Electro-acupuncture (EA) in Children Undergoing Procedures for Congenital Heart Defects.
Phase: NA
Conditions: Congenital Heart Defect
Sponsor: West Virginia University

 
 
 
 
 
 
 
 
 
 
 
 
Title: Electro-acupuncture (EA) in Children Undergoing Procedures for Congenital Heart Defects. 
 
NCT number (unavailable), 
 
Date 9/20/2017 
 
Primary investigator: David A Rosen MD 
 
Affiliation:  West Virginia University, Morgantown, WV 
 
Address:  
1 Medical Center Drive 
PO box 8255 
Morgantown WV 26506 
 

 
Research plan 
Background 
Managing the child with congenital heart disease has become increasingly complex. The goal is to not only have 
the child survives, but has him or her recover with comfort and preservation of the heart and other vital organs through 
reduced complications.  Despite optimal pharmacologic management, these problems continue to occur. Additionally, 
recent concerns about the crisis surrounding opiate use/abuse have had an effect reducing the use of these drugs even in 
situations where they are indicated.   
 
Moving beyond pharmacologic strategies is one way to consider reaching the goal of increased comfort and 
reduced complications.  Acupuncture has been used for centuries to diagnose and treat a variety of medical conditions 
and is the practice of using certain anatomical points to achieve well-being in the patient.  Conventional acupuncture 
techniques involve needle manipulation at a specific anatomical point, but this approach may be difficult, if not 
impossible, to use in the operating room (OR) because of physical access and time constraints.    
Electro-acupuncture (EA) can achieve the results of standard acupuncture with less time and utilizes electric 
current instead of needle manipulation to achieve its effects.  The electric stimulation is provided through an acupuncture 
needle or a small electrode pad, and can be transmitted using different wave forms. These waveforms have the following 
theorized advantages1:  Continuous and/or a dense-disperse wave for analgesia, and dense-disperse wave for blood 
circulation.  
With electro-acupuncture, the stimulation frequency plays an important role in the release of naturally occurring 
analgesics.  Evidence suggests that lower frequencies( 2 Hz) result in the release of enkephalins and endorphins, whereas 
higher frequencies (100 Hz) result in the release of dynorphins.2  Varying between high and low frequencies (continuous 
plus dense-disperse) endogenous opioid peptides should release resulting in their synergistic interaction.   
There is controversy about the optimal current. Most studies have used current in the milliampere range and 
adjusted the current to be just below the threshold where electrically stimulated movement is observed, or typically in the 
mid-range (1-14mA). In contrast, there is a belief that the optimal current utilized should be in the microampere range.  
The Arndt-Shultz Law postulates that weak currents increase physiologic activity while strong current inhibit it.  
Adherents believe that micro currents (50 microamps -1000 microamp (1 Milliamp)) increase ATP concentrations while 
currents above 1000 micro amp do not increased ATP production and higher currents 5000 microamps may decrease 
ATP. Micro current techniques have been shown to increase microvascular blood flow, enhance circulation, reduce 
edema, and stimulate the growth of new blood vessels which significantly increases angiogenesis and tissue perfusion. 3.  
Current literature discussed below identifies a number of points that experienced acupuncturist have found 
effective in dealing with issues encountered during cardiac surgery. The only recent pediatric cardiac acupuncture study 
was a randomized control trial done by Ni X et al.4 Their study looked at 70 non-complex congenital heart patients age 2-
12 that underwent cardiopulmonary bypass (CPB) with an aortic cross clamp. They stimulated point pericardial 6 (PC 6) 
bilaterally for 30 min using a dense-disperse wave at a frequency of 2 Hz. The mean amplitude used was 14±3mA. 
Lower troponin and C-reactive proteins were observed in children receiving stimulation. Shorter ventilation times, 
shorter PICU stays, higher levels of naturally occurring pain killers (β-endorphin) and lower levels of stress hormones 
(serotonin levels (5-HT)) were seen in the EA group. 
Other adult cardiovascular studies have found similar advantages of stimulation of the PC-6 point. Ma et al. found 
that EA stimulation at PC 6 for 30 minutes before and during cardiac valve replacement had a positive effect on ischemic 
re-perfused myocardium by alleviating oxidative stress injury.5 The patients receiving EA at PC 6 had higher superoxide 
dismutase levels and lower troponin levels than the control group.4 Yang et al. stimulated PC 6 along with LieQue lung 
(LU) 7 and Yunmen LU 2 at 0.8-1.9 mA and frequency of 5 and 30 Hz for 30 minutes for 5 days before valve surgery. 
The EA group had shorter ICU stays and significantly lower troponin I levels at 6, 12 and 24 hours after cross clamp 
removal. Inotropic scores were also significantly lower at 12, 24 and 48 hours after ICU arrival.6  
To optimize the effects of EA, there is a question as to when the EA should be initiated and how long it should be 
continued into the postoperative period.  Adult studies have employed preoperative treatments from one hour to 3 days in 
advance of the procedure, then intraoperative therapy followed by post-operative therapy.  Chen et al. performed EA at 
30 minutes prior and continued their therapy postoperatively every 12 hours for 3 days. Their treatment group had lower 
serotonin levels, less nausea, required less analgesics, and had higher β-endorphin levels at 24, 48 and 72 hours post-
operative than the sham EA group.7  
Not only is the comfort of the patient increased, but acupuncture techniques have been shown to decrease 
complications. Qiang et al. added PC 4 to PC 6.  They stimulated for 30 minutes one to two hours prior to the procedure. 
Compared to their control group that did not get EA, the EA treatment group (stimulated with 2 and15 Hz at 7-11mA) 
had a decreased incidence of major adverse cardiac and cerebrovascular events (odds ratio 0.327, 95% CI 0.140–0.767, P 

