RESEARCH PROTOCOL

I. TITLE:

A comparative study between conservative and operative management of clavicular fracture

among military personnel of the armed forces of the Philippines

II. RESEARCHER:

Antonio Manuel T. Saludo, MD

III. INTRODUCTION:

Orthopaedic infections are associated with significant morbidity and can be very difficult to
treat. Although prompt diagnosis is the key for prevention of these morbidities, this is not always the
case. This is because orthopaedic infections, particularly those affecting the bone or osteomyelitis often
go undetected at the early stages because of its nonspecific constitutional symptoms. Furthermore,
Laboratory examinations such as WBC counts, ESR and CRP although sensitive for osteomyelitis are
not highly specific for the said disease. Radiographic changes may be helpful but are usually detected
in the late stages of the disease. Therefore patients usually present at a chronic stage and become more
difficult to treat. A high index of suspicion is therefore needed, especially in cases of open fractures.
Open fractures, especially barnyard injuries or even only slightly contaminated ones are associated with
osteomyelitis which could be brought about by direct inoculation of the bacteria to the bone. Incidence
of osteomyelitis following open fractures increases if there is a delay between the time of injury and the
time debridement is done. In a study done by Robson et al, it was noted that the threshold to sustain an
infection was 105 organisms. They also found that this threshold was reached in 5.17 hours. Which is
why they recommended that debridement should be done within 6 hours from the time of injury. This
was supported by another study done by Cooney et al wherein it was noted that the immune system is
overwhelmed once a level of 100,000 organisms per gram of tissue is present and infection usually
begins after this threshold is reached.
Treatment of these infections has evolved considerably from the time of the early Sumerians,
who used honey and donkey feces for treatment, to the 1920’s when Alexander Fleming discovered
penicillin. A staged protocol for the management of chronic osteomyelitis which includes debridement,
systemic and local antibiotic treatment and skeletal stabilization was eventually developed in the
1940’s. The first stage of this staged protocol involves a radical debridement of all nonviable tissues
and skeletal stabilization. Debridement is done until bleeding, which is indicative of viable tissues is
observed at the resection margins. This procedure would however create dead space which could also
serve as a nidus for infection by allowing room for hematoma formation and bacterial colonization.
Skeletal stabilization on the other hand is also necessary for infection control as it would prevent further
damage to the surrounding soft tissue envelope. Iit was in the 1960’s that more proper antibiotics for
the treatment of osteomyelitis became available. Intravenous antibiotic administration is a key part of
the treatment of chronic osteomyelitis. There is however little data on the adequate duration that
antibiotics should be given. It is currently recommended to start with a 2 to 6 week course of antibiotic
treatment which may be extended based on clinical findings that would suggest persistence of infection.
However considerable morbidity has been attributed to prolonged use of intravenous antibiotics. This
morbidity would include the development of resistance by the bacteria and the development of
neutropenia in some patients. In a study on 50 patients done by McCluskey et al at the University of
Philadelphia, it was found that 30% of the patients developed neutropenia. All of the patients who
developed neutropenia had been undergoing antibiotic treatment for more than 3 weeks. Because of
these facts, ways have been devised to shorten the duration of intravenous antibiotic treatment.
New oral agents have been developed to allow early step down from intravenous antibiotics
and lessen the morbidity associated with its prolonged use. In the 1970’s, the concept of administering
local antibiotics to the site of injuries was first conceptualized. This was initially used to reduce the
