Example: Research Protocol Randomized Controlled Trial

PROTOCOL TITLE: Continuous infusion versus bolus dosing for pain control after pediatric

cardiothoracic surgery Ver1_9.16.14

HRP-503 Template Protocol

Owner: Cheryl Lefaiver, PhD, RN, Director, ACPR of 16 Use most current version on IRB website and complete all sections

Example: Research Protocol Randomized Controlled Trial This protocol is being used as an example with permission from the author, Jamie Penk, MD. The

content in this protocol is to serve only as an example. Please download the most recent version of the

Advocate IRB Research Protocol Template (HRP_503) from their website

(http://www.advocatehealth.com/forms2) to write your own research protocol.

Principal Investigator: [Name, credentials]

Sub-Investigator(s): [Name, credentials] as appropriate

Research Coordinator: [Name, credentials] as appropriate

1) Protocol Title

'Continuous infusion versus bolus dosing for pain control after pediatric cardiothoracic surgery'

2) IRB Review History*

NA.

3) Objectives*

Pain control in the modern era of pediatric cardiothoracic surgery is evolving. In the

last decade many centers have moved toward an early extubation strategy in the post-

operative period. This is in contrast to earlier eras when positive pressure ventilation

and heavy sedation were the rule. This early extubation strategy has been the clinical

practice at Advocate Children’s Hospital-Oak Lawn for years.

The best way to achieve good pain control in patients who are not intubated and heavily

sedated has not been well studied. Practice at various centers is heterogeneous. Some

use continuous infusions of sedatives and analgesics and others use bolus dosing.

The purpose of this study is to test both of these pain treatment strategies and evaluate

the amount of analgesic medication administered and pain control in the first 24 hours

of the post-operative period.

The specific aims are to:

1) Evaluate the differences between groups in the total amount of analgesic

(morphine) and sedative (midazolam) medication administered between the groups.

2) Evaluate the difference in pain scores (i.e. average and maximum pain scores)

between groups.

3) Evaluate secondary outcomes between groups including length of stay in ICU and

total hospital length of stay, mortality and re-intubation rates.

Our hypothesis is that bolus dosing of analgesics and sedatives will result in the same

amount of pain control post-operatively while reducing the total use of these

medications.

4) Background*

Example

http://www.advocatehealth.com/forms2





Prior data on this subject has been scarce. This is due to the shift in practice to early

extubation. The PI has experience with several pain and sedation strategies. In an ICU

fellowship the PI used bolus dosing for pain control after early extubation. The PI also

volunteers for International Children's Heart Foundation where early extubation is the rule.

Pain control is augmented with early and around the clock use of acetaminophen and ibuprofen

and little opiate or midazolam use is necessary. This practice has been shown to be beneficial

in previous studies by reducing opiate use (4). Especially when the bolus only strategy is

applied in the Pediatric Surgical Heart Unit (PSHU), these adjunctive medications are used to

augment pain control.

Previous studies related to pain control after cardiothoracic surgery are sparse in

pediatrics. An anesthesia study used a continuous infusion of levobupivacaine subcutaneously

into the surgical site and showed the treatment group required less morphine and midazolam

(1). This is a useful adjunctive medication, but is difficult to institute widely because of the

technical difficulties of using continuous subcutaneous infusions.

Adjunctive medications, acetaminophen and ketorolac, are more widely available and

likely to be used by other institutions. These medications will help limit our morphine and

midazolam requirements. It has been shown previously that when used in combination with

other analgesic dugs (multi-modal analgesia) NSAIDs decreased opioid consumption by 30-

40% (13, 14, 15) and improve analgesia quality (13).

There are no existing studies directly comparing continuous infusion to bolus dosing.

Bolus dosing is the use of these medications when needed rather than constantly. By targeting

times when they will be helpful, we will be able to control pain without giving unnecessary

medication. This will be beneficial as it will limit the negative side effects experienced with

morphine and midazolam. An example of this benefit is from a study involving children

(n=50), rectal diclofenac was as effective as morphine, but caused significantly less nausea and

vomiting following squint surgery (12).

Our current approach to pain control in the PSHU is mixed. Some children after early

extubation are managed with continuous drips and bolus dosing and some are managed with

bolus dosing only. Based on our experience, pain control as evaluated with the Face, Legs,

Activity, Cry, Consolability (FLACC) scores (17), has been very good with either strategy.