= 0.010) at 24 months. They also found significant reduction in myocardial infarctions based on in serum troponin levels 
at 24 hours after percutaneous coronary intervention.8   
The effects of EA do dissipate, but these techniques do not necessarily need to be started before the incision or 
insult. Syuu et al. looked at the effects of EA at PC 6 in a hemorrhaging dog model. EA was started 30 after the 
hemorrhage was initiated. This study illustrated that stimulation of PC 6 prevented the fall in left ventricular performance 
and rise of plasma vasopressin. Improved left ventricular performance was also noted as long as EA was maintained.  
Once the stimulation was stopped, the effects dissipated over 120 minutes. This confirmed that stimulation of the point 
can be initiated after incision or insult, and that the effects of EA dissipate over time.9 
Though stimulation at PC-6 has been done by many investigators, other points have been used as well for 
cardiovascular surgery.  Zhou et al. studied 100 patients with standard general anesthesia and 100 patients with combined 
acupuncture plus midazolam.10  Those in the acupuncture group had significantly less opiate use, fewer pulmonary 
infections, shorter ICU stays, and lower cost. The points stimulated for this study were ZhongFU (Lung 1), Lung 7 and 
PC 4.10 Points used by Chi et al. included Lung 1, Chize (Lung 5) and PC 4.10.  Their acupuncture group needed 
significantly less blood transfusion, less antibiotics for pulmonary infections, and had shorter duration of hospitalization, 
shorter ICU stays and lower medical costs. They stimulated their points at 3-4 Hz and 2.0-2.2 mA for 20 minutes .11 A 
common point in these papers was stimulation at PC 4 and PC 6. Another advantage of these points is that they are distal 
to the surgical field and usually readily accessible.  
Stimulation at PC 6 has advantages in the kidney as well.  Fifty percent of children undergoing cardiovascular 
surgery develop at least stage 1 acute kidney injury (AKI). It is speculated that this AKI is related to activation of 
sympathoexcitatory inputs modulated through renal afferent nerves. Recent studies have tried to decrease this incidence 
by modulation of the renotubular feedback loop with adenosine receptor antagonism 11 This has been able to decrease the 
need for renal replacement therapy after CPB, but has not been shown to prevent the development of AKI.12  EA can 
affect sympathoexcitatory inputs.  Yu et al. stimulated rabbits in an AKI model and found stimulation at PC 6 and ST 36 
using a dense disperse wave at 2 and 15 Hz with 1 mA reduced morphologic renal damage and attenuated renal tubular 
apoptosis.13  
A special consideration during cardiac surgery is that organ blood flow is also often affected by non-pulsatile 
flow or hypotension. Lele et al., in a controlled hypotension model in dogs, found that EA helped maintain better blood 
flow to the stomach and kidney, resulting in reduced apoptosis in those organs. Further, the apoptosis that was observed 
in the control animals’ brains did not occur in the animals receiving EA. Points used were large intestine (LI)-4, ST-36 
spleen (SP)- 6 and LI-11 stimulated bilaterally at 2 Hz with 3-5 mA.14  
Research Plan: 
This study will help to identify whether electroacustimulation is a beneficial anesthesia adjunct in children undergoing 
procedures on their congenital heart defects. 
 
Electroacustimulation is a technique with minimal risks, which enhances the body’s innate abilities to deal with the 
stresses and pain of surgery.  Our goal is to optimize care for those patients with congenital heart disease by increasing 
comfort and reducing complications.   This study will examine comfort using age appropriate pain scoring systems. The 
complications this study will focus on are myocardial injury which will be assessed by measuring Troponin levels, and 
renal injury assessed using AKIN criteria 
   
Treatment Groups: 
Subjects will be randomized. Randomization will be done using block randomization with block sizes between 4 and 8.  
The sham procedure will use the identical set up as the treatment group, but those participants in the sham group will not 
receive the electro-stimulation.   
 
Group 1: Will have electrodes placed  at Pericardial 4 and 6, Large Intestine 4, and Stomach 36  and receive 
electroacustimulation (treatment) frequency will be at 2Hz and 100 Hz the amplitude will be 1000mA. 
 
Group 2: Will have electrodes placed  at Pericardial 4 and 6, Large Intestine 4, and Stomach 36 and  receive sham 
electroacustimulation (control) will not have stimulation. 
 
