Abstract
Background: Although infrequently reported in amputees previously,
heterotopic ossification has proven to be a common and problematic clinical
entity in our recent experience in the treatment of traumatic and
combat-related amputations related to Operation Enduring Freedom and Operation
Iraqi Freedom. The purpose of the present study was to report the prevalence
of and risk factors for heterotopic ossification following trauma-related
amputation as well as the preliminary results of operative excision.
Methods: We identified 330 patients with a total of 373 traumatic
and combat-related amputations who had been managed at our centers between
September 11, 2001 and November 30, 2005. We reviewed the medical records and
radiographs of 187 patients with 213 amputations who had adequate radiographic
follow-up. Additional analysis was performed for twenty-four patients with
twenty-five limbs that required excision of symptomatic lesions. The mechanism
and zone of injury, amputation level, timing of excision, use of prophylaxis
against recurrence, and other confounding variables were examined. Outcomes
were assessed by determining clinical and radiographic recurrence rates,
perioperative complications, preoperative and follow-up pain medication
requirements, and the ability to be fit with a functional prosthesis.
Results: Heterotopic ossification was present in 134 (63%) of 213
residual limbs, with twenty-five lesions requiring excision. A final
amputation level within the zone of injury was a risk factor for both the
development and the grade of heterotopic ossification (p < 0.05). A blast
mechanism was predictive of occurrence (p < 0.05) but did not correlate
with grade. All patients who had been managed with excision were tolerating
the prosthetic limb at an average of twelve months of follow-up. Twenty-three
limbs demonstrated no evidence of recurrence, and two limbs had development of
clinically asymptomatic, radiographically minimal recurrences. Six patients
experienced wound-related complications that required reoperation, and two
patients required subsequent minor revision surgery. There was a significant
decrease in the use of pain medication following surgery (p < 0.05).
Conclusions: Heterotopic ossification following trauma-related
amputation is more common than the literature would suggest, particularly
following amputations that are performed within the initial zone of injury and
those that are due to blast injuries. Many patients are asymptomatic or can be
successfully managed with modification of the prosthesis. For patients with
refractory symptoms, surgical excision is associated with low recurrence rates
and decreased medication requirements, with acceptable complication rates.
Level of Evidence: Prognostic Level II. See Instructions
to Authors for a complete description of levels of evidence.
Heterotopic ossification refers to the formation of mature lamellar bone in
nonosseous tissue. It is commonly observed following inciting events such as
spinal cord or traumatic brain injury, total hip arthroplasty, substantial
thermal or electrical burns, and acetabular or elbow fractures, particularly
those requiring operative treatment. Multiple general patient-related risk
factors for heterotopic ossification formation, as well as two genetic forms
of dysregulated skeletogenesis, have been
identified1.
In addition to the aforementioned causes, heterotopic ossification is
frequently noted as a potential cause of residual limb pain in
amputees2,3.
Indeed, in caring for several hundred traumatic and combat-related amputees
for the last four years as part of Operation Enduring Freedom and Operation
Iraqi Freedom, we have found it to be a common and problematic clinical
entity. Nonetheless, the literature to date contains only a few case reports
of amputations that have been complicated by heterotopic ossification, none of
which have required operative
treatment3-5.
Furthermore, an abundance of otherwise thorough manuscripts discussing
combat-related amputations from recent and distant historical conflicts made
no mention of heterotopic
bone6-11.
This would seem to suggest that, until now, heterotopic ossification was not a
common problem following either military or civilian trauma-related
amputations. However, historical texts suggest that it was appreciated as a
common problem following combat-related amputations at least as far back as
the American Civil
War12 and World War
I, as described by
Brackett13:
"Excessive terminal bone production in guillotined stumps was the rule.
The most common form was an irregular mushrooming, with a tendency to spurs on
the inner aspect of the femur. Occasionally, sharp exostoses were seen. These
often were sharp enough and long enough to cause sufficient pain to warrant
their removal."
The purpose of the present report was to review the recent experience at
two United States military amputee centers with heterotopic ossification in
amputees, with an emphasis on the clinical and radiographic recurrence rates
and complications after surgical excision of ectopic bone in appropriately
selected symptomatic patients. Additionally, we have attempted to identify the
prevalence of and risk factors for the occurrence of heterotopic ossification
in the residual limbs of traumatic and combat-related amputees who have been
managed at our two institutions since September 11, 2001. The results of the
current study were presented at a symposium on extremity war injuries
sponsored by the American Academy of Orthopaedic Surgeons, and the material
was previously published in
part14.
