Stimulation of the local femoral
inflammatory response to fracture and
intramedullary reaming
A PRELIMINARY STUDY OF THE SOURCE OF THE SECOND HIT
PHENOMENON
J. R. Morley,
R. M. Smith,
H. C. Pape,
D. A. MacDonald,
L. K. Trejdosiewitz,
P. V. Giannoudis
From Leeds General
Infirmary University
Hospital, Leeds,
England
J. R. Morley, MD, FRCSEd,
Lecturer in Orthopaedic and
Trauma Surgery
D. A. MacDonald, MB, BS,
FRCS, Consultant Orthopaedic
and Trauma Surgeon
L. K. Trejdosiewitz, PhD,
Reader in Immunology
P. V. Giannoudis, MD, EEC
(Orth), Professor of
Orthopaedic and Trauma
Surgery
Academic Department of
Orthopaedic and Trauma
Surgery, Leeds University, The
General Infirmary at Leeds,
Clarendon Wing, Great George
Street, Leeds LS1 3EX, UK.
R. M. Smith, MD, FRCS, Chief
of Trauma Surgery
Orthopaedic Trauma Service
Massachusetts General
Hospital, YAW 3600, 55 Fruit
Street, Boston, Massachusetts
02114, USA.
H. C. Pape, MD, Chief of
Orthopaedic Trauma Surgery
Division of Trauma
University of Pittsburgh
Medical Center, Pittsburgh
15213, USA.
Correspondence should be sent
to Professor P. V. Giannoudis;
e-mail: [email protected]
©2008 British Editorial Society
of Bone and Joint Surgery
doi:10.1302/0301-620X.90B3.
19688 $2.00
J Bone Joint Surg [Br]
2008;90-B:393-9.
Received 11 May 2007;
Accepted after revision 30
October 2007
VOL. 90-B, No. 3, MARCH 2008
We have undertaken a prospective study in patients with a fracture of the femoral shaft
requiring intramedullary nailing to test the hypothesis that the femoral canal could be a
potential source of the second hit phenomenon. We determined the local femoral
intramedullary and peripheral release of interleukin-6 (IL-6) after fracture and subsequent
intramedullary reaming.
In all patients, the fracture caused a significant increase in the local femoral
concentrations of IL-6 compared to a femoral control group. The concentration of IL-6 in the
local femoral environment was significantly higher than in the patients own matched blood
samples from their peripheral circulation. The magnitude of the local femoral release of IL-6
after femoral fracture was independent of the injury severity score and whether the fracture
was closed or open.
In patients who underwent intramedullary reaming of the femoral canal a further
significant local release of IL-6 was demonstrated, providing evidence that intramedullary
reaming can cause a significant local inflammatory reaction.
In the ‘two hit’ model of the inflammatory
response to injury proposed by Bone,1 the initial
injury causes a release of inflammatory mediators and a systemic inflammatory response. As a
result, priming of the inflammatory system
occurs which is thought to result in the increased
sensitivity to further stimuli, such as surgery or
infection.1 After a moderate primary inflammatory reaction, a secondary response has been
shown to occur after surgery in already traumatised patients. This is known as the ‘second hit’
phenomenon2 which, if not controlled, may lead
to complications such as the systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS) and multiple
organ dysfunction syndrome (MODS).3 The
effects of the second hit phenomenon, including
significant morbidity and mortality, have been
described in previous studies.4-6
The release of inflammatory mediators, particularly interleukin-6 (IL-6), after surgery in
the traumatised patient has been shown to be a
good marker for measuring the magnitude of
the second hit response.7-9 A significant
increase in the systemic concentration of IL-6
has been demonstrated after femoral intramedullary nailing.7-10 The source of the pro-inflammatory cytokine IL-6 detected in the peripheral
circulation as part of the second hit phenomenon after femoral intramedullary nailing has
not been established. The central hypothesis of
this research was that femoral shaft fracture
and intramedullary nailing produce a local
femoral inflammatory reaction characterised
by the release of Il-6, which spreads into the
peripheral circulation, resulting in the second
hit phenomenon.