 
Duration of Treatment: 
The duration of treatment (stimulation or sham) for subjects will be length of surgical procedures on their congenital 
heart defects.  Patients will be followed for 6 hours to collect data on myocardial injury and48 hours to collect data on 
pain, and renal injury.   

 
Objectives: 
 
Primary Objective: 
The primary objective of this study is to identify whether electroacustimulation is a beneficial anesthesia adjunct in 
children undergoing procedures on their congenital heart defects. Does it decrease myocardial injury and or need for 
myocardial support. Differences between the groups Troponin I levels pre-operative and six hours postoperative will be 
evaluated.    
 
 
Secondary Objectives: 
1) Evaluate the incidence discomfort in the post- operative period. 
 
To evaluate the incidence and severity of pain assessed by using age appropriate West Virginia University Hospital 
approved nurse guided pain scoring the Neonatal/Infant Pain Scale (NIPS) ( children age birth to 2 months) FLACC (2 
months to 7 years or unable to communicate, or VAS(age 8-18) every 2 hours for 48 hours post procedure.  
 
2) Determine the incidence of Acute kidney injury (AKI) between these two treatment groups. Acute Kidney Injury will 
be evaluated by AKIN criteria. Creatinine and urines will be measured at 6, 12, 24 and 48 hours after bypass. 
 
 
Need for post-operative myocardial support:  
 
To assess the need for myocardial support an inotropic score will be used and compared between the two groups. The 
Inotropic score will be evaluated every 6 hours for 48 hour between the 2 groups 
. 
 
Study Design: 
 
This is a single site, randomized, blinded, sham controlled, parallel group study to identify whether electroacustimulation 
is a beneficial anesthesia adjunct in children undergoing procedures on their congenital heart defects. 
 
Study subjects age’s birth to eighteen years, undergoing cardiac surgery for their congenital heart lesions will be 
considered for entrance into the study. The randomized subjects will receive either electrostimulation or sham during 
their surgery for CHD. Subjects are expected to remain in the hospital 48 hours post procedure. Standard of care blood 
samples will be obtained pre-operative and post-operative. The only study specific blood sample will be Troponin I 
levels which will be obtained presurgically after the lines have been placed and a 6 hours post bypass/aortic clamp 
removal.  Urine samples will be obtained pre-surgically after placement of the Foley  and every 6 hours post bypass for 
48 hours while the Foley catheter is still in place . 
 
Number of Subjects planned: 
Approximately 108 patients, over the two years, with randomization of 54 allocated to each group. 
● Electroacustimulation (treatment) frequency will be at 2Hz and 100 Hz the amplitude will be 1000mA. 
● Sham electroacustimulation (control) will not have stimulation 
 
Study Population: 
Inclusion criteria:  
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the study: 
 
1) Patients 0-18 years of age undergoing procedures on their congenital heart defects. 
Additionally, patients with coarctation of the aorta for repair will be considered as a separate group and eligible 
for enrollment.  
2) Willing to provide written Assent/Consent in English. 
 
Exclusion criteria:  
Subjects will be excluded if they fulfill any of the following exclusion criteria: 

1) Patients with skin lesion over more than 50% of acupuncture sites.   
2) Patients in renal failure.  
3) Patients on chronic opioid therapy.  
4) Unwilling to provide written Assent/Consent in English. 
 
Concomitant Treatment: 
  All subjects will receive a standard anesthetic of propofol, remifentanil and dexmedetomidine at doses needed to 
maintain a stable BIS number and lack of movement.  When possible neuromuscular blocking agents will not be used. A 
morphine infusion will be used for postoperative pain control based on need.  Those allergic to morphine will receive a 
substitute opiate by continuous infusion.  
 
 
Study Procedures: 
Screening: 
Review of consent form- Subjects that provide written assent/consent and meet all inclusion and no exclusion criteria will 
be included into the study. Subjects may withdraw consent to participate at any time. Participation in the study is 
voluntary. Adverse events will be recorded after informed assent/consent obtained. 
 
Surgery: Treatment/Sham 
Eligible subjects will undergo blood sampling (3.5cc) and urine sample (0.5-2cc) will be obtained prior to 
stimulation/sham.  
 
All subjects will have electroacustimulation pads applied at four points bilaterally:  pericardial 4 (PC 4), pericardial 6 (PC 
6), large intestine 4 (LI 4) and stomach 36 (ST 36).  No needles will be used. (Appendix A; 1) 
 
Subjects will be randomized. Randomization will be done using block randomization with block sizes between 4 and 8.  
The sham procedure will use the identical set up as the treatment group, but those participants in the sham group will not 
receive the electro-stimulation.  Stimulation/sham will begin as soon as possible after induction of anesthesia and 
obtaining baseline laboratory samples of urine and blood. 
 
Group 1: Receive electroacustimulation (treatment) frequency will be at 2Hz and 100 Hz the amplitude will be 1000mA. 
 
Group 2: Receive sham electroacustimulation (control) will not have stimulation. 
Subjects will undergo procedures on their congenital heart defects. 
 
