standardized difference. The incidences of AKI in infants with and 
without renal desaturation were compared using conditional logistic regression. The 
effect size was quantified by the odds ratio (OR) and 95% confidence interval (CI). A 
two-sided P value of less than 0.05 was considered statistically significant for the 
primary outcome. The multiple testing for the secondary outcomes was adjusted using 
the Holm-Bonferroni method. 
The Kaplan-Meier curves of the cumulative incidences of AKI in infants with and 
without renal desaturation based on the propensity score-matched cohort were 
constructed. The log-rank test was used to compare the distributions of cumulative AKI 
incidences in infants with and without renal desaturation. We then fitted a stratified Cox 
proportional-hazards model to analyze the association between renal desaturation and 
AKI. The effect size was quantified by the hazard ratio (HR) and 95% CI. 
The incidences of AKI in infants with and without renal desaturation based on the 
original cohort were compared using multivariable logistic regression controlled for 

NCT03941015 
Document Date: November 1, 2018 
confounders. This served as a sensitivity analysis to corroborate the primary analysis 
based on the propensity score-matched cohort. The confounders included the known 
risk factors for AKI (age, preoperative creatinine, preoperative hemoglobin, and CPB 
time) and the factors that had an imbalance (i.e., standardized difference ≥0.2) between 
infants with and without renal desaturation. To avoid collinearity, we included only one 
factor if two factors were correlated (i.e., Pearson’s correlation coefficient >0.5). 
Additionally, we explored the correlation between the duration of renal 
desaturation and the ratio of postoperative peak creatinine to preoperative baseline 
creatinine using the Spearman’s rank correlation coefficient. 
The statistical analyses were performed using R (version 3.5.3, R Foundation for 
Statistical Computing, Vienna, Austria) and SPSS software (version 17.0, SPSS, 
Chicago, IL, USA). A P value <0.05 was considered statistically significant for the 
primary hypothesis.