Clinical trial NCT01660412
Conditions: Pain
Keywords: Pain Alkalinization Technetium 99m Sulfur Colloid sentinel lymphoscintigraphy?
Sponsor: University of Arkansas
Start date: 2012-08-01; Completion date: 2016-12-30
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Pain during nuclear medicine breast lymphnode detection procedures has been reported as high as 8.8/10. Using Sodium Bicarbonate to alkalinize the radio-pharmaceutical injection, pain can safely be reduced from 6.6/10 to 4.7/10, during breast lymph node detection procedures.

In sites other then the breast, using Bicarbonate to make the injection's pH closer to natural, attempts to lower the pain levels will be performed.

Hypothesis: The perceived pain level during non breast sentinel lymph node techniques can be reduced by raising the pH of the injectate (Tc-99m SC) to near the physiologic level of pH 7.40.

Detailed description:

Arms: arm 1: The first injection administered will be the pH altered solution. The second injection will be the standard of care solution (opposite order). The remaining injections will be randomly assigned as either standard of care or pH altered. arm 2: The first injection administered will be the standard of care solution (SOC). The second injection will be the pH altered solution. The remaining injections will be randomly assigned as either standard of care or pH altered.
Interventions: intervention 1: Standard of Care First intervention 2: ph Altered first
Intervention descriptions: intervention 1: For the second injection, and randomly after that, Sodium Bicarbonate will be compounded with Tc-99m SC, to raise the pH up to \~7.40. intervention 2: For the first injection, Sodium Bicarbonate will be compounded with Tc-99m SC, to raise the pH up to \~7.40. For the second injection, the standard of care will be given, and randomly after that either standard of care, or pH altered will be given.

Protocol documents:
Prot_SAP_000.pdf: 
Title: Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived pain levels during non-
breast sentinel lymphoscintigraphy? 
PI: Mickaila Johnston, MD 
Version #: 2.9 
Date: 1.17.12 
Page 1 
Study Title:  Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived 
pain levels during non-breast sentinel lymphoscintigraphy? 
Principal Investigator: 
Sub-Investigator:   
Study location:
James A Ntambi, MD
Dept of Radiology, Division of Nuclear Medicine 
University of Arkansas for Medical Sciences 
4301 West Markham St., slot #556 
Little Rock, AR 72205 
Phone: 501-526-5062
Email: jantambi@uams.edu
Nicki L. Hilliard, PharmD, BCNP, FAPhA 
UAMS College of Pharmacy 
University of Arkansas for Medical Sciences 
4301 West Markham St., slot #522 
Little Rock, AR 72205 
Phone: 501-686-6398 
Email: nlhilliard@uams.edu 
Mickaila Johnston, MD 
Dept of Radiology, Division of Nuclear 
Medicine University of Arkansas for Medical 
Sciences 4301 West Markham St., slot #556 
Little Rock, AR 72205 
Phone: 501-405-8503 
Email: mjohnston@uams.edu 
University of Arkansas for Medical Sciences 
Sub-Investigator: 


Title: Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived pain levels during non-
breast sentinel lymphoscintigraphy? 
PI: Mickaila Johnston, MD 
 
Version #: 2.9 
Date: 1.17.12 
Page 2 
 
 
Table of Contents 
 
I. 
Abbreviations/Definitions 
II. 
Protocol Summary 
III. 
Background and Rationale 
IV. 
Hypothesis and/or Specific Aims 
V. 
Study Design and Procedures 
VI. 
Study Population 
VII. 
Risks and Benefits 
VIII. 
Efficacy Assessments   
IX. 
Safety Assessments 
X. 
Data Handling and Recordkeeping 
XI. 
Statistical Plan 
XII. 
Ethical Considerations 
XIII. 
Quality Control and Quality Assurance 
XIV. 
Study Registration and Publication 
XV. 
References 
XVI. 
Appendices 
 
 
 
 