Blind: 
The anesthesia provider will be blinded as to whether the electroacustimulation device is actually turned on or not. The 
research coordinator will hold the blind. The electroacustimulation machine will be placed in an opaque bag to secure the 
blind. The current is below the threshold to stimulate the muscle so that no movement will be visible. It is also below the 
sensory threshold so that it will not produce any discomfort in the subjects.  
 
Stimulation/Sham will be continued until the patient is ready for transport to the PICU.  
 
Post-Operative: PICU 
Stimulation/Sham will be discontinued. 
 
PICU care givers will be blinded as to which group the patients were randomized. 
 
Subject comfort will be assessed using age appropriate West Virginia University Hospital approved nurse guide pain 
scoring based on Universal Pain Assessment Tool or the Neonatal/Infant Pain Scale (NIPS) will be recorded in the 
electronic medical record (EMR) every 6 hours for 48 hours.  
 
The amount of opiate infused, Nausea, Vomiting, and urine output will be assessed every 6 hours for the first 48 hours 
and recorded in the EMR.  
 
Research blood samples for troponin I will be obtained at 6 hours post surgery. Total amount of 7cc of blood will be 

obtained for this study. WVUH lab will process samples. 
 
Research urine samples (.05-2cc) will be collected at 6, 12, 24, and 48 hours after bypass. The urine samples will be 
stored in a -80 degree freezer and analyzed by ELISA testing at the end of the study for Superoxide dismutase, 
Neutrophil gelatinase – associated lipocalcin (NGAL), WNT4.  
 
AKIN criteria will be used to evaluate AKI every 6 hours. Inotropic score will be recorded every 6 hours. 
 
Daily chest x-ray will be used to assess pulmonary status.  
 
The AKIN criteria, inotropic scores, chest x-ray and creatinine levels, (used for AKIN), are standard of care 
measurements and the data will be collected for this research project. 
 
An Electrostimulation Documentation Guide has been developed for the staffing. (Appendix A2) 
 
Tool/Instruments to be used in data collection: 
Tools and instruments for data collection: secured Excel data base; Neonatal/Infant Pain Scale (NIPS); AKIN stage; 
Inotropic Scores; RACHS categories (Appendix A3-6).  
 
Variables: 
Detailed descriptions of the variables are given in Appendix B.  The information collected for each patient will include 
the following variables.  Outcomes: Pain score; inotropic score; Narcotic use; renal laboratory values: creatinine, 
neutrophil gelatinase-associated lipocalin (NGAL), WNT4, AKIN score; superoxide dismutase; indicator for pneumonia; 
time-to-extubation (intubation time, extubation time); length of pediatric intensive care unit (PICU) stay (arrival time, 
discharge time).  Other variables: Age, sex, cardiac defect, cyanosis, RACHS score, cardiopulmonary bypass time 
(CPB), cross clamp time and  surgery start and end time, occurrence of nausea, vomiting event, urine output, number of 
lobes with atelectasis. 
 
Analytic methodology 
Randomization:  Eligible participants will be randomized to the acupuncture treatment or control group using a randomly 
varying block randomization method to ensure equal distribution among treatment groups.22 The project statistician, who 
will have no contact with the participants or any of the personnel assessing the patients, will generate a randomized 
assignment master list and provide this information only the study personnel who will be setting up the acupuncture 
device.  Each participant will be assigned a unique number that will follow the patient through the study.  The study 
number and participant’s name will be retained on a secure electronic database; this information will be linked to the 
randomization assignment to create a crosswalk file.  It will be stored in a separate password-protected database.  At the 
end of the study, the cross-walk file will be used to link the patient data and treatment allocation. 
 
Sample size: 
Predicated on the primary aim, the sample size for this pilot study we used a two-sided two-sample t-test with unequal 
variance t-test with an alpha level of 0.05 and power of 80%.  A morphine equivalent dose of 0.71 mg/kg was used for 
the control group and 0.57 mg/kg for the acupuncture group. This represents a conservative 20% change between the 
control and acupuncture group. The standard deviation of the control group was estimated to be 0.3 mg/kg for the control 
group and 0.2 for the experimental group. The total estimated sample size is 108 patients, over the two years, with 54 
allocated to each group.  Historically, we would have had a potential enrollment and retention of approximately 74 
patients per year accounting for a 25% non-consent rate and a 2% drop-out rate. This project is well powered for 
statistical significance and feasibility for a 2-year study.  
 
Data collection:  
The data will be retrieved from the EMR and imported or entered into a secured EXCEL database.   
 
