Journal of Neurotrauma
Douglas K. Anderson, Ph.D. Chung Y. Hsu, M.D., Ph.D.
Editor-in-Chief Reorganization and Repair Taipei Medical University
Department of Neuroscience Taiwan
John T. Povlishock, Ph.D. University of Florida, College of Claire E. Hulsebosch, Ph.D.
VCU Neuroscience Center Medicine
Virginia Commonwealth University University of Texas Medical Branch
Medical College of Virginia Campus David I. Graham, M.B., Ph.D. Galveston
1101 E. Marshall St. Neuropathology John A. Jane, M.D., Ph.D.
P.O. Box 980709 Department of Neuropathology University of Virginia
Richmond, VA 23298-0709 Institute of Neurological Sciences Charlottesville
(804) 828-9623 Southern General Hospital
Fax: (804) 828-9477 Ji-yao Jiang, M.D., Ph.D.
Yoichi Katayama, M.D., Ph.D.
E-mail: email@example.com Shanghai Jiaotong University
Neurophysiology and Metabolism School of Medicine
Department of Neurological Surgery People’s Republic of China
Nihon University School of Medicine
Tokyo Patrick M. Kochanek, M.D.
Critical Care Medicine
Harvey Levin, Ph.D.
Deputy Editor Neuropsychology and Behavior
Safar Center for Resuscitation
Physical Medicine & Rehabilitation Pittsburgh
M. Ross Bullock, M.D., Ph.D. Baylor College of Medicine
Department of Neurosurgery Morimichi Koshinaga, M.D., Ph.D.
Virginia Commonwealth University M. Ross Bullock, M.D., Ph.D. Nihon University School of Medicine
Medical College of Virginia Campus Clinical Management of Brain Injury Tokyo
1200 E. Broad St. Medical College of Virginia Campus of
Virginia Commonwealth University Bruce G. Lyeth, Ph.D.
P.O. Box 980631 University of California
Richmond, VA 23298-0631 Richmond
(804) 828-9165 John F. Ditunno, Jr., M.D.
Fax: (804) 827-1693 William L. Maxwell, Ph.D.
E-mail: firstname.lastname@example.org University of Glasgow
Department of Rehabilitation Medicine
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University of Pennsylvania
R.J. Moulton, M.D.
Editorial Board St. Michael’s Hospital
European Editor Andrew R. Blight, Ph.D.
ACORDA Therapeutics, Inc. J. Paul Muizelaar, M.D., Ph.D.
Lars T. Hillered, M.D., Ph.D. Hawthorne, NY University of California at Davis
Department of Neuroscience,
Neurosurgery Peter C. Blumbergs, M.D. Linda Noble, Ph.D.
Uppsala University Hospital Institute of Medical & Veterinary Science University of California
SE-751 85 Uppsala Adelaide, SA San Francisco
Sweden Claudia Robertson, M.D.
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Fax: 46-18-558-617 Ohio State University
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Pak H. Chan, Ph.D.
Stanford University Medical Center Bernhard A. Sabel, Ph.D.
Otto-von-Guericke University of
Robert S. Clark, M.D. Magdeburg
Children’s Hospital of Pittsburgh Germany
Guy L. Clifton, M.D. Stephen W. Scheff, Ph.D.
Yoichi Katayama, M.D., Ph.D. University of Texas Medical School University of Kentucky
Department of Neurological Surgery Houston Lexington
Nihon University School of Medicine Douglas S. DeWitt, Ph.D. Lisa Schnell, Ph.D.
30-1 Oyaguchi-Kamimachi University of Texas University Zurich—Irchel
Itabashi-ku, Tokyo 173-8610 Galveston Esther Shohami, Ph.D.
Japan The Hebrew University School of
81-3-3972-8111 W. Dalton Dietrich, III, Ph.D.
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E-mail: firstname.lastname@example.org School of Medicine Douglas Smith, M.D.
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University of Pittsburgh of Medicine
Michael Fehlings, M.D., Ph.D. Joe E. Springer, Ph.D.
Toronto Western Hospital University of Kentucky Medical
Section Editors Center
Fred H. Gage, Ph.D. Lexington
Charles H. Tator, M.D., Ph.D. The Salk Institute Oswald Steward, Ph.D.
Clinical Management of Spinal Cord University of California
Injury M. Sean Grady, M.D.