Currently, most are now treated with ketorolac on the first post-operative night, but the start

time is physician dependent. Bolus dosing has required 2-4 doses which is approximately a

quarter of the total dose given over 24 hours for the continuous infusions. We used some of

our early experience and a previous study of pain control in children with Down syndrome

(DS) to derive our power estimates and to help with study design (5). Part of our design is to

randomize by Down syndrome as our experience has been that they are harder to sedate. This

was shown to be true in a retrospective review of morphine usage in children with and without

Down syndrome after cardiac surgery (16).

This study will advance current research by demonstrating that good pain control can

be achieved in a more targeted approach. Our bolus only strategy will use significantly less

morphine and midazolam which also may lead to shorter length of stay, vomiting etc.. This

will help other institutions design their pain control strategies and may lead to fewer children

on continuous infusions when not needed. Our overall goal in conducting this study is to

examine whether we can reduce opiate use in children after cardiothoracic surgery while

maintaining adequate pain control.

Example





5) Inclusion and Exclusion Criteria*

Patients scheduled for pediatric cardiothoracic surgery at Advocate Children’s Hospital – Oak

Lawn (ACH_OL) will be screened for eligibility.

Inclusion criteria:

Age 3 months – 4 years (48 months)

Anticipated cardiothoracic surgery with midline sternotomy incision

Planned early extubation (e.g. within 3 hours post surgery)

Planned admission to the PSHU

Exclusion Criteria: (limits on ketorolac set per prospective study of ketorolac safety (6))

Presence of renal insufficiency defined as a creatinine greater than 0.8mg/dL on the

standard basic metabolic profile sent after surgery or history of chronic renal failure.

Significant development delay that the bedside nurse or treating physician judges would

make pain scoring difficult (Down syndrome is not excluded)

History of bleeding disorder or gastrointestinal bleed within the past 2 months.

Presence of chronic hepatic disease or elevation of AST or ALT greater than 250 U/L

before or after surgery.

More than 3 previous surgeries with a sternotomy incision (this may alter pain

perception).

Children on immunosuppressents

Children whose parents have provided permission prior to surgery, will be evaluated for

randomization after surgery. Children who have any of the following exclusion criteria will not

be randomized or undergo any study procedures, and after surgery will receive conventional

care.

Platelet count less than 80,000 due to limitation on ketorolac use (6)

Admission to the PICU (due to use of different nursing staff)

Creatinine of more than 0.8mg/dL

Not extubated within three hours of arriving in the PSHU

6) Study-Wide Number of Subjects*

We will enroll 60 subjects, 30 in each pain strategy group. All patients will be enrolled from a

single site. We anticipate 15 parents may refuse and another 10 may be excluded post surgery.

Furthermore, we anticipate 20 patients will be excluded pre-surgery due to renal/hepatic

disease, thoracotomies rather than midline sternotomies or other factors based on our data from

2012. We anticipate needing to screen 105 patients to reach our goal of 60 for the study.

Example





7) Study-Wide Recruitment Methods*

Potential subjects will be recruited from patients scheduled for cardiothoracic surgery at

Advocate Children's Hospital-Oak Lawn. The scheduling coordinator currently sends a

letter (Attachment A) to each family and with it will be included a description of our

study (see Attachment B). The coordinator has clinical experience and sits in on our

pre-surgery planning. She will perform the initial screening based on our inclusion

criteria and will include the study description in communication with parents of

potential subjects. The family will be offered the opportunity to speak with the PI to

learn more about the study and answer any questions prior to their pre-surgery visit.

Parents will also have time to ask questions and give consent at the pre-surgery visit

where the consent/parent permission process will take place.

8) Study Timelines*

Based on the surgical volume from 2013 a total of 133 cardiovascular surgeries were

performed on children in our defined age group. Approximately 90 would have met our

inclusion criteria, therefore we anticipate subject enrollment to be accomplished 8-12

months after approval.

See below for a timeline of overall study activities:

Calendar

Year

2014 2015

Month Feb Mar Apr May Jun Aug Sept Oct Nov Dec Jan Feb Mar Apr May Jun

Advocate IRB

Review

PSHU

Training

Subject

Enrollment

Data Analysis

Dissemination

9) Study Endpoints*

The primary endpoints in this study are the total dosage of morphine and midazolam

given to patients in the PSHU after surgery over the first 24 hours.

Secondary endpoints include total and median pain scores in the first 24 hours, number

of bolus doses given of morphine and midazolam, length of stay in ICU and total

hospital length of stay, mortality and re-intubation rates.

10) Procedures Involved*

Example





This study will compare two different specific, comprehensive pain management strategies

using medications that have been approved for use and are currently in use for this population

of patients in the PSHU. No procedures that are outside our standard of care will be performed

as part of this study.

