Conditions: Neuroblastoma
Keywords: local Injection pain Medication propofol ropivacaine 16-1417
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 56
Healthy volunteers: no

Brief summary:
The purpose of this study is to identify whether or not the addition of a numbing medicine that is injected directly into the site of the bone marrow procedure can reduce pain and the use of opioid pain medication after bone marrow procedures. The addition of this medicine, called ropivacaine, is the experimental part of this study. This is the first time ropivacaine will be directly injected into the bone marrow site at MSKCC Pediatrics.

Detailed description:

Arms:
arm 1: 1st Bone Marrow procedure (BM) Intervention A: propofol first. Then second BM procedure with propofol \& ropivacaine arm 2: 1st BM procedure: Intervention B: propofol \& ropivacaine first. Then second BM procedure with propofol

Interventions: intervention 1: propofol intervention 2: ropivacaine intervention 3: Wong-Baker FACES® Pain Rating Scale intervention 4: Post-procedural quality of life (QOL)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: Nurses will record patient-reported pain scores. intervention 4: None

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
Page 1 of 23 
 
 
OneMSK Sites 
Manhattan 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
RePPAIR –Reducing Procedural Pain and Improving Recovery of Quality of Life in 
Pediatric Neuroblastoma Patients Undergoing Bone Marrow Procedures: A Prospective 
Randomized Cross-over Clinical Trial 
PROTOCOL FACE PAGE FOR 
MSK  THER APEUT IC/DIAG NOSTIC  PROTOCOL 
Principal 
Sara Zarnegar-Lumley, M.D 
Pediatrics 
Investigator/Department: 
Co-Principal 
Ellen Basu, M.D., 
Investigator(s)/Department: 
Ph.D. 
P diatrics 
Investigator(s)/Department: 
Miho Nakajima-Hatano, M.D. 
P
Ugochi             Ogu,              M.D. 
 
Pe 
Michael            Ortiz,            M.D. 
 
Pe 
Katharine          Lange,          M.D. 
 
Pe 
Shakeel           Modak,           M.D. 
 
Pe 
Brian           Kushner,            M.D. 
 
Pe 
Stephen Roberts, M.D. 
P
Nai-Kong V. Cheung, M.D., Ph.D 
diatrics 
diatrics 
diatrics 
diatrics 
diatrics 
diatrics 
diatrics 
diatrics 
idemiology & Biostatistics 
nesthesiology & Critical Care Medicine 
nesthesiology & Critical Care Medicine 
armacy 
Consenting 
Ellen Basu, M.D., Ph.D. 
P
Professional(s)/Department: 
Sara Zarnegar-Lumley, M.D. 
P
Miho Nakajima-Hatano, M.D. 
P
Ugochi Ogu, M.D. 
P
Michael Ortiz, M.D. 
P
Katharine Lange, M.D. 
P
Shakeel Modak, M.D. 
P
Brian Kushner, M.D. 
P
Stephen Roberts, M.D. 
P
Ellen Basu, M.D., Ph.D. 
P
Nai-Kong V. Cheung, M.D., Ph.D 
P
diatrics 
diatrics 
diatrics 
diatrics 
diatrics 
diatrics 
diatrics 
diatrics 
diatrics 
diatrics 
diatrics 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human Subjects 
Education and Certification Program. 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue New York, New York 10065 


Page 2 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................. 4 
3.0 
BACKGROUND AND RATIONALE .................................................................................. 4 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................ 7 
4.1 
Design................................................................................................................................7 
4.2 
Intervention ............................................................................................................................. 7 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .......................................................................... 8 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ..............................................................................8 
6.1 
Subject Inclusion Criteria ....................................................................................................8 
6.2 
Subject Exclusion Criteria ..................................................................................................9 
7.0 
RECRUITMENT PLAN ................................................................................................................... 9 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 9 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 9 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ................................................. 10 
11.0 
TOXICITIES/SIDE EFFECTS ................................................................................................. 11 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 11 
13.0 
CRITERIA FOR REMOVAL FROM STUDY .................................................................... 13 
14.0 
BIOSTATISTICS ............................................................................................................ 13 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration .................................................................................... 15 
16.0 
DAT A M ANAGEMENT ISSUES ..................................................................................... 16 
16.1 
Quality Assurance............................................................................................................ 16 
16.2 
Data and Safety Monitoring ................................................................................................. 17 
17.0 
PROTECTION OF HUMAN SUBJECTS ......................................................................... 18 
17.1 
Privacy ............................................................................................................................. 18 
17.2 
Serious Adverse Event (SAE) Reporting............................................................................. 18 
18.0 
INFORMED CONSENT PROCEDURES................................................................................ 20 
19.0 
REFERENCES .................................................................................................................... 21 
20.0 
APPENDICES ................................................................................................................ 23 


Page 3 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
1.0     PROTOCOL SUMMARY AND/OR SCHEMA 
This is prospective double-arm, randomized cross-over clinical trial that will assess whether the 
addition of a local analgesic agent, ropivacaine, to the standard of care of propofol will reduce 
the percentage of pediatric neuroblastoma patients who require opioid analgesia after bone 
marrow procedures compared to propofol alone. A “bone marrow procedure” will be defined as 
4 bone marrow aspirations and 2-4 bone marrow biopsies. Pediatric neuroblastoma patients will 
receive the standard of care (Intervention A) or the standard of care with the addition of 
subcutaneous and periosteal infiltration of ropivacaine (Intervention B). We will compare the 
percentage of patients requiring post-procedural opioid analgesia in each Intervention as the 
primary endpoint, as well as total opioid consumption, time to first opioid, percentage requiring 
non-opioid analgesia, standardized pain scores and quality of life metrics. Based on statistical 
considerations and extrapolation from an informal needs assessment, we  expect  to  enroll 
enough patients for adequate power within 6 months of study opening. 
 
