Protocol for a randomized controlled trial on risk adapted damage control orthopedic surgery of femur shaft fractures in multiple trauma patients.

Abstract

Fractures of the long bones and femur fractures in particular are common in multiple trauma patients, but the optimal management of femur fractures in these patients is not yet resolved. Although there is a trend towards the concept of "Damage Control Orthopedics" (DCO) in the management of multiple trauma patients with long bone fractures as reflected by a significant increase in primary external fixation of femur fractures, current literature is insufficient. Thus, in the era of "evidence-based medicine", there is the need for a more specific, clarifying trial.
The trial is designed as a randomized controlled open-label multicenter study. Multiple trauma patients with femur shaft fractures and a calculated probability of death between 20 and 60% will be randomized to either temporary fracture fixation with fixateur externe and defined secondary definitive treatment (DCO) or primary reamed nailing (early total care). The primary objective is to reduce the extent of organ failure as measured by the maximum sepsis-related organ failure assessment (SOFA) score.
The Damage Control Study is the first to evaluate the risk adapted damage control orthopedic surgery concept of femur shaft fractures in multiple trauma patients in a randomized controlled design. The trial investigates the differences in clinical outcome of two currently accepted different ways of treating multiple trauma patients with femoral shaft fractures. This study will help to answer the question whether the "early total care" or the "damage control" concept is associated with better outcome.
Current Controlled Trials ISRCTN10321620.

Full text

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BioMed Central
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Trials
Open Access
Study protocol
Protocol for a randomized controlled trial on risk adapted damage
control orthopedic surgery of femur shaft fractures in multiple
trauma patients
Dieter Rixen*1, Eva Steinhausen1, Stefan Sauerland2, Rolf Lefering2,
Matthias Meier3, Marc G Maegele1, Bertil Bouillon1 and
Edmund AM Neugebauer2
Address: 1Department of Trauma and Orthopedic Surgery, University of Witten-Herdecke at the Hospital Cologne-Merheim, Ostmerheimer Str.
200, 51109 Cologne, Germany, 2Institute for Research in Operative Medicine, University of Witten-Herdecke, Ostmerheimer Str. 200, 51109
Cologne, Germany and 3Department for Trauma, Hand and Reconstructive Surgery, University of Cologne, 50937 Cologne, Germany
Email: Dieter Rixen* - RixenD@kliniken-koeln.de; Eva Steinhausen - SteinhausenE@kliniken-koeln.de;
Stefan Sauerland - Stefan.Sauerland@ifom-uni-wh.de; Rolf Lefering - Rolf.Lefering@ifom-uni-wh.de; Matthias Meier - Matthias.Meier@uk-
koeln.de; Marc G Maegele - MaegeleM@kliniken-koeln.de; Bertil Bouillon - BouillonB@kliniken-koeln.de;
Edmund AM Neugebauer - Edmund.Neugebauer@uni-wh.de
* Corresponding author
Abstract
Background: Fractures of the long bones and femur fractures in particular are common in
multiple trauma patients, but the optimal management of femur fractures in these patients is not
yet resolved. Although there is a trend towards the concept of "Damage Control Orthopedics"
(DCO) in the management of multiple trauma patients with long bone fractures as reflected by a
significant increase in primary external fixation of femur fractures, current literature is insufficient.
Thus, in the era of "evidence-based medicine", there is the need for a more specific, clarifying trial.
Methods/Design: The trial is designed as a randomized controlled open-label multicenter study.
Multiple trauma patients with femur shaft fractures and a calculated probability of death between
20 and 60% will be randomized to either temporary fracture fixation with fixateur externe and
defined secondary definitive treatment (DCO) or primary reamed nailing (early total care). The
primary objective is to reduce the extent of organ failure as measured by the maximum sepsis-
related organ failure assessment (SOFA) score.
Discussion: The Damage Control Study is the first to evaluate the risk adapted damage control
orthopedic surgery concept of femur shaft fractures in multiple trauma patients in a randomized
controlled design. The trial investigates the differences in clinical outcome of two currently
accepted different ways of treating multiple trauma patients with femoral shaft fractures. This study
will help to answer the question whether the "early total care" or the „damage control” concept
is associated with better outcome.
Trial registration: Current Controlled Trials ISRCTN10321620
Published: 19 August 2009
Trials 2009, 10:72doi:10.1186/1745-6215-10-72
Received: 1 March 2009
Accepted: 19 August 2009
This article is available from: http://www.trialsjournal.com/content/10/1/72
© 2009 Rixen et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Background
Trauma is a major medical and economical issue of health
care systems today and the leading cause of death between
the age of 1 and 45 years [1]. The World Health Organiza-
tion assumes that death caused by accidents, violence and
war will even increase until 2020. The implications for the
society are serious, as most of the trauma victims are
young and at the beginning of their careers [2,3].
Fractures of the long bones and femur fractures in partic-
ular are common in multiple trauma patients, but the
optimal management of femur fractures in these patients
is not yet resolved [4,5]. In principle, there are five meth-
ods for the treatment of these fractures: cast, extension,
external fracture fixation with fixateur externe, and inter-
nal fixation with either intramedullary nail or plate osteo-
synthesis.
