SUPPLEMENT ARTICLE
Diagnosis and Management of Polytraumatized Patients
With Severe Extremity Trauma
Todd O. McKinley, MD,* Greg E. Gaski, MD,* Yoram Vodovotz, PhD,† Benjamin T. Corona, PhD,‡
and Timothy R. Billiar, MD†
Downloaded from http://journals.lww.com/jorthotrauma by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 05/08/2022
Summary: Multiply injured patients with severe extremity trauma
are at risk of acute systemic complications and are at high risk of
developing longer term orthopaedic complications including soft-
tissue infection, osteomyelitis, posttraumatic osteoarthritis, and
nonunion. It is becoming increasingly recognized that injury
magnitude and response to injury have major jurisdiction
pertaining to patient outcomes and complications. The complex-
ities of injury and injury response that affect outcomes present
opportunities to apply precision approaches to understand and
quantify injury magnitude and injury response on a patient-
specific basis. Here, we present novel approaches to measure
injury magnitude by adopting methods that quantify both
mechanical and ischemic tissue injury specific to each patient.
We also present evolving computational approaches that have
provided new insight into the complexities of inflammation and
immunologic response to injury specific to each patient. These
precision approaches are on the forefront of understanding how to
stratify individualized injury and injury response in an effort to
optimize titrated orthopaedic surgical interventions, which invari-
ably involve most of the multiply injured patients. Finally, we
present novel methods directed at mangled limbs with severe soft-
tissue injury that comprise severely injured patients. Specifically,
methods being developed to treat mangled limbs with volumetric
muscle loss have the potential to improve limb outcomes and
also mitigate uncompensated inflammation that occurs in these
patients.
Key Words: precision medicine, computational biology, multiply
injured patients, volumetric muscle loss
(J Orthop Trauma 2018;32:S1–S6)
Accepted for publication December 8, 2018.
From the *Department of Orthopaedic Surgery, Indiana University School of
Medicine, Indianapolis, IN; †Department of Surgery, University of Pitts-
burgh School of Medicine, Pittsburgh, PA; and ‡Department of Extremity
Trauma and Regenerative Medicine, US Army Institute of Surgical
Research, San Antonio, TX.
The authors report no conflict of interest.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF
versions of this article on the journal’s Web site (www.jorthotrauma.
com).
Reprints: Todd O. McKinley, MD, Department Orthopaedic Surgery,
Anatomy and Cell Biology, Indiana University Health Methodist
Hospital, 1801 North Senate Boulevard, Suite 535, Indianapolis, IN
46202 (e-mail: tmckinley@iuhealth.org).
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/BOT.0000000000001114
J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018
Copyright Ó 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
INTRODUCTION
Multiply injured patients (MIPs) sustaining fractures
are at risk of developing orthopaedic complications including
nonunions and infections leading to poor long-term out-
comes.1–3 In addition, orthopaedic wounds in MIPs are typ-
ically severe with complex bone, muscle, and skin injuries
and often present with tissue defects.4–7 Taken together, MIPs
with orthopaedic injuries are at high risk of complications
because of the severity of the orthopaedic injury combined
with dysregulated physiology that frequently accompanies
polytrauma. However, the effects of dysregulated inflamma-
tion and immunologic response that accompany polytrauma
and musculoskeletal injuries are not well delineated.