The specific procedures we will use during this study are as follows:

Prior to surgery, eligible patients scheduled for surgery will be sent our standard surgery letter

(Attachment A) along with our study informational sheet (Attachment B) describing our study.

The study informational sheet will have a telephone number to call to set up a phone

appointment to discuss the study with the PI should parents have questions not answered on the

sheet. During the pre-operative visit, the study will again be discussed with the parents. Our

nurse practitioners will be trained on this study and will obtain written consent at this time. If

the parents would like to further discuss the study directly with the PI, this will be arranged

prior to surgery.

The PI will be notified by the NPs of all parents who give permission for their child to

participate in the study, and he will notify the on service medical team. On the day of surgery,

a computerized order for the study will be entered to notify the pharmacy to randomize the

subject to the control or treatment group. Randomization will be stratified based on whether

the child has DS, as children with DS are known to have a heightened pain response and

require large doses of medication to treat pain. Only the pharmacist will know the random

assignment, health care providers and subjects/families will be blinded as to treatment arm.

Treatment Group:

Intravenous (IV) drip of 0.03 mg/kg/hour morphine and 0.03 mg/kg/hour midazolam

Control Group:

IV drip of normal saline (NS) at same volume as what the morphine/midazolam drip would be

Both Groups

Subjects in both the control and treatment group will receive the following post-operative pain

control orders that are currently in use in the PSHU:

1. Morphine 0.05 mg/kg/dose IV q 2 hours prn pain score 4 or greater

2. Midazolam 0.05 mg/kg/dose IV q1 hours prn agitation

3. Additional prn doses of morphine and midazolam may be given as determined by the

treating team (these doses will be recorded in the EMR)

4. Acetaminophen 30 mg/kg PR x 1 to be given on admission to PSHU post surgery

5. Acetaminophen 15 mg/kg PR q4 hours to be started 4 hours after first dose

6. Acetaminophen 15 mg/kg PO q4 hours to be started after subject starts drinking by

mouth and PR doses stopped

7. Ketorolac 0.5 mg/kg/dose IV q 6 hours to start 6-12 hours after surgery when chest tube

drainage criteria are met. Will start when chest tube drainage is no longer frankly

bloody and if chest tube drainage is less than 3 cc/kg/hour for two hours in a row

If the subject is extubated, or is extubated in the first three hours, the IV drip sent from the

pharmacy with either NS or morphine/midazolam (according to treatment arm) will be started.

Additional pain control will be provided to all subjects with scheduled acetaminophen every

Example





four hours (rectally or orally as tolerated). Ketorolac will be started as well in both groups no

earlier than six hours after surgery. Consistent with routine PSHU practice for this patient

population, pain scores as measured by the FLACC will be recorded by the bedside nurse

every hour and charted in the medical record. As needed, unblinded, single dose morphine will

be given for pain score of 4 or greater and unblinded, single dose midazolam, may be given for

agitation as needed. This pain regimen will continue for the first 24 hours after arrival in the

PSHU. Every medication given (acetaminophen, ketorolac, morphine and midazolam) will be

recorded in the electronic medical record as is our current practice. After 24 hours, the infusion

(morphine/midazolam or saline) will be discontinued and further pain control treatments will

be at the discretion of the attending physician. After discharge, a chart abstraction will be

performed.

Data to be recorded:

Demographics(age, gender, presence of Down syndrome, history of liver/renal

dysfunction, history of bleeding disorders or recent gastrointestinal bleeds, type of

surgery)

Laboratory values(AST/ALT, creatinine, hemoglobin level, platelet count)

Hourly FLACC pain scores

Total amount of morphine and midazolam used in 24 hours

Total amount of Phenobarbital received in 24 hours

Number of times a patient vomits

Number of 'as needed' (prn) morphine and midazolam doses in 24 hours

Length of stay in both the PSHU and the hospital

Episodes of re-intubation

Episodes of gastrointestinal bleeding (stool, from nasogastric tube or emesis, graded as

clinically significant or not using practical judgment (6)

Episodes of excessive bleeding from chest tube defined as 5cc/kg in one hour of bright

red blood

Time to first oral intake

11) Data and Specimen Banking*

NA

12) Data Management*

Sample Size Estimation

Sample size estimation was calculated using PASS 12 (9) based on the number of

subjects needed to compare the difference in total amount of morphine dosed in the 24

hour study period between treatment groups. Power analysis was run based on

published up to a 60% narcotic dose difference when acetaminophen and ketorolac are

used proactively(4) A sample size of 28 achieves 80% power to detect a dose difference

of 30% with an estimated standard deviation of 0.9 and with a significance level (alpha)

of 0.05 using a two sample t-test. We will enroll 30 subjects in each group to

accommodate for any subjects that may be withdrawn due to medical condition.