Of the five possibilities of treating femoral fractures, cast
or extension therapy was considered standard therapy for
long bone fractures in multiply injured patients in the
1960s, but this strategy gradually became obsolete. Obser-
vational studies showed that mortality rates were reduced
by initial fracture stabilization, independent of the proce-
dure performed (fixateur externe, nail or plate). This led to
a new standard therapeutic concept for long bone fracture
treatment in multiple trauma patients from the mid 1980s
on, termed "early total care" [4,5].
But, the question remained whether primary internal
(nail/plate) or external fixation (fixateur externe) is
advantageous for this patient population, especially in
high risk patients with additional chest or head injuries
[4,5]. While nailing (in contrast to plate osteosynthesis) is
considered the gold standard for treatment of isolated
femur shaft fractures because of its undeniable advantage
of weight-bearing structure, it is compromised by the sig-
nificant distress caused by operation time, blood loss, and
insertion of the nail, which may act as a "second hit".
Studies comparing reamed and unreamed intramedullary
nails show the superiority of the reamed nail [6,7].
On the other hand, advocates of temporary external fixa-
tion in multiple trauma patients assert its simplicity with
regard to initial treatment, as well as hypothetic advan-
tages regarding patient security with less blood loss and
possible reduction in systemic response as well as mortal-
ity in specific subgroups of trauma patients, e.g. with addi-
tional chest or head injuries. However, hypothetic
disadvantages of temporary external fixation must also be
considered: planned additional surgery for the secondary
definitive procedure with prolonged mechanical ventila-
tion and intensive care unit (ICU) stay, planned addi-
tional burden for the patient at secondary surgery,
increased infection rates by conversion of external to
internal fixation, a certain number of patients in which a
conversion will not be possible resulting in impaired
functional results, moreover the planned conversion
within the first days after trauma may also act as a "second
hit" to the patient. The optimal time for conversion from
external fixation to a definitive procedure is not clear in
patients treated with temporary external fixation and sec-
ondary intramedullary nailing [8,9].
With respect to the question of "early total care" or tem-
porary fracture fixation by fixateur externe in all multiple
trauma patients regardless of their anatomic or physio-
logic injury severity the literature presents a diversity of
studies supporting different views. Both a recently pub-
lished evidence based guideline [4] as well as a current
systematic literature review [5] could neither clarify the
optimal time point nor procedure of femoral fracture fix-
ation in multiple trauma patients. In addition, an analysis
of the German Trauma Registry including more than 8000
multiple trauma patients showed that management dif-
fers widely and depends on both the individual hospital
strategy as well as on patient/trauma characteristics [5].
In this respect increasing literature evidence suggests that
neither "early total care" nor temporary external fixation
with secondary definitive internal osteosynthesis should
be considered as standard therapy in all patients. Instead,
decision making should be dependent on the patient's
individual risk by its anatomic, physiologic and immuno-
logic injury severity (risk adapted damage control con-
cept): patients with a low mortality risk can be treated by
primary definitive fracture fixation while patients at a
higher mortality risk should be treated by damage control
in the sense of temporary fracture fixation with a fixateur
externe and later secondary definitive treatment when the
patients' physiologic and immunological situation has
been stabilized on the ICU.
Criteria, which have been recommended by various
authors in order to define patients, in whom early defini-
tive osteosynthesis might be disadvantageous are named
in table 1[10-20]. Unfortunately, up to date, there is no
proof for the superiority of the risk adapted damage con-
trol concept with regard to evidence based randomized
controlled trials nor are the criteria listed in table 1 vali-
dated.
Thus, both the evidence-based guideline of the EAST
organization [4] as well as a systematic literature analysis
[5] concluded that a randomized trial is urgently needed
to clarify the question whether primary internal fixation
(early total care) or temporary external fixation with inter-
nal fixation in a second step (in the sense of risk adapted
damage control) should be performed in patients with
multiple trauma [4,5].

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This trial investigates the differences in clinical outcome
of primary internal fixation (early total care) or temporary
external fixation (damage control) in multiple trauma
patients with femoral shaft fractures. The two procedures
will be examined concerning the severity of organ failure
[sepsis-related organ failure assessment- (SOFA) score as
primary endpoint] [21,22]. Furthermore, it shall be scru-
tinized to what extent the choice of treatment depends on
anatomic and physiologic damage severity.
Methods/Design
Trial design
This trial is designed as a randomized controlled two-arm
interventional multicenter trial. No blinding is per-
formed. Both damage control and primary definitive sur-
gery are standard care.
Objectives
Primary objective of the trial is to clarify the question of
whether a risk adapted procedure in treating femoral shaft
fractures in multiple trauma patients as opposed to an
early definitive treatment strategy leads to an improved
outcome with respect to morbidity and mortality and if
yes at what costs.
Furthermore, it shall be scrutinized to what extent the
choice of treatment depends on anatomic and physiologic
damage severity.
Eligibility
Inclusion criteria
• Multiple trauma (injury of at least two body regions)
• Injury severity score (ISS) ≥ 16
• Femoral shaft fracture which can be treated in principle
by nail or fixateur externe
• Beginning of surgical treatment within 24 hours after
trauma
• Patient aged 18 years and older
• Calculated probability of death between 20% and 60%
[23,24]
• All factors known which are needed for the calculation
of probability of death [age, ISS, Glasgow Coma Scale
(GCS), base excess (BE), prothrombin time]
Table 1: Criteria, which have been recommended by various authors in order to define patients in whom early definitive
osteosynthesis might be disadvantageous: Variables not validated.