Following a protocol approval by both institutional review boards, we
performed a retrospective review of all traumatic and combat-related (i.e.,
nononcologic, nondiabetic, and non-vasculopathic) amputations in patients who
were managed at our centers between September 11, 2001 and November 30, 2005.
This yielded 330 patients with 373 amputations, including four triple
amputees. Of these, 187 patients (56.7%) with 213 amputations (57.1%) had
radiographs of the residual limbs made at least two months after the injury.
These patients constituted our study sample. The relationship between the
occurrence and magnitude of heterotopic ossification was then assessed on the
basis of patient gender, age (less than thirty years as opposed to thirty
years or more), the number of irrigation and débridement procedures,
the time from the injury to definitive revision and closure, and the
occurrence of early infection or wound dehiscence within three months after
attempted definitive closure. Detailed assessment of the occurrence and
magnitude of heterotopic ossification was also performed with regard to the
mechanism of injury (explosive blast [e.g., improvised explosive device or
rocket-propelled grenade] or nonblast [e.g., gunshot wound or motor-vehicle
collision]) and the level of the final amputation within or proximal to the
zone of injury. Amputations were considered to be within the initial zone of
injury if the area of the initial soft tissue and/or osseous injury was at or
proximal to the final level of definitive amputation (for example, at or
proximal to the middle part of the calf in a patient with a transtibial
amputation).
A number of radiographic grading and classification systems for heterotopic
ossification about the hip, knee, and elbow have been proposed. However, none
of those systems were directly applicable or readily adaptable to evaluate
ectopic bone within the residual limbs of amputees, particularly because of
the variety of amputation levels and anatomic regions involved. Therefore, we
developed a new, simple system for describing the magnitude of heterotopic
ossification on the basis of anteroposterior and lateral radiographs of the
residual limbs. We graded each limb on the basis of the single radiographic
view (either anteroposterior or lateral) of the residual limb that
demonstrated the greatest amount of ectopic bone. Heterotopic ossification was
considered to be absent if no soft-tissue mineralization was evident on
radiographs made at least two months after the injury. The ectopic bone was
considered to be mild if it occupied an estimated <25% of the
cross-sectional area of the residual limb on either the anteroposterior or
lateral radiograph (Figs. 1-A and
1-B), as moderate if it occupied 25% to 50% of the cross-sectional
area of the residual limb on either the anteroposterior or lateral radiograph
(Figs. 1-C and 1-D), and as
severe if it occupied >50% of the cross-sectional area of the residual limb
on either the anteroposterior or lateral radiograph
(Figs. 1-E and 1-F).
Furthermore, detailed assessment was then performed on the twenty-four
patients (twenty-five limbs) with symptomatic heterotopic ossification who had
undergone operative excision. All patients requiring operative excision were
male, with an average age of 26.2 years (range, nineteen to forty-six years).
Prior to excision, all patients underwent a trial of repeated activity and
prosthetic socket and liner modifications as well as assessment of other
potential sources of residual limb symptoms and medication adjustments as
appropriate. For these patients, the mechanism of injury, the level of the
final amputation, the zone of injury, the grade of heterotopic ossification,
the time between the injury and the excision of ectopic bone, the use of
perioperative adjunctive prophylaxis against recurrence with use of
nonsteroidal anti-inflammatory drugs and/or local irradiation, and potential
confounding variables (e.g., traumatic brain injury or spinal cord injury)
were recorded and analyzed. Although not routinely done, intraoperative
culture specimens that were obtained at the time of heterotopic ossification
excision were also reviewed when available. Outcome assessment for patients
requiring excision was performed on the basis of clinical and radiographic
evidence of recurrence, the ability to be fitted with a functional prosthesis
(as was universally not possible prior to surgery), preoperative and follow-up
narcotic and neuropathic medication requirements, perioperative complications,
and subsequent amputation revisions.