Example





Data Management

Dosing of medication, lab values and pain scores will be recorded in the electronic

medical record (EMR) per routine procedure in the PSHU. Investigators will extract

study data from the EMR and enter it into a REDCap password protected web-based

database. A REDCap data collection form (see Attachment C) is attached.

Analysis

Data analysis will include measures of central tendency for all demographic and

outcome variables. Number of adverse events (as determined by lab values out of

range) that occurred within each group will also be described. The primary endpoint of

total morphine dose in the first 24 hours will be compared between groups using a

Student’s t-test and a p-value less than, or equal to, 0.05 will be regarded statistically

significant.

Secondary outcomes to be compared between groups include the median and maximum

pain score recorded in the first 24 hours, PSHU length of stay, hospital length of stay

and episodes of re-intubation. Analysis will be done using ANOVA, Student’s t-test or

chi-square according to appropriate level of measurement and a p-value less than, or

equal to, 0.05 will be regarded statistically significant.

Data Storage

All information gathered during this study will be kept confidential. Subjects will be

assigned case numbers and data collection forms that including the patient name will

only be seen by the research team. These forms will be placed in a confidential folder

within the principal investigator’s locked office. Tabulation of data will be stored in a

into a REDCap password protected web-based database.. The results of this study may

be published in scientific journals or be presented at professional meetings, but no

individuals will be identified. The collection and handling of data will be in complete

accordance with the HIPPA regulations. The research-related records for this study may

be inspected by a federal regulatory agency and the Institutional Review Board.

13) Provisions to Monitor the Data to Ensure the Safety of Subjects*

MONITORING PLAN

The individuals responsible for data safety and monitoring will be Dr. Penk (PI) and

Kim Wittmayer (Pediatric Pain APN). Quality control will include regular data

verification and protocol compliance checks by Dr. Penk.

COLLECTION AND REPORTING OF SAEs AND AEs

Throughout the study, Dr. Penk will monitor study participants for adverse events. Dr.

Penk will review all adverse events (AEs) and serious adverse events (SAEs)

individually and in aggregate on a biweekly basis. Dr. Penk will report all AEs and

SAEs to the Advocate Health Care IRB according to the AE reporting guidelines.

Events determined by the PI to involve injury or to be unanticipated problems involving

risks will be reported by the PI to the IRB within 24 hours per policy. Adverse events

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that are determined by the PI not to involve injury or not to be unanticipated problems

involving risks will be reported per IRB policy at the time of continuing review.

For this study, the following standard AE definitions will be used:

Adverse event: Any unfavorable and unintended sign (including an abnormal

laboratory finding), symptom or disease, that did not exist at the time of the subject’s

entry into the study and that is temporally associated with the use of the study

medication, regardless of whether it is considered related to the study medication.

Serious Adverse Event: A significant hazard or side effect, regardless of the

Investigator’s opinion on the relationship to treatment group. A serious adverse event

is any untoward medical occurrence that at any dose:

• Results in death

• Is life-threatening (defined in this case as an event in which the subject

was at risk of death at the time of the event/reaction; it does not refer to an

event/reaction which hypothetically might have caused death if it were

more severe)

• Requiring prolongation of existing hospitalization

• Results in persistent or significant disability/incapacity

• Is a medically important event or reaction

AEs will be graded by the investigator according to the following scale:

Mild: An event that is easily tolerated by the subject, causing minimal

discomfort and not interfering with everyday activities. This includes transient

laboratory test alterations.

Moderate: An event that is sufficiently discomforting to interfere with normal

everyday activities. This includes laboratory test alterations indicating injury,

but without long-term risk.

Severe: An event that prevents normal everyday activities. If prolongation of

hospitalization is required for treatment it becomes an SAE. (An AE that is

severe should not be confused with a SAE. Severity is a category utilized for

rating the intensity of an event; and both AEs and SAEs can be assessed as

mild, moderate or severe.)

However, relating the intensity of clinical AEs to functional daily life and everyday

activities may not be assessable in children in the PSHU. Therefore, if not possible to

assess, the intensity of clinical AEs will be assessed by the investigator as per his/her

best judgment.

The study will use the following AE attribution scale:

Unrelated: The AE is clearly related to other factors such as the subject’s

clinical state, therapeutic interventions, or concomitant drugs administered to

the subject (i.e., another cause of the event is most plausible and/or a clinically

plausible temporal sequence is inconsistent with the onset of the event).