Statistical analysis plan:  
For all aims, univariate statistics (e.g. mean, median, standard deviation, min, max and skew) will be used to describe 
the collected data.  Parametric approaches (e.g. t-test, Pearson’s correlation, and chi-squared test) will be used when the 
data satisfy the required statistical assumptions; they will be used to compare the demographic and clinical characteristics 
between treatment and control.  If the distributional assumptions are untenable, then the Mann-Whitney test, Spearman 

correlation, and Fisher’s exact test will be used.  We will use the Box-Cox or the exponential transformation when the 
absolute value of skew is greater than 0.4. 
To address the overall difference between the control and the acupuncture group, we will look at the score changes 
between baseline and 48 hours.  For the continuous outcomes, a t-test based on the difference in outcome will be used to 
compare the two treatment groups.  For the categorical outcomes, a logistic regression model (generalized linear model 
with binary or multinomial outcome) will be used to compare the two treatment groups’ at baseline and 48 hours.  The 
generalized linear hypothesis methodology will be used to contrast the two time points.  This approach will provide 
consistency of modeling methodology for the secondary analyses.  Adjusted models will be considered (e.g. glm 
regression with identity and/or logit links) to account for any data imbalances, potential confounders, etc.  Minimally, a 
RACHS score adjustment will be assessed for its relevance. 
A secondary analysis will be used to describe the longitudinal (repeated measures) outcome trends.  A generalized 
linear mixed-effects regression model will be used for longitudinal data.  Both unadjusted and adjusted trends will be 
assessed. We will account for both heteroscedasticity and autocorrelation variance-covariance structures.  The 
generalized linear model approach will permit trend characterizations for either continuous or categorical outcomes under 
the same generalized linear model framework.  
All results, predicated on formal hypothesis testing methodology, will use an alpha-level of 0.05 for statistical 
significance.  Bonferroni or Scheffe adjustments will be used, when appropriate, to retain the family-wise alpha level of 
0.05 when performing multiple tests under the same global hypothesis or construct.  Every effort will be used to ensure 
all relevant information is collected.  In the event of missing data, generalized estimating equations for longitudinal 
analysis will be used. All statistical analysis will be done using the most recent version of the R language for statistical 
computing and graphics. 
 
Tentative time table: Approximately 2 years to enroll 108 subjects. 
 
References: 
1) Instruction manual for KWD-808I Multipurpose health device, Ying Di page 21. 
http://www.ib3health.com/products/Acupunctoscope/KWD808_I.asp#808I_Instruct [Accessed 
Sept. 5, 2016] 
2) Huang S, Peng W, Tian X, et al: Effects of transcutaneous electrical acupoint stimulation at 
different frequencies on perioperative anesthetic dosage, recovery, complications, and prognosis 
in video-assisted thoracic surgical lobectomy: a randomized, double-blinded, placebo-controlled 
trial. J Anesth. 1-8, 2015. DOI:10.1007/s00540-015-2057-1 
3) Gabriel A1, Sobota R, Gialich S, Maxwell GP. The use of Targeted MicroCurrent Therapy in 
postoperative pain management Plast Surg Nurs. 2013 Jan-Mar;33(1):6-8; quiz 9-10. doi: 
10.1097/PSN.0b013e3182844219. 
4) Ni X1, Xie Y, Wang Q, et al: Cardioprotective effect of transcutaneous electric acupoint 
stimulation in the pediatric cardiac patients: a randomized controlled clinical trial. Pediatr Anesth 
22: 805-811, 2012. DOI: 10.1111/j.1460-9592.2012.03822.x. 
5) Ma F, Zhang Y, Chen H, et al: Impacts on oxidative stress in the patients with cardiac valve 
replacement treated with electroacupuncture at Neiguan (PC 6). Zhongguo Zhen Jiu 35:707-710, 
2015. 
6) Yang L, Yang J, Wang Q, et al: Cardioprotective effects of electroacupuncture pretreatment on 
patients undergoing heart valve replacement surgery: a randomized controlled trial. Ann Thorac 
Surg 89:781-786, 2010. DOI:10.1016/j.athoracsur.2009.12.003 
7) Chen T, Wang K, Xu J, et al: Electroacupuncture Reduces Postoperative Pain and Analgesic 
Consumption in Patients Undergoing Thoracic Surgery: A Randomized Study. Evid Based 
Complement Alternat Med.:2126416, 2016. DOI: 10.1155/2016/2126416 
8) Qiang W, Dong L, Feng W, et al: Efficacy of electroacupuncture pretreatment for myocardial 
injury in patients undergoing percutaneous coronary intervention: A randomized clinical trial with 
a 2-year follow-up.J Cardiol 194: 28-35, 2015. DOI: 
http://dx.doi.org/10.1016/j.ijcard.2015.05.043 
9) Syuu Y, Matsubara H, Hosogi S, et al: Pressor effect of electroacupuncture on hemorrhagic 
hypotension. Am JPhysiol - Regul, Integr CompPhysiol 285: R1446-R1452, 2003. 
DOI:10.1152/ajpregu.00243.2003 
10) Zhou J, Chi H, Cheng TO, et al: .Acupuncture anesthesia for open heart surgery in contemporary 
China Int J Cardiol. 150:12-16, 2011. DOI: 10.1016/j.ijcard.2011.04.002 