Author (year)[Reference]
Suggested dependent variable
Trentz (1978) [10]Cardiopulmonary, coagulation and metabolic criteria
Sturm (1984) [11] Thoracic trauma
Seibel (1985) [12] Oxygen transport, coagulation
Burchardi (1990) [13]Circulation, coagulation
Van Os (1994) [14]Cardiovascular condition
Reynolds (1995) [15]Resuscitation, additional injuries (head, chest, pelvic fracture), delay
Friedl (1996) [16]ISS
Scalea (2000) [17]Physiology, additional injuries (head, thorax, abdomen)
Rixen (2001) [24]Prognostic factors: Age, ISS, GCS, BE, coagulation
Pape (2001) [18]ISS, additional injuries (thorax, abdomen, pelvis), cardiopulmonary criteria, coagulation, temperature, IL-6,
„borderline patients“
Kutscha-Lissberg (2001) [19]Circulation, volume loss, coagulation
Brundage (2002) [20]Hemodynamics, preoperative resuscitation
ISS: Injury Severity Score; GCS: Glasgow Coma Scale; BE: Base Excess; IL-6: Interleukin 6

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Exclusion criteria
• III° open fractures
• Endangerment of the patient by one of both strategies
• Refusal of one of both strategies by either the investiga-
tor or the patient
• Start of internal or external fracture fixation before ran-
domization
• Participation in concurrent interventional trials
• Pregnancy
Reasoning for inclusion and exclusion criteria
The inclusion of patients with multiple trauma and corre-
sponding fractures arises from the question of the study
itself. Patients with thoracic or cranial trauma will be
included according to systematic review of literature.
As patients might be randomized into the group "primary
definitive surgery", patients in whom this procedure is not
feasible or can not be performed (begin of surgery not
within 24 hours possible or different procedure initiated)
must be excluded.
The calculation of the probability of death with the given
formula (see below) is a validated method of estimating
the probability of death in multiple trauma patients [23-
25]. It is essential though that all parameters entered are
present at the time of calculation. Patients with missing
values that are needed can not be included into the study.
Considering probability of death at randomization will
allow an equal distribution of global prognosis in both
treatment arms. Because the most important factors that
determine prognosis in multiple trauma patients are con-
sidered, a comparison of this heterogenic patient collec-
tive is possible.
Open fractures are not an exclusion criteria per se [26].
Only III° open fractures will be excluded from this study
as many surgeons do not favour the option of nailing in
such severe open fractures [27,28].
Patients included in or about to be included in other inter-
ventional trials or trials involving drugs of any kind must
be excluded out of judicial and scientific reasons.
Interventions
Experimental intervention
Temporary fracture fixation with fixateur externe and sec-
ondary reamed intramedullary nailing not earlier than 48
hours after trauma.
Control intervention
Primary reamed nailing of the femoral shaft fracture.
Early treatment will be performed, depending on the
result of randomization, within 24 h (early) with defini-
tive internal stabilization (control intervention) or in two
separate procedures with primary temporary fixation (fix-
ateur externe) and definitive internal stabilization at a
later time point (experimental intervention).
The second procedure may not be initiated before 48
hours after trauma unless there are urgent medical reasons
demanding early management. These reasons must be
documented.
Thus, as soon as the patient stabilizes with ventilation,
coagulation, hemodynamics, and the metabolic system
secondary surgery can be performed (but not earlier than
48 hours after trauma).
The following criteria are defined as a sign of patient sta-
bilization:
1. Ventilation paO2/FiO2 > 200 (if ventilated) or no need
for ventilation
2. Coagulation prothrombin time > 60% and platelets >
60,000/μl
3. Hemodynamics no need for Noradrenalin or Adrena-
lin and MAP > 60 mmHg
4. Metabolic system BE >-6.0 mmol/l
Furthermore, none of the signs listed below of systemic or
local inflammation should be present:
Temperature > 38.5°C
White blood cell count > 20,000/μl or < 4,000/μl
Local pin infection
Control/Comparators
The chosen control regimen (primary reamed nailing) is
currently as well established in routine care as the experi-
mental intervention (temporary fracture fixation with fix-
ateur externe and secondary reamed nailing not earlier
than 48 hours after trauma). As discussed above, so far
there is no evidence that one of the treatment regimens is
superior to the other [4,5].
Method of assigning patients to treatment groups
All multiple trauma patients with femur shaft fractures
and age > or = 18 years that present to the involved hospi-

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tals will be recorded and eligibility will be checked. The
probability of death will be calculated on the trial website
using clinical data as described below. If all inclusion cri-
teria are fulfilled the patient will be randomized and doc-
umentation will be started (figure 1). Reasons for non-
inclusions must be recorded. Allocation concealment will
be guaranteed by internet randomization where patients
have to be named before allocation to one of the therapy
arms. The validated system for internet randomization
will be provided by the Coordinating Center for Clinical
Studies Cologne (KKSK). This system generates the alloca-
tion sequence as follows: The randomisation sequence is
blocked using varying block sizes between 6 and 10. Fur-
thermore, randomisation is stratified by study center, in
order to adjust for center-specific variation in treatment
routines.
Calculation of probability of death
The probability of death will be calculated according to
the following formula of Rixen et al. [23,24]:
With:
BE Base Excess (mmol/l)
Quick Prothrombin time (%)
Age Age of patient
GCS Glasgow Coma Scale
ISS Injury Severity Score
This calculation can be done by entering the five variables
at the trial website just before randomization. The indi-
vidual probability of death is visible to the investigator.