Example





Not likely related: The event was most likely produced by other factors such

as the subject’s clinical state, therapeutic interventions or concomitant drugs

administered to the subject, and does not follow a known response pattern to the

study drug.

Possibly related: The event follows a reasonable temporal sequence from the

time of drug administration and/or follows a known response pattern to the

study drug; but it could have been produced by other factors such as the

subject’s clinical state, therapeutic interventions, or concomitant drugs

administered to the subject.

Probably related: The event follows a reasonable temporal sequence from the

time of drug administration and follows a known response pattern to the study

drug; and it cannot be reasonably explained by other factors such as the

subject’s clinical state, therapeutic interventions, or concomitant drugs

administered to the subject.

AEs will be monitored throughout the time that a subject is in the trial (24 hours). AEs

and SAEs still ongoing after study drug discontinuation will be followed until 30 days

after study drug discontinuation or until resolution or stabilization or until the event is

otherwise explained. AEs will be assessed through a review of the hospital chart on a

weekly basis and with a physical examination of the subject, if indicated. SAEs will be

reported to the AHC IRB within 24 hours of the investigator’s awareness of the SAE.

DATA ANALYSIS PLANS AND INTERRIM REPORTS

An independent Data Safety Monitoring Board (DSMB) will perform a statistical

review of the study data and will have access to fully unblinded* patient data if

necessary, to ensure patient safety. The DSMB will be empowered to recommend,

based on safety considerations, modifications to the protocol or early termination of the

study. The board will function independently of the investigators. AEs and SAEs (i.e.

presence of gastrointestinal bleed, excessive chest tube bleeding, renal injury, liver

function as measured by AST/ALT) will be monitored by the DSMB in an unblinded*

manner during the study at the following time points:

• after half of the subjects (N=30, 15 in each group) are enrolled

*The randomization code will be kept strictly confidential. It will be provided to the

DSMB by the research pharmacist (Chris Steffensen, PharmD) to ensure patient safety.

Interim analyses will be performed to evaluate differences in AE and SAE rates

between the two treatment groups, and to evaluate the primary endpoint (total dose of

morphine and midazolam). The DSMB will prepare a report after each review which

will be given to the PI, and, in turn, this report will be submitted by Dr. Penk to the

IRB.

The DSMB will be comprised of the following individuals:

Denise Angst, PhD, RN – Chair of DSMB, Director, Advocate Center for

Pediatric Research

Example





Jackie Kessler, MS, FASHP – Clinical Pharmacist, Investigational Drug

Services, Advocate Lutheran General Hospital

Luis E. Torero, MD – Pediatric Pulmonologist, Torero Pulmonary Specialists,

S.C.

14) Withdrawal of Subjects*

At any time, the attending physician can withdraw a patient from this study if they feel

pain control is not adequate. If, for any other reason, including suspected complication,

the attending would like to withdraw the patient so as to ascertain which medications

are being given or to change medication class, they may do so. Parents will be notified

by the attending physician. The new plan for pain management will be discussed at

that time.

AFTER the decision is made to withdraw, the attending may ask the pharmacy to

disclose which study arm the patient is in and may then switch medications as

necessary. The attending physician is responsible for notifying the PI why the patient

was withdrawn. Data collection will continue to discharge.

Subjects will be withdrawn from the study if lab values or bleeding lead to

discontinuation of ketorolac. Subjects to be withdrawn for doubling of creatinine value

compared to immediate post-operative AND it is over 1 mg/dL. Frankly bloody chest

tube drainage or drainage not less than 3 cc/kg/hour for two consecutive hours 12 hours

post surgery. This bleeding criteria means that if we cannot start the ketorolac 12 hours

post operatively, the patient will be withdrawn as they are not receiving the same pain

control as other subjects. Additionally, if a patient has 5cc/kg over an hour of bright

red blood from the chest tube after initiation of ketorolac, this is considered significant

bleeding and the subject will be withdrawn. Platelet count less than 80,000 on post-

operative day one would lead to discontinuation of ketorolac so those subjects will be

withdrawn. Finally, a significant GI bleed will also lead to withdrawal from the study.

Due to use of around the clock acetaminophen, we will also withdraw subjects with

doubling of AST or ALT between post-operative values and post-operative day one

values if the absolute value is over 300 U/L.

15) Risks to Subjects*

There are minimal risks to the study subjects related to pain management because subjects will

receive adequate pain management in both study groups. Both strategies outlined in this study

have been used in clinical practice and study participants are not at increased risk compared to

other patients undergoing the clinical procedure and not in this study.