 
Assess for eligibility 
Randomize 
Allocate to Arm 1 
st 
1   BM procedure 
Intervention A: propofol alone 
Allocate to Arm 2 
st 
1   BM procedure: 
Intervention B: propofol & ropivacaine 
Crossover for second BM procedure 
Intervention B: propofol and 
ropivacaine 
Intervention A: propofol 
alone 


Page 4 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective: 
 
• 
Determine whether there is a reduction in the percentage of pediatric neuroblastoma 
patients undergoing a bone marrow procedure who require post-procedural opioid 
analgesia within 24 hours (+/- 4 hours) of the procedure with the addition of local 
ropivacaine. 
Secondary Objective: 
 
Determine whether there is a difference in: 
 
• 
24 hours (+/- 4 hours) post-procedure opioid consumption in morphine equivalents 
(mg/kg/day) 
• 
Percentage of patients requiring non-opioid analgesia within 24 hours (+/- 4 hours) of 
procedure 
• 
Standardized pain scores (Wong-Baker FACES®    Scale) 
• 
Time to first opioid medication 
• 
Short-term quality of life 
• 
Adverse outcomes with the addition of local ropivacaine 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Background 
 
Pediatric neuroblastoma patients undergo bone marrow aspiration (BMA) and biopsy 
(BMB) procedures as a part of their extent of disease evaluation at regular intervals during 
treatment and surveillance. Many studies of both pediatric and adult oncology patients have 
shown that bone marrow aspirations and biopsies are painful procedures .1-3 Not only do patients 
report procedural pain, but health care professionals and parents also acknowledge that these 
procedures are painful. 
A study asked Italian Pediatric Hematology-Oncology health 
professionals (medical directors, physicians, nurses, psychologists) their perceptions of 
procedural pain and found that providers considered BMA and BMB to be above 5 on a scale of 
0-10 in 97.5% and 99.5% of cases, respectively.4 Another study looking at pediatric oncology 
patients and their parents showed procedures to be the most frequent cause of distress.5 
Exposure to repeated painful procedures has been found to exacerbate anxiety and distress in 
children.6,7 
The American Academy of Pediatrics (AAP) developed a report in 1990 stating that 
strategies to reduce pain and anxiety are integral  to the care of pediatric oncology patients.8 
Pediatric oncology departments such as the Memorial Sloan Kettering Cancer Center (MSKCC) 
Department of Pediatrics have adopted institutional practices in an effort to reduce bone-marrow 
procedure-related pain and anxiety. The standard of care at MSKCC for pediatric patients 
undergoing BMA and BMB is to receive propofol. While propofol has amnestic and anesthetic 
properties, it lacks any analgesic properties.9 


Page 5 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
3.2 
Needs assessment 
 
In order to better understand bone marrow procedural pain for pediatric patients  at 
MSKCC, we conducted a needs assessment of 25 pediatric patients and 1 adult patient, asking 
about their experience with BMA and BMB, done with the standard of care administration. We 
found that 8/26 = 30.7% of patients required opioid analgesia within 24 hours of the procedure - 
7/8 post-procedurally and one patient with systemic opioid given with anesthesia. We also 
discovered that many children had persistent pain and reduced activity level the day following 
the procedure - 12/26 = 46% and 8/26 = 31%, respectively. Based on this data, we identified a 
need to improve the experience of pediatric neuroblastoma patients with bone marrow 
procedures. Although there are no standard clinical guidelines, the AAP recommends an 
individualized and age-based approach and encourages the use of both non-pharmacologic and 
pharmacologic interventions that includes both anesthesia and analgesia.
8 We also conducted 
an informal survey of seven other major pediatric oncology centers and found that each of these 
centers uses analgesia, either systemic or local, in addition to general anesthesia for bone 
marrow biopsy procedures. 
3.3 
Rationale 
 
The purpose of this study is to investigate whether subcutaneous and periosteal 
infiltration of a local anesthetic agent, ropivacaine, will reduce the percentage of  patients 
requiring post-procedural opioid analgesia and improve quality of life in the day following the 
procedure. A similar study recently demonstrated that topical analgesia for lumbar punctures 
reduced the amount of propofol used in pediatric oncology patients.9 However, no study has 
been done to investigate the efficacy of local analgesia in combination with propofol for bone 
marrow procedures. For this reason, a trial evaluating the effect of the addition  of  local 
analgesia is both justified and necessary. Local analgesia acts to limit the initiation of 
nociceptive pathways prior to the traumatic insult, in this case, subcutaneous and periosteal 
infiltration by a bone marrow aspiration or biopsy needle. Ropivacaine is an example of a local 
anesthetic agent that blocks both the initiation and conduction of nerve impulses by decreasing 
the neuronal membrane‟s permeability to sodium ions.10 It is an amino-amide local anesthetic 
that is a pure S-(-)-enantiomer with lower lipid solubility than racemic mixtures; these features 
allow ropivacaine to have a higher safety profile with less cardiovascular and central nervous 
system toxicity than racemic lidocaine and bupivacaine.10 Its onset of action is listed as “fast” 
with infiltration. i.e. within 3 to 15 minutes.11 Its duration of action is 3 to15 hours.11 Therefore, 
due to its effect on nociceptive pathways, rapid onset and moderate duration of action while 
maintaining a low toxicity profile, ropivacaine is a reasonable option for local analgesia for bone 
marrow procedures. This  is  the first time ropivacaine will be directly injected into the bone 
marrow site at MSKCC Pediatrics. 
 
Primary and secondary outcome measures were carefully selected after reviewing 
pediatric pain literature. Within pain clinical trials, analgesic efficacy can be measured by the 
ability to reduce or eliminate the need for rescue analgesia. “Rescue analgesia-sparing” has 
been identified as practical and feasible surrogate primary endpoint 12,13. A systematic review of 