Statistical Analysis
Statistical analysis was performed with use of SPSS software (v.12.0.1;
SPSS, Chicago, Illinois). Descriptive statistics were performed for all
groups, and potential differences between rates and proportions of occurrences
were assessed with use of chi-square analysis and the Fisher exact test, as
appropriate, with the level of significance set at p < 0.05. Differences in
the number of irrigation and débridement procedures and in the number
of days from the injury to definitive closure were assessed by means of the
Mann-Whitney rank-sum test.
Heterotopic Ossification: Prevalence, Magnitude, and Risk
Factors
Of the 213 residual limbs with radiographs that had been made at least two
months after the injury, 134 (63%) demonstrated evidence of heterotopic
ossification. The lesion was graded as moderate or severe in seventy-two limbs
(34%) (Table I). There was no
apparent relationship between gender (?2 = 0.37; p = 0.55) or
age (?2 = 0.07; p = 0.78) and the occurrence of heterotopic
ossification; of the five female amputees with adequate radiographic
follow-up, two had mild heterotopic ossification and three had no heterotopic
ossification.
Both a final amputation level within the initial zone of injury
(?2 = 59.8; p < 0.0001) and a blast mechanism of injury
(?2 = 4.43; p = 0.035) were significant predictors of the
occurrence of heterotopic ossification. Indeed, of the 147 amputations that
were due to blast injuries and that occurred within the initial zone of
injury, 117 (80%) were associated with the development of ectopic bone, which
was graded moderate or severe in sixty-six limbs (45%); conversely, of the six
amputations that were due to nonblast mechanisms and that occurred proximal to
the initial zone of injury, none was associated with the development of
heterotopic ossification. A final amputation level within the initial zone of
injury also was predictive of the magnitude and grade of heterotopic
ossification (?2 = 24.5; p < 0.0001). A blast mechanism of
injury was predictive of the occurrence of heterotopic ossification but was
not associated with the magnitude or grade of heterotopic bone
(?2 = 2.12; p = 0.15).
Patients underwent an average of 6.5 irrigation and débridement
procedures prior to attempted definitive residual limb revision and closure at
an average of 17.3 days after the injury
(Table II). We found no
significant differences in the number of procedures or the time to closure
between patients with amputations within or proximal to the zone of injury or
between those with a blast or a nonblast mechanism of injury. However, we did
note a trend toward significantly more procedures and more time to closure for
patients who later had development of heterotopic ossification as compared
with those who did not. When patients who had moderate or severe heterotopic
ossification were compared with those who had mild or absent heterotopic
ossification, significant differences were observed with regard to the number
of procedures (7.26 compared with 6.04 procedures, p = 0.008) and the time
until closure (19.21 compared with 16.38 days, p = 0.01); however, the
clinical differences between these groups were relatively small, with an
average of an additional 1.22 procedures and 2.83 days to closure.
Overall, twenty-seven residual limbs (12.7%) had wound dehiscence or
infection necessitating an unplanned return to the operating room within three
months after attempted definitive closure. With the numbers available, we did
not find significant differences in the rate of early wound complications on
the basis of the zone of injury, the mechanism of injury, or the presence or
grade of heterotopic ossification. Surprisingly, however, amputations that had
been performed proximal to the initial zone of injury were associated with a
higher rate of infections and wound complications (19.6%) than those that had
been performed within the zone of injury (10.8%), although this difference did
not reach significance (?2 = 0.74; p = 0.18).
Of the 134 limbs with radiographic evidence of heterotopic ossification,
only twenty-five required operative excision; thus, 109 limbs (81%) were
either asymptomatic or had been successfully managed with prosthetic
modifications as of the time of the most recent follow-up. With inclusion of
the patients without two months of radiographic follow-up, only twenty-five
(6.7%) of 373 amputations required operative excision of symptomatic
heterotopic ossification.
Clinical and Radiographic Results of Excision
Of the twenty-five limbs that required operative excision of heterotopic
ossification lesions, all had had the amputation within the initial zone of
injury. Twenty-one limbs had sustained a blast injury, and the remaining four
limbs had been injured in motor-vehicle (two), boating (one), and electrical
burn (one) accidents (see Appendix). The involved levels of amputation
included two hip disarticulations, nine transfemoral amputations, one knee
disarticulation, eight transtibial amputations, one shoulder disarticulation,
one transhumeral amputation, and three transradial amputations. Two patients
had sustained documented mild traumatic brain injury, which had resolved
completely by two months after the injury. No patient had sustained an
associated spinal cord injury. Radiographically, the heterotopic ossification
was graded as mild in seven residual limbs, moderate in ten, and severe in
eight.