incidence of infected arthroplasties but was later on used in the development of antibiotic impregnated
bone cement (otherwise known as antibiotic depot devices) for treating osteomyelitis. In a study done
by Keating et al on open fractures of the tibia, it was noted that there was only a 4 % infection rate in
patients treated with antibiotic beads. Another study done by Ostermann et al. studied the infection rate
with grade IIIB fractures treated with parenteral antibiotics and aminoglycoside beads compared with
those treated with parenteral antibiotics alone. The study reported a 6.9% infection rate in those who
received combined therapy versus 40.7% infection rate in those who received parenteral antibiotics
alone. These depot devices allow distribution of a high local concentration of antibiotic with little
systemic absorption thereby minimizing the side effects of long term use of systemic antibiotics.
Furthermore, the dead space that results from debridement is filled by the depot devices therefore
eliminating the space that would be available for hematoma formation and bacterial colonization.
Elution or release of the antibiotics from the depot devices is biphasic with most occurring during the
first few days to weeks and the rest being released until several weeks after the application of the depot
devices. Elution of the antibiotic beads is also based on a diffusion gradient which is why only the outer
1 cm of the large volume depots will elute antibiotics. The antibiotics remaining at the core of the depot
devices will not be eluted and will lead to a decrease in the supposed local concentration of the
antibiotic. Several institutions have resorted to using these antibiotic depot devices in conjunction with
a thorough debridement and parenteral antibiotics. Antibiotic beads are the more popularly used form
of these depot devices. However, some authors have recommended the use of antibiotic discs rather
than antibiotic beads. This is because they have been found to fit better between tissue planes and are
less likely to cause compressive effects. Furthermore, it has been shown in some studies that increasing
the surface area of a depot device will lead to a greater elution of antibiotics. In a study done by
Anagnostakos et al on the elution of gentamycin and vancomycin from polymethylmethacrylate beads
and hip spacers in vivo, it was found that beads showed a higher elution characteristic as compared to
the spacer due to their larger surface area. In another study done by J Samuel Preston et al, the Stochastic
Collocation Method for the Uncertainty Quantification of Drug Concentration due to Depot Shape
Variability was studied. The study used stochastic collocation to determine amount of elution of the
drug base on the variability of its shape. Results showed that the rate of diffusion of the antibiotic was
the same for both antibiotic beads and discs. However the greater surface area of the discs allowed a
greater amount of local antibiotic delivery for the antibiotic discs. As mentioned earlier only the outer
1 cm of the device elutes antibiotics, therefore, the thinner discs eliminates the factor of diffusion
gradient in the inner core of the bead and allows for greater local delivery of antibiotic. Despite of these
studies, there is no current literature that clarifies whether the dose of antibiotics or length of antibiotic
therapy can be shortened if local concentrations of the antibiotic can be increased by a change in the
shape of the depot device. There are also no current studies comparing antibiotic beads and discs with
regards to effectivity in treating osteomyelitis. If it is proven in this study that such a simple measure
of changing the shape of the antibiotic depot device could lead to an earlier resolution of chronic
osteomyelitis as shown by a shortened course of antibiotic therapy, then changes in the protocol of
application of antibiotic depot devices can be made. Furthermore, the earlier resolution of the chronic
osteomyelitis will allow early return to work on the part of the patient and lessen the deleterious effects
of prolonged antibiotic use. Data gathered in this study may also be used as future reference for further
studies regarding improvements in the management of chronic osteomyelitis.