Other baseline characteristics
The pattern and severity of injuries will be documented in
detail. For each body region the AIS (abbreviated injury
scale) will be used to quantify injury severity. This allows
to calculate standard prognostic scores, such as the ISS
and the New ISS. In addition the TRISS score will be used
to describe injury severity. A fourth more recent score will
also be used to describe the severity of trauma. This score,
the revised injury severity classification (RISC) score,
includes nine variables and has been shown to have very
good prognostic capacity. However, as the RISC requires
more variables (some of which may not be available in
the emergency room quickly), this score will only be used
for explorative adjustment of analyses.
In addition to these variables, standard demographic
parameters (gender, body mass index, etc.), further phys-
iologic variables (heart rate, temperature, etc.), routine
laboratory results on admission (hemoglobin, leukocytes,
creatinine, etc.), comorbidities (liver cirrhosis, immuno-
suppression, renal insufficiency, acute myocardial infarc-
tion, etc.) and medical management before
Pe
Death
BE
*
Quick
*
Age
=+
−−−+−
1 1/(
01551 0 084 { [ ,0 0359,0 0438,0,*,2 2067 0 0252,**]})
GCS ISS
+
Frequency and scope of study visits: Simplified visit plan
Figure 1
Frequency and scope of study visits: Simplified visit plan. R = Recruitment and Randomisation; Fix. ex. = Fixateur
externe; F/U = Follow-Up; Data marked with an asterisk (*) will be collected only if they are available from routine measure-
ments.
6-m.
F/U
ICU data
recording
Clinical data
recording
12-m.
F/U
Treatment
progress
R
Quality of life
assessment
Laboratory
parameters
Immunology
sampling
Nail
until dis-
charge
Elegibility
and consent
as
available
First week
• •• • 5 • •
Second week
• • 10 •• • •
Third week
15 •• • • 20 •
Fourth week
• • • 25 •• 28
Day
0
X
X X X X X X XXX X X X X X X
X X X X X X XX X X X X X X
X
XX
X
X
X
X
X
X
Dis-
charge
Fix.
ext.
Nail
X X X X X X XX X X X X X X
X X X X X X XXX
X*X* X*X* X* X*X*X*X* X*X* X* X*X*
XXXX X X X X X XX X X X X X X
X*X* X*X* X* X*X* X*X* X*X* X* X*X*
Discharge
from ICU
Discharge
from ICU
as
available

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randomisation (volume loading in the field and in the
emergency room, need for thoracic drainage, radiographs
done on admission, etc.) will be recorded.
Prior and Concomitant Therapy
All concomitant surgical and non-surgical therapy is
allowed and key aspects (ventilation, surgery etc.) will be
recorded.
Outcome measures
Primary efficacy endpoint
Primary endpoint is the reduction of organ failure as
measured by the maximum SOFA score within 28 days
after trauma.
The SOFA score has been developed for the sequential
evaluation and description of organ failure and has been
shown to be a suitable indicator of prognosis in trauma
patients [29]. For the present trial, the 5 item SOFA score
(exluding CNS) will be used. The central nervous system
(CNS) will be excluded due to the known problems in
receiving valid data from patients who were intubated and
ventilated. Thus the maximum SOFA score will be 20
points (4 points for each organ).
The SOFA score will be assessed daily for the first 28 days
after trauma (figure 1). Documentation will start on ICU
and will be continued until the patient is returned to a
normal ward, where the SOFA score will be set to zero. If
the patient is discharged home within the first 28 days,
SOFA score is set to zero by definition. If the patient is
transferred to another hospital, the last observation will
be continued until day 28. Patients who died during the
first 28 days after trauma will be assigned the maximum
possible SOFA score (20 points) for each day after death.
From the daily assessment of SOFA score, the worst value
within the first 28 days will be used as primary endpoint.
This corresponds to the intuitive mechanism of reducing
the "second hit" which is induced by the operative
trauma.
Secondary endpoints
• Hospital mortality
• Cumulative organ failure = sum of SOFA score points for
the first 28 days
• Incidence of Acute Respiratory Distress Syndrome
(ARDS)
• Incidence of Systemic Inflammatory Response Syn-
drome (SIRS) and sepsis during ICU stay
• Quantity and duration of surgical interventions, anaes-
thetics, and costs of surgery (material, time)
• Length of ICU stay
• Length of hospital stay
• Number of ventilator-free days
• Therapeutic Intervention Scoring System (TISS) 28 dur-
ing ICU stay
• Rate of phlegmona of the medullary cavity
• Rate in which conversion to internal fixation was not
possible (DCO group only)
• Rate of pseudarthrosis
• Functional outcome at discharge, 6 and 12 months after
trauma
• Quality of life at 6 and 12 months after trauma (deter-
mined by POLO chart [30])
• Glasgow Outcome Scale (GOS) at discharge, 6 and 12
months after trauma
• Return to work
Adverse events
All adverse events (AE) during hospital stay will be docu-
mented for both study groups. Rate of serious adverse
events (SAE), e.g. mortality or ARDS incidence, are part of
the secondary endpoints and will be monitored closely.
Serious adverse events will be reported to the Principle
Coordinating Investigator as soon as possible, at the latest
within 24 hours.