Patients and Methods
Skeletally mature patients who had sustained a
diaphyseal fracture of the femur requiring an
intramedullary nail between 2001 and 2004
were asked to participate in the study. Local
ethical committee approval was granted and
informed consent or assent was obtained from
the patient or their representative prior to their
inclusion in this investigation. Those with a
history of malignancy, age > 70 years, autoimmune disease or pregnancy were excluded.
Details concerning the age, gender, the mechanism of injury and all associated injuries were
recorded, and the Injury Severity score (ISS)
determined.11
Management of the fracture and the technique
of nailing. Patients underwent primary stabili-
sation of the fracture, either by intramedullary
nailing or by external fixation as part of a
‘damage control’ approach, within 24 hours of
injury. Primary nailing was carried out in
patients who were clinically stable using either
393
394
J. R. MORLEY, R. M. SMITH, H. C. PAPE, D. A. MACDONALD, L. K. TREJDOSIEWITZ, P. V. GIANNOUDIS
a reamed or an unreamed technique with insertion of a
solid femoral intramedullary nail (Synthes, West Chester,
Pennsylvania). The decision as to which technique was
used was made by the consultant responsible for the management of the patient. Routine antibiotic prophylaxis of
1.5 g intravenous cefuroxime was given to all patients at
induction of anaesthesia. Reaming was performed using
reamers (Synthes) in 0.5 mm increments to at least 1.5 mm
above the selected diameter of the nail, with radiological
screening to assess reduction of the fracture and insertion
of the nail.
A damage control approach was taken when patients
had either a thoracic injury (abbreviated injury scale
(AIS)11 ≥ 3) in addition to a femoral fracture, bilateral
femoral fractures, or were clinically unstable.9-12 The decision to use this approach was made by the surgeon (PVG).
Primary external fixation was carried out in these patients
using the Hoffmann II external fixator (Stryker, Kalamazoo, Michigan). They then had femoral nailing when they
were clinically stable following resuscitation. Their clinical course was monitored daily and specific complications, including ARDS, sepsis, MODS and death, were
recorded using established diagnostic criteria and scoring
systems.13,14
Control groups. A control group was established to define
the cytokine content of the normal femur. This femoral
control group consisted of patients undergoing elective
total hip replacement (THR) for osteoarthritis (OA).
Patients with auto-immune conditions such as rheumatoid
arthritis (RA) or a history of malignancy were excluded. A
cemented THR (Charnley Prosthesis, Depuy, Leeds,
United Kingdom) was carried out on these patients
through a lateral approach with an osteotomy of the
greater trochanter. The femoral neck was divided and
blood samples were acquired as detailed below, prior to
the preparation of the femoral canal.
A second control group of healthy volunteers attending
orthopaedic clinics was also used. Peripheral venous IL-6
concentrations had previously been measured in these
patients. This was designated the peripheral control
group.
Blood sample acquisition. Peripheral and femoral blood
samples were collected in Vacutainer bottles (Becton Dickinson, Oxford, United Kingdom) containing potassium ethylenediamine tetra-acetic acid (EDTA), to allow the
preparation of plasma samples. Peripheral blood samples
were taken on admission to hospital and throughout surgery at specific points in time. In the operating theatre,
samples were taken at the induction of anaesthesia to
establish a baseline, at the inital entry into the femoral
canal, after reaming if performed, and at the end of the
nailing procedure. Peripheral blood samples were also collected on days 1, 3, 5, and 7 after surgery.
Femoral blood samples were obtained using a Levintype Gastro duodenal feeding tube (Vygon, Cirencester,
United Kingdom). These tubes were 125 cm long with a
diameter of 10 Fr (French gauge). They had a closed distal
tip, facilitating non-traumatic passage of the tube, and two
opposed lateral eyes that allowed sampling. Samples were
taken from the femoral diaphysis at least 10 cm from the
entry point in the piriform fossa.