Title: Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived pain levels during non-
breast sentinel lymphoscintigraphy? 
PI: Mickaila Johnston, MD 
 
Version #: 2.9 
Date: 1.17.12 
Page 3 
 
 
I. 
Abbreviations/Definitions 
A. Tc-99m: Technetium 99m 
B. SC: Sulfur Colloid 
C. UAMS: University of Arkansas for Medical Sciences 
D. NM: Nuclear Medicine  
E. DEPT: Department 
F. SLN: Sentinel Lymph Node 
G. SOC: Standard of Care 
 
 
 
 


Title: Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived pain levels during non-
breast sentinel lymphoscintigraphy? 
PI: Mickaila Johnston, MD 
 
Version #: 2.9 
Date: 1.17.12 
Page 4 
 
II. 
Protocol Summary  
 
Approximately weekly, a patient presents to the UAMS Nuclear Medicine 
DEPT for a Sentinel Lymph Node (SLN) lymphoscintigraphy study.  Classically, four 
injections of Technetium-99m (TC-99m) Sulfur Colloid (SC) are injected intra-dermally.  
The injections are in the immediate vicinity of a dermatologic malignancy or recent 
biopsy site.  This allows identification of sentinel lymph nodes, in anticipation of surgical 
removal.   
** The UAMS Nuclear Medicine DEPT does not do SLN injections of breasts ** 
 
 
Pain during breast SLN procedures has been reported as high as 8.8/10 
(1).  Using Bicarbonate to alkalinize the radio-pharmaceutical injection, pain can safely 
be reduced from 6.6/10 to 4.7/10 during breast SLN procedures (2).  There have been 
no discoverable studies assessing alkalinization to reduce pain during SLN procedures 
other than in the breast. 
 
It has been common practice in Emergency Rooms to buffer lidocaine at a 
ratio of 1:10 with Bicarbonate, to reduce the "chemical" pain from lidocaine's acidic 
nature.  Similarly, Tc-99m SC is normally acidic with a pH of ~6.04 (2).  Initial lab work 
reveals that a similar approach to altering the pH of Tc-99m SC should not significantly 
reduce the effectiveness of the Tc-99m SC.  Alkalinization should significantly reduce 
the subjective pain. 
 
Study Objectives 
1. To quantify the reduction of perceived pain levels during SLN procedures, by 
altering the pH of the Tc-99m SC to near the physiologic value of 7.40. 
 
Hypothesis 
1. The perceived pain level during SLN techniques can be reduced by raising 
the pH of Tc-99m SC to near the physiologic level of pH 7.40.   
 
Research Methods 
1. Design: Randomized and double blinded prospective cross-over study. 
2. After signing an informed consent, 60 serial subjects will undergo SLN 
injections and imaging as per normal routine—genitourinary, breast, and 
those requiring only a singular injection will be excluded.   
3. The Tc-99m SC injections will have been randomized into two groups---
standard of care solution (unaltered) injected first and experimental solution 
(pH buffered with Sodium Bicarbonate) injected first.   
4. A Nuclear Pharmacist will prepare the injections and label them such that the 
physician (not involved in the data assessment) performing the SLN injections 
is blinded as to which injections contain standard of care solution and which 
contain experimental solution. 
5. Prior to beginning the procedure and after signing informed consent, the 
subject will be asked by a blinded research support assistant, to fill out a 


Title: Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived pain levels during non-
breast sentinel lymphoscintigraphy? 
PI: Mickaila Johnston, MD 
 
Version #: 2.9 
Date: 1.17.12 
Page 5 
 
questionnaire addressing background information.   Prior to beginning and 
after each injection, the subject will be asked to quantify the pain of each 
injection using a validated 0 through 10 scale, with 0 being no pain and 10 
being severe pain that is disabling; unable to perform Activities of Daily Living. 
 