University of Pennsylvania Irvine
Division of Neurosurgery
University of Toronto Ronald L. Hayes, Ph.D. Robert Vink, Ph.D.
University of Florida Adelaide University
Edward D. Hall, Ph.D. Australia
Neuroprotective and Neurorestorative College of Medicine
Pharmacology David A. Hovda, Ph.D. Kevin K.W. Wang, Ph.D.
Department of Anatomy and Neurobiology University of California School of University of Florida
University of Kentucky–College of Medicine Stephen G. Waxman, M.D., Ph.D.
Medicine Los Angeles Yale University School of Medicine
Journal of Neurotrauma
VOLUME 24 SUPPLEMENT 1 2007
GUIDELINES FOR THE MANAGEMENT
OF SEVERE TRAUMATIC BRAIN INJURY
M.R. Bullock and J.T. Povlishock
I. Blood Pressure and Oxygenation S-7
II. Hyperosmolar Therapy S-14
III. Prophylactic Hypothermia S-21
IV. Infection Prophylaxis S-26
V. Deep Vein Thrombosis Prophylaxis S-32
VI. Indications for Intracranial Pressure Monitoring S-37
VII. Intracranial Pressure Monitoring Technology S-45
VIII. Intracranial Pressure Thresholds S-55
IX. Cerebral Perfusion Thresholds S-59
X. Brain Oxygen Monitoring and Thresholds S-65
XI. Anesthetics, Analgesics, and Sedatives S-71
XII. Nutrition S-77
XIII. Antiseizure Prophylaxis S-83
XIV. Hyperventilation S-87
XV. Steroids S-91
Appendix A. Changes in Quality Ratings from the 2nd Edition S-96
to the 3rd Edition
Appendix B. Electronic Literature Search Strategies S-99
(Database: Ovid MEDLINE)
Appendix C. Criteria for Including a Study in which the Sample Includes S-105
TBI Patients and Patients with Other Pathologies or Pediatric Patients
Appendix D. Electronic Literature Search Yield S-106
Appendix E. Evidence Table Template S-106
Instructions for Authors can be found on our website at www.liebertpub.com
Finally, the Brain Trauma Foundation would also like to acknowledge and thank the following individuals for
their contribution to the 3rd Edition of the Guidelines for the Management of Severe Traumatic Brain Injury:
Susan Carson, MPH, Oregon Health & Science University
Cynthia Davis-O’Reilly, BSc, Brain Trauma Foundation Center for Guidelines Management
Pamela Drexel, Brain Trauma Foundation
Rochelle Fu, PhD, Oregon Health & Science University
Susan Norris, MD, MPH, MSc, Oregon Evidence-based Practice Center
Michelle Pappas, BA, Brain Trauma Foundation Center for Guidelines Management
Kimberly Peterson, MS, Oregon Health & Science University
Adair Prall, MD, South Denver Neurosurgery
Patricia Raksin, MD, Cook County Hospital
Susan Carson, Rochelle Fu, Susan Norris, Kimberly Peterson, and Nancy Carney are staff or affiliates of the
Oregon Evidence-Based Practice Center (EPC). The EPC’s role in the development of these guidelines is described
within this report. The Agency for Healthcare Research and Quality has not reviewed this report.
Disclaimer of Liability
T HE INFORMATION CONTAINED in the Guidelines for the Management of Severe Traumatic Brain Injury reflects the
current state of knowledge at the time of publication. The Brain Trauma Foundation (BTF), American Associ-
ation of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS), and other collaborating orga-
nizations are not engaged in rendering professional medical services and assume no responsibility for patient out-
comes resulting from application of these general recommendations in specific patient circumstances. Accordingly,
the BTF, AANS, and CNS consider adherence to these clinical practice guidelines will not necessarily assure a suc-
cessful medical outcome. The information contained in these guidelines reflects published scientific evidence at the
time of completion of the guidelines and cannot anticipate subsequent findings and/or additional evidence, and there-
fore should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests
that are reasonably directed to obtaining the same result. Medical advice and decisions are appropriately made only
by a competent and licensed physician who must make decisions in light of all the facts and circumstances in each
individual and particular case and on the basis of availability of resources and expertise. Guidelines are not intended
to supplant physician judgment with respect to particular patients or special clinical situations and are not a substi-
tute for physician-patient consultation. Accordingly, the BTF, AANS, and CNS consider adherence to these guide-
lines to be voluntary, with the ultimate determination regarding their application to be made by the physician in light
of each patient’s individual circumstances.