Femoral blood sampling was carried out on entry into
the femoral canal, after reaming, prior to insertion of the
nail. Matched peripheral blood samples were taken at the
same time. A similar sampling procedure was carried out in
the femoral control group, in which peripheral blood was
taken at the induction of anaesthesia, on entry to the femoral canal, and at the end of the operation. Samples were
taken immediately after the femoral neck had been divided
and the head removed. The femoral canal was then opened
and blood samples were taken from the diaphysis.
All peripheral and femoral blood samples were processed
immediately after collection. The EDTA Vacutainer tubes
containing blood were centrifuged at 400 g (Mistral 3000;
MSE Scientific Instruments, Crawley, United Kingdom) for
ten minutes. The plasma collected was placed into 1.8 ml
test tubes and initially frozen at -20ºC. Samples were then
transferred to a freezer at -80ºC after 24 hours for longer
term storage.
Analysis of samples. For the detection of IL-6 in the plasma
samples a Human Cytokine Antibody 10-plex Bead Kit
(Biosource, Paisley, United Kingdom) or enzyme-linked
immunosorbent assay kit (ELISA) (R&D systems, Minneapolis, Minnesota) was used. Luminex and ELISA assays
correlate closely, with the ELISA value being equivalent to
the Luminex value multiplied by a correction factor (1.02
in the case of IL-6, from Biosource data).15
The majority of samples from the fracture and the femoral control group (n = 25) were analysed using the Cytokine Antibody Bead Kit technique on the Luminex 100 IS
System running StarStation Software (Applied Cytometry
Systems, Sheffield, United Kingdom).
Blood samples from six of the patients with fractures
were acquired after samples had been analysed using the
Luminex system. As the results of the ELISA and Luminex
techniques are comparable for economic reasons the determination of IL-6 concentrations in these six patients was
performed by the ELISA technique. A human IL-6 ELISA
kit (R&D systems) was used and samples were analysed on
an Opsys microplate reader (Dynatech Technologies, Horsham, Pennsylvania). The ELISA technique had previously
been used for the determination of IL-6 in the historical
peripheral control group using commercially-available IL-6
kits (R&D Systems).
Statistical analysis. As not all the data were normally distributed, a non-parametric test was used for all comparisons in order to maintain consistency. Statistical analysis of
non-parametric data was made using the Mann-Whitney
U-test and Spearman’s rank correlation. GraphPad Instat 3
statistical software (San Diego, California) was used for
processing and analysis of data. A two-tailed p-value of
< 0.05 was considered significant.
THE JOURNAL OF BONE AND JOINT SURGERY
STIMULATION OF THE LOCAL FEMORAL INFLAMMATORY RESPONSE TO FRACTURE AND INTRAMEDULLARY REAMING
395
Table I. Demographic data, including the injury severity score11 and the mechanism of injury, in patients who had unreamed femoral nailing. Highlighted patients had a damage control approach to their management, as detailed in Materials and Methods
Patient
1
Gender
Male
Age (yrs)
48
Mechanism of
RTA*
injury
13
Injury severity
score11
Abbreviated injury
score
Head & neck
Face
2
Thorax
Extremity
3
Abdomen
Open or closed
Open
Unreamed nail
Y
Complication
Timing of
secondary
nailing from injury
(hrs)
2
3
4
6
7
12
13
14
15
16
Male
54
RTA
Male
57
Crush
injury
34
Female Male
67
21
RTA
RTA
Male
17
RTA
Female Male
35
40
RTA
RTA
Male
18
RTA
Male
16
RTA
Male
16
RTA
Male
56
RTA
Female
24
RTA
18
13
Female Female Male
58
67
58
RTA
Fall
Crush
injury
15
16
9
33
16
32
16
2
3
Closed
Y
-
2
1
3
4
3
Closed Closed Closed
Y
Y
Y
-
1
4
4
4
3
4
3
3
4
Closed Closed Closed Closed Closed Open
Y
Y
Y
Y
Y
Y
96
96
96
29
3
4
2
Open
Y
36
3
3
5
3
Closed Open
Y
Y
-
5
9
3
Closed
Y
-
8
9
10
11
9
9
9
4
Open
Y
-
* RTA, road traffic accident
Table II. Demographic data, including the injury severity score11 and the mechanism of injury, in patients who had unreamed femoral nailing.