III. 
Background and Rationale 
A. Approximately weekly, a patient presents to the UAMS NM DEPT for a SLN 
lymphoscintigraphy study.  Classically, four injections of TC-99m SC are injected 
intra-dermally.  The injections are in the immediate vicinity of a dermatologic 
malignancy or recent biopsy site.  This allows for identification of SLNs, in 
anticipation of surgical removal. The UAMS NM DEPT does not do SLN 
injections of breasts. 
 
B. Pain during breast SLN procedures has been reported as high as 8.8/10 (1).  
Using Sodium Bicarbonate to alkalinize the radio-pharmaceutical injection, pain 
can safely be reduced from 6.6/10 to 4.7/10 during breast SLN procedures (2).  
There have been no discoverable studies assessing alkalinization to reduce pain 
during SLN procedures other than in the breast. 
 
C. It has been common practice in Emergency Rooms to buffer lidocaine at a ratio 
of 1:10 with Sodium Bicarbonate, to reduce the "chemical" pain from lidocaine's 
acidic nature.  Similarly, Tc-99m SC is normally acidic with a pH of ~6.04 (2). 
Initial lab work reveals that a similar approach to altering the pH of Tc-99m SC 
should not significantly reduce the effectiveness of the Tc-99m SC.   
 
D. Alkalinization should significantly reduce the subjective pain experienced by 
patients undergoing SLN procedures at UAMS. 
 
IV. 
Hypothesis and/or Specific Aims 
A. Hypothesis: 
1.  The perceived pain level during SLN techniques can be reduced by raising 
the pH of Tc-99m SC to near the physiologic level of pH 7.40.   
 
B. Specific Aim: 
1.  To quantify the reduction of perceived pain levels during SLN procedures, by 
altering the pH of the Tc-99m SC to near the physiologic value of 7.40. 
 
V. 
Study Design and Procedures 
A. Design:  
1. Randomized, double blinded, and prospective cross-over design.  
2. Prior to beginning the procedure and after signing informed consent, 60 serial  


Title: Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived pain levels during non-
breast sentinel lymphoscintigraphy? 
PI: Mickaila Johnston, MD 
 
Version #: 2.9 
Date: 1.17.12 
Page 6 
 
subjects will be asked by a blinded research support assistant, to fill out a 
questionnaire addressing background information.   Before the first injection 
and after each injection, the subject will be asked to quantify the pain of each 
injection using a validated 0 through 10 scale, with 0 being no pain and 10 
being severe pain that is disabling; unable to perform Activities of Daily Living. 
3. Subjects will be randomized into one of two sequence groups (A & B): 
a. Sequence group A.  The first injection administered will be the standard of 
care solution (SOC).  The second injection will be the pH altered solution.  
The remaining injections will be randomly assigned as either standard of 
care or pH altered.   
b. Sequence group B.  The first injection administered be the pH altered 
solution.  The second injection will be the standard of care solution 
(opposite order).  The remaining injections will be randomly assigned as 
either standard of care or pH altered.   
Injection order for the two groupings which enrollees will be randomly assigned: 
 Sequence group A: SOC, pH altered, random, random, random, etc. 
 Sequence group B: pH altered, SOC, random, random, random, etc. 
4. A Nuclear Pharmacist will prepare the injections and label them such that the 
physician (not involved in the data assessment) performing the SLN injections 
is blinded as to which injections contain standard of care solution and which 
contain the pH altered solution.  A planned dose range of 0.1 to 1.0 mCi will 
be used.  The maximum activity injected will be 1.0 mCi with a maximum 
volume of 1.0 mL.  Neither the addition of Sodium Bicarbonate nor the 
alteration of the pH result in any discernible change in the observable 
characteristics of the injectate---there is no clouding, there is no color change, 
there is no precipitate formation, etc. 
5. As per normal routine—genitourinary, breast, and those requiring only a 
singular injection will be excluded.   
 