The average time between the initial injury and excision was 8.2 months
(range, three to twenty-four months; median, six months). Three patients
underwent only partial excision of the ectopic bone lesions because of the
focal nature of their symptoms and the substantial residual limb compromise
and shortening that would have resulted from complete excision. Thirteen
patients (thirteen limbs) were treated with a six-week postoperative course of
nonsteroidal anti-inflammatory drugs, consisting of indomethacin (nine
patients), cyclooxygenase-2 inhibitors (two patients), and naproxen and
ibuprofen (one patient each). Twenty limbs underwent local radiation therapy,
within twenty-four hours postoperatively, consisting of 700 cGy in a single
dose. Twelve limbs received both nonsteroidal anti-inflammatory drugs and
local radiation therapy, and four limbs received no postoperative
prophylaxis.
Preoperatively, all patients undergoing operative excision used narcotic
pain medications and fourteen (58%) of twenty-four patients took medications
for the treatment of neuropathic pain. At the time of the most recent
follow-up at an average of twelve months postoperatively, fifteen patients
(63%) had been able to stop all narcotics and five additional patients had
substantially decreased their dosages and utilization frequency, with only
three patients still requiring neuropathic pain medications. Thus, twenty of
twenty-four patients were able to stop or reduce narcotic consumption (p <
0.0001), and neuropathic pain medication was also significantly reduced
postoperatively (p = 0.002). Four patients continued to require narcotics at
essentially the same levels as before excision.
Intraoperative specimens from six patients were sent for culture at the
time of ectopic bone excision, and all of the cultures were positive. Three of
these patients had a history of a documented deep infection (one patient) or
an intermittently draining sinus that was strongly suggestive of infection
(two patients). These infections were treated postoperatively with a short,
two-week course of culture-specific antibiotics in four patients and with a
six-week course of intravenous antibiotics in two patients, both of whom had a
history that was suggestive of preoperative infection.
After an average duration of follow-up of twelve months (range, six to
twenty-four months), twenty-three limbs demonstrated no evidence of recurrent
heterotopic ossification and two limbs had development of clinically
asymptomatic, radiographically mild juxtacortical recurrent heterotopic
ossification (Figs. 2-A and
2-B). Including the two patients with positive intraoperative
cultures and a postoperative deep infection requiring six weeks of intravenous
antibiotics, a total of six patients experienced early wound-related
complications that required at least one return to the operating room. These
additional operations were performed because of deep infection in three
patients, sterile hematoma formation in two patients, and wound dehiscence in
one patient. The latter three patients all had negative cultures at the time
of the return to the operating room. Two additional patients required late
minor revision surgery on the residual limb because of symptomatic neuromas.
With the numbers available, there was no significant difference in the rates
of recurrence or complications according to postoperative prophylaxis against
recurrence, the grade of initial heterotopic ossification, the completeness of
excision, or the time from the injury to the excision.
At the time of final follow-up all patients had been fitted with a
functional prosthesis. The ability to run and the use of assistive devices
varied and depended on both the level of amputation and associated
injuries.
Etiology and Prevalence of Traumatic and Combat-Related
Amputations
With the modernization of battlefield evacuation resources, the forward
movement of medical facilities, and advancements in medical technology,
amputation rates have declined
historically15,16.
Simultaneously, a transition has occurred in which the majority of extremity
injuries are due to blast and fragmentation mechanisms as opposed to
high-velocity
missiles17.
Additionally, modern personal body armor and medical advancements have
increased the survivability of otherwise devastating personnel injuries
through the protection and preservation of vital organ systems and rapid
treatment. Thus, in spite of the tremendously increased primary and secondary
blast injury forces produced by modern explosives, patient survival has
increased18.