It is generally accepted that injury magnitude corre-
sponds to an overall physiologic response in MIPs.8–10 How-
ever, the physiologic effects of polytrauma are complex and
only partially understood. Evidence clearly demonstrates that
polytrauma and hemorrhagic shock provoke high levels of
inflammation that can progress to a dysregulated immuno-
logic response. Patients with a heightened immunologic
response and dysregulated inflammation are at risk of devel-
oping organ dysfunction, which can lead to multiple organ
failure (MOF).11,12 Accordingly, clinicians have tried to pre-
dict response to injury and stratify outcomes based on indices
of injury magnitude. The Injury Severity Score (ISS), the
most widely adopted injury magnitude surrogate, has been
demonstrated to predict mortality.8,9 However, the ISS corre-
sponds poorly to immunologic changes and organ dysfunc-
tion, making it less useful to predict the physiologic response
to injury. In addition, characterizing the immunologic
response to injury has also been challenging, primarily due
to the complexity of the network of mediators that are
affected by injury.13–15 Leading investigators have quantified
time-dependent changes in multiple circulating inflammatory
mediators including interleukin (IL)-6, IL-8, and monocyte
chemotactic protein-1.16–18 However, in many trials spanning
several decades, targeted immunotherapy specifically block-
ing isolated immunologic mediators has uniformly failed to
improve outcomes after injury. Leading researchers have con-
cluded that targeting isolated pathways within a highly com-
plex trauma-associated immunologic response network has
led to consistent treatment failures.19–21
In summary, the magnitude of injury and response to
injury clearly affect patient outcomes after trauma. However,
the complexities of quantifying injury magnitude, measuring
the response to injury, and deciphering how injury magnitude
affects injury response and outcomes remain a major
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McKinley et al J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018
challenge in understanding the effects of polytrauma. These
challenges have led to novel approaches with researchers
increasingly adopting bioinformatics approaches to better
understand how trauma affects the complex immunologic
response in MIPs.12,19,22 These computational approaches
have uncovered changes in inflammatory/immune networks
that are likely affected by multiple factors including preinjury
genomic and demographic indices, injury specifics, and are
likely modulated by interventions. Likewise, new methods
have been investigated to measure patient-specific indices that
characterize both mechanical and ischemic injury severity in
trauma patients.23–25 Collectively, these novel patient-specific
approaches to characterize injury magnitude and injury
response are an initial foundation of a precision medicine
approach for polytraumatized patients. Ultimately, precision
models that account for patient-specific indices that quantify
injury and response to injury will optimally predict clinical
trajectories and direct treatment (see Fig. 1, Supplement
Digital Content 1, http://links.lww.com/JOT/A280).
In this study, we have summarized formative evidence
on precision methods to characterize injury magnitude and
immunologic response to injury. Novel methods that define
and quantify both mechanical and ischemic tissue injury are
presented. In addition, advanced methods and analyses to
better understand the immunology-based response to injury
are discussed. Finally, we present foundational basic scientific
evidence of an emerging method designed to improve
outcomes in MIPs with mangled extremities. MIPs often
sustain limb-threatening injuries that include fractures with
severe muscle injury and muscle loss. Volumetric muscle loss
(VML) leads to nonunion, pain, and weakness, placing an
injured limb at risk of poor outcome and amputation. The
effects of VML adjacent to a fracture are largely immuno-
logically mediated. In addition, the presence of polytrauma
likely affects the early immunologically mediated healing
mechanisms that heal bone and soft-tissue injury. In this
study, we present novel basic and translational research that
has great potential to improve outcomes in MIPs with VML.
QUANTIFYING INJURY USING A PRECISION
APPROACH IMPROVES CORRESPONDENCE OF
PATIENT-SPECIFIC INJURY INDICES WITH
ACUTE CLINICAL OUTCOMES
Trauma patients sustain various magnitudes of mechan-
ical and ischemic tissue injury. Some MIPs recover unevent-
fully, whereas other MIPs with seemingly similar demographic
and injury profiles (by current measurement standards) develop
complications and organ failure. The marked variation in
physiologic response and subsequent clinical course after
injury and resuscitation in a trauma population may in part
be due to patient-specific and injury-specific factors that current
prediction models and scoring systems cannot quantify
accurately.
Precise quantification of injury magnitude using
patient-specific indices that describe mechanical and ischemic
tissue damage and initial metabolic response to injury has the
potential to better predict a trauma patient’s clinical trajectory.
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Current anatomically based scoring systems, including the
ISS, are calculated retrospectively and poorly account for
patient-specific injury characteristics.26,27 Patient-specific
characterization of injury burden and metabolic response
would afford clinicians essential information to guide surgical
and resuscitation decisions.
Recently, we have developed techniques to measure
injury burden by quantifying mechanical [computed tomog-
raphy (CT)-based injury quantification] and ischemic (cumu-
lative hypoperfusion via time-magnitude integration of serial
Shock Index values) tissue damage specific to each trauma
patient.23–25 This line of investigation sought to correlate
short-term patient outcomes with patient-specific precision
metrics of injury and a patient’s early response after trauma.