11) Chi H, Zhou WX, Wu YY, et al.: [Electroacupuncture intervention combined with general 
anesthesia for 80 cases of heart valve replacement surgery under cardiopulmonary bypass.] 
Zhen Ci Yan Jiu 39:1-6, 2014 (Chinese) 
12) Onder A, Rosen D, Mullett C, et al: Comparison of intra-operative aminophylline versus 
furosemide in the treatment of oliguria during pediatric cardiac surgery. Pediatric Critical Care 
Medicine 17: 753-763, 2016 . DOI : 10.1097/PCC.0000000000000834. 
13) Yu JB, Shi J, Zhang Y, et a: Electroacupuncture Ameliorates Acute Renal Injury in 
Lipopolysaccharide-Stimulated Rabbits via Induction of HO-1 through the PI3K/Akt/Nrf2 
Pathways. PLoS One 10:e0141622, 2015. DOI: 10.1371/journal.pone.0141622 
14) Lele Z, Xiaomei S, Chuanlong Z,et al: Transcutaneous Electrical Nerve Stimulation Regulates 
Organ Blood Flow and Apoptosis during Controlled Hypotension in Dogs. PLoS One. 9: e94368, 
2014. DOI: 10.1371/journal.pone.0094368 
15) Box, G. E. P. & Cox, D. R. (1964). An Analysis of Transformations. Journal of the Royal Statistical 
Society. Series B (Methodological), 26(2): 211-252. 
16) Diggle, J.P., Haegerty, P., Liang, K., Zeger, S.L. (2002) Analysis of longitudinal data, 2nd ed. 
Oxford Univeristy Press Inc, New York, NY. 
17) Manly, B. F. J. (1976). Exponential Data Transformations. Journal of the Royal Statistical Society. 
Series D (the Statistician), 25(1), 37-42. http://doi.org/10.2307/2988129 
18) Molenberghs, G and Verbeke, G. (2010) Models for Discrete Longitudinal Data. Springer Verlag, 
New York, NY. 
19) Pinheiro, J.C. and Bates D.M. (2002). Mixed-effects Models in S and S-Plus. Springer Verlag, 
New York, NY. 
20) R Core Team. (2016) R: A Language and Environment for Statistical Computing. R Foundation 
for Statistical Computing, Vienna, Austria. http://www.R-project.org 
21) Verbeke, G. and Molenberghs, G. (2009). Linear Mixed Models for Longitudinal Data. Springer 
Verlag, New York, NY. 
22) Vickers A.J. How to randomize. J. Soc. Integr. Oncol. 2006 Fall 2006;4(4):194-198. 
23) Rosen KR, Rosen DA. Caudal epidural morphine for control of pain following open heart surgery 
in children. Anesthesiology, 70(3): 418-421, 1989. 
 

 
 
Appendix A 1 

 
 
 
Appendix A. 2 
 
 
Acupuncture Study Documentation Guide (record in EMR) 
 
Baseline (pre- acupuncture/sham) 
 
Procedure/Lab 
Date/Time 
Creatinine 
Urine sample 
RACHS score 
Cyanosis: yes or no 
 
Acupuncture/sham 
Date/Start time 
Date/End time 
Pre-surgery 
Post-surgery 
 
Aortic clamp removed date/time: 
CPB end date/time: 
 PICU: 
 
 
 
 
 
 
 
 
 
 
 
 
Labs: 
 
Times post CPB 
Date/Time 
Creatinine 
Urine Sample 
6 hours: 
12 hours: 
24 hours 
48 hours 
 
Scores: 
 
Times post CPB 
Date/Time 
AKIN/AKI 
lnotropic 
6 hours: 
12 hours: 
18 hours 
24 hours 
30 hours 
36 hours 
42 hours 
48 hours 
 
*Daily chest x-ray 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Times post 
CPB 
Date/Time 
Pain scale 
Number 
0-10 
Nausea 
(Yes/No) 
Vomiting 
(number of 
episodes) 
Urine output 
6 hours: 
12 hours: 
18 hours 
24 hours 
30 hours 
36 hours 
42 hours 
48 hours 
 

 
 
Appendix 3 
 
Neonatal/Infant Pain Scale (NIPS) 
 
(Recommended for children less than 1year old) A score greater than 3 indicates pain. 
 
Pain Assessment 
Score 
Facial Expression 
0 - Relaxed Muscles 
Restful face, neutral expression 
1- Grimace 
Tight facial muscles; furrowed brow,chin, jaw (negative facial 
expression - nose, mouth brow) 
Cry 
O - No cry 
Quiet, not crying 
1- Whimper 
Mild moaning, intermittent 
2 - Vigorous cry 
Loud scream; rising, shrill, continuous (Note:Silent cry may be 
scored if baby is intubated as evidenced by obvious mouth and 
facial movement 
Breathing Pattern 
0 - Relaxed 
Usual pattern for this infant 
1- Change in breathing 
Lndrawing. n,irregular, faster than usual ;gagging,, breath 
Arms 
0 - Relaxed/Restrained 
No Muscular rigidity; occasional random movements of arms 
1- Flexed/Extended 
Tense, straight arms; rigid and/or rapid extension, flexion 
Legs 
0 - Relaxed/Restrai ned 
No Muscular rigidity; occasional random movements of legs 
1- Flexed/Extended 
Tense, straight legs; rigid and/or rapid extension,flexion 
State of Arousal 
0 - Sleeping/Awake 
Quiet, peaceful, sleeping or alert, random leg movements 
1- Fussy 
Alert, restless and thrashing 
 