Page 6 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
33 pediatric trials that used opioid as the study drug showed that percentage requiring rescue 
medication was a useful outcome measure in small procedures when the time and amount of 
rescue medication needed was low relative to surgical procedures.13 This will be the primary 
outcome in the current study. Time to first rescue opioid and total opioid dose were alternate 
outcomes that are commonly studied;13 in this protocol, they are selected as secondary 
outcomes. Relative differences in pain scores, either over time or with an intervention, are 
frequently used as an outcome measure in pain clinical trials and will be a secondary outcome 
in this study.1 2,15 We selected the Wong-Baker FACES® Pain Rating Scale (WBFPRS) 
(Appendix 1) for this study because it is a validated scale intended for use for our patient 
population.14,15 Advantages of this scale include its reliability over time, ease of administration, 
and children have been shown to prefer this scale over others.
15 It is routinely used clinically at 
MSKCC Department of Pediatrics. An extensive review of various pediatric pain scales 
concluded that many of the pain scales in use are equivalent, and encouraged the use of a 
scale familiar to the institution for clinical purposes.16 
This study will use a pain management algorithm for consistency in post-procedural pain 
management (Appendix 2.1 and 2.2). This algorithm relies on the WHO Analgesic Ladder for 
escalation of therapy. We referred to the previously mentioned needs assessment as well as 
commonly used categories for pain severity to determine the interventions starting from heat 
packs, moving to the non-opioid analgesic: acetaminophen and escalating to a low dose strong 
opioid for moderate pain as defined as pain greater than but not equal to a 4 on the WBFPRS. 
The decision to use a low dose strong opioid instead of a weak opioid as suggested by the 
WHO Analgesic Ladder is based both on institutional practice and recent multi-center study in 
patients with cancer and moderate pain demonstrating better pain relief with a low dose strong 
opioid instead of weak opioid.17 
Groups such as the Pediatric Initiative on Methods, Measurement, and Pain Assessment 
in Clinical Trials (PedIMMPACT) have recommended multidimensional outcome domains and 
measures for pediatric pain clinical trials.15,18 The PediIMMPACT consensus guidelines for 
investigators conducting clinical trials addressing acute pain include 6 domains including pain 
intensity, physical recovery and emotional response.18 We aim to incorporate these additional 
domains into this study by utilizing a quality of life metric adapted from a validated pain 
interference inventory. We will use an abbreviated version of the National Institutes of Health 
(NIH) Patient Reported Outcomes Measurement Information System (PROMIS®) Parent Proxy 
measure for pain interference.19,20  This full item bank has been validated for use by the parents 
of 8-17 year olds and has been extended for use in 5-7 year olds.19,20 We will extrapolate its use 
for our patient population and have selected 4 of the 13 items from the item bank to assess how 
procedural pain affects physical recovery in the context of activity and sleep as well as social 
and emotional functioning (Appendix 3). 
 
This study is  clinically  relevant in the care of pediatric neuroblastoma patients who 
undergo repeated painful procedures in an effort to optimize pain alleviation and reduce the 
potential for  distress  related to procedures. We specifically selected pediatric  neuroblastoma 


Page 7 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
patients since they undergo repeated bone marrow procedures during the course of their care 
and these procedures often involves four sites. Therefore, it would benefit these young patients 
to identify pain associated with recurrent procedures and optimize its management. We have 
selected a single patient population to allow for better standardization in our assessment and 
outcome measures. As a result of this study, we hope to improve standard institutional practice 
for any pediatric patient undergoing a bone marrow procedure. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This study will be a prospective double-arm randomized controlled single-blinded crossover 
design. The two interventions are: 
 
• 
Intervention A: MSKCC standard of care 
• 
Intervention B: MSKCC standard of care plus local analgesia with ropivacaine. 
 
Pediatric neuroblastoma patients will be enrolled based on eligibility criteria and randomized to 
one of two arms representing a specific sequence of each intervention. 
 
• 
Arm 1 (AB): standard of care only during the first procedure, then standard of care plus 
ropivacaine during the second procedure. 
• 
Arm 2 (BA): Standard of care plus ropivacaine during the first procedure, then standard 
of care only during the second procedure. 
 
Each patient will serve as his or her own control. The patients and parents will be blinded to the 
study arm. The procedural attending physicians and pharmacy will have to coordinate and 
administer the treatment agent (ropivacaine), and they will not be blinded to the study arm. The 
registered nurse (RN) in the procedure room  will similarly not be blinded to the study. The 
Pediatric Day Hospital (PDH) Procedure Recovery Room (PRR) RNs will be blinded as they will 
also be responsible for data collection as described below. The study investigators who will be 
responsible for post-procedural data collection will similarly be blinded to the study combination. 
 
4.3 
Intervention 
 
Intervention A: The standard of care agent will be administered intravenously by an 
anesthesiologist as per current institutional practice. An empty decoy syringe will be provided by 
the pharmacy and taken to the procedure room by appropriate staff as sometimes parents 
accompany their children into the procedure room prior to anesthesia administration. The empty 
syringe will be clearly marked and discarded. 
 
Intervention B: The standard of care agent will be administered intravenously by an 
anesthesiologist as per current institutional practice. Once the anesthetic effect is achieved as 
determined by the anesthesiologist, the proceduralist physician will inject subcutaneous and 
periosteal ropivacaine prior to bone marrow aspiration and biopsy at each site (bilateral anterior 
and posterior iliac crests). Ropivacaine will be provided by the MSKCC PDH Pharmacy and will 


Page 8 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
be administered at standard dosing of 2mg/kg of a 0.5% solution (5mg/ml) and delivered to the 
procedure room by appropriate staff. 
 
The following process occurs after every procedure. Patients will complete the procedure and 
recover in the PRR for an approximate time of 30 to 90 minutes. In the PRR, trained RNs who 
are blinded to the study combination will assess patient pain based on a validated self-report 
pain scale and administer pain medication when necessary based on a standard pain 
management algorithm (Appendix 2.2). After recovery in the PRR, patients will be discharge 
home. Parents/parents will assess their child‟s pain on a validated self-report pain scale and 
administer pain medication when necessary based on a standard pain management algorithm 
(Appendix 2.2). 
 