Measuring Patient-Specific Mechanical Tissue
Injury
Novel CT-based imaging techniques were used to
quantify all presenting injuries identified on initial trauma
pan CT. Characteristic dimensions measured from orthogonal
CT-based images of each individual injury were used to
calculate injury volumes (see Fig. 2, Supplement Digital
Content 2, http://links.lww.com/JOT/A281). The resultant
volume summation of all mechanical tissue injury was termed
the Tissue Damage Volume (TDV) score. In a retrospective
investigation of 74 MIPs, the mean total TDV thresholds
identified patients at risk of developing MOF and sustained
systemic inflammatory response syndrome.23 Subsequent
investigation demonstrated that a greater degree of pelvic
and retroperitoneal tissue damage was associated with more
severe organ dysfunction and an increased risk of developing
MOF.24
Measuring Patient-Specific Ischemic Tissue
Injury
A patient-specific metric of cumulative hypoperfusion,
termed “shock volume (SV),” was developed to represent the
dynamic and accumulating nature of hemorrhagic shock after
trauma.25 SV is a time–magnitude integration of serial shock
index (heart rate/systolic blood pressure) measurements.28,29
SV integrates the magnitude and duration that shock index
values exceed 0.9, a validated threshold indicative of hypo-
perfusion (see Fig. 3, Supplement Digital Content 3, http://
links.lww.com/JOT/A282, example patient). A retrospective
study of MIPs found that SV thresholds (40 units at 6 hours
and 100 units at 24 hours) predicted organ dysfunction.
Formulating a Patient-Specific Injury Score to
Predict Clinical Outcomes in MIPs
A composite precision index of injury termed the
Patient-Specific Injury (PSI) score was calculated by com-
bining mechanical tissue injury (TDV), ischemic tissue injury
(SV), and a surrogate of patient-specific metabolic response.
Individualized metabolic response was estimated using
minimum pH values recorded during the first 48 hours after
injury. PSI formulas were subsequently optimized to predict
organ dysfunction [mean modified Sequential Organ Failure
Assessment (SOFA) scores] by iterative modeling. The
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J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018
optimized PSI formula converged on: PSI = [0.2 TDV+ 24 h
SV] · [14.80 2 (min pH0–24 h + min pH24–48 h)]. PSI scores
demonstrated statistically significant correspondence to mean
modified SOFA scores (see Fig. 4, Supplement Digital
Content 4, http://links.lww.com/JOT/A283). Conversely,
ISS demonstrated no correspondence to organ dysfunction.
Future Directions
This investigation interrogated a precision medicine
approach to patient-specific injury quantification to predict
short-term clinical outcomes. Although these data are pre-
liminary and retrospective, we demonstrated that a precision
approach using patient-specific metrics of mechanical injury,
ischemic injury, and metabolic response effectively stratified
clinical trajectories in MIPs compared with traditional
measures of injury severity, which demonstrated no corre-
spondence to organ dysfunction. Future studies should
investigate precision injury metrics in a prospective fashion
and consider incorporation of the patient-specific immuno-
logic response.
COMPUTATIONAL BIOLOGIC APPROACHES TO
UNDERSTAND OUTCOMES IN MIPs
Blunt trauma patients who survive the first 24 hours
undergo a syndrome that involves inflammation, immune
dysregulation, nosocomial infection/sepsis, and MOF, which
can eventually lead to death. At present, this complex,
multisystem process has stymied precision medicine ap-
proaches to diagnosis and treatment.30 To address the com-
plexity of this dynamic process, our group at the University of
Pittsburgh has focused on the use of computational modeling
to better understand the immunologic response to major
injury. Two broad categories of computational approaches
have been used: data-driven models and mechanistic models.