* The procedure for injection of Tc99m SC is currently being used as a diagnostic 
procedure and is in accordance with the community based standard of care.  This 
study does not change the procedure; it only changes the pH of the solute being 
injected during a randomized number of injections. 
* For the purposes of this study, the protocol is ended for each subject upon 
completion of the final pain assessment.  The subjects will then continue on to 
the standard of care imaging and continued clinical management. 
 
B. Survey instrument:  
1. A questionnaire addressing pain quantity will be used.  A validated 0 through 
10 scale, with 0 being no pain and 10 being severe pain that is disabling; 
unable to perform Activities of Daily Living.  Additionally, background 


Title: Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived pain levels during non-
breast sentinel lymphoscintigraphy? 
PI: Mickaila Johnston, MD 
 
Version #: 2.9 
Date: 1.17.12 
Page 7 
 
information will be collected for subset analysis. 
 
VI. 
Study Population 
A. Recruitment: Serial voluntary enrollment of 60 subjects. 
 
B. Study population: All patients, age 18 years and older, who present to UAMS NM 
DEPT for SLN evaluation.   
 
C. Inclusion criteria:  
 
1. Male and female patients of all races and ethnicities, age 18 years and older, 
presenting for SLN imaging for melanoma or who have had an excisional 
biopsy for melanoma of the thorax and appendicular structures; 
2. Patients scheduled to receive two or more injections of Tc-99m SC for the 
purpose of clinical management of melanoma or who have had an excisional 
biopsy for melanoma of the thorax and appendicular structures. 
 
D. Exclusion criteria:  
1. All patients presenting for SLN imaging of lesions involving the breast, ear, 
nose, and genitourinary regions; 
2. Patients scheduled to receive only a single injection of Tc-99m SC; 
3. All pregnant or breast feeding women.  Women will be screened according to 
UAMS NM DEPT routine operating procedures prior to being considered for 
enrollment.  Subsequently, only women who are found to be non-pregnant 
AND non-breast feeding will be invited for enrollment.  
VII. 
Risks and Benefits 
A. Risks:  
1. Loss of patient personally identifiable information: In order to mitigate this, 
investigators shall maintain all personally identifiable information in 
accordance with UAMS policies.  Moreover, only the primary investigator will 
have access to the code that identifies the subjects. 
2. Listed potential adverse reactions include: 
a.  For Tc-99m: Cardiopulmonary arrest, seizures, anaphylactic shock, 
hypotension, dyspnea, abdominal pain, fever, chills, bronchospasm, 
nausea, vomiting, perspiration, redness, urticaria, numbness, dizziness 
and burning at the injection site. Several deaths and cases of lung and 
soft tissue uptake other than RES have been reported in association with 
the use of Technetium Tc 99m Sulfur Colloid Injection. 
b.  For Sodium Bicarbonate: Chemical cellulitis. 
 
B. Benefits: Significantly less pain and suffering could potentially be experienced by 
future patients. 
 


Title: Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived pain levels during non-
breast sentinel lymphoscintigraphy? 
PI: Mickaila Johnston, MD 
 
Version #: 2.9 
Date: 1.17.12 
Page 8 
 
VIII. 
Efficacy Assessments   
A. Prior to beginning and after each injection, subjects will be asked, by a blinded 
clinical assistant, to quantify the pain of each injection.   Prior to beginning the 
injections, subjects will provide relevant background information by filling out a 
questionnaire. 
 
IX. 
Safety Assessments 
A. 
Injection site pain of 8 out of 10 or less will not be considered an adverse 
event.  Any adverse events will be appropriately documented and reported to the 
IRB in accordance with institutional policy.   
 
B. 
The principal investigator will assess the relationship of the adverse event to 
the investigational compound. The relationship will be assessed using the 
following categories: 
1. Definitely Related: A direct cause and effect relationship between the 
investigational compound and the adverse event exists. 
2. Possibly Related: A direct cause and effect relationship between the 
investigational compound and the adverse event has not been clearly 
demonstrated, but is likely or very likely. 
3. Unlikely Related: A direct cause and effect relationship between the 
investigational compound and the adverse event is improbable, but not 
impossible. 
4. Unrelated: The adverse event is definitely not associated with the 
investigational compound. 
 