Possible complications of the risk-adaptive treatment
(„damage control orthopedics”, DCO):
Since there are at least two interventions in this treatment
arm, there is a hypothetical higher risk of infection in
these patients, longer ventilation time, and a certain rate
of patients in whom no change from fixateur externe to
intramedullary nail is possible and thus, resulting in a
higher rate of pseudarthrosis, worse functional result,
delayed weight bearing and lower quality of life.
Complications of the primary definitive treatment are pri-
marily the hypothetically higher mortality, increase in
duration and rate of SIRS, sepsis and/or multi organ fail-
ure (MOF).
Expected Adverse Events
Complications of surgery include:

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• Infection
• Delayed healing
• Bleeding
• Nerve injury
• Tendon and muscle injury
• Thrombosis/embolism
• Pseudarthrosis
• Compartment syndrome
Proposed sample size/Power calculations
The primary hypothesis is that the damage control princi-
ple is able to reduce the extent of organ failure. Organ fail-
ure is measured daily by the SOFA score (five organs,
excluding CNS, 04 points per organ). The maximum
SOFA score during ICU stay is used as primary outcome
measure. It is assumed that the maximum SOFA score
could be reduced by 12 points. This corresponds to a
reduction from "organ failure" to "organ dysfunction", or
from "organ dysfunction" to "normal organ function" for
one organ. Data from Ferreira et al. indicate that a 2 point
increase in SOFA score correlates with an average 10%
increase in mortality [29]. According to the database of
the Deutsche Interdisziplinäre Vereinigung Intensiv-
medizin (DIVI; quality assessment in intensive care;
45.000 admissions 20002004) maximum SOFA score is
about 3.2 ± 3.2 in a general ICU population, and 3.3 ± 3.1
in emergency admissions with trauma. Thus the estimated
effect (1.5 points reduction) corresponds to a standard-
ized effect size of 0.5. Assuming usual error rates (a = 0.05;
b = 0.20), 64 patients per group would be required. How-
ever, due to the non-normal nature of the distribution and
the use of non-parametric statistics, the number of
patients to be randomized has to be increased by 10%.
Thus, the total sample size is set to 140 patients (70 per
group). Compliance and rate of loss to follow-up do not
affect primary outcome measures.
Feasibility of recruitment
According to the Trauma Registry of the DGU (1993
2004, n = 20.815), 12% of multiple trauma cases had a
fracture of the femoral shaft. The limitation to patients
with ISS ≥ 16 does not change this rate. A level 1 trauma
center treats 50100 severe trauma patients each year (as
observed in the German Trauma Registry). Thus, 15 par-
ticipating centers will be able to screen at least 1000
patients per year. The number of appropriate patients with
femur shaft fractures is 6 12 per year per center. Regarding
the fact that not every case could be included due to
organisational difficulties, only about half of these cases
will be included and randomized.
Statistical analyses
The main outcome variable is the maximum SOFA score
during ICU stay. In order to have comparable periods, the
time period for SOFA score assessment is limited to the
first 28 days after trauma. Documentation of daily SOFA
scores is continued in intermediate care or other high
dependency units.
The maximum SOFA score will be compared using non-
parametric statistics (U-test) due to the substantial skew-
ness of the distribution. Since severity of trauma is
assumed to be a major determinant of outcome (includ-
ing rate of organ failure) the comparability regarding
Injury Severity Score (ISS) is tested before analysis. In case
of substantial imbalance (p < 0.15; U-test) a stratified
analysis of outcome will be performed (two groups; ISS ≤/
> 30 points).
Analysis will be done according to intention to treat;
regarding to the per protocol (PP) analysis we expect the
PP-population to be 5% less.
There will be one interim analysis of data collection when
about half of the expected sample size has been included
(70 cases). The p-value for the interim analysis will be set
at 0.005 so that the final analysis will be done at a signif-
icance level of 0.048, according to Fleming and O'Brien
[31].
During interim and final analysis, a detailed safety analy-
sis will be performed by comparing predicted and
observed survival within each group and reviewing indi-
vidual cases of non-survivors.
In addition, all secondary endpoints mentioned in the
protocol will be considered for explorative analysis,
because these factors are repeatedly named in the discus-
sion about the advantages of damage control orthopedics.
The aim of presenting all these data is not a confirmative
statistical testing, but rather to serve as a basis for compar-
ative analyses in future meta-analyses regarding damage
control orthopedics versus early total care strategies.
The hospital perspective on costs includes the initial and
all secondary operations or readmissions until one year
after randomization. As most costs during hospital stay
are caused by surgery itself and ICU care, data collection
and statistical analysis will focus on these two aspects. The
results will be reported as a cost-effectiveness analysis
using life-years lost as the measure of treatment benefit.

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These analyses will employ decision-analytic models for
the optimum management of multiply injured patients
with femoral shaft fracture.
Trial organization
Prof. Dr. med. Dieter Rixen is the Principle Coordinating
Investigator.
Participating trial centers and Investigators are listed in
the Acknowledgements. Additional trial centres may be
added.
Trial Steering Committee
The Trial Steering Committee will monitor and supervise
the trial and comment on any proposed major protocol
amendments (see Acknowledgements).
Data safety monitoring board
The data safety monitoring board (DSMB) will ensure the
safety of the trial.
Trial-supporting facilities
The Coordinating Center for Clinical Trials Cologne
(KKSK) will provide the infrastructure for data manage-
ment and internet randomization.
Statistical analysis will be performed in collaboration
with the Institute for Operative Medicine (IFOM) at the
University of Witten-Herdecke.
