The American Journal of Medical Sciences and Pharmaceutical Research
01
https://www.theamericanjournals.com/index.php/tajmspr
TYPE
Original Research
PAGE NO.
1-5
OPEN ACCESS
SUBMITED
02 January 2025
ACCEPTED
03 February 2025
PUBLISHED
01 March 2025
VOLUME
Vol.07 Issue03 2025
CITATION
COPYRIGHT
© 2025 Original content from this work may be used under the terms
of the creative commons attributes 4.0 License.
Exploring the div-wide
effects of traumatic brain
injury: a narrative review
Florin Vasile
Department of Neurology and Rehabilitation Medicine, Elias Emergency
University Hospital, 17 Marasti Bd., District 1, 011461 Bucharest, Romania
Stefan Gheorghe
Department of Neurology and Rehabilitation Medicine, Elias Emergency
University Hospital, 17 Marasti Bd., District 1, 011461 Bucharest, Romania
Abstract:
Traumatic Brain Injury (TBI) is widely
recognized for its profound impact on brain function,
but its consequences often extend beyond the brain to
affect various extracranial systems. This narrative
review explores the extracranial effects of TBI, focusing
on the cardiovascular, respiratory, endocrine, and
musculoskeletal systems, as well as immune response
and metabolic changes. The review synthesizes current
literature on how TBI-induced pathophysiological
changes extend throughout the div and influence
long-term outcomes, including physical and mental
health. The interplay between intracranial injury and
extracranial effects is critical for understanding the full
scope of TBI’s impact. Future resea
rch should
emphasize the development of comprehensive
treatment protocols that address both intracranial and
extracranial effects to improve outcomes for TBI
patients.
Keywords:
Traumatic Brain Injury, extracranial effects,
cardiovascular complications, respiratory dysfunction,
endocrine
dysfunction,
musculoskeletal
effects,
immune response, systemic inflammation, post-TBI
rehabilitation,
pituitary
dysfunction,
autonomic
dysregulation, coagulopathy, multi-organ dysfunction,
long-term outcomes.
Introduction:
Traumatic Brain Injury (TBI) is a leading
cause of death and disability worldwide, resulting in
significant morbidity for millions of people annually.
While the primary focus of clinical care has traditionally
been on managing the intracranial effects of TBI, such as
cerebral contusions, hemorrhage, and intracranial
The American Journal of Medical Sciences and Pharmaceutical Research
2
https://www.theamericanjournals.com/index.php/tajmspr
The American Journal of Medical Sciences and Pharmaceutical Research
pressure, research has increasingly revealed that TBI’s
impact is not confined to the brain. The consequences
of TBI are often systemic, affecting multiple
extracranial organ systems, which contribute to both
acute complications and long-term sequelae.
TBI can have profound effects on a variety of
extracranial systems, including the cardiovascular,
respiratory, endocrine, and musculoskeletal systems.
Additionally,
changes
in
immune
function,
metabolism, and gastrointestinal health can also be
observed following TBI. These extracranial effects can
complicate the clinical management of TBI and are
associated with worsened prognosis and quality of life.
The purpose of this narrative review is to provide a
comprehensive overview of the extracranial effects of
TBI. Specifically, it aims to:
1.
Examine the pathophysiology underlying the
extracranial complications that arise after TBI.
2.
Discuss the clinical significance of these effects
for patient outcomes.
3.
Review the latest literature and propose areas
where future research should focus to improve
understanding and treatment.
METHODS
This narrative review followed a structured approach
to gather and analyze relevant studies regarding the
extracranial effects of Traumatic Brain Injury (TBI). A
detailed search strategy was employed across several
prominent
academic
databases
to
ensure
comprehensive coverage of the available literature.
Below is a detailed explanation of the methods used in
this review:
1. Literature Search Strategy
A thorough and systematic search of peer-reviewed
articles was conducted using the following academic
databases:
•
PubMed (National Library of Medicine)
•
Scopus
•
Google Scholar
•
Cochrane Library
•
Web of Science
The search terms used in this study were:
•
"extracranial effects of TBI"
•
"systemic consequences of traumatic brain
injury"
•
"post-TBI cardiovascular complications"
•
"traumatic brain injury and respiratory
dysfunction"
•
"endocrine effects of TBI"
•
"musculoskeletal effects in TBI"
•
"trauma-induced systemic inflammation"
•
"multi-organ dysfunction in TBI"
The inclusion criteria for articles were:
•
Human studies published between 2000 and
2023.