IV. RESEARCH QUESTION:

Among adult patients who developed chronic osteomyelitis after sustaining open tibial
fractures; will the administration of antibiotic discs be better than the administration of antibiotic beads
in shortening the course of intravenous antibiotic therapy?

V. HYPOTHESIS:
Null Hypothesis
– There is no significant difference in the course of intravenous antibiotic therapy between patients
with chronic osteomyelitis who underwent application of antibiotic discs and patients with chronic
osteomyelitis who underwent application of antibiotic beads

True Hypothesis
– There is a significant difference in the course of intravenous antibiotic therapy between patients with
chronic osteomyelitis who underwent application of antibiotic discs and patients with chronic
osteomyelitis who underwent application of antibiotic beads

VI. OBJECTIVES:

A. General Objective
To determine if antibiotic discs will be more effective than antibiotic beads in
shortening the duration of parenteral antibiotic treatment in adult patients who developed
chronic osteomyelitis after sustaining open fractures of the tibia.

B. Specific Objectives

1. To determine the demographic data of patients who developed chronic osteomyelitis after
sustaining type 2 open fractures of the tibia

2. To evaluate if the shape of antibiotic depot devices will have an effect in improving
outcome in chronic osteomyelitis patients by comparing the mean duration to
improvement of the following parameters
a. ESR
b. CRP
c. WBC count

3. To compare the outcome of treatment in chronic osteomyelitis patients who received

antibiotic discs with those who received antibiotic beads by determining the length of
time to resolution or improvement of signs and symptoms (eg. wound discharge, sinus
tracts) and positive growth in wound GS/CS .

VII. STUDY DESIGN:

Randomized Controlled Trial

VIII. SUBJECT SELECTION CRITERIA:

 a. Target population
Adult patients diagnosed with chronic osteomyelitis of the tibia after sustaining open
fractures who are admitted at the Department of Orthopaedic surgery and Traumatology,
Armed Forces of The Philippines Medical Center.

b. Study Population

Adult patients aged 20 – 45 years old with Chronic Osteomyelitis of the tibia diagnosed
at least 1 month after sustaining an open fracture of the tibia, admitted at the Department
of Orthopaedic Surgery and Traumatology, Armed Forces of the Philippines Medical
Center from May 2012 to April 2014

c. Inclusion Criteria
1. Adult patients aged 20 -45 years old
2. Patients previously diagnosed with type 2 open fractures of the tibia secondary to
VA
3. Patients with chronic osteomyelitis of the tibia detected not longer than 1 month
after the history of open fracture
4. Patients diagnosed with chronic osteomyelitis via the following parameters
a. Presence of signs and symptoms (wound discharge, sinus tracts, fever)
b. Elevated ESR and CRP
c. Elevated WBC count on CBC
d. Positive growth on wound GS/CS

d. Exclusion Criteria
1. Patients with poor nutritional status
2. Immunocompromised patients
3. Patients with comorbidities such as diabetes mellitus, renal and liver disease
4. Patients who have been diagnosed with chronic osteomyelitis more than 1 month
after the date of injury
5. Type 1 and 3 open fractures
6. Patients who had undergone previous application of antibiotic depot devices
7. Patients with skin defects

IX. SAMPLING
 Patients will be randomly assigned into groups A and B

Group A will include patients with chronic osteomyelitis who will undergo debridement with
application of antibiotic discs

Group B will include patients with chronic osteomyelitis who will undergo debridement with
application of antibiotic beads

Random assignment of the patients into groups A and B will be done by using computer
generated random numbers (MS EXCEL). The subjects will be assigned to either the control or
experimental group based on the number that will be generated for them by the computer upon their
admission. All patients who are given an odd number will be assigned to Group A and all patients who
are given an even number will be assigned to group B

The sample size will be based on the number of patients with osteomyelitis of the tibia in
AFPMC. Based on the census for the last two years, 25% of the admitted patients per year are due to
osteomyelitis. This would account for about 175 patients. 30% of this 175 patients involves the tibia.
The population of patients admitted per year for osteomyelitis of the tibia is therefore approximately 53
patients. Given a confidence level of 95% and a confidence interval of 4 the sample size that would be
significant for this study is a population of 49.

X. RESEARCH SETTING

The study will be limited to adult patients admitted to all 4 wards of the Department of
Orthopaedic Surgery and Traumatology, VLGH, Armed Forces of the Philippines Medical Center

XI. MATERIALS AND METHODS

Prior to the gathering of subjects, the research will first be presented to the Bioethics Review
Board of the Department of Research of The Armed Forces of the Philippines Medical Center for
approval. Once the study is approved; an informed consent will be obtained from the subjects prior to
their inclusion in the study.
Clinical Assessment

Initial assessment of the patient will begin with a thorough history taking and physical
examination. It is important to extract pertinent data such as the type of open fracture and the period
from the date of injury to manifestations of signs and symptoms as this may be contributory to the
severity of the infection. Co morbidities that may affect the course of the healing process such as DM
and PTB should be detected for proper exclusion of subjects from the study. Laboratory examinations
will then be requested to support the diagnosis and for baseline data. These examinations would include
a CBC, ESR and CRP values and wound GS/CS. Radiographs will also be taken to check for the
presence or absence of radiographic signs of chronic osteomyelitis. Once inclusion of the patient has
been confirmed, randomization into the control or experimental group via computer generated numbers
will be done as mentioned earlier.