A safety and monitoring plan is being proposed as described in section 13 of this protocol.

Ketorolac and acetaminophen have been previously studied and shown to be safe. We would

like to add to that literature again documenting the safety of these medications. Adverse events

related to the use of ketorolac may include risk of bleeding, thus we will monitor the presence of

gastrointestinal bleeds and for excessive chest tube bleeding. We will also evaluate for renal

injury defined as creatinine twice the immediate post-operative value (7). Previous studies done

Example





on our specific population as young as 3 months have shown no increase in bleeding, chest tube

drainage or incidence of renal injury with the use of these medications (6,7). Finally, as we are

using acetaminophen around the clock we will evaluate for a two fold increase in AST/ALT on

post-operative day 2 over post-operative day 1. A previous study of acetaminophen dose of 30

mg/kg did not find any increase in adverse events (8).

16) Potential Benefits to Subjects*

There are no guaranteed benefits to subjects given that all medications proposed in this study

are currently in use. The results of this study will be used to guide clinical management of pain

and provide support for a single pain management strategy for this population. Future benefits

are possible as many of our patients require multiple surgeries and data from this study may

improve our pain control regimen.

17) Vulnerable Populations*

This research involves children as a vulnerable population (see Attachment D, Checklist HRP-

416). Informed consent/parental permission will be assured by offering parents multiple

opportunities to ask and have their questions answered about the study before enrollment and

throughout the study time period. Informed consent/parental permission documentation will be

completed as discussed in protocol section 29. Subjects will be too young to provide assent as

they will all be under 4 years of age. Our study does not exceed minimal risk as the treatment in

both arms of our study have been used for clinical management. There is no guarantee that

individual subjects will benefit from participating in this study but this research will enhance our

understanding of the effectiveness of these two pain control strategies and may benefit future

patients. This research presents a reasonable opportunity to determine a method of providing

good pain control while limiting the untoward effects of opioid and sedative medications.

18) Multi-Site Research*

NA

19) Community-Based Participatory Research*

NA

20) Sharing of Results with Subjects*

The results of some study outcomes including pain medication boluses, pain scores and lab

values may be shared with the family by the physician involved in the care. No further sharing of

group assignment or data will be provided.

21) Setting

Example





This study will be conducted at Advocate Children's Hospital-Oak Lawn will be the

only site. Recruitment performed in the Heart Institute for Children. Study performed

in the Pediatric Surgical Heart Unit.

22) Resources Available

Dr. Penk, the PI has extensive experience in pain control related and unrelated to

cardiothoracic surgery. Significant experience includes 1.5 years as a pediatric

hospitalist covering the emergency room, PICU and NICU. Sedation service was also

covered for one week per month with a wide variety of sedation techniques employed.

Pain control post cardiothoracic surgery specifically was observed and performed as a

cardiology fellow at Lurie Children's Hospital. He also provided continued sedation,

pain management and airway management in general ICU patients and in the

cardiothoracic ICU at Children's National Medical Center as a critical care fellow.

Finally, the PI has worked with International Children's Heart Foundation with a total

of 3 months spent on volunteer missions using pain control strategies described above.

PI also has experience in carrying out and designing scientific studies. Publications

include reference 2 and 3 with a third study regarding unplanned admissions to the

cardiothoracic ICU submitted for publication.

Kim Wittmayer, is an advance practice nurse (APN), board certified as a pediatric

clinical nurse specialist, who is also certified in pain management. She started the

pediatric pain service program 5 years ago at Advocate Children’s Hospital-Oak Lawn

and works primarily with patients experiencing acute pain. Prior to working with the

pain service, she was a staff nurse within the pediatric intensive care unit (PICU) for

four years and participated in several research studies. She served as the site nurse co-

investigator for the NIH-funded RESTORE study, which examined the effects of a

nurse driven pain and sedation protocol in the mechanically ventilated child, as well as

the site PI for BALI (an ancillary study to RESTORE looking at genetic variation and

Biomarkers in Children with Acute Lung Injury) (10). In 2012, The American Society

for Pain Management Nursing presented her with the Nurse Exemplar Award for the

Pediatric Patient. Publications include the topics related to nonmedical use and abuse of

prescription opioids in older children, as well as pediatric pain quality improvement

(11).

Pharmacy staff will be available to the study team for randomization. They will also

prepare the normal saline or morphine/midazolam drips and deliver them to the PSHU

so as to keep the PSHU staff blinded to the contents.