•
Studies that explored systemic effects of TBI,
including effects on the cardiovascular, respiratory,
endocrine, musculoskeletal, and immune systems.
•
Observational studies, randomized clinical
trials, systematic reviews, and meta-analyses.
•
Studies providing pathophysiological insights
into the extracranial consequences of TBI.
The exclusion criteria were:
•
Studies focused on mild TBI or concussions
without significant extracranial findings.
•
Studies conducted primarily in pediatric
populations or on animals.
•
Articles focusing exclusively on intracranial
effects of TBI or neurological rehabilitation.
2. Study Selection and Review
After the initial search, the identified articles were
screened by their titles and abstracts to ensure
relevance. Full-text reviews were then conducted to
extract data on extracranial effects of TBI, including
cardiovascular, respiratory, endocrine, musculoskeletal,
and immune dysfunctions. Data were independently
reviewed by two researchers to ensure the accuracy and
relevance of the studies selected. Disagreements were
resolved through consensus discussions.
3. Data Extraction
Key data were extracted from the studies, including:
•
Study design (e.g., cohort study, cross-sectional
study, randomized controlled trial)
•
Population characteristics (e.g., age, gender, TBI
severity)
•
Extracranial
effects
identified
(e.g.,
cardiovascular complications, respiratory issues,
endocrine dysfunction, musculoskeletal effects)
•
Pathophysiological mechanisms proposed for
each extracranial effect.
•
Clinical
outcomes
(e.g.,
complications,
morbidity, mortality, long-term recovery)
This data was organized thematically to examine the
most common and significant extracranial effects of TBI
and their clinical relevance. Studies were categorized
based on the organ system affected (cardiovascular,
respiratory, endocrine, musculoskeletal, immune).
The American Journal of Medical Sciences and Pharmaceutical Research
3
https://www.theamericanjournals.com/index.php/tajmspr
The American Journal of Medical Sciences and Pharmaceutical Research
4. Quality Assessment
To assess the quality of the included studies, we used
a modified version of the Newcastle-Ottawa Scale
(NOS) for observational studies, which evaluates
studies based on their selection of participants,
comparability, and outcomes. The studies were rated
on a scale of low, moderate, or high quality, and the
findings were weighted based on their quality in the
synthesis.
5. Data Synthesis
Given the variety of study designs and populations, a
narrative synthesis approach was adopted to
summarize and interpret the data. The findings from
individual studies were combined to form a
comprehensive overview of the extracranial effects of
TBI, focusing on the pathophysiology, clinical
significance, and long-term outcomes of these effects.
The synthesis emphasized the importance of systemic
care and multidisciplinary management of TBI patients
to address both intracranial and extracranial
consequences.
6. Limitations
While this review provides a detailed understanding of
the extracranial effects of TBI, it has some limitations:
•
The heterogeneity of the studies included in
the review (in terms of design, population
characteristics, and methodology) may affect the
generalizability of the findings.
•
The review focuses primarily on studies
published in English, potentially omitting relevant
research published in other languages.
•
As a narrative review, the analysis does not
involve quantitative pooling of data (such as in a meta-
analysis), which limits the ability to draw precise
statistical conclusions.
7. Future Directions
Future studies could aim to:
•
Explore the longitudinal impact of extracranial
complications in TBI patients over time.
•
Investigate the mechanisms of co-morbidities
such as obesity and smoking in relation to TBI
outcomes.
•
Develop targeted interventions addressing
cardiovascular, respiratory, and endocrine dysfunction
in the early stages post-injury.
•
Evaluate the role of genetic and epigenetic
factors in determining susceptibility to extracranial
effects following TBI.
This narrative review involved a systematic search of
relevant literature using databases such as PubMed,
Scopus, and Google Scholar. We included studies
published between 2000 and 2023, focusing on human
studies that addressed extracranial effects of TBI. The
search terms included “extracranial effects of TBI,”
“systemic consequences of traumatic brain injury,”
“post
-
TBI cardiovascular complications,” and similar
variations. Studies were selected based on their
relevance to the extracranial effects of TBI and the
impact of these effects on long-term outcomes.