5.0     THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 Study agent: ROPIVACAINE11,  25-28 
 
5.1.1 Source and Pharmacology: A local anesthetic. Mechanism of action is by 
blockade of both the initiation and conduction of nerve impulses by  decreasing the 
neuronal membrane's permeability to sodium ions, which results in inhibition of 
depolarization with resultant blockade of conduction. The half-life is 5 to 7 hours when 
used as an epidural infusion and has a terminal half-life of 111 ± 62 minutes. It is 
metabolized by the liver and excreted through the urine. 
5.1.2 Formulation and Stability: Supplied in single-dose containers in 2 mg/ml (0.2%), 
5 mg/ml (0.5%), 7.5 mg/ml (0.75%) and 10 mg/ml (1%). Store at 20°C to 25°C. 
In this study, the PDH pharmacy will prepare four (4) syringes from a single vial of the 
5mg/ml (0.5%) ropivacaine at a dose of 2mg/kg/patient divided evenly into 
0.5mg/kg/syringe with a maximum dose of a single 20 ml vial = 100 mg. 
5.1.3 Guidelines for Administration: Doses are administered via local infiltration. 
 
5.1.4 Supplier: Commercially available. See package insert for further information. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
• 
Diagnosis of neuroblastoma as defined by the International Neuroblastoma Risk 
Group Staging System (INRGSS)
22
 
• 
3 - 18 years of age 
• 
Patient has had prior bone marrow procedures 
• 
English speaking 


Page 9 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
6.3 
Subject Exclusion Criteria 
 
• 
History of allergy to investigational agent: ropivacaine or other amino amide 
analgesics 
• 
History of allergy to standard agent: propofol 
• 
Chronic daily opioid requirement 
• 
Lansky/Karnofsky Score < 60 
• 
Inability to comply with protocol requirements including refusal to forego pre- 
procedural opioid use 
• 
Patient is receiving additional potentially painful interventions (e.g. central line 
insertion/removal) concurrent with the bone marrow procedure 
7.0       RECRUITMENT PLAN 
 
All consecutive eligible patients will be offered participation in this study by a physician in the 
Department of Pediatrics at Memorial Sloan Kettering Cancer Center. No patients will  be 
identified by chart review or direct advertising. Every week, the Neuroblastoma Personal Office 
Assistant (POA) will circulate an email to the consenting investigators on this study that includes 
the name and medical record number of every neuroblastoma patient receiving a bone marrow 
procedure in the following week. Every  day, the consenting investigators on this study  are 
included on an email notice of new patients being seen by the Pediatric Neuroblastoma service. 
In this way, potential study participants will be identified for recruitment. The consenting 
professional will be responsible for explaining the study and obtaining written informed consent. 
Participants in the study will receive neither financial payment nor  reimbursement.  Eligible 
patients of all genders and racial groups will be equally offered enrollment in the study. 
8.0     PRETREATMENT EVALUATION 
 
Before each bone marrow procedure, the patient will be re-evaluated for continued eligibility. If 
the patient does not meet eligibility at the time of the scheduled bone marrow procedure, the 
intervention may be postponed until a subsequent bone marrow procedure when the patient 
meets eligibility criteria. 
 
9.0     TREATMENT/INTERVENTION PLAN 
 
Each enrolled patient will serve as his/her own control. On two  bone  marrow  procedures, 
patients will receive either intervention A or B. 
Each procedure will occur at approximately a two to four month interval. The timing of bone 
marrow procedures will be determined by the patient's clinical course. 
In Intervention A, standard of care dosing and administration will be at the discretion of the 
anesthesiologist according to standard of care in the Department of Anesthesia at Memorial 
Sloan Kettering Cancer Center. In Intervention B, 2mg/kg of 0.5% ropivacaine will be drawn into 


Page 10 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
pre-filled syringes with a maximum dose of 20ml = 100mg. The physician performing bone 
marrow procedures will administer ropivacaine. 
 
Ropivacaine will be injected into the subcutaneous tissue in an area approximately 1 cm in 
diameter. Subsequently, the ropivacaine will be administered to the periosteum in an area 
approximately 2-3 cm in diameter. Four pre-filled syringes will be provided and proceduralist 
physicians will be advised to administer one full syringe volume for each site (0.5mg/kg) with 
equal distribution between the subcutaneous and periosteal injection per site. Currently, 
propofol alone is the standard of care in the Department of Pediatrics  at  Memorial  Sloan 
Kettering Cancer Center. While ropivacaine is a well described local anesthetic agent,  the 
addition of ropivacaine to propofol to minimize post procedure pain is an experimental 
intervention. 
 
10.0   EVALUATION DURING TREATMENT/INTERVENTION 
 
Pain will be assessed in the post-anesthesia care unit (PRR). Directly upon emergence from 
anesthesia after the procedure and every 15 minutes subsequently, PRR nurses will use the 
Wong-Baker FACES® Pain Rating Scale (Appendix 1). Nurses will record patient-reported pain 
scores and administered analgesia in the Electronic Medical Record (EMR). Analgesia doses 
will be recorded at the time of administration. The PRR nurses will follow a standardized post- 
procedural algorithm (Appendix 2.1). Patients will recover in the PRR for approximately 30 to 90 
minutes prior to discharge from MSKCC. In some instances, patients will be discharged from the 
PRR to the Neuroblastoma Clinic in the Pediatric Day Hospital (PDH). We anticipate that all 
patients will be discharged from MSKCC before 6 hours from the end of their procedure. In the 
unexpected case that a patient is admitted to the hospital for any reason during the study period 
(28 hours post-procedure), study investigators will provide the inpatient RN with the post- 
procedural opioid management algorithm (Appendix 2.1). Only if the admission is due to a study 
related life-threatening grade 4 toxicity, will the admitted patient be removed from the study as 
described in Section 13.0. 
Families will be provided a 2 part, 12 item written questionnaire with 4 items and 8 items in each 
part, respectively (Appendix 3). They will be asked to complete Part 1 at 6 hours (+/- 1 hour) 
and Part 2 at 24 hours (+/- 4 hours) following the procedure. This questionnaire will have items 
regarding pain intensity and management to be answered at both time points. Families will be 
asked to follow a post-procedure pain management plan (Appendix 2.2). Post-procedural quality 
of life (QOL) will be assessed using a four-item questionnaire (Appendix 3) adapted from the 
NIH PROMIS® Parent Proxy Item Bank for Pain Interference and approved for use by the 
MSKCC Behavioral Research Methods Core Facility. These four questions will include  the 
domains of physical recovery, emotional and social functioning. QOL will be assessed about 24 
hours (+/- 4 hours) following the procedure. Principal Investigators,  Co-Investigators, 
Investigators or appropriate clinic staff will call families 24-72  hours  following  procedure  to 
obtain answers to the questionnaire. 