This increased survival has been accompanied by appropriately aggressive
limb salvage and, when traumatic amputation has occurred or early amputation
is indicated, more aggressive "level salvage." That is, in all but
the most dire circumstances, concerted efforts are directed to maintain as
much residual limb length as practicable and, in particular, to maintain
remaining functional joint levels. The reasons for this include both surgeon
recognition of the increased function that is generally afforded by retention
of distal limb length and more distal amputation levels and the reality that,
in many cases, more proximal tissue has also been damaged at the time of the
initial injury, decreasing the potential appeal and practical feasibility of
simply revising to a more proximal, undamaged level. This may explain, at
least in part, the apparently increased prevalence of heterotopic ossification
in the residual limbs of patients with traumatic and combat-related
amputations in the present series. Indeed, we found that a blast mechanism of
injury and amputation within the zone of initial injury were significant
predictors of ectopic bone formation and that the zone of injury was also
predictive of the magnitude of heterotopic ossification. However, given the
relatively successful results of symptomatic treatment in this series, coupled
with the noted difficulties in revising to more proximal levels, we believe
that our present approach of aggressive residual limb length and joint level
salvage is justified.
Several other risk factors cannot be entirely excluded as contributing to
the high prevalence of heterotopic ossification in this series. Mild, occult
traumatic brain injury may occur secondary to the initial blast injury in a
high percentage of patients. As many patients with multiple organ system
injuries require intubation and sedation during the early evacuation and
treatment period when mild traumatic brain injury might be most apparent,
occult injury is difficult to exclude as a contributing factor.
Additionally, our military treatment facilities frequently utilize
pulsatile lavage irrigation systems (Stryker, Kalamazoo, Michigan) and
subatmospheric pressure dressing devices (V.A.C.; Kinetic Concepts, San
Antonio, Texas). Pulsatile irrigation systems have proven to be effective for
the removal of devitalized tissue and bacterial
contaminates19, but
they have also been demonstrated to cause considerable gross and histological
soft-tissue
damage20, a
prerequisite for heterotopic ossification formation due to most other causes.
Negative pressure dressings have been shown to reduce edema and bacterial
loads, to increase vascularity, and to accelerate wound-healing in both animal
and human models through combined mechanical and fluid-based mechanisms of
action21-23.
Vacuum treatment of wounds and flaps also has been demonstrated to salvage the
viability of damaged and congested
tissue24,25.
Furthermore, cellular mechanical shear stresses secondary to subatmospheric
pressure dressing application activate the vascular endothelial cell growth
factor pathway (in the absence of the growth factor) and increase levels of
numerous proto-oncogenes, leading to further growth factor production and new
tissue
growth23,26,27.
Although theoretically desirable, these attributes also may promote the
formation of heterotopic ossification through the salvage of damaged cells and
growth promotion, subsequently triggering stem cell metaplasia and ectopic
bone development. The capability of these interactions to actually cause
heterotopic ossification has not yet been investigated, to our knowledge.
The ubiquity of these devices in the treatment process makes excluding
either as a complicating factor difficult; virtually all amputees in our
series were exposed to both devices. Their utilization, independent of the
mechanism of injury, amputation level, and zone of injury, would seem to
suggest that the contribution of these treatment modalities to the development
of heterotopic ossification was not great in the present series. We did find a
significant difference between the number of procedures (i.e., the number of
exposures to pulsatile lavage) and the number of days to closure (i.e., the
duration of exposure to vacuum dressings) between patients with moderate to
severe heterotopic ossification and those with mild or absent ectopic bone. We
did not find significant differences in the number of exposures according to
the mechanism of injury, the zone of injury, or the presence of heterotopic
ossification, and, as noted, the actual differences in potential exposures to
procedures or devices were clinically small. Conversely, the theoretical
potential for these devices to contribute to ectopic bone growth certainly
exists. The absence of these serial and prolonged exposures to vacuum
dressings and pulsatile irrigation may explain the lower historical prevalence
of heterotopic ossification in combat-related amputees implied by other
series6-11.
Finally, infection has been proven to be a detriment to bone formation and
fracture-healing in both basic-science and clinical studies and appears to
favor osteoblast apoptosis and osteoclastogenesis through a complex
inflammatory
cascade28-31.
However, in our series, all cultures of specimens that were obtained at the
time of heterotopic ossification excision were positive. Notwithstanding the
obvious potential selection bias resulting from the fact that culture
specimens were not obtained during most of the procedures and the fact that
three of the six patients from whom culture specimens were obtained had a
history that suggested or documented a prior infection, this trend is too
great to ignore. We now obtain intraoperative culture specimens during all
ectopic bone excisions. The possibility that subacute infection may play a
role in the development of heterotopic ossification in patients with traumatic
wounds warrants additional study.