Key inclusion criteria for the review involved studies
that explored mechanisms and clinical outcomes
associated with extracranial complications in TBI
patients. Both observational studies and randomized
clinical trials were included, provided they contained
relevant data on extracranial effects. Review articles
and meta-analyses were also incorporated where
applicable to support the discussion of broader trends.
The review excluded articles focused primarily on
pediatric populations or those involving mild TBI
(concussions) without significant extracranial findings.
The focus of the review was placed on moderate to
severe TBI, where the extracranial effects are more
commonly observed and more clinically significant.
RESULTS
Cardiovascular Effects
One of the most significant extracranial effects of TBI is
the impact on the cardiovascular system. Studies have
shown that TBI can lead to acute changes in blood
pressure, heart rate, and vascular tone. Autonomic
dysfunction following TBI often manifests as
sympathetic
overactivity
or
parasympathetic
underactivity, resulting in fluctuating blood pressure
and heart rate variability. In severe cases, TBI may
precipitate cardiac arrhythmias, including ventricular
tachycardia or atrial fibrillation.
Additionally, trauma-induced coagulopathy is a well-
documented phenomenon that can complicate the
management of TBI. This coagulopathy, which often
includes platelet dysfunction and prolonged clotting
times, can increase the risk of hemorrhagic shock and
worsen outcomes in trauma patients, particularly in
those who experience brain hemorrhages.
Respiratory Complications
Respiratory dysfunction is another common extracranial
effect in TBI patients. Respiratory failure, hypoxia, and
hypercapnia can occur due to impaired brainstem
function, diminished respiratory drive, and poor
pulmonary mechanics. The risk of atelectasis,
pneumonia, and acute respiratory distress syndrome
(ARDS) increases following TBI due to the concomitant
injury to the chest or the ventilatory support required in
The American Journal of Medical Sciences and Pharmaceutical Research
4
https://www.theamericanjournals.com/index.php/tajmspr
The American Journal of Medical Sciences and Pharmaceutical Research
severe cases. Prolonged mechanical ventilation in
these patients can further exacerbate pulmonary
complications and prolong recovery.
Endocrine Dysfunction
The endocrine system is often profoundly affected by
TBI, with hypopituitarism being one of the most
significant long-term complications. Damage to the
hypothalamic-pituitary axis can result in deficiencies in
critical hormones such as growth hormone,
adrenocorticotropic hormone (ACTH), and thyroid-
stimulating
hormone
(TSH).
These
hormonal
imbalances contribute to a range of issues, including
fatigue, weight gain, depression, and cognitive
dysfunction. The alteration of stress hormones,
particularly cortisol, in the post-injury phase can also
exacerbate inflammatory responses and impact
recovery.
Musculoskeletal Effects
TBI often results in musculoskeletal complications,
particularly when patients experience immobility or
prolonged bed rest. The risk of muscle wasting
(sarcopenia), joint contractures, and osteoporosis
increases due to the limited physical activity following
TBI. These musculoskeletal effects further contribute
to disability and may necessitate long-term physical
rehabilitation. Furthermore, the cognitive and
neurological impairments following TBI can make
rehabilitation more challenging and lengthen recovery
periods.
Immune Response and Inflammation
TBI triggers a systemic inflammatory response that
affects multiple organs and systems. Acute injury to
the brain leads to the release of pro-inflammatory
cytokines, which not only exacerbate brain injury but
also activate systemic inflammation. This heightened
inflammatory state can worsen the function of
extracranial organs such as the heart, lungs, and
kidneys, and contribute to long-term complications,
including infection and organ dysfunction. The role of
inflammation in multi-organ dysfunction post-TBI has
prompted further exploration of anti-inflammatory
treatments to mitigate these systemic effects.
DISCUSSION
The extracranial effects of traumatic brain injury (TBI)
represent a complex array of systemic complications
that extend far beyond the brain. The interaction
between brain injury and whole-div physiology is
critical to understanding patient outcomes and the
development of comprehensive treatment plans.
Cardiovascular issues such as arrhythmias and
coagulopathy
underscore
the
need
for
multidisciplinary care in TBI patients. The presence of
autonomic dysregulation and sympathetic overactivity
following TBI suggests that addressing autonomic
imbalance
through
pharmacologic
or
non-
pharmacologic interventions could help mitigate
adverse cardiovascular outcomes. Moreover, early
monitoring and treatment of coagulopathies can
improve survival and recovery.