Page 11 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 
DEFINITION OF TOXICITIES: 
 
• Common - Happens to 20-100 patients out of every 100 
• Occasional - Happens to 4-20 patients out of every 100 
• Rare - Happens to 3 or fewer patients out of every 100 
 
11.2 LOCAL INFILTRATION OF ROPIVACAINE11,  25-28 
 
Common 
Occasional 
Rare 
None 
None 
• 
Allergic reaction with any route of 
administration 
• 
Arrhythmia with intravascular 
administration* 
• 
Seizure with intravascular 
administration* 
*Reported with inadvertent 
intravascular administration 
 
 
12.0   CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1 To assess primary objective, we will determine and compare for each study intervention 
the percentage of patients who required opioid analgesia between the time of bone marrow 
procedure and 24 hours (+/- 4 hours) after the procedure. 
12.2 For the secondary objectives: 
 
a) We will determine and compare for each study intervention the percentage of patients who 
used any non-opioid analgesia within 24 hours (+/- 4 hours) after bone marrow procedure. 
b) We will calculate and compare for each study intervention the total dose of opioid 
consumption within 24 hours (+/- 4 hours) of the bone marrow procedure using mg/kg/day 
morphine equivalent. 


Page 12 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
 
Drug 
IV conversion 
factor 
PO conversion 
factor 
Morphine 
10mg 
30mg 
Fentanyl 
0.250mg 
(250mcg) 
ー 
Hydromorphone 
2mg 
8mg 
Oxycodone 
ー 
20mg 
Oxymorphone 
1mg 
10mg 
Codeine 
75mg 
130mg 
Methadone 
1mg 
2mg 
Hydrocodone 
ー 
30mg 
 
 
c) We will also determine the time to the first opioid administration. The starting point for this 
time will be the time of transfer to the PRR which will be documented by the PRR RN. This time 
will be recorded on the parent worksheet by the PRR RN. 
d) We will assess standardized pain scores at 3 time points: (1) the maximum recorded pain 
score in the PRR, (2) at 6 hours (+/-1 hour) and (3) 24 hours (+/- 4 hours) after the bone marrow 
procedure. Pain scores 2 and 3 will be recorded by the parent after discharge from MSKCC. We 
will use the following validated pain scales: Wong-Baker FACES® Pain Rating  Scale  for 
patients between 3-18 years of age for patient-reported pain when asked by post-anesthesia 
recovery room nurses upon emergence from anesthesia and by inpatient nurses or family 
members in the outpatient setting upon discharge from the post-anesthesia recovery unit. We 
will compare pain scores between study interventions. 
 
e) The QOL metric is a brief instrument that will assess post-procedural quality of life within 24 
hours (+/- 4 hours) of the bone marrow procedure. This instrument assesses the following 
domains: sleep, physical functioning, emotional functioning and social functioning. This brief 
measurement tool will be adapted from a validated metric for pain interference in pediatric 
patients: NIH PROMIS® Parent Proxy Item Bank v1.0 – Pain Interference, which is a 13-item 
questionnaire. However, given that our study has rapid, frequent assessments, we will use an 


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abbreviated version for feasibility purposes and to minimize participant burden. Parents will be 
asked to assess QOL at 24 hours (+/- 4 hours) following the procedure by completing the 
questionnaire at that time. Principal Investigators or Research Staff will call families 24-72 hours 
following procedure to obtain answers to survey. This phone call will be for the purposes of data 
collection only and not for survey administration. 
f) Patients will be under medical observation during the expected time when most adverse 
effects from ropivacaine will be experienced. Families will be advised to call the hospital for any 
symptoms beyond this time period. 
 
13.0   CRITERIA FOR REMOVAL FROM STUDY 
 
a) A patient will come off study if the patient/parent administers an opioid or any analgesic within 
24 (+4 hours) after the bone marrow procedure that is not in accordance to the algorithm 
provided to them. 
 
b) If at any time the patient develops life-threatening grade 4 toxicity during the study period, 
he/she will be removed from study. 
 
c) If a patient is found to be ineligible for two sequential bone marrow procedures as designated 
in Section 6, the patient will be removed from study. 
 
d) The patient may withdraw from study at any time if the patient/parent desires. 
 
14.0   BIOSTATISTICS 
 
This is a randomized two arm cross-over study investigating the effectiveness of the 
addition of ropivacaine to the standard of care on pain among pediatric neuroblastoma patients 
undergoing repeated procedures. The two drug combinations are standard of care (Intervention 
A) or standard of care plus ropivacaine (Intervention B, see Section 4.1). Patients will be 
randomized to either Arm 1 (AB sequence) or Arm 2 (BA sequence, see Figure in Section 1) to 
determine whether standard of care or standard of care plus ropivacaine will be administered in 
the first of two procedures. Patients will cross over during the second procedure. Sample size 
calculation is based on the primary outcome: the proportion of patients requiring post-procedural 
opioid analgesia (“rescue opioids”) within 24 hours (+/- 4 hours) post procedure. A needs 
assessment conducted in pediatric patients at MSKCC suggests that this proportion is about 
30% under Intervention A (standard of care). We plan to enroll 50 patients (total of 100 
procedures). 
 
This is a crossover study in which we assume that there will be no period effect (i.e., if 
patient‟s response in the subsequent procedure is affected by the drug from the first procedure). 
Due to the estimated two month interval between the two procedures and the duration of action 
of less than 15 hours for either drug combinations, we can assume no period effect. The primary 
outcome (whether the patient received rescue opioids) will be evaluated with GEE (generalized 
estimating equations) for binary data with logit link function clustered by patients 23. The model 


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Approval date: 30-Jan-2018 
 
 
 
 
will include the drug indicator, procedure order, and an exchangeable correlation structure to 
address the correlation between multiple observations from the same patient. GEE has the 
advantage of being able to include data from only one of a patient‟s two procedures, in order to 
accommodate the (rare) case in which the patient drops out / withdraws prior to the second 
procedure. With complete data, however, this approach simplifies to a McNemar‟s test. The 
power and sample size calculations will be based on McNemar‟s test. 
 