The trial is financially supported by the Deutsche Forsc-
hungsgemeinschaft (DFG) [grant number: RI 929/3-1].
Trial documentation and data collection
Electronic case report forms (eCRF) will be used for docu-
mentation. However, quality of life and other self rating
parameters are regarded as source data and will only be
contained in paper based CRF.
Quality assurance/Monitoring
In order to guarantee a high quality of the study and data
retrieval, all participating centers will be visited on a regu-
lar base on site by monitors. Data protection rights will be
respected. Randomly selected patients files will be ana-
lyzed to control original data and to verify accurate data
registration and management (100% source data verifica-
tion in 15% of the patients). The presence of a written
informed consent form and the correct interpretation of
inclusion and exclusion criteria will be controlled in all
patients. The monitor will particularly concentrate on
adverse events, the number of drop-outs, and excluded
patients. The investigators in the participating centers will
support the monitor in his/her activities.
The steering committee or its designees (clinical moni-
tors) may visit participating centers to control adherence
to the protocol. Surgical procedures may be evaluated by
the Steering Committee, the DSMB or qualified personnel
assigned by it.
The database will be checked for faults and validated by
the database programmer. Thereafter the database will be
approved for data entry (including full audit trail). Com-
plete and incremental data backup will be performed reg-
ularly.
Ethical consideration
The pros and cons of both treatment principles have been
discussed above. Clear evidence for the superiority of one
of the strategies does not exist. Nowadays, patients with
multiple trauma are treated either with primary external
fixation or primary internal nail fixation in the sense of
early total care or risk adapted damage control. Which of
these two principles will be performed often depends on
the general hospital strategy. To give a clear cut picture:
which treatment will be applicated depends on the hospi-
tal the patient enters by chance, the surgeon on duty by
chance, as well as patient characteristics.
Participating centers must be trauma level I centers with
great experience in multiple trauma care. Both strategies
must be established in the hospital, the operating surgeon
must be experienced in both strategies as well. Only
patients are enrolled in whom both strategies can be per-
formed and only if the surgeon is capable to perform both
strategies in this particular patient. The surgeon is allowed
to switch the treatment if there are technical or medical
reasons for this.
Ethics Committee (EC) or Institutional Review Board (IRB)
The final study protocol, including the final version of the
written informed consent form, was approved by the eth-
ics committee of the University of Cologne, who is
responsible for the Clinical Principal Investigator before
commencement of the study.
Ethical Conduct of the Study
The study is conducted according to ICH-GCP (Interna-
tional Conference on Harmonisation for Good Clinical
Practice in clinical research), as set out in the European
Union Clinical Trials Directive (2001) and associated UK
Regulations (2004), which adhere to the principles of the
Helsinki Declaration.
Particular aspects are the study protocol, patient informa-
tion sheet, informed consent form, submission to EC,
administrative documents, data registration, registration

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of adverse events, preparation for inspection and internal
audit by authorized personal or the DSMB, and storage of
study documents.
Before inclusion (i. e. before randomization or any other
study specific procedure is undertaken), patients will be
informed about the trial. However, it is expected that at
time of admission, the majority of patients suitable to par-
ticipate in this trial will not be able to give consent due to
the severity of their injuries and/or the nature of prehos-
pital therapy (i.e. intubation). If this situation occurs,
informed consent could only be obtained from the
patient's legally authorized representative. In the event
that the patient's legally authorized representative is not
available, the patient can be enrolled under waiver of
informed consent. This way of enrollment requires a
"Physician Authorization Form", where an independent
physician and an impartial witness confirm by signature
that all above-mentioned regulations were adhered to.
The waiver of informed consent also requires that there is
no clue either from the patient's side or from the family
members objecting against trial enrollment. The Physi-
cian Authorization Form will also be signed by the inves-
tigator.
This process of enrollment using the waiver of informed
consent is in accordance with German law and interna-
tional standards of research. Due to the urgency of surgical
treatment, it is not possible to obtain informed consent
from a legal representative appointed by jurisdiction (i.e.
Vormundschaftsgericht). It also is impossible to inform
the general public about the trial through public notifica-
tions.
The patient will be informed about the trial as soon as
possible and will be asked to sign the applicable informed
consent form to continue participation in the trial. This
consent (or its withdrawal thereof) supersede the author-
ity of any previous authorization for trial enrollment.
Patient information will be updated if new relevant infor-
mation gets available changing the risk-benefit assess-
ment. Patients already enrolled into the study will be
informed by the investigator especially if patient's safety is
concerned.
The patient will not pay any costs attributed to the type of
procedure or investigational device.
Publication
Results of the study will be published after approval by the
clinical and scientific advisors, Principal Coordinating
Investigators, and statistician in an international scientific
journal and/or presented on international scientific meet-
ings.
The Principal Investigators will provide the Ethics com-
mittee with a summary of the trials outcome, and if appli-
cable the regulatory authorities with any reports required.
All publication will maintain data protection of patient
data as well as data of the participating investigators.
Time Schedule
Inclusion first patient (FPFV): 01.07.2007
Inclusion last patient (Randomization): 01.07.2010
Last patient out (LPLV): 01.07.2011
Database closure: 01.10.2011
Termination statistical analysis: 31.01.2012
Study report: 01.07.2012
Discussion
Today, there is a trend towards the concept of "Damage
Control Orthopedics" in the management of multiple
trauma patients with long bone fractures. But, evidence
from the current literature is insufficient. As discussed
above, results are contradictory, a generalized manage-
ment strategy is missing. Thus, in the era of "evidence-
based medicine", there is the need for a more specific,
clarifying randomized controlled trial. Therefore this new
trial was initiated.