Operative Excision of Heterotopic Ossification Lesions in
Amputees
Once heterotopic ossification is present and established within the
residual limb of an amputee, efforts should be made to determine the degree of
symptoms attributable to it and to exclude or identify and treat other
potential causes of chronic residual limb
pain2. Conservative
treatment measures then focus on activity modification and repeated socket and
liner modifications in cooperation with skilled prosthetists and physiatrists
in an effort to avoid the need for operative excision.
In the present series, conservative treatment generally consisted of a
period of rest and medication adjustment, followed by liner changes and serial
manual recession of symptomatic areas within sockets, which had already been
customized to the residual limbs through stereolithographic surface-contour
mapping. Prosthesis suspension mechanisms were adjusted, and alternate
techniques were utilized when feasible. If these measures failed, patients
frequently underwent three-dimensional computed tomographic modeling of the
residual limb while wearing the socket, with the resulting physical model
providing additional information regarding the proximity of the symptomatic
regions of heterotopic ossification with load-bearing areas that could then be
modified. Indeed, a large proportion of amputees with ectopic bone in the
present series were either asymptomatic or were successfully managed with
conservative modalities, as reflected by the relatively small proportion of
all amputations (6.7%) that were associated with the need for operative
excision.
Historical teaching regarding the operative excision of heterotopic
ossification has often recommended a prolonged observation period to permit
maturation as manifested radiographically, by quiescence on three-phase bone
scans, and by normalization of the serum alkaline phosphatase
level32-35.
However, several studies have questioned the reliability and validity of these
criteria in predicting "maturity" and recurrence following
excision36-39.
Additionally, much of the evidence in support of these criteria has been
anecdotal or extrapolated from patients with traumatic brain and spinal cord
injuries, in whom at least a portion of the original inciting mechanisms
persists and the extent of both persistent neurologic injury and initial
heterotopic ossification may be more predictive of
recurrence36,37.
A prolonged waiting period is undesirable in an amputee population because
it substantially restricts prosthetic rehabilitation and training and limits
walking capabilities for the duration of the waiting period. Furthermore,
numerous recent studies have demonstrated successful early excision of
symptomatic heterotopic ossification, frequently with adjunctive perioperative
nonsteroidal anti-inflammatory medications and/or local radiation for
prophylaxis against recurrence following fracture, burn, and even spinal cord
injuries40-45.
Therefore, we did not make a concerted effort to assess the aforementioned
markers of ectopic bone maturity prior to surgical treatment. Rather, we
proceeded with surgical excision as soon as symptoms warranted following
appropriate efforts at conservative treatment. We found excellent functional
outcomes with regard to prosthetic fitting as well as minimal radiographic and
no clinically symptomatic recurrences following operative excision with
frequent use of the perioperative prophylactic measures.
Primary and Secondary Prophylaxis Against Heterotopic
Ossification
Numerous level-I studies have documented the effectiveness of primary
prophylaxis with use of nonsteroidal anti-inflammatory drugs and local
radiation therapy, particularly following the operative treatment of
acetabular fractures and total hip arthroplasty, with essentially equivalent
efficacy46-52.
There is substantial case-control evidence that combined nonsteroidal
anti-inflammatory medications and local radiation therapy may have an additive
or synergistic beneficial effect in the prevention of recurrence as compared
with the effect of monotherapy with either modality
alone53-56.
Numerous other agents, including the early bisphosphonate etidronate, have
been studied in human and animal trials of heterotopic ossification
prevention, with varying levels of success and supporting
evidence57-66.
In spite of the proven and/or potential efficacy of these modalities,
numerous barriers limit the initiation of primary prophylaxis measures
following trauma-related amputation. These include, but are not limited to,
the presence of residual open wounds; concomitant local and remote long-bone
fractures; multisystem injuries placing patients at risk for renal,
gastrointestinal, and hemorrhagic complications of prophylaxis; potential
local or systemic immunosuppression; and the need for serial additional
surgical procedures. Furthermore, particularly in a combat setting, logistical
barriers may prevent the initiation of early prophylactic therapy within the
desired timeframe. Finally, as has been done in other patient
populations1, the
amputees most at risk for ectopic bone formation require identification in
order to allow for an appropriately judicious utilization of any proposed
prophylactic measures. We believe that we successfully identified two such
risk factors in our series, namely, the final amputation level within the zone
of injury and a blast-related mechanism of injury. However, these patients,
particularly those who have sustained blast injuries, also would seem more
likely to be critically ill and to have sustained multiple other injuries as
obstacles to primary prophylaxis, and the eventual final level of amputation
cannot always be predicted early in the post-injury setting.