There is limited publication on the correlation among longitudinal measures of pediatric 
pain scores, particularly those reported by the parent instead of the child; one study reported 
correlation of 0.63 between times 1 and 2 (6 months apart) of parent-proxy reported pain 
scores
24. Assuming a conservative correlation of 0.4 between the two outcomes (from two 
procedures) of the same patient, a sample size of 45 patients will allow 80% power to detect an 
absolute difference of 20% in proportions between the treatments at an alpha level of 0.05 
(assuming rates of 30% in Intervention A and 10% in Intervention B). This sample size allows 
for an interim assessment of futility at the half way point (23 out of 45 patients with both 
procedures completed). If p>0.703, then the trial will stop for futility; if p≤0.703 then the study 
will continue until completion. The target enrollment of 50 patients allows for an anticipated 
drop-out rate (due to any reason) of 10% in the power analysis calculation. This power 
calculation was generated using the proc power procedure in SAS 9.4, specifying paired 
proportions and correlation for McNemar exact conditional test. Based on an accrual rate of 15 
patients in month 1, 10 patients in months 2 and 3 and 5 patients per month in months 4, 5, and 
6, we anticipate completion of enrollment in 6 months. 
 
The potential variability between attending physicians performing the procedure will be 
explored by including specification of patients nested within physicians as clusters in the GEE 
models. Other potential factors to include in the GEE models as fixed effects may include total 
number of biopsies and aspirations per procedure and/or different dose of ropivacaine. 
 
Secondary outcome of standardized cumulative opioid consumption within 24 hours (+/- 
4 hours) (morphine equivalents, mg/kg/day) will be summarized and compared between the two 
drugs using linear GEE models with the same factors as described above, including of the other 
potential factors identified from the analysis of the primary outcome. Additionally, time to first 
opioid use within the first 24 hours (+/- 4 hours) post procedure will be estimated using the 
Kaplan-Meier method and compared between the two drugs using the clustered logrank test. 
This is appropriate as patients may never require any opioids and will hence be censored at 24- 
hours. The proportion of patients requiring non-opioid analgesia within 24 hours (+/- 4 hours) of 
procedure will be compared between the two drugs using GEE (for binary data) as described for 
the primary outcome. 
 
Post-operative pain reported on the Wong-Baker FACES® Pain Rating Scale (converted 
to scale of 0-10) will be measured at 3 time points: in the PRR, at 6 hours (+/- 1 hour) and 24 
hours (+/- 4 hours) after the procedure. If more than one pain score is recorded during the PRR, 


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Approval date: 30-Jan-2018 
 
 
 
 
then the maximum pain score during the PRR will be included in analyses. Pain scores will be 
compared between the two drugs using a linear GEE model with drug indicator, procedure order 
and the exchangeable correlation structure for the 3 time points. The GEE models appropriately 
account for correlation among within-individual repeated measures, sequence of drugs, and 
allow for missingness (i.e., if the respondent does not provide complete follow-up data). Short- 
term QOL and activity level will be reported based on the (NIH PROMIS® Parent Proxy Item 
Bank v1.0 – Pain Interference) as individual items. QOL measures will only be recorded once at 
24-hours post-procedure. We will use a linear GEE model to analyze the differences in QOL 
item-measures between the two drugs. Drug indicator and procedure order will be included as 
covariates. Overall rate of any complications or major adverse events and the rates of specific 
adverse outcomes related to the addition of local ropivacaine will also be compared between 
drugs using GEE (for binary data) These analyses are exploratory because they are of 
secondary interest and we do not have prior data to estimate statistical power. 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.2 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan Kettering Cancer Center. PPR is available Monday through Friday from 8:30am 
– 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic Registration 
System (http://ppr/). The completed signature page of the written consent/RA or verbal 
script/RA, a completed Eligibility Checklist and other relevant documents must be uploaded via 
the PPR Electronic Registration System. 
 
The study arm will be assigned by randomization at the time of study registration. 


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Approval date: 30-Jan-2018 
 
 
 
 
16.0   DATA MANAGEMENT ISSUES 
 
Data to be collected: 
Age 
Diagnosis 
Gender 
Opiates used during procedure 
Any analgesia used through 24 hours (+/- 4 hours)post procedure 
Pain scores 
Quality of life scores 
 
Data will be collected via chart review post procedure, and personal phone calls to 
families/patients on the day after the procedure. 
 
Data will be collected on a secured database and stored on an MSKCC server. Data will not be 
stored on personal devices or removed from MSKCC. 
 
We expect to achieve the following accrual rate 
Month 1: 15 patients 
Months 2, 3: 10 patients/month 
Months 4, 5, 6: 5 patients/month 
We will need approximately 6 months to achieve our enrollment goal based on power analysis. 
 
Given that each patient will complete two bone marrow procedures and there can be up to four 
months between procedures, we expect a study duration of approximately 10 months for all 
enrolled patients to complete both interventions. 
 
16.1 
Quality Assurance 
 
Quality assurance is the responsibility of PI and Study team it will be achieved by frequent 
review of the data. 
 
The data will be obtained from medical records and personal phone calls. The clinic team will 
educate the procedure room/recovery room on validated pain scales to ensure accurate capture 
of patients pain. The clinic team will also provide families with written validated pain scales to 
reference at home as well as a written form of questions to be asked on phone call. 
 