 
 
 
 
 
 
 
 
 

Appendix 4 
The AKIN classification/staging system of acute kidney injury  
Stage  
SCr  
UO  
1  
↑ SCr ≥26.5 μmol/L (≥0.3 mg/dL) or ↑SCr ≥150- 200% (1.5 - 2×)  
<0.5 mL/kg/h (>6 h)  
2  
↑ SCr >200-  300% (>2 - 3×)  
<0.5 mL/kg/h (>12 h)  
3  
↑ SCr >300% (>3×) or if baseline SCr ≥353.6 μmol/L (≥4 mg/dL) 
↑SCr ≥44.2 μmol/L (≥0.5 mg/dL)  
<0.3 mL/kg/h (24 h) or 
anuria (12 h)  

Appendix A 5 
 
Inotrope Score (IS) = 
Dopamine dose (mcg/kg/min) + Dobutamine dose (mcg/kg/min) + 100 x Epinephrine dose 
(mcg/kg/min) 
 
Vasoactive-Inotropic Score (VIS) = 
 
IS + 10 x Milrinone dose (mcg/kg/min) + 10,000 x Vasopressin dose (units/kg/min) + 100 x 
Norepinephrine dose (mcg/kg/min) 
 
Classification system based on inotropic score 
Group† 
IS or VIS 
1st 24 hours 
IS or VIS 
24–48 hours 
1 
<10 
<5 
2 
10–14 
5–9 
3 
15–19 
10–14 
4 
20–24 
15–19 
5 
≥25 
≥20 
†Group assignment based on highest support level in either time period. 
(Example: Patient with maximum IS 22 in first 24 hours, and 14 in the subsequent 24 hours, would be classified 
as group 4. Similarly, a patient with maximum IS 10 in the first 24 hours and maximum IS 25 in the second 24 
hours would be classified as group 5.) 
 
 
Michael G. Gaies, MD,1,2 Howard E. Jeffries, MD,3 Robert A. Niebler, MD,4 Sara K. Pasquali, MD,1,2 Janet E. 
Donohue, MPH,2 Sunkyung Yu, MS,2 Christine Gall, MS,5 Tom B. Rice, MD,4 and Ravi R. Thiagarajan, MD6 
Vasoactive-Inotropic Score (VIS) is Associated with Outcome After Infant Cardiac Surgery: An Analysis from 
the Pediatric Cardiac Critical Care Consortium (PC4) and Virtual PICU System Registries. Pediatr Crit Care 
Med. 2014 Jul; 15(6): 529–537.  
 

 
 
 
Appendix A.6 
 
 
RACHS category 1: 
 
1. Secundum ASD 
 
2. Aortopexy 
 
3. PDA (> 30 days of age) 
 
4. Coarctation (> 30 days of age) 
 
5. PAPVR repair 
 
RACHS category 2: 
 
1. Aortic valvuloplasty (> 30 days of age) 
 
2. SubAS resection 
 
3. Pulmonary valvuloplasty or replacement 
 
4. RV infundibulectomy 
 
5. RVOT augmentation 
 
6. Coronary fistula repair 
 
7. ASD & VSD repair 
 
8. Primum ASD repair 
 
9. VSD repair 
 
10. Tetralogy repair 
 
11. VSD closure with PA band removal 
 
12. Repair of unspecified septa! defect 
 
13. TAPVR repair (> 30 days of age) 
 
14. Glenn shunt 
 
15. Vascular ring surgery 
 
16. A-P window repair 

 
 
 
17. Coarctation repair (:5 30 days of age) 
 
18. PA stenosis repair 
 
19. Common atrium closure 
 
20. LV-RA shunt repair 
 
RACHS category 3: 
 
1. AVR 
 
2. Ross procedure 
 
3. LVOT patch 
 
4. Ventriculomyotomy 
 
5. Aortoplasty 
 
6. Mitra! valvuloplasty or replacement 
 
7. Tricusp id valvuloplasty or valvectomy or replacement 
 
8. Tricuspid valve repositioning (Ebstein's) (> 30 days of age) 
 
9. Anomalous coronary artery repair with or without intrapulmonary tunnel (Takeuchi) 
 
10. Closure of semilunar valve (aortic or pulmonary valve) 
 
11. RV-PA conduit 
 
12. LV-PA conduit 
 
13. DORV repair with or without RV obstruction 
 
14. Fontan 
 
15. AVSD (complete or transitional) repair with or without valve replacement 
 
16. PA banding 
 
17. Tetralogy with Pulm. Atresia repair 

 
 
 
 
 
18. Cor triatriatum repair 
 
19. Systemic-Pulmonary artery shunt 
 
20. Atrial switch operation 
 
21. Arterial switch operation 
 
22. Pulmonary artery reimplantation 
23. Annuloplasty 
24. Coarctation & VSD repair 
 
25. Cardiac tumor excision 
RACHS category 4: 
 
1. Aortic valvuloplasty (:::; 30 days of age) 
 
2. Konno procedure 
 
3. Complex defect (Single ventricle) repair with VSD enlargement 
 
4. TAPVR repair (:::; 30 days of age) 
 
5. Rastelli procedure 
 
6. Atrial switch with VSD closure 
 
7. Atrial switch with subpulmonary stenosis repair 
 
8. Arterial switch with PA band removal 
 
9. Arteria l switch with VSD closure 
 
10. Arterial switch with subpulmonary stenosis repair 
 
11. Truncus repair 
 
12. Repair of ... or interrupted aortic arch with or without VSD repair 
 
13. Unifocalization ... Tetralogy-PA 
 
14. ... 