The evidence supporting secondary prophylaxis following surgical excision
is far more limited and has been largely extrapolated from primary prevention
studies. To our knowledge, there have been no randomized trials of any
secondary prevention modality following the excision of symptomatic
heterotopic ossification. In amputees, recurrences requiring repeat excision
may compromise the remaining soft-tissue envelope needed to tolerate
high-demand prosthetic use or may require the sacrifice of residual limb
length or a functional joint level. In the present series, our perioperative
adjunctive treatment was not standardized because of the involvement of
multiple surgeons as well as our evolving recognition of the magnitude and
prevalence of this problem. We believe that our results and the absence of
clinically symptomatic recurrences support relatively early excision in
symptomatic patients with trauma-related amputations and heterotopic
ossification. Although not directly supported by our data, we believe that
secondary perioperative prophylaxis against recurrence with use of
nonsteroidal anti-inflammatory medications and local radiation therapy is
reasonable for these patients on the basis of the theoretical benefit, and we
continue to utilize these modalities in our practices.
Limitations of the Study
All clinical studies must be interpreted in the context of their
limitations, and the present series is no exception. First, our study was
retrospective in nature and therefore was prone to the same biases and
limitations in data collection as other reviews. We limited our initial study
group to patients with radiographs of the residual limb that were made at
least two months after the injury. Although introducing a potential source of
positive selection bias (patients with palpable or symptomatic heterotopic
ossification would seem more likely to have late follow-up radiographs), this
cutoff was selected on the basis of previous studies from other surgical
patient populations demonstrating that heterotopic ossification, both when it
initially occurs and when it recurs following excision, is reliably evident
radiographically by less than two months after the inciting
event40,46,47,67.
Additionally, a number of patients without heterotopic ossification had more
recent follow-up radiographs, and none of those patients had new evidence of
heterotopic ossification after this two-month period. Even if one were to
assume that no patient without two-month post-injury radiographs had
development of ectopic bone, the overall prevalence would be 35.9%, with 19.3%
of all amputees having moderate or severe heterotopic ossification. Our
findings would thus be no less noteworthy, particularly given the absence of
preexisting literature concerning the prevalence of heterotopic ossification
in amputees.
As noted, perioperative adjunctive prophylaxis was not standardized as some
patients received no prophylaxis and several different nonsteroidal
anti-inflammatory drugs were used. However, local radiation therapy was
administered with use of the same timing and dosing protocol. Furthermore, the
clinical and radiographic follow-up periods were relatively short. We believed
that this was justified on the basis of the timeliness and rarity of our topic
as well as the adequacy of our postoperative surveillance to document our
principal clinical and radiographic outcomes of
recurrence40,46,47,67,
perioperative complications, and successful prosthetic fitting and wear.
Finally, we did not utilize validated outcome questionnaires to assess
clinical outcomes. Preoperative and follow-up medication requirements were
assessed but may have been confounded by the associated injuries that several
patients sustained as well as the interval increase in follow-up and recovery
from the initial injury. A long-term study to assess the outcomes of limb
salvage and amputation in this patient population is underway at our
institutions.
Overview
Our results suggest that heterotopic ossification is increasing in
prevalence and/or is more common than previously appreciated following
traumatic and combat-related amputations, particularly amputations within the
initial zone of injury and those secondary to blast mechanisms. While many
patients are asymptomatic or may be managed successfully with activity and
prosthesis modifications, surgical excision of persistently symptomatic
lesions coupled with perioperative adjunctive prophylaxis results in a
reliable ability to fit the limb with a functional prosthesis and is
associated with a low recurrence rate and a moderate but acceptable rate of
wound-related complications. Additional research is necessary to identify an
effective and practicable regimen of primary prophylaxis for amputees who are
at high risk for heterotopic ossification.
A table showing data on the twenty-five operatively treated limbs is
available with the electronic versions of this article, on our web site at
(go to
the article citation and click on "Supplementary Material") and on
our quarterly CD-ROM (call our subscription department, at 781-449-9780, to
order the CD-ROM). ?
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