Eligibility will be verified for all enrolled patients by secondary review of the eligibility checklist. 
This will be completed by the data team. 
Registration reports will be generated by the RSA to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates  and extext  and accuracy of evaluations  and  follow-up will be 


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monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team on an ongoing basis. 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the  National Cancer Institute in September 2001. The plans  address  the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for 
Data 
and 
Safety 
Monitoring 
of  Clinical  Trials” 
which 
can 
be 
found 
at:  
http://cancertrials.nci.nih.gov/researchers/dsm/index.html.  The  DSM  Plans  at  MSKCC  were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety 
Monitoring 
Plans 
 can 
be  
found 
on 
the  
MSKCC 
 Intranet 
at:  
https://one.mskcc.org/sites/pub/clinresearch/Pages/protocol-review-committees/data-and-  safety-
monitoring-committee.aspx. 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center‟s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its level 
of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and the 
monitoring procedures will be established at the time of protocol activation. 
Institutional monitoring plan for phase I and phase II trials: Memorial Sloan-Kettering Cancer 
Center (MSKCC) has established standard procedures for data safety monitoring of clinical 
research. For Phase II trials, these procedures include consideration of accrual rates, toxicity, 
adherence to dose-escalation schedules, adverse event notification and data recording. 
Therapeutic responses are logged on a central database and approximately 50% are reviewed 
by an independent committee. An annual report of the trial‟s progress is sent to the IRB. All of 
the procedures for Phase II studies outlined in MSKCC‟s policy are applicable to the current trial 
and will be followed by the investigators. The analysis of safety will include all patients who 
receive at least one dose of study medication. Adverse events, including all toxic effects of 
treatment, will be tabulated individually, and summarized by body system, according to study 
medication, and according to severity or toxicity grade. Laboratory data will be tabulated and 
summarized by descriptive statistics, as well as on the basis of MSKCC specified normal range. 


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IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
17.0   PROTECTION OF HUMAN SUBJECTS 
 
Patient participation in this protocol is completely voluntary. Patients will be provided with 
documentation explaining the protocol rationale and objectives, as well as its potential risks, 
benefits, toxicities/side effects, inconveniences and financial costs/burdens. Alternative options 
for therapy will also be discussed. Patients who choose to participate will sign an informed 
consent conforming to the MSKCC IRB guidelines. The protocol will protect the rights and 
privacy of all participants. Children, adolescents and young adults are eligible for this study. 
Patients of both sexes and all ethnic/racial backgrounds  are eligible for this study. Alternative 
treatments are available and will be discussed with the patients and/or legal guardian. 
 
It is not known whether this treatment will improve the overall survival  of  the  patient.  The 
potential risks of this therapy are described in Section 11 of this protocol and may outweigh the 
potential benefits in an individual patient. Reporting of serious adverse  events  is  found  in 
section 17.2. 
 
Costs: Patients are responsible for the costs of physician visits and usual laboratory tests, 
hospitalizations, radiographic studies, drug administration and outpatient care. If there is an 
injury as a result of the research study, emergency care, hospitalization, and outpatient care will 
be made available by Memorial Hospital and billed to the patient as part of the  medical 
expenses. No money will be provided by Memorial Hospital as compensation for research- 
related injury.  Patients will not be paid for taking part in this study. 
17.1 
Privacy 
 
It is the responsibility of the Research Staff to ensure that protocol subjects  received  the 
Center‟s Notice of Privacy Practices. If the subject has not received one, MSK personnel must 
provide a Notice of Privacy Practices and obtain acknowledgment before the subject 
participates in the study. 
 
MSK‟s Privacy Office may allow the use and disclosure of protected health information pursuant 
to a completed and signed Research Authorization form. The use and disclosure of protected 
health information will be limited to the individuals described in the Research Authorization form. 
A Research Authorization form must be completed by the Principal Investigator and approved 
by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 


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IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is  not considered 
an SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant‟s last investigational treatment or intervention. 
Any events that occur after the 30-day period and that are at least possibly related to 
protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of 
Serious Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar days 
of the event. The IRB requires a Clinical Research Database (CRDB) SAE report be 
submitted electronically to the SAE Office as follows: 
 
Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All other 
reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‟s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 


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IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
o A explanation of how the AE was handled 
o A description of the subject‟s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The PI‟s signature and the date it was signed are required on the completed report. 
 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 


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19.1 
REFERENCES 
 
1. Vanhelleputte P, Nijs K, Delforge  M,  Evers  G,  Vanderschueren  S.  Pain  during 
bone marrow aspiration: prevalence and prevention. J Pain Symptom Manage. 2003 
Sep;26(3):860-6. 
2. Shokrani  O,  Saghaei  M,  Ashrafi  F,  Sadeghi  A.   Electrical   stimulation   of 
acupuncture points for analgesia during bone marrow aspiration and biopsy: A 
randomized double-blind placebo-controlled trial. Adv  Biomed  Res.  2014  May 
28;3:125. 
3. Lidén Y, Landgren O, Arnér S, Sjölund KF, Johansson E.  Procedure-related  pain 
among adult patients with hematologic malignancies. Acta Anaesthesiol Scand. 2009 
Mar;53(3):354-63. 
4. Po' C,  Benini   F,  Sainati   L,  Frigo  AC,  Cesaro  S,  Farina   MI,  Agosto   C.  The 
opinion of clinical staff regarding painfulness of procedures in pediatric hematology-
oncology: an Italian survey. Ital J Pediatr. 2011 Jun 10;37(1):27. 
5. Hedström M, Haglund K, Skolin  I,  von  Essen  L.  Distressing  events  for  children 
and  adolescents  with  cancer:  child,  parent,  and  nurse   perceptions.   J   Pediatr 
Oncol Nurs. 2003 May-Jun;20(3):120-32. 
6. Chen E, Zeltzer LK, Craske MG, Katz ER. Children's memories for painful cancer 
treatment procedures: implications for distress. Child Dev. 2000 Jul-Aug;71(4):933-47. 
7. Hjortholm  N,  Jaddini  E,  Hałaburda  K,  Snarski  E.  Strategies   of   pain   reduction 
during the bone marrow biopsy. Ann Hematol. 2013 Jan;92(2):145-9. 
8. Zeltzer LK, Altman A, Cohen D, LeBaron S, Munuksela EL, Schechter NL. American 
Academy of Pediatrics Report of the Subcommittee on the Management of Pain 
Associated with Procedures in Children with Cancer. Pediatrics. 1990 Nov;86(5 Pt 
2):826-31. 
9. Whitlow PG, Saboda K, Roe DJ,  Bazzell  S,  Wilson  C.  Topical  analgesia  treats 
pain and decreases propofol use during lumbar punctures in a randomized pediatric 
leukemia trial. Pediatr Blood Cancer. 2015 Jan;62(1):85-90. 
10. De Negri P, Ivani G, Tirri T, Del Piano AC. New local anesthetics for pediatric 
anesthesia. Curr Opin Anaesthesiol. 2005 Jun;18(3):289-92. 
11. Ropivacaine. Lexicomp Online, Pediatric & Neonatal Lexi-Drugs, Hudson, Ohio: Lexi- 
Comp, Inc; Accessed January 30, 2016. 
12. Kossowsky J, Donado C, Berde CB. Immediate rescue designs in pediatric analgesic 
trials: a systematic review and meta-analysis. Anesthesiology. 2015 Jan;122(1):150-71. 
13. Berde CB, Walco GA, Krane EJ, Anand KJ, Aranda JV, Craig KD, Dampier CD, Finkel 
JC, Grabois M, Johnston C, Lantos J, Lebel A, Maxwell LG, McGrath P, Oberlander TF, 
Schanberg LE, Stevens B, Taddio A, von Baeyer CL, Yaster M, Zempsky WT. Pediatric 
analgesic clinical trial designs, measures, and extrapolation: report of an FDA scientific 
workshop. Pediatrics. 2012 Feb;129(2):354-64. 
14. Wong-Baker FACES Foundation (2015). Wong-Baker FACES® Pain Rating Scale. 
Retrieved [December 21, 2015] with permission from http://www.W ongBakerFACES.org. 