 
 
 
 
 
 
 
RACHS category 5: 
 
1. Tricuspid valve repositioning for neonatal Ebstein's (:S 30 days of age) 
 
2. Truncus with Interrupted aortic arch repair 
 
 
 
RACHS category 6: 
 
1. Norwood operation 
 
2. ... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Appendix B: Variable descriptions. 
Variable 
Description 
Measurement times 
Measurement scale 
Outcomes 
Pain score 
Age appropriate WVUH 
approved Nurse guided pain 
scoring.  The pain scale score 
will be recorded in the 
electronic medical record. 
Every 2 hours for 48 
hours 
Tool: NIPS score, FLACC 
score or  Visual analog scale  
Scale: 0-10; 
0=none, 10=worst pain 
 
 
Inoptropic score 
IS or VIS 1st 24 hours 
IS or VIS 24-48 hours 
Every 6 hours for the 
first 48 hours of 
observation 
Group 1-5 
Narcotic use 
Opiate use will be its own 
variable as well as a surrogate 
for pain as comfort will be 
maintained at a score less than 
40% of the max possible score 
for the pain scoring system 
used.   
 
Every 2 hours for 48 
hours 
mcg/kg/hr 
Creatinine/Urine  
Assessment of AKI-renal 
complication 
Baseline, 6, 12, 24, and 
48 hrs post CPB 
Creatinine mg/dl 
Urine ml/kg/hr 
Neutrophil gelatinase-
associated lipocalin 
(NGAL) 
Renal biomarker-urine sample 
collected and frozen-renal 
complication 
Baseline, 6, 12, 24, and 
48 hrs post CPB 
ELIZA 
WNT4 
Renal Biomarker-urine sample 
collected and frozen-renal 
complication 
Baseline, 6, 12, 24, and 
48 hrs post CPB 
ELIZA 
AKIN score 
Acute kidney injury (AKI)-renal 
complication 
Every 6 hours for the 
first 48 hours of 
observation (EMR) 
Stage 1-3 
Superoxide dismutase 
Renal Biomarker-urine sample 
collected and frozen-cardiac 
injury-complication 
Baseline,6, 12, 24, and 
48 hrs post CPB 
ELIZA 
Pneumonia 
complication 
Daily (Chest x-ray) 
Indicator: 0=No, 1=Yes 
Intubation time 
The date and time of 
intubation as part of surgery 
prep. 
Obtained from patient’s  
EMR 
Date and time 
Extubation time 
The date and time of 
extubation as part of surgery 
prep. 
Obtained from patient’s  
EMR 
Date and time 
PICU arrival 
The date and time of arrival in 
the PICU 
Obtained from patient’s  
EMR 
Date and time 
PICU discharge 
The date and time of discharge 
from the PICU 
Obtained from patient’s  
EMR 
Date and time 
Other variables 
Age 
Age of the patient 
Baseline 
In days 
Sex 
Sex of the patient 
Baseline 
Indicator: 0=Male, 1=Female 
Cardiac defect 
Type of CD  
Baseline 
Diagnosis 

 
 
Cyanosis 
Blueness of skin- based on 
room air oxygen level less than 
90% sat-guide for opiate 
amount-complication 
Baseline 
1=yes 2=no 
RACHS score 
Randomization Guide 
Baseline 
Categorical: 1 through 6 
CPB start time/ Aortic 
clamp time 
Cardiopulmonary bypass (CPB) 
start time/ Placement of artic 
clamp 
Obtained from patient’s  
EMR 
Date and time 
CPB end time/Removal of 
aortic clamp 
Cardiopulmonary bypass (CPB)  
end time/ removal of aortic 
clamp 
Obtained from patient’s  
EMR 
Date and time 
Surgery start time 
Surgery start time 
Obtained from patient’s  
EMR 
Date and time 
Surgery stop time 
Surgery stop time 
Obtained from patient’s  
EMR 
Date and time 
Nausea 
Occurrence of nausea within a 
6 hour period 
Every 6 hours for the 
first 48 hours of 
observation (EMR) 
Indicator: 0=No, 1=Yes 
Vomiting 
Number of episodes in a 6 
hour period 
Every 6 hours for the 
first 48 hours of 
observation (EMR) 
Count of occurrences 
Urine output 
AKI 
Every 6 hours for the 
first 48 hours of 
observation (EMR) 
 ml/kg/hr 
Atelectasis 
Graded by number of lobes 
with atelectasis. 
Daily (Chest x-ray) 
Count of the number of 
lobes