Full details of these approaches are outlined in detail in
several recent publications.31–35
Briefly, data-driven models are typically statistical in
origin and thus are based on associations and correlations
among variables. This class of models may suggest principal
drivers and may be used to infer either static (single time
point) or dynamic (multiple time points) networks. As
expected based on their interrelation with more common
statistical approaches such as multivariate regression models,
data-driven models make little use of previous knowledge. In
this sense, data-driven models can be considered quite
objective and agnostic with regard to previous assumptions
about how a complex biological system actually functions,
which is typically considered a strength. The accuracy of
data-driven models typically depends on the amount and
quality of their underlying data and hence has been developed
to address the so-called big data challenges. The main
weakness of data-driven models is that they are generally
only capable of prediction within the scope of the data on
which they have been trained, and yet these models are often
used incorrectly to make predictions in circumstances that lie
outside their underlying data.31–35
The other broad class of approaches used by our group
and others consists of mechanistic models. Roughly speaking,
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Polytraumatized Patients with Severe Extremity Trauma
they can be classified as being the opposite of data-driven
models, although they are often calibrated to data to make
quantitative predictions. Mechanistic models are highly
causal and represent an abstraction of the underlying complex
biology in a manner that, at least to the individuals or teams
that generate these models, represents the core functions and
key variables necessary to solve a given problem. As such,
mechanistic models may suggest nonintuitive aspects and
emergent phenomena, that is, the whole is greater than the
sum of the parts. Mechanistic modeling requires extensive use
of previous knowledge and is hence generally more difficult
to perform as compared to data-driven modeling. The reward
for this hard work, however, is the potential for qualitative
and quantitative predictions outside the underlying training
data.31–35
Our work on data-driven modeling of the response to
trauma was focused initially on experimental studies in mice,
in which we adapted standard tools such as principal
component analysis and developed key techniques such as
dynamic network analysis.22 These tools were leveraged to
the clinical setting, under the auspices of a National Institutes
of Health–funded trauma center grant that included an
observation cohort of ;500 polytrauma patients.36 Data-
driven modeling studies on patient subgroups were facili-
tated by the use a stringent cohort-matching approach, for
example comparing patients with graded injury severity,37
hypotensive versus normotensive patients,38 patients with
nosocomial infection versus matched controls,39 and trauma
nonsurvivors versus survivors.40 In these clinical studies,
principal component analysis was used in a patient-specific
fashion, in which 3 sequential measurements of circulating
inflammation biomarkers within the first 24 hours stratified
trauma patients into high versus low multiple organ dys-
function trajectories.12
Studies of dynamic networks suggested multiple
pattern characteristics of the aforementioned patient sub-
groups. One intriguing insight from this analysis was the
finding of rising dynamic connectivity of inflammatory
networks in trauma patients who died after their stay in
the intensive care unit, in contrast to a bland, low-level
network connectivity pattern in highly matched survi-
vors.40 This network connectivity pattern mirrored the
rise in the extent of multiple organ dysfunctions.40
Another central hypothesis gleaned from this computa-
tional analysis was the potential for a “switch” between
predominantly lymphoid, low-level, and ultimately resolv-
ing inflammation versus a predominantly innate immune,
self-sustaining inflammatory response in patients who died
of their injuries.40
Parallel studies using mechanistic modeling also lever-
aged initial models calibrated to data from mice41 and swine42
to simulate human responses to injury.43 These studies sug-
gested an important role, at the individual level, for the cyto-
kine IL-6 in driving outcomes but this role may be much less
apparent at the population level.43 Leveraging previous in
silico clinical trial studies on the inflammatory response to
bacterial infection44,45 and wound healing,46 the in silico
trauma model was also used to test potential interventions
in trauma, including anti-IL-6.43
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McKinley et al J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018
These studies are beginning to unravel some of the
complex, dynamic responses to trauma, including defining
networks characteristic of orthopaedic injury (unpublished),
and to raise the possibility of driving novel precision
medicine approaches to trauma.
FOUNDATIONAL INVESTIGATIONS OF VML IN
SEVERE EXTREMITY TRAUMA
The hallmark of orthopaedic trauma in polytraumatized
patients is open fracture with nonunion rates of 5%–50%.47,48
Notably, soft-tissue comorbidities such as vascular injury,
contamination, and loss of skeletal muscle are a major deter-
minant of complicated musculoskeletal healing. Current stan-
dard of care mitigates the deleterious effects of concomitant
vascular injuries and infection; however, muscle loss is only
directly treated with free or rotational flaps in the most severe
open fractures, leaving most VML injuries without acute ther-
apeutic treatment. Given the persistent incidence of delayed
and nonunion in nonflapped open fractures,49 even ostensibly
less severe concomitant muscle loss can be deleterious to
fracture healing. Moreover, severe soft-tissue injuries are rec-
ognized as a significant factor leading to chronic disability
after limb salvage4,49 Together, these observations highlight
that traumatic muscle loss plays a pivotal role in acute and
prolonged musculoskeletal healing outcomes.