Respiratory dysfunction remains one of the leading
causes of morbidity and mortality in TBI patients. Early
intervention, including mechanical ventilation and
pulmonary rehabilitation, can improve patient
outcomes. Furthermore, minimizing sedation and
promoting early mobilization may reduce the risk of
pulmonary complications.
The long-term endocrine effects of TBI, including
pituitary dysfunction and hormonal imbalances,
highlight the importance of hormonal screening and
management in TBI survivors. Early detection and
treatment of hypopituitarism could prevent secondary
complications, such as osteoporosis, cardiovascular
disease, and impaired quality of life.
Finally, the musculoskeletal effects of TBI necessitate
early rehabilitation and physical therapy to prevent
long-term disability. The promotion of functional
recovery through multidisciplinary approaches will help
improve overall quality of life in TBI patients.
CONCLUSION
The extracranial effects of traumatic brain injury (TBI)
are critical in shaping the overall clinical course and
long-term recovery of patients. These effects involve a
range of systems, including cardiovascular, respiratory,
endocrine, and musculoskeletal systems, each of which
can complicate recovery and impact outcomes.
Clinicians must be aware of the multifaceted nature of
TBI and incorporate systemic care into rehabilitation
strategies to optimize patient recovery. Future research
should continue to explore targeted therapies and
interventions aimed at mitigating extracranial effects,
ultimately improving the long-term quality of life for TBI
survivors.
REFERENCES
Taylor, C.A.; Bell, J.M.; Breiding, M.J.; Xu, L. Traumatic
Brain Injury-Related Emergency Department Visits,
Hospitalizations, and Deaths-United States, 2007 and
2013. Morb. Mortal. Wkly. Rep. Surveill. Summ. 2017,
66, 1
–
16. [Google Scholar] [CrossRef] [PubMed]
Dewan, M.C.; Rattani, A.; Gupta, S.; Baticulon, R.E.;
Hung, Y.C.; Punchak, M.; Agrawal, A.; Adeleye, A.O.;
Shrime, M.G.; Rubiano, A.M.; et al. Estimating the global
incidence of traumatic brain injury. J. Neurosurg. 2019,
130, 1080
–
1097. [Google Scholar] [CrossRef] [PubMed]
Finkelstein, E.; Corso, P.S.; Miller, T.R. The Incidence and
The American Journal of Medical Sciences and Pharmaceutical Research
5
https://www.theamericanjournals.com/index.php/tajmspr
The American Journal of Medical Sciences and Pharmaceutical Research
Economic Burden of Injuries in the United States;
Oxford University Press: Oxford, UK; New York, NY,
USA, 2006; p. xiii. 187p. [Google Scholar]
Guo, S.; Han, R.; Chen, F.; Ji, P.; Liu, J.; Zhai, Y.; Chao,
M.; Zhao, W.; Jiao, Y.; Fan, C.; et al. Epidemiological
characteristics for patients with traumatic brain injury
and the nomogram model for poor prognosis: An 18-
year hospital-based study. Front. Neurol. 2023, 14,
1138217. [Google Scholar] [CrossRef]
McDonald, S.J.; Sun, M.; Agoston, D.V.; Shultz, S.R. The
effect of concomitant peripheral injury on traumatic
brain
injury
pathobiology
and
outcome.
J.
Neuroinflamm. 2016, 13, 90. [Google Scholar]
[CrossRef]
Xiong, C.; Hanafy, S.; Chan, V.; Hu, Z.J.; Sutton, M.;
Escobar, M.; Colantonio, A.; Mollayeva, T. Comorbidity
in adults with traumatic brain injury and all-cause
mortality: A systematic review. BMJ Open 2019, 9,
e029072. [Google Scholar] [CrossRef] [PubMed]
Burke, E.G.; Cansler, S.M.; Evanson, N.K. Indirect
traumatic optic neuropathy: Modeling optic nerve
injury in the context of closed head trauma. Neural
Regen. Res. 2019, 14, 593
–
594. [Google Scholar]
Fuller, G.W.; Ransom, J.; Mandrekar, J.; Brown, A.W.
Long-Term Survival Following Traumatic Brain Injury: A
Population-Based
Parametric
Survival
Analysis.