X. 
Data Handling and Recordkeeping 
A. Data form: A paper questionnaire to quantify the pain will be used.  Additionally, it 
will collect background demographics---Appendix 1. 
 
B. The PI will carefully monitor study procedures to protect the safety of research 
subjects, the quality of the data and the integrity of the study.  All study subject 
material will be assigned a unique identifying code or number.  The key to the 
code will be kept in a locked file in the principal investigator’s office.  Only Dr. 
Mickaila Johnston or designated study staff will have access to the code and 
information that identifies the subject in this study.   
 
C. Upon completion of the study, all hard copy and electronic study records 
containing PHI will be destroyed or cleansed. 
 
XI. 
Statistical Considerations 


Title: Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived pain levels during non-
breast sentinel lymphoscintigraphy? 
PI: Mickaila Johnston, MD 
 
Version #: 2.9 
Date: 1.17.12 
Page 9 
 
A. Planned Data Analysis: Reported pain responses to SOC and pH altered 
injections will be assessed using a basic cross-over design.  Specifically, the two 
treatments will be studied within each subject; however, the sequence in which 
subjects will receive treatment will be randomized.  Subjects randomized to one 
sequence group will receive the SOC injection first followed by the pH altered, 
while the other sequence group will receive pH altered then SOC injections.  The 
following table succinctly presents this design.   
 
Period 
Sequence Group 
A 
B 
1 
SOC 
pH altered 
2 
pH altered 
SOC 
 
In addition to the effect of treatment, the statistical model used to analyze this 
data must account for the effect of the sequence group, as well as the effect of 
period; therefore, the following mixed-effect analysis of variance model is 
proposed: 
  
Yijk = µ + SEQi + subij + PERk + TRTh + eijk, where 
  
Yijk is the pain assessment  for the jth subject during the kth period  in the ith 
sequence group (i = 1,2; j = 1, 2, .., ni; k = 1,2), SEQi is the effect of the ith 
sequence group, subij is the effect of the jth subject in the ith sequence, PERk  is 
the effect of the kth period, TRTh is the effect of the hth treatment (h=1,2), and eijk 
is the error.  The sequence, period and treatment effects will be modeled as fixed 
effects, while the subject effect and the error will be modeled random effects. An 
α-level of 5% will be used to determine the statistical significance of the treatment 
effect, as well as the other fixed effects. 
 
One potential shortcoming of the proposed cross-over design is that the pain 
assessments will be made within minutes of one another; thus, a period or “carry-
over” effect may be present.  The proposed model will be able to detect such 
effects and, if present, only data from the first period will be used to evaluate the 
effect of treatment.  In this case, the model reduces to a simple two-sample t-
test. 
 
B. Sample Size Justification: We wish the study to be sufficiently powered in the 
event that a significant “carry-over” or period effect is detected and only the first 
period data is used to evaluate the effect of treatment.  To this end, the following 
sample size calculation is based on a two-sample t-test.  A recent study by 
Stojadinovic et al. reported a pain scale standard deviation of 2.65 for a SOC 
group.  We anticipate that the pH adjusted group will reduce pain, on average, by 
2 points.  Given this information, a two-sample t-test will have over 80% power to 
detect this difference assuming 30 subjects per group (60 in total) are enrolled.  
(It should be noted that if no carry-over effect is detected and both periods are 


Title: Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived pain levels during non-
breast sentinel lymphoscintigraphy? 
PI: Mickaila Johnston, MD 
 
Version #: 2.9 
Date: 1.17.12 
Page 10 
 
used in the analysis, the proposed sample size will provide the test of the 
treatment effect with over 98% power to detect a 2 point difference and with over 
80% power to detect a 1 point difference). 
 