Antibiotic Coverage

Empiric parenteral antibiotic will be given to the patients while waiting for the wound GS/CS
results. To better control this aspect of the study, patients will be given the same antibiotic for empiric
treatment in the form of Cefuroxime 750 mg/vial. Once results are available, Antibiotics will be shifted
and be culture guided.

Debridement and Irrigation

Patient will then undergo debridement. Only one person will be performing the debridement
for all the subjects to avoid differences in technique of debridement. Thorough debridement with
curettes and rongeur if necessary will be done until viable tissues are visualized. In case the patient has
previously undergone open reduction with internal fixation, the implant will be removed and replaced
with an external fixator to maintain stability of the bone and avoid further soft tissue damage which
could aggravate the infection. Irrigation will also be controlled by assuring the same amount of washing
(10 liters) for all cases. Wash used will be PNSS with no other additives such as betadine or hydrogen
peroxide. Antibiotic wash will also be excluded.

Preparation of Antibiotic Depot Device

Depot devices will be made using Polymethylmethacrylate (PMMA) material. The antibiotic
used will also be uniform for all patients in the form of Gentamycin. The Depot devices will be made
during the surgery and will be shaped into either discs or beads depending on the group to which the
patient was randomly assigned. 3 strands of depot devices each with 20 beads or discs will be used for
all patients. One end of the wire holding the depot devices will be left outside so the strands can be
removed without undergoing another operation. It must be assured that the discs or beads are placed in
a manner that they can be easily pulled out to assure that no depot device will be left inside.
Post-operative care and data gathering

The depot devices will be maintained inside the extremity for 1 week to allow completion of
the first phase of elution. After this period, the depot devices will be pulled out one per day Daily wound
dressing for the first 3 postoperative days will be done, after which dressing will be done every 3 days
and. Weekly monitoring of ESR, CRP, and CBC will be done and changes in the result will be recorded.
Specimen for wound GS/CS will also be collected every 2 weeks to watch for the persistence or
elimination of the offending microorganisms. The resolution of the signs and symptoms of osteomyelitis
such as wound discharge or draining sinus will also be monitored and recorded.

XII. RESULTS AND OUTCOME

A. Results
Results will be assessed on a weekly basis for the WBC count, ESR and CRP. The mean
values of the said examinations for all of the patients under each group will be computed and compared
per week. To determine the effect of each intervention on the outcome, clinical signs and symptoms
will also be assessed on a weekly basis for each group to document the time to resolution of signs and
symptoms. Specimen for wound GS/CS with Quantitative count will also be collected every 2 weeks.

B. Statistical Analysis
The mean value of the WBC count, ESR and CRP counts will be compared using the
student’s t-test. Relative Risk ratio will be used to determine the effect of intervention to the outcome
in terms of resolution of signs and symptoms and time needed to achieve no growth in wound GS/CS.
The time needed to achieve a negative wound GS/CS result will then be compared using a Kaplan-
Meier Plot.

XIII. BUDGET

The cost for both control and experimental groups will be the same as the materials and
antibiotics that will be used will be controlled and it is only the shape that will differ. The PMMA with
gentamycin will cost 12500 pesos per patient. All Expenses incurred in this study will be shouldered by
the AFP.

XIV. TIMELINE
 This will be a 30 month study and is projected to begin on May 2012 with an estimated date of
completion on October 2014. Collection of subjects will stop on April 2014 and Final data collection
for outcome measures will be on July 2014. Timeline for the said study from the time of approval is
shown in the table below.