Additionally, Cheryl Lefaiver, PhD, RN, CCRP, Manager, Pediatric Research Support

& Analytics as part of the Advocate Center for Pediatric Research will be a collaborator

on this project and will assist with data management and statistical analysis.

Feasibility of patient recruitment has been derived from previous years surgical

volume. In 2012, 115 patients were eligible for enrollment in this study. Some of those

may have been excluded according to post-surgery exclusion criteria (late extubation,

low platelet count, bleeding etc..) but that is rare. We anticipate if only 60% of the

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remaining patients consent, our target numbers can be met in one year. We anticipate a

much higher consent rate and that the study can be completed much earlier.

All investigators, pediatric cardiovascular surgeons and clinicians in the Pediatric

Surgical Heart Unit (PSHU) in the study have been informed about the purpose and

specifics of the study. Nurses in the PSHU will be trained on the specific medication

administration for the study protocol. In addition, re-training will be provided to nurses

on the use of the FLACC (pain scoring instrument) to ensure internal consistency of the

pain scores.

23) Prior Approvals

NA

Recruitment Methods

See protocol section 7 above.

24) Local Number of Subjects

See protocol section 6 above.

25) Confidentiality

All information gathered during this study will be kept confidential. Data collection forms and

the database that include the patient name and other PHI will be seen only by the principal

investigator and research team. All information and data gathered in this study will be placed in a

password protected computer with restricted access by only the investigative team. The results of

this study may be published in scientific journals or be presented at professional meetings, but no

individuals will be identified. The research-related records for this study may be inspected by a

federal regulatory agency and the Institutional Review Board.

Data will be stored on Advocate’s secure computer network which will only be accessible by the

study investigators.

26) Provisions to Protect the Privacy Interests of Subjects

Study participants data will be collected via the electronic medical record. This data will be

stored it into a REDCap password protected web-based database.. Only the PI and co-

investigators will have access to the data.

27) Compensation for Research-Related InjuryThe procedures used in the two study arms are currently in use for clinical care. Appropriate

medical care will be provided for any adverse event. Adverse events are not anticipated and there

is no compensation available for research-related injury.

Example





28) Economic Burden to Subjects

None. Participants will not be billed for either NS or morphine/midazolam drips. The pharmacy

will absorb the cost of the drips being used in this study.

29) Consent Process

Consent from parents will be obtained prior to enrollment.

Where will the consent process take place

-The consent/parental permission process will take place at the pre-screening

visit at the Heart Institute for Children. Our nurse practitioners, Carrie Miller or

Jane Flanagan, will obtain consent/parental permission for this study. The PI may

also obtain consent.

Any waiting period available between informing the prospective subject and

obtaining the consent.

-After scheduling the surgery, a packet of information that includes a

description of the study will be sent to parents. A phone conversation will be

scheduled prior to the pre-operative visit. Final questions will be answered at the

pre-operative visit itself and there is again opportunity for questions on the day of

surgery.

We will follow HRP-090 to obtain informed consent/parental permission.

Non-English Speaking Subjects

During the pre-operative visit a translator or translating service will be provided

per our usual practice.

Waiver or Alteration of Consent Process (consent will not be obtained, required

information will not be disclosed, or the research involves deception)

NA

Subjects who are not yet adults (infants, children, teenagers)

All of our patients will be under four years of age, thus are considered children and

due to age will be too young to give assent.

Consent/parental permission will be obtained from one parent before any study

procedures are performed.

Example





30) Process to Document Consent in Writing

We will be following HRP-091. See Attachment E – informed consent/parental

permission form. See Attachment F for HIPPA form.

31) Drugs or Devices

All of the drugs being used in this study are approved for use in this study population

by the pharmacy. All except ketorolac are approved by the FDA. However, ketorolac is

widely used in this population with safety data included in the background above. An

IND for ketorolac has been submitted to the FDA for this study. Medications will be

stored and distributed by the Children’s Hospital pharmacy.

References:

1.Tirotta CF, Munro HM, Salvaggio J, et al. Continuous incisional infusion of local anesthetic

in pediatric patients following open heart surgery. Paediatr Anaesth, 2009 Jun;19(6):571-6

2. Penk J, Webb C, Shulman S, Anderson E. Echocardiography in Infective Endocarditis. Pediatric

Infectious Disease Journal 2012 January

3. Jamie Penk, Angira Patel, Amy Lay, Catherine Webb. Longitudinal Strain and Strain Rate in

Patients With Hemodynamically Significant Ventricular Septal Defects.