The highlighted patient had a damage control approach to their management, as detailed in Materials and Methods
Patient
17
18
19
20
21
22
23
24
25
26
27
28
Gender
Age (yrs)
Mechanism of injury
Injury severity score
Abbreviated injury score
Head & neck
Face
Thorax
Extremity
Abdomen
Open or closed
Type of nail
Complication
Timing of secondary
nailing from injury (hrs)
Male
22
RTA*
27
Female
16
RTA
9
Female
18
RTA
9
Male
35
RTA
9
Male
18
RTA
16
Male
34
RTA
9
Male
38
RTA
11
Female
47
RTA
18
Male
55
RTA
19
Female
22
RTA
26
Male
50
RTA
10
Male
61
RTA
22
3
3
3
3
3
4
3
Open
Closed Closed Closed Open
Reamed Reamed Reamed Reamed Reamed
UTI†
ARDS‡
288
1
1
3
3
Open
Closed
Reamed Reamed
-
1
1
1
3
3
3
3
3
3
3
3
4
2
Closed Closed Closed Closed Closed
Reamed Reamed Reamed Reamed Reamed
ARDS
* RTA, road traffic accident
† UTI, urinary tract infection
‡ ARDS, acute respiratory distress syndrome
Results
There were 28 patients with fractures of the femoral shaft
included in the study. However, only 27 femoral samples
were analysed, as one sample from patient number 19 in
the reamed group was spoiled during the running of the
samples. An unreamed nailing was carried out in 16
patients and reaming in 12. The demographic data are
shown in Tables I and II. Demographically, no statistically
significant difference was demonstrated between the groups
(Table III). Patients who had a damage control approach
applied to their management are highlighted in Tables I and
II (n = 4 in unreamed group, n = 1 in reamed group). Two
patients who had a reamed femoral nail developed ARDS.13
Both received respiratory support and went on to make a
VOL. 90-B, No. 3, MARCH 2008
full recovery. Another five patients, all with a high ISS
(≥ 27), were admitted to the intensive care unit for respiratory support as they had associated chest injuries, but none
developed ARDS. No patients developed MODS or died.
The femoral control group consisted of three patients
(median age 31 years; 18 to 74). The peripheral control
group comprised 20 healthy uninjured patients (median age
54 years; 23 to 85).
An analysis of the second hit phenomenon: the peripheral
IL-6 response to fracture of the femoral shaft and intramedullary nailing. Patients with a fracture had a significantly
elevated peripheral Il-6 concentration on admission to hospital compared to the peripheral control group
(p < 0.0001). Their median Il-6 concentration on admis-
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J. R. MORLEY, R. M. SMITH, H. C. PAPE, D. A. MACDONALD, L. K. TREJDOSIEWITZ, P. V. GIANNOUDIS
Table III. Summary of demographic data and injury severity score11 of patients treated with unreamed and
reamed femoral nailing techniques
All patients
Unreamed femoral nail group
Reamed femoral nail group
Number of patients
28
16
12
Gender
Female
Male
9
19
5
11
4
8
Age (yrs)
Mean (SD)*
Median
38 (8)
36 (16 to 67)
41 (19)
44 (16 to 67)
34 (16)
35 (16 to 61)
Injury severity score
Mean (SD)*
Median
17 (8)
16 (9 to 34)
18 (9)
16 (9 to 34)
16 (7)
14 (9 to 27)
* SD, standard deviation
Unreamed nail
Reamed nail
350
100000
| p = 0.0005 |
300
200
150
100
168 hrs
120 hrs
72 hrs
24 hrs
Canal entry
End of nailing
0
Induction
50
IL-6 concentration (pg/ml)
10000
250
Admission
IL-6 concentration (pg/ml)
400
Median
1000
100
10
______ Median
1
Control
Time of blood collection
Femoral fracture
Group
Fig. 1
Fig. 2
Graph showing median peripheral interleukin (IL)-6 concentration as a
function of time in the unreamed and the reamed nailing groups and
95% confidence intervals.