PROPOSED TIME FRAME

Preparation of Materials 1st month
Start of recruitment of subjects 2nd month
End of recruitment of subjects 26th Month
Data analysis 27th to 29th Month
Completion of Study 30th Month

XV. CONTINGENCY TABLES

A.
MEAN WBC VALUE
ANTIBIOTIC DISCS
ANTIBIOTIC BEADS

B.
MEAN ESR VALUE
ANTIBIOTIC DISCS
ANTIBIOTIC BEADS

C.
MEAN CRP VALUE
ANTIBIOTIC DISCS
ANTIBIOTIC BEADS

D.
 ANTIBIOTIC DISCS ANTIBIOTIC BEADS
PRESENCE OF WOUND YES NO YES NO
DISCHARGE
PATIENT # 1
PATIENT # 2
PATIENT # 3

E.
ANTIBIOTIC DISCS ANTIBIOTIC BEADS
NEGATIVE WOUND GS/CS YES NO YES NO
PATIENT # 1
PATIENT # 2
PATIENT # 3

F.

4.5

3.5

2.5 ANTIBIOTIC DISCS

ANTIBIOTIC BEADS
2

1.5

0.5

0
WEEK 2 WEEK 4 WEEK 6 WEEK 8

XVI REFERENCES
 1. Rockwood and Green’s Fractures in Adults, 7th Edition, Volume 1, c 2006

2. Stochastic Collocation Method for the Uncertainty Quantification of Drug Concentration Due
to Depot Shape Variability; J. Samuel Preston et al, University of Utah, 2010

3. Elution of gentamicin and vancomycin from polymethylmethacrylate beads and hip spacers in
vivo; Anagnostakos et al; Klinik fur Orthopadie und Orthopadische Chirurgie, Universitat des
Saarlandes, Homburg/Saar, Germany, 2009 April; 80 (2): 193-7

4. Reamed nailing of open tibial fractures: Does the antibiotic bead puch reduce the deep
infection rate?; Keating JF, Blachut PA, O’Brien PI et al, J Orthop Trauma, 1996; 10:298-303

5. Value of Adjuvant Local Antibiotic administration in therapy of open fractures. A

comparative analysis of 704 consecutive cases; Osterman PA, Henry SL et al; Langenbecks
arch Cir, 1993; 378 32-36

6. Neutropenia complicating parenteral antibiotic treatment of infected nonunion of the tibia;

Mckluskey WP, Esterhai JL, Brighton CT et al; Department of Orthopaedics, University of
Pensylvania; 1989; 124(11):1309-12

APPENDIX A
 SAMPLE DATA FORM:

Patient’s initials

Age

Sex

Date of Injury

Questions:
1. Do you have any of the following diseases (put a check)
_ HPN _ DM _ PTB
_Renal Disease _ HIV _Others:_______

2. What was the nature of your Injury?

_ Vehicular Accident _ Direct Trauma
_ Fall _ Others: ____________________

3. Type of Fracture
_ Closed _ Open Type I
_ Open Type II _ Open Type III

4. Did you undergo Debridement? _ Yes _ No

5. If Yes, How many times? ______________________________

6. Were antibiotic depot devices placed? _ Yes _ No

7. Was Internal fixation with any form of implant done? _ Yes _No

8. Are you currently on antibiotics? _ Yes _ No

9. If yes, what antibiotics are being given? __________________

APPENDIX B
CONSENT FOR ENROLLMENT AS SUBJECT FOR THE STUDY ENTITLED

The effectivity of antibiotic discs in shortening the course of antibiotic treatment for adult patients

who developed chronic osteomyelitis of the tibia after sustaining a type 2 open fracture secondary

to VA as compared to antibiotic beads.

Name of Patient: Date: Time:

Age: Sex: Civil Status:

Address:

Rank:

1. I, Mr/MS __________________________________, hereby agree to take part in this study

(Ako si Mr/Ms_________________________________, ay pumapayag na makilahok sa pagaaaral

na ito)

2. The nature and purpose of the procedure, the risk involved and possible complications have been
explained to me. (Ang mga detalye at dahilan ng pagaaral na ito ganun din ang mga posibleng
komplikasyon ay naipaliwanag sa akin)

I hereby certify that I have read and understood the above consent.(Nanunumpa ako na nabasa
ko ang nakalahad sa itaas at naintindihan ko)

_____________________________ __________________________________

Signature of Patient Signature of Patient’s Husband, Wife, relative

(Pirma ng pasyente ) (Pirma ng asawa o Kamaganak ng pasyente)