To our knowledge, this trial is the first to evaluate the risk
adapted damage control orthopedic surgery of femur shaft
fracutres in multiple trauma patients in a randomized
controlled design. In 2003, Pape et al. [32] presented their
results of a randomized controlled trial. They investigated
the impact of intramedullary instrumentation versus
damage control for femoral fractures on immunoinflam-
matory parameters and complications [32,33]. But, in
contrast to this study, where a risk adaption is performed,
they excluded multiple trauma patients with severe brain
and thoracic injuries (AIS > 3) and patients in unstable or
critical condition, too. In summary, the included patients
were injured less severely. Furthermore, Pape et al. did not
define criteria that must be fulfilled for performing the
secondary definitive procedure. Therefore these two trials
are not comparable in the authors' opinion.
Since there is still no clear evidence for the superiority of
one of the strategies participation in the trial is not associ-
ated with an increased risk by itself. If one of the strategies
proves superiority the benefit (reducing the organ failure)
is evident. The main endpoint is a surrogate endpoint for
mortality, i. e. the trial may lead to a definite treatment
strategy in patients with multiple trauma lowering the

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overall mortality. If non-inferiority of the primary internal
fixation can be proven, it can be assumed that hospital
stay, number of operations etc. are lower in this group,
thus lowering the expenses.
Although mortality would have been the most appreci-
ated endpoint, a trial with mortality as the main endpoint
would need approximately 1300 patients per arm. In
addition to the fact that such a trial is almost undoable for
practical reasons the concentration on mortality does not
cover all aspects of the planned intervention since the
damage control approach primarily tries to limit the
sequelae of the "second hit" by surgical intervention. This
is reflected by the measurement of organ failure by
appointing maximum values for patients who died. The
SOFA score has been developed for the sequential evalua-
tion and description of organ failure and has been shown
to be a suitable indicator of prognosis in trauma patients
[29].
A significant effect may only be shown in a group of
medium probability of death (2060%), especially con-
cerning maximum SOFA-score, as the type of procedure
chosen in patient groups of very high or very low mortal-
ity will most likely have only a minimal effect on this end-
point.
Because the most important factors that determine prog-
nosis in multiple trauma patients are considered, a com-
parison of this heterogenic patient collective is possible.
In the current literature, another facet of the optimal sur-
gical treatment in multiple trauma patients is discussed:
Biochemical/immunologic factors. It has been shown that
the traumatic tissue damage stimulates a maximal activa-
tion of the immune system, which leads to its depletion
and debilitation [34-36]. As a consequence of a failing
immune system a systemic inflammatory response syn-
drome (SIRS) or sepsis can occur. Both are potentially life
threatening complications, in the course of which all
organ systems can be affected [34,37,38].
Some of the best analyzed pro-inflammatory cytokines are
tumor necrosis factor (TNF)-α [39,40], and the interleuk-
ines (IL)-6 and IL-8 [41-43]. Circulating IL-6 is quickly
detectable after trauma [42] and has been shown to corre-
late with trauma load [44].
But so far, the transfer of results into clinical context and
the verification for potential decision making (therapy)
with respect to risk reduction during secondary surgical
procedures after trauma failed.
In extension to the clinical part of the present research a
further investigation is planned to monitor both study
groups for potential differences in immunofunction/-dys-
function as reflected by temporal patterns of selected cir-
culating mediators and markers for immuno-competence.
This approach may result in optimum individualized con-
cepts for fracture repair depending on the patient's indi-
vidual immuno-competence [45].
Nevertheless, the prerequisites for performing this study
give rise to hope for answering the question whether the
"early total care" or the „damage control” concept is asso-
ciated with better outcome.
Abbreviations
AE: adverse event; AIS: abbreviated injury scale; ARDS:
adult respiratory distress syndrome; BE: base excess; CNS:
central nervous system; CRF: case report form; CT: com-
puter tomography; DIVI: Deutsche Interdisziplinäre
Vereinigung Intensivmedizin; DSMB: data safety monitor-
ing board; DCO: damage control orthopedics; ETC: early
total care; GCP: good clinical practice; GCS: Glasgow
coma scale; GOS: Glasgow outcome scale; ICU: intensive
care unit; ISS: injury severity score; KKSK: coordinating
center for clinical studies Cologne; MODS: multi organ
dysfunction syndrome; MOF: multi organ failure; OF:
organ failure; PI: primary investigator (principle coordi-
nating investigator); RISC: revised injury severity classifi-
cation; SAE: serious adverse event; SIRS: systemic
inflammatory response syndrome; SOFA: sepsis-related
organ failure assessment; TISS: therapeutic intervention
scoring system; TRISS: Trauma Injury Severity Score.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
DR conceived and designed the trial, drafted the manu-
script and secured trial funding. ES prepared the trial's
standard operating procedures and eCRF and coordinates
multi-centre management. SS contributed to trial design
and prepared the trial's standard operating procedures. RL
participated in development of the trial protocol and
coordinates statistical analyses. MM participated in devel-
opment of the trial protocol and drafted the manuscript.
MGM participated in development of the trial protocol
(immunology). BB contributed to trial design. EAMN
conceived and designed the trial and secured trial fund-
ing. All authors read and approved the final manuscript.