C. Randomization: To ensure the number of subjects randomly assigned to each 
sequence group is equal, the technique of permuted block randomization will be 
employed.  The randomization procedure will also be stratified according to the 
following, broadly defined sites of injection: 
1. Thorax, including neck and buttocks; 
2. Head; 
3. Appendicular structures, including shoulder to wrist, including back of hand, 
and hip to ankle; 
4. Other (remainder of hand and feet). 
 
Randomization will be applied independently within each stratum.  That is, a 
separate randomization “schedule” will be applied within each stratum.  This will 
ensure that the injection site distribution of the sequence groups will be similar. 
 
XII. 
Ethical Considerations 
A. This study will be conducted in accordance with all applicable government 
regulations and University of Arkansas for Medical Sciences research policies 
and procedures.  This protocol and any amendments will be submitted and 
approved by the UAMS Institutional Review Board (IRB) to conduct the study. 
 
B. The formal consent of each subject, using the IRB-approved consent form, will 
be obtained before that subject is submitted to any study procedure.  All subjects 
for this study will be provided a consent form describing this study and providing 
sufficient information in language suitable for subjects to make an informed 
decision about their participation in this study.  The person obtaining consent will 
thoroughly explain each element of the document and outline the risks and 
benefits and alternate treatment(s).  The consent process will take place in a 
quiet and private room, and subjects may take as much time as needed to make 
a decision about their trial participation.  Participation privacy will be maintained 
and questions regarding participation will be answered.  No coercion or undue 
influence will be used in the consent process.  This consent form must be signed 
by the subject or legally acceptable surrogate, and the investigator-designated 
research professional obtaining the consent.  A copy of the signed consent will 
be given to the participant, and the informed consent process will be documented 
in each subject’s research record.  
 


Title: Does Alkalinization of Technetium-99m Sulfur Colloid reduce perceived pain levels during non-
breast sentinel lymphoscintigraphy? 
PI: Mickaila Johnston, MD 
 
Version #: 2.9 
Date: 1.17.12 
Page 11 
 
C. At any time during the clinical encounter, any participant may opt out of the study 
by providing written direction or by simply verbally communicating to any staff 
member that the participant no longer wisher to be enrolled in the study.  At that 
time, the participant would be no longer enrolled in the study, and the remainder 
of their care would only be that of the routine standard of care, without bias. 
 
D. In the event that a participant reports pain associated with the procedure and 
requests analgesia, no analgesia will be provided by the UAMS NM DEPT.  None 
is provided as the standard of care in day-to-day routine. 
 
XIII. 
Quality Control and Quality Assurance 
A. Industry standard quality control tests have already been run on initial bench 
work versions---all tests passed quality control appropriately.  
 
B. Prior to beginning administration of controls and experimental interventions to 
subjects, the buffering procedure will be validated in vitro with more sensitive pH 
metering.  Quality control will again be assessed on the pH altered samples.  
After the buffering procedure is proven to be reliable and reproducible, 
administration with subjects will begin according to the verified buffering 
procedure. 
 
XIV. 
Study Registration and Publication 
A. Results of this study may be used for presentations, posters, or publications. The 
publications will not contain any identifiable information that could be linked to a 
subject. The study will be registered with www.clinicaltrials.gov. 
 
XV. 
References 
(1) Relieving the pain of sentinel lymph node biopsy tracer injection. S Fetzer and S 
Holmes, Clin J Oncol Nurs. 2008 Aug;12(4):668-70. 
 
(2) Standard versus pH-adjusted and lidocaine supplemented radiocolloid for 
patients undergoing sentinel-lymph-node mapping and biopsy for early breast 
cancer (PASSION-P trial): a double-blind, randomized controlled trial. A 
Stojadinovic, etal. Lancet Oncol. 2009 Sep;10(9):849-54. Epub 2009 Aug 5. 
 
XVI. 
Appendices 
 
Attached as separate documents.