Page 22 of 23 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1417 A(3) 
Approval date: 30-Jan-2018 
 
 
 
 
15. Stinson JN, Kavanagh T, Yamada J, Gill N, Stevens B. Systematic review of the 
psychometric properties, interpretability and feasibility of self-report pain intensity 
measures for use in clinical trials in children and adolescents. Pain. 2006 Nov;125(1- 
2):143-57. 
16. Tomlinson D, von Baeyer CL, Stinson JN, Sung L. A systematic review of Faces scales 
for the self-report of pain intensity in children. Pediatrics. 2010 Nov;126(5):e1168-98. 
17. Bandieri E, Romero M, Ripamonti CI, Artioli F, Sichetti D, Fanizza  C,  Santini  D, 
Cavanna L, Melotti B, Conte PF, Roila F, Cascinu S, Bruera E, Tognoni G, Luppi M. 
Randomized Trial of Low-Dose Morphine Versus Weak Opioids in Moderate Cancer 
Pain. J Clin Oncol. 2015 Dec 7. 
18. McGrath PJ, Walco GA, Turk DC, Dworkin RH, Brown MT, Davidson K, Eccleston C, 
Finley GA, Goldschneider K, Haverkos L, Hertz SH, Ljungman G, Palermo T, Rappaport 
BA, Rhodes T, Schechter N, Scott J, Sethna N, Svensson OK, Stinson J, von Baeyer 
CL, Walker L, Weisman S, White RE, Zajicek A, Zeltzer L; PedIMMPACT. Core outcome 
domains and measures for pediatric acute and chronic/recurrent pain clinical trials: 
PedIMMPACT recommendations. J Pain. 2008 Sep;9(9):771-83. 
19. Varni JW, Thissen D, Stucky BD, Liu Y, Gorder H, Irwin DE, DeWitt EM, Lai  JS, 
Amtmann D, DeWalt DA. PROMIS® Parent Proxy Report Scales: an item response 
theory 
analysis of the parent proxy 
report item banks. Qual Life Res. 2012 
Sep;21(7):1223-40. 
20. Varni JW, Thissen D, Stucky BD, Liu Y, Magnus B, Quinn H, Irwin DE, DeWitt EM, Lai 
JS, Amtmann D, Gross HE, DeWalt DA. PROMIS® Parent Proxy Report Scales for 
children ages 5-7 years: an item response theory analysis of differential item functioning 
across age groups. Qual Life Res. 2014 Feb;23(1):349-61. 
21. Propofol. Lexicomp Online, Pediatric & Neonatal Lexi-Drugs, Hudson, Ohio: Lexi-Comp, 
Inc; Accessed January 30, 2016. 
22. Monclair T, et al. The International Neuroblastoma Risk Group (INRG) Staging System: 
An INRG Task Force Report J Clin Oncol. 2009 Jan 10; 27(2): 298 –303. 
23. Liang  and  Zeger,  1986.  Longitudinal  data  analysis  using  generalized  linear  models. 
Biometrika. 73 (1), 13-22. 
24. Varni JW, Burwinkle TM, Katz ER. The PedsQL in pediatric cancer pain: a prospective 
longitudinal analysis of pain and emotional distress. J Dev Behav. Pediatr. 2004 
Aug;25(4):239-46. 
25. Ross, Allison K., and Robert B. Bryskin. Smith's Anesthesia for Infants and Children. 
Edited by Peter J. Davis. By Franklyn P. Cladis and Etsuro K. Motoyama. 8th ed. St. 
Louis, MO: Mosby, 2011. 
26. Kuthiala G, Chaudhary G. Ropivacaine: A review of its pharmacology and clinical use. 
Indian J Anaesth. 2011 Mar;55(2):104-10. 
 
27. Locatelli B, Ingelmo P, Sonzogni V, Zanella A, Gatti V, Spotti A, Di Marco S, Fumagalli 
R.  Randomized,  double-blind,  phase  III,  controlled  trial  comparing  levobupivacaine 


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0.25%, ropivacaine 0.25% and bupivacaine 0.25% by the caudal route in children. Br J 
Anaesth. 2005 Mar;94(3):366-71. 
28. Bosenberg A, Thomas  J, Lopez  T, Lybeck A, Huizar K, Larsson LE. The efficacy of 
caudal ropivacaine 1, 2 and 3 mg x l(-1) for postoperative analgesia in children. Paediatr 
Anaesth. 2002 Jan;12(1):53-8. 
 
 
 
20.0 
APPENDICES 
 
Appendix 1: Wong-Baker FACES®  Pain Rating Scale 
Appendix 2: Post-procedure pain management algorithm 
Appendix 2.1: For Procedure Recovery Room RNs 
Appendix 2.2: For parent/legal guardian 
Appendix 3: Post-procedural quality of life (QOL) questionnaire