In complicated open fracture healing, maintenance of
muscle–bone communications is critical to timely bone
regeneration.50 Animal studies have demonstrated that the
support that surrounding skeletal muscle provides to re-
generating bone is much more diverse than solely ascribed to
revascularization. For example, concurrent contribution of
local skeletal muscle stem and progenitor cells and myokines
(eg, insulin-like growth factor 1) has also been shown to
support adjacent fracture healing.51–54 The influence of
muscle-derived cellular and trophic support is highlighted in
experiments in which controlled muscle trauma is associated
with impaired fracture healing, despite adequate vasculariza-
tion of the fracture.55–58 It is teleological that VML injuries
impair fracture healing because of ablation of these support-
ive elements. However, recent observations indicate that
a relatively small muscle defect (eg, ,20% of muscle weight)
may perturb skeletal healing.59 In fact, targeted partial VML
in the quadriceps and tibialis anterior muscles has been shown
to impair the potent osteoinductive action of rhBMP-2 in rat
femur60 and tibia,61 respectively. These findings suggest that
it is not that the surrounding musculature is necessarily
depleted of supportive osteogenic factors but rather that
changes to the local milieu secondary to muscle trauma are
inhibitory to osteogenic activity.
In 2 separate studies, we have demonstrated that
broadly “controlling” the traumatized muscle wound environ-
ment is beneficial to fracture healing. Both studies used a rat
model of open fracture in which concomitant tibialis anterior
muscle volumetric loss injury delays tibia regeneration 28
days after injury and presents exacerbated macrophage and
T lymphocyte immune responses in the traumatized bone and
muscle compared with an osteotomy without muscle trauma
during the first 14 days after injury.59 In the first study, repair
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of VML injury with autologous minced muscle grafts (1 mm3
pieces of muscle tissue) restored skeletal muscle strength62
and the rate of fracture healing at 28 days after injury. In
association with amelioration of musculoskeletal healing,
minced muscle graft repair acutely modulated local and sys-
temic immune responses and IGF-1 levels toward a prorege-
nerative phenotype (submitted for publications). In the second
study, systemic administration of FK506, an FDA-approved
immunosuppressant (Tacrolimus), also improved the recovery
of tibia mechanical properties after simple osteotomy and
local VML injury. Notably, the improvement in healing medi-
ated by FK506 was associated with reduction but not sup-
pression of the local musculoskeletal immune response during
the first 2 weeks after injury (submitted for publication).
Although FK506 may also function as an osteoinductive
agent,63 drug delivery did not improve fracture healing when
concomitant VML was not introduced in our study or a pre-
vious study,64 suggesting primary efficacy under conditions
of heightened inflammation. Collectively, these studies dem-
onstrate both the significant impact of muscle trauma on
fracture healing and the therapeutic potential of addressing
muscle trauma–related perturbations of the local musculo-
skeletal healing environment, specifically attenuation of
heightened and prolonged innate and adaptive immune
responses.
In summary, it is appreciated that exacerbated inflam-
mation is deleterious to musculoskeletal healing and that
proinflammatory cytokines may disrupt osteogenesis through
inhibition of BMP-2 signaling.65 Given the heightened
immune response to composite skeletal injury59 and polytrau-
ma,66 it is plausible that attenuation of exacerbated systemic
and/or local inflammation may ameliorate musculoskeletal
healing. The observations presented encourage continued
exploration of immunomodulation to improve musculoskele-
tal healing after complex injuries.
Summary
The data presented in this study underscore the
complexity of understanding injury, response to injury, and
difficulties treating severe limb trauma in MIPs. Inflammation
and the ensuing immunologic cascade comprise a fundamental
response to injury. In severe injury, the immunologic
response can become dysregulated and lead to poor outcomes
including orthopaedic healing complications. The severe
nature of limb trauma that occurs in this patient population
further compounds inflammation-associated complications
that occur in MIPs. It is becoming increasingly recognized
that injury and injury response demonstrate patient specific-
ity, and advancing precision methods will be an important
adjunct in injury and orthopaedic trauma research.
Future Directions
These presentations highlighted the importance of
continuing to understand injury and response to injury on
a patient-specific basis. Data continue to accumulate that
physiologic response and outcomes after injury are notably
different for seemingly similar injury magnitudes between
individuals. Differences in outcomes are likely affected
by discrepancies in patient-specific response to injury.
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J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018
Alternatively, differences in outcomes may reflect injury
magnitude stratification methods that are poor. Taken
together, clinicians and researchers need to continue to work
toward understanding patient-specific components of injury
and better define and quantify meaningful components of
response to injury.
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