Graph showing local femoral interleukin (IL)-6 concentration at the
time of femoral canal entry in the femoral control group (n = 3) and the
femoral fracture group (n = 27) (♦, mean and 95% confidence intervals). The dotted line represents the assay sensitivity.
sion was 169 pg/ml (72 to 3205). The peripheral IL-6 concentration remained significantly elevated throughout the
seven days of the study (p < 0.0001). There was no statistically significant difference between the median peripheral
IL-6 concentrations in the unreamed and reamed groups
(Fig. 1).
There was a small rise in the peripheral IL-6 concentration immediately after reaming, although this change was
not statistically significant. The median concentration
before reaming was 186 pg/ml (61 to 297), and afterwards
was 201 pg/ml (67 to 329). At 24 hours after operation the
median peripheral IL-6 concentration was higher in the
reamed than in the unreamed group, but this difference was
not statistically significant.
The effect of the fracture on the local femoral and peripheral
IL-6 concentrations. Following the fracture there was a
significant elevation in the median intramedullary IL-6 concentration compared with the femoral control group
(p = 0.0005). The median femoral Il-6 concentration on
entry into the canal in patients with a fracture (n = 27) was
3947 pg/ml (128 to 25 689). The median femoral IL-6 concentration in the control group (n = 3) was 8 pg/ml (5 to 11)
(Fig. 2). The assay sensitivity was 3 pg/ml.
The median IL-6 concentration in the peripheral circulation after fracture was significantly elevated compared with
the peripheral control group (p < 0.0001). In the patients
with a fracture (n = 27) the median peripheral IL-6 concentration at the time of entry into the femoral canal was
THE JOURNAL OF BONE AND JOINT SURGERY
STIMULATION OF THE LOCAL FEMORAL INFLAMMATORY RESPONSE TO FRACTURE AND INTRAMEDULLARY REAMING
100000
| p < 0.0001 |
10000
Median
1000
Median
100
10
Femoral IL-6 concentration (pg/ml)
IL-6 concentration (pg/ml)
100000
397
10000
1000
100
10
1
1
Peripheral
Femoral canal
1
10
100
1000
10000
Peripheral IL-6 concentration (pg/ml)
Fig. 3
Fig. 4
Graph showing peripheral and local femoral interleukin (IL)-6 concentrations at the time of femoral canal entry in the femoral fracture group
(n = 27) (♦, mean and 95% confidence intervals). The dotted line represents the assay sensitivity.
Graph showing correlation between peripheral and femoral interleukin (IL)-6 concentrations in femoral fracture patients (n = 27) at the
time of femoral canal entry during intramedullary nailing.
215 pg/ml (60 to 1977). The median peripheral IL-6 concentration in the peripheral control group (n = 20) was
4 pg/ml (3 to 5).
The median femoral intramedullary IL-6 concentration
was significantly elevated compared with the median
peripheral IL-6 concentration at the time of entry into the
femoral canal in patients with a fracture (p < 0.0001)
(Fig. 3).
No statistically significant difference in the median local
femoral IL-6 concentration at the time of entry into the
canal was demonstrated between patients who had an open
or closed fracture of the femoral shaft. No correlation was
established between the median peripheral and femoral IL-6
concentrations (Spearman’s r value = 0.05, p-value not
significant, Fig. 4).
The effect of the ISS on peripheral and local femoral concentrations of IL-6. A correlation between an increasing ISS and
an increasing peripheral concentration of IL-6
was demonstrated (Spearman’s r value = 0.77, p < 0.0001).
This has been shown previously.16 No relationship was
established between the ISS and the femoral concentration
of IL-6 at the time of entry into the femoral canal (Spearman’s r value = -0.05; p-value not significant, Fig. 5).