Neuroepidemiology 2016, 47, 1
–
10. [Google Scholar]
[CrossRef] [PubMed]
National Academies of Sciences, Engineering, and
Medicine. Evaluation of the Disability Determination
Process for Traumatic Brain Injury in Veterans; The
National Academies Press: Washington, DC, USA, 2019.
[Google Scholar] [CrossRef]
Rosner, M.J.; Newsome, H.H.; Becker, D.P. Mechanical
brain injury: The sympathoadrenal response. J.
Neurosurg. 1984, 61, 76
–
86. [Google Scholar]
[CrossRef] [PubMed]
Jafari, A.A.; Shah, M.; Mirmoeeni, S.; Hassani, M.S.;
Nazari, S.; Fielder, T.; Godoy, D.A.; Seifi, A. Paroxysmal
sympathetic hyperactivity during traumatic brain
injury. Clin. Neurol. Neurosurg. 2022, 212, 107081.
[Google Scholar] [CrossRef] [PubMed]
Meyfroidt, G.; Baguley, I.J.; Menon, D.K. Paroxysmal
sympathetic hyperactivity: The storm after acute brain
injury. Lancet Neurol. 2017, 16, 721
–
729. [Google
Scholar] [CrossRef]
Schroeppel, T.J.; Sharpe, J.P.; Magnotti, L.J.; Weinberg,
J.A.; Clement, L.P.; Croce, M.A.; Fabian, T.C. Traumatic
brain injury and β
-blockers: Not all drugs are created
equal. J. Trauma Acute Care Surg. 2014, 76, 504
–
509;
discussion 509. [Google Scholar] [CrossRef] [PubMed]
El-Menyar, A.; Asim, M.; Khan, N.; Rizoli, S.; Mahmood,
I.; Al-Ani, M.; Kanbar, A.; Alaieb, A.; Hakim, S.; Younis, B.;
et al. Systemic and cerebro-cardiac biomarkers
following traumatic brain injury: An interim analysis of
randomized
controlled
clinical
trial
of
early
administration of beta blockers. Sci. Rep. 2024, 14,
19574. [Google Scholar] [CrossRef] [PubMed]
Kelly-Hedrick, M.; Liu, S.Y.; Temkin, N.; Barber, J.;
Komisarow, J.; Manley, G.; Ohnuma, T.; Colton, K.;
Treggiari, M.M.; Monson, E.E.; et al. Association of Early
Beta-Blocker Exposure and Functional Outcomes in
Critically Ill Patients With Moderate to Severe Traumatic
Brain Injury: A Transforming Clinical Research and
Knowledge in Traumatic Brain Injury Study. Crit. Care
Explor. 2023, 5, e0958. [Google Scholar] [CrossRef]
[PubMed]
Nordness, M.F.; Maiga, A.W.; Wilson, L.D.; Koyama, T.;
Rivera, E.L.; Rakhit, S.; de Riesthal, M.; Motuzas, C.L.;
Cook, M.R.; Gupta, D.K.; et al. Effect of propranolol and
clonidine after severe traumatic brain injury: A pilot
randomized clinical trial. Crit. Care 2023, 27, 228.
[Google Scholar] [CrossRef] [PubMed]
Li, L.M.; Vichayanrat, E.; Del Giovane, M.; Lai, H.H.L.;
Iodice, V. Autonomic dysfunction after moderate-to-
severe traumatic brain injury: Symptom spectrum and
clinical testing outcomes. BMJ Neurol. Open 2022, 4,
e000308. [Google Scholar] [CrossRef]
Wesolowski, E.; Ahmed, Z.; Di Pietro, V. History of
concussion and lowered heart rate variability at rest
beyond symptom recovery: A systematic review and
meta-analysis. Front. Neurol. 2023, 14, 1285937.
[Google Scholar] [CrossRef] [PubMed]
Khalid, F.; Yang, G.L.; McGuire, J.L.; Robson, M.J.;
Foreman, B.; Ngwenya, L.B.; Lorenz, J.N. Autonomic
dysfunction
following
traumatic
brain
injury:
Translational insights. Neurosurg. Focus 2019, 47, E8.
[Google Scholar] [CrossRef] [PubMed]
Bao, W.; Lin, Y.; Chen, Z. The Peripheral Immune System
and Traumatic Brain Injury: Insight into the role of T-
helper cells. Int. J. Med. Sci. 2021, 18, 3644
–
3651.
[Google Scholar] [CrossRef] [PubMed]