World Journal for Pediatric and Congenital Heart Surgery. Accepted, pending publication.

4. Hong JY. Fentanyl sparing effects of combined ketorolac and acetaminophen for outpatient inguinal

hernia repair in children. J Urol. 2010 Apr;183(4):1551-5

5. Van Driest SL. Opioid use after cardiac surgery in children with Down syndrome. Pediatr Crit

Care Med. 2013 Nov;14(9):862-8

6. Gupta A. Prospective Randomized Trial of Ketorolac After Congenital Heart Surgery. Journal of

Cariothoracic and Vascular Anesthesia. 2004 August;18 (4):454-457

7. Dawkins T. Saftey of intravenous use of ketorolac in infants following cardiothoracic surgery.

Cardiol Young. 2009;19:105-108

8. Treluyer J. Antipyretic Efficacy of an Initial 30 mg/kg Loading Dose of Acetaminophen Versus a

15 mg/kg maintenance dose. Pediatrics. 2001;108:73

9. Hintze, J. (2013). PASS 12. NCSS, LLC. Kaysville, Utah, USA. www.ncss.com.

Example





10. Frese, W. A., & Eiden, K. (2011). Prescription opioids: Nonmedical use and abuse in older

children. Pediatrics in Review, 32(4), e44-52.

11. Kimberly Eiden, MS, APRN, PCNS-BC. Improving pain assessment and management on pediatric

medical-surgical units. (p. 93-97). In Duncan, J., Montalvo, I., & Dunton, N., NDNQI Case Studies in

Nursing Quality Improvement. (2011). Nursesbooks.org

12. Wernnstrom, B and Reinsfelt, B. (2002). Rectally administered diclofenac (voltaren) reduces

vomiting compared with opioid (morphine) after strabismus surgery in children, Acta

Anaesthesiologica Scandanavica, 46 (4): 430-434.

13. Morton, N.S. and O'Brien, K. (1999). Analgesic efficacy of paracetamol and diclofenac in children

receiving PCA morphine, British Journal of Anaesthesia, 82: 715-717

14. Pickering, A.E., Bridge, H.S., Nolan, J. and Stoddart, P.A. (2002). Double-blinded placebo-controlled analgesic study of ibuprofen or rofecoxib in combination with paracetamol fortonsillectomy in children, British Journal of Anaesthesia. 88(1): 72-77

15. Vittanen, H., Tuominen, N., Vaaraniemi, H., Nikanne, E. and Annila, P. (2003). Analgesic effacy

of rectal acetaminophen and ibuprofen alone or in combination for paediatric day-case adenoidectomy,

British Journal of Anaesthesia, 91: 363-367.

16. Gakhal B1, Scott CS, MacNab AJ. Comparison of morphine requirements for sedation in Down's

syndrome and non-Down's patients following paediatric cardiac surgery. Paediatr

Anaesth.1998;8(3):229-33.

17. Merkel SI1, Voepel-Lewis T, Shayevitz JR, Malviya S.. The FLACC: a behavioral scale for

scoring postoperative pain in young children. Pediatr Nurs 1997 May-Jun;23(3):293-7.

ATTACHMENTS

Attachment A = Standard surgery letter

Attachment B = Study information sheet

Attachment C = Data collection form

Attachment D = Checklist HRP-416

Attachment E = Informed consent/Parental Permission document

Attachment F = HIPPA document

Example

http://www.ncbi.nlm.nih.gov/pubmed?term=Gakhal%20B%5BAuthor%5D&cauthor=true&cauthor_uid=9608968

http://www.ncbi.nlm.nih.gov/pubmed?term=Scott%20CS%5BAuthor%5D&cauthor=true&cauthor_uid=9608968

http://www.ncbi.nlm.nih.gov/pubmed?term=MacNab%20AJ%5BAuthor%5D&cauthor=true&cauthor_uid=9608968

http://www.ncbi.nlm.nih.gov/pubmed?term=Merkel%20SI%5BAuthor%5D&cauthor=true&cauthor_uid=9220806

http://www.ncbi.nlm.nih.gov/pubmed?term=Voepel-Lewis%20T%5BAuthor%5D&cauthor=true&cauthor_uid=9220806

http://www.ncbi.nlm.nih.gov/pubmed?term=Shayevitz%20JR%5BAuthor%5D&cauthor=true&cauthor_uid=9220806

http://www.ncbi.nlm.nih.gov/pubmed?term=Malviya%20S%5BAuthor%5D&cauthor=true&cauthor_uid=9220806

Example: Research Protocol Randomized Controlled Trial

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