The effect of femoral intramedullary reaming on local femoral concentrations of IL-6. In the patients who had a reamed
femoral nail (n = 11), reaming caused a significant elevation
in the local femoral concentration of IL-6 (p = 0.01). The
median IL-6 concentration in the femoral canal before
reaming was 3699 pg/ml (923 to 18 299) and after was
15903 pg/ml (1854 to 44922) (Fig. 6). There was no significant increase in the peripheral Il-6 concentration after femoral reaming or at 24 hours after the nailing procedure.
VOL. 90-B, No. 3, MARCH 2008
Discussion
Trauma, including fracture of the shaft of the femur, has
previously been shown to cause significant stimulation of
the inflammatory response system, resulting in the release
of cytokines and mediators such as IL-6 which are responsible for driving the inflammatory response.2,7,17 The proinflammatory cytokines and mediators released after injury
have been implicated in the development of the potentially
fatal complications ARDS and MODS.18-21 A further
increase in the systemic concentration of IL-6 has been
demonstrated after surgical procedures, including
intramedullary nailing of the femur.7,10
In this study, the concentrations of IL-6 within the femur
were significantly elevated compared with the femoral controls following fracture. As well as a local increase in IL-6
concentration, a significant elevation in the peripheral IL-6
concentration
compared
to
peripheral
controls
(p < 0.0001) was found in patients after injury, which
agrees with other published studies.2,7,16 However, the local
femoral elevation in IL-6 concentration was significantly
greater than the elevation in the peripheral circulation
(p < 0.0001), providing support for the view that a local
reaction in the femoral canal is responsible for the rise in
IL-6 found in the femur. One potential source might be the
osteoblasts, which are known to produce IL-6.22
The local femoral intramedullary inflammatory response
to trauma has not previously been described. Previous
research has documented the inflammatory constituents
present in the haematoma at the fracture site after injury.23
A massively elevated local concentration of IL-6 (mean
12 538 pg/ml) has been reported in haematoma sampled at
the time of surgery for open reduction and fixation of frac-
398
J. R. MORLEY, R. M. SMITH, H. C. PAPE, D. A. MACDONALD, L. K. TREJDOSIEWITZ, P. V. GIANNOUDIS
100000
100000
p = 0.006
|
|
Median
10000
IL-6 concentration (pg/ml)
IL-6 concentration (pg/ml)
|
1000
100
10
1
p = 0.006
|
0
5
10
15
20
25
30
35
40
Injury severity score
10000
Median
1000
p = 0.01
|
|
100
10
Median
1
Control
Pre-reamed
Post-reamed
Fig. 5
Fig. 6
Injury severity score and local femoral interleukin (IL)-6 concentration
at the time of femoral canal entry in all femoral fracture patients.
Local femoral interleukin (IL)-6 concentration at the time of femoral
canal entry in the femoral control group (n = 3), and in the reamed femoral nail group (n = 11) and after intramedullary reaming in the reamed
femoral nail group (n = 11) (♦, mean and 95% confidence intervals).
tures of long bones.23 A dramatic increase in the local concentration of IL-6, significantly greater than that in the
peripheral circulation, has been shown to occur in other
local inflammatory conditions, including bacterial peritonitis (mean 2595 pg/ml (SD 1360)) and in the peritoneal fluid
of patients with burns and an associated abdominal compartment syndrome (mean 6462 pg/ml (SEM 2052)).24,25
The finding that both trauma and infection can cause
dramatically elevated local concentrations of proinflammatory cytokines raises the question as to why these
cytokines are there. The local environment may be acting as
a cell-priming or stimulating zone. For example, the femur
has a rich vascular supply, and after a traumatic insult circulating cells involved in the inflammatory response such as
macrophages and leucocytes, will pass through the femoral
environment, where they may be stimulated or primed by
the pro-inflammatory cytokines present. The inflammatory
cells may then leave the local environment in a primed or
stimulated state, which may lead to either a local or a systemic effect by mechanisms previously discussed. An alternative explanation could be that the local reservoir of IL-6
sets up a pro-inflammatory cytokine gradient, where cytokines may travel from a local zone of higher concentration
to one of a lower concentration in the systemic circulation,
thereby modulating the inflammatory response.23 These
two hypotheses are not mutually exclusive, and it is
conceivable that a combination of these processes could
occur.