Participating centers
Initiated centers (in alphabetical order)
1. Prof. N. P. Haas, Center for Musculosceletal Surgery,
Department of Trauma and Reconstructive Surgery, Uni-
versity of Berlin, Campus Virchow, 13353 Berlin
2. Prof. A. Ekkernkamp, Department of Trauma and
Reconstructive Surgery, Unfallkrankenhaus Berlin (UKB),
12687 Berlin

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3. Dr. J. Schmidt, Department of Trauma, Hand and
Reconstructive Surgery, Helios Hospital Berlin-Buch,
13125 Berlin
4. PD W. Zenker, Department of Trauma and Reconstruc-
tive Surgery, Vivantes Hospital Im Friedrichshain, 10249
Berlin
5. Prof. C. Wirtz, Department of Trauma Surgery, Univer-
sity of Bonn, 53127 Bonn
6. Prof. B. Bouillon, Department of Trauma and Ortho-
pedic Surgery, University of Witten-Herdecke at the Hos-
pital Cologne-Merheim, 51109 Cologne
7. Prof. K. E. Rehm, Department of Trauma, Hand and
Reconstructive Surgery, University of Cologne, 50937
Cologne
8. Prof. J. Windolf, Department of Trauma and Hand Sur-
gery, University of Düsseldorf, 40225 Düsseldorf
9. Prof. D. Nast-Kolb, Department of Trauma Surgery,
University of Essen, 45147 Essen
10. Prof. I. Marzi, Department of Trauma Surgery, Univer-
sity of Frankfurt, 60590 Frankfurt (Main)
11. Prof. R. Hoffmann, Center for Trauma Surgery, Beruf-
sgenossenschaftliche Unfallklinik
Frankfurt (Main)
Frankfurt, 60389
12. Dr. K. Brehme, Department of Trauma and Rehabilita-
tion Surgery, University of Halle, 06120 Halle (Saale)
13. Prof. C. Krettek, Department of Trauma Surgery, Med-
ical University Hannover, 30625 Hannover
14. PD F. X. Huber, Department of Trauma Surgery, Uni-
versity of Heidelberg, 69120 Heidelberg
15. Prof. T. Pohlemann, Department of Trauma, Hand
and Reconstructive Surgery, Saarland University Hospital,
66424 Homburg/Saar
16. PD M. Wenzl, Department of Trauma, Reconstructive
and Hand Surgery, Ingolstadt,
85049 Ingolstadt
17. Prof. A. Seekamp, Department of Trauma Surgery,
University Hospitals Schleswig-Holstein, Campus Kiel,
24105 Kiel
18. Prof. C. Josten, Department of Trauma and Recon-
structive Surgery, University of Leipzig, 04103 Leipzig
19. Prof. A. Wentzensen, Department of Trauma Surgery,
Berufsgenossenschaftliche Unfallklinik Ludwigshafen,
67071 Ludwigshafen
20. Prof. C. Jürgens, Department of Trauma Surgery, Uni-
versity Hospitals Schleswig-Holstein, Campus Lübeck,
23538 Lübeck
21. Dr. R. Ziegelmüller, Department of Trauma Surgery,
St. Marien-Hospital Lünen, 44534 Lünen
22. Prof. S. Ruchholtz, Department of Trauma, Recon-
structive and Hand Surgery, University Marburg/Giessen,
35043 Marburg
23. Prof. W. Mutschler, Department of Trauma Surgery,
University of München, Campus Innenstadt, 80336
Munich
24. PD S. Piltz, Department of Trauma Surgery, University
of München, Campus Großhadern, 81377 Munich
25. Prof. M. Nerlich, Department of Trauma Surgery, Uni-
versity of Regensburg, 93053 Regensburg
26. Prof. T. Mittlmeier, Department of Trauma and Recon-
structive Surgery, University of Rostock, 18057 Rostock
Participating centers, not yet initiated (in alphabetical order)
1. Prof. H.-J. Oestern, Department of Trauma and Recon-
structive Surgery, General Hospital Celle, 29233 Celle
2. Prof. K. M. Stürmer, Department of Trauma and Recon-
structive Surgery, University of Göttingen, 37075 Göttin-
gen
3. Prof. J. Rueger, Department of Trauma, Hand and
Reconstructive Surgery, University of Hamburg, 20246
Hamburg
4. Prof. U. Stöckle, Department of Trauma Surgery, Uni-
versity Hospital Rechts der Isar of the Munich Technical
University, 81675 Munich
Trial Steering Committee
Prof. Dr. med. Dieter Rixen, Department of Trauma and
Orthopedic Surgery, University of Witten-Herdecke at the
Hospital Cologne-Merheim, Ostmerheimer Str. 200,
51109 Cologne, Germany

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PD Dr. rer. medic. Rolf Lefering, Institute for Research in
Operative Medicine, University of Witten-Herdecke, Ost-
merheimer Str. 200, 51109 Cologne, Germany
Prof. Dr. med. Marc Maegele, Department of Trauma and
Orthopedic Surgery, University of Witten-Herdecke at the
Hospital Cologne-Merheim, Ostmerheimer Str. 200,
51109 Cologne, Germany
Acknowledgements
The Damage Control Study is entirely funded by the Deutsche Forschungs-
gemeinschaft (DFG).
We are grateful to the members of the Trial Steering Committee, the Data
Safety Monitoring Board and the Ethics Committee for their inputs which
led to the final protocol.
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