The rise in the peripheral IL-6 concentration correlated
in a linear fashion with the ISS.16 However, no such relationship was found between the rise in local femoral IL-6
concentration and the ISS, and there was correlation
between the peripheral and femoral IL-6 concentrations at
the time of entry to the femoral canal. Patients with both
closed and open fractures of the femoral shaft were
included in this study. It was thought that patients with an
open fracture might have a lower intramedullary concentration of IL-6, as IL-6 could be lost to the external environment both at the time of and after injury, but there was no
significant diference. Prior to reaming, the local femoral IL-6
concentration in patients with a fracture was significantly
elevated compared to the femoral control group
(p = 0.006). Reaming produced a further significant
increase in the local femoral concentration of IL-6
(p = 0.01) but did not have a similar effect on the peripheral
concentration. We were not able to compare the effect of
reamed with unreamed nailing on the local femoral IL-6
concentration. After insertion of the solid nail the femoral
canal was full and so did not allow further sampling of the
blood.
Femoral reaming has been shown to have beneficial local
effects, with improved times to fracture union compared to
unreamed nailing.26 This may be a result of the improved
stability of a reamed nail with a larger diameter. The reamings may also have osteogenic potential as does bone graft,
and come to be deposited at the fracture site. Our finding of
increased local concentrations of IL-6 after reaming raises
the question as to whether additional local action of IL-6
may be to contribute to bone remodelling, but further
investigation of this hypothesis is required.
Reaming of the femoral canal normally takes less than 30
minutes to perform. Up-regulation of mRNA for IL-6 in
inflammatory cells after stimulation has been shown to take
two to four hours, with maximal production of IL-6 occurring after four to six hours.27 Our finding of a significant
increase in local IL-6 concentrations within 30 minutes
THE JOURNAL OF BONE AND JOINT SURGERY
STIMULATION OF THE LOCAL FEMORAL INFLAMMATORY RESPONSE TO FRACTURE AND INTRAMEDULLARY REAMING
after intramedullary reaming poses the question as to the
possible molecular mechanisms responsible.
We found that the peripheral concentration of IL-6 was
significantly elevated at 24 hours after intramedullary nailing compared to healthy volunteer controls (p < 0.0001).
When the concentrations of IL-6, 24 hours after operation
in both the unreamed and reamed groups were compared to
the pre-operative concentrations, no significant difference
was seen. No significant further elevation or second hit phenomenon was demonstrated. The inflammatory state that
was demonstrated pre-operatively persisted after surgery
and was characterised by a significant elevation of peripheral IL-6 concentrations throughout the study. In previous
similar investigations femoral intramedullary nailing has
been shown to produce a second hit phenomenon. It is possible that the failure to demonstrate a significant second hit
phenomenon in our study could have been a cause of a type
II statistical error.7,9
Having established that the IL-6 concentration is
increased in the femoral canal following fracture and
intramedullary reaming, we wished to determine whether
the femoral canal could be the source of the second hit phenomenon. However, we were not able to determine whether
the IL-6 detected in the peripheral circulation originated
from the femoral canal or was produced in the peripheral
circulation. Sampling directly from the venous drainage
could have been achieved by cannulating the femoral vein
on the fractured side and sampling peri- and postoperatively. However, this additional procedure could have
inflicted further morbidity on the already traumatised
patient and it was decided not to undertake this.
A further way to study the processes occurring during
femoral intramedullary nailing would be to use a large animal model. Previous researchers have used sheep, allowing
the study of local and systemic changes during intramedullary nailing.28,29 The use of such a model could allow continuous monitoring of the venous outflow from the femur
both during and after femoral nailing and intramedullary
reaming to determine whether IL-6 and other proinflammatory cytokines were being released into the systemic circulation, generating the second hit phenomenon.
No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
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