REFERENCES 7. Gabriel EJ, Ghajar J, Jagoda A, Pons PT, Scalea T, Wal-
ters BC. Guidelines for Pre-Hospital Management of
1. Bullock R, Chestnut R, Ghajar J, et al. Guidelines for the Traumatic Brain Injury. Brain Trauma Foundation: New
management of severe traumatic brain injury. J Neurotrauma York, 2000.
2000;17:449–554. 8. Guidelines for the management of penetrating brain injury.
2. Bullock R, Chestnut R, Ghajar J, et al. Guidelines for the J Trauma 2001;51:S3–S6.
surgical management of traumatic brain injury. Neuro-
3. Fakhry SM, Trask AL, Waller MA, et al. IRTC Neurotrauma
Task Force: management of brain injured patients by an ev- SURVEY REFERENCES
idence-based medicine protocol improves outcomes and de-
creases hospital charges. J Trauma 2004;56:492–493. 1. Ghajar J, Hariri RJ, Narayan RK et al. Crit. Care Med.
4. Palmer S, Bader M, Qureshi A, et al. The impact of out- 1995;23:560–567.
comes in a community hospital setting using the AANS 2. Hesdorffer DC, Ghajar J, Jacouo L. J Trauma 2002;52:
Traumatic Brain Injury Guidelines. American Association 1202–1209.
of Neurological Surgeons. J Trauma 2001;50:657–664. 3. Hesdorffer DC, and Ghajar J. Marked improvement in ad-
5. Vukic L, Negovetic D, Kovac D, et al. The effect of imple- herence to traumatic brain injury guidelines in United States
mentation of guidelines for the management of severe head trauma centers. J Trauma (in press).
injury on patient treatment and outcomes. Acta Neurochir
6. Adelson PD, Bratton SL, Carney NA, et al. Guidelines for —M. Ross Bullock, M.D., Ph.D.
the acute medical management of severe traumatic brain in- Deputy Editor
jury in infants, children and adolescents. Pediatr Crit Care —John T. Povlishock, Ph.D.
Med 2003;4:S417–S491. Editor-in-Chief
the Cochrane Collaboration.12 The goal was to establish REFERENCES
a process for Guidelines development that was scientifi-
cally rigorous, consistent across all topics, and indepen- 1. Lu J, Marmarou A, Choi S, et al. Mortality from traumatic
dent of the interests and biases of contributing authors. brain injury. Acta Neurochir 2005[suppl];95:281–285.
The partnership also recommended appointing a Re- 2. Ghajar J, Hariri RJ, Narayan RK, et al. Survey of critical
view Committee to consist of a small number of indi- care management of comatose, head-injured patients in the
viduals who would serve as liaison between the guide- United States. Crit Care Med 1995;23:560–567.
lines development process and the key medical societies 3. Hesdorffer D, Ghajar J, Iacono L. Predictors of compliance
related to TBI. These representatives of neurosurgery, with the evidence-based guidelines for traumatic brain in-
trauma, neurointensive care, pediatrics, emergency med- jury care: a survey of United States trauma centers. J
icine, and prehospital care, as well as international orga- Trauma 2002;52:1202–1209.
nizations, are standing members of the Committee across 4. Fakhry SM, Trask AL, Waller MA, et al. IRTC Neuro-
all Guidelines updates. The current members of this Com- trauma Task Force: Management of brain-injured patients
mittee, listed at the front of this document, reviewed this by an evidence-based medicine protocol improves out-
edition of the Guidelines. comes and decreases hospital charges. J Trauma 2004;56:
In order to continue to improve outcomes for TBI pa- 492–493.
tients, it is necessary to generate strong research capable 5. Palmer S, Bader M, Qureshi A, et al. The impact on out-
of answering key questions, and to assess, synthesize, and comes in a community hospital setting of using the AANS
disseminate the findings of that research so that practi- traumatic brain injury guidelines. American Association of
tioners have access to evidence-based information. Neurological Surgeons. J Trauma 2001;50:657–664.
Therefore, this document should not only be used as a 6. Vitaz T, McIlvoy L, Raque G, et al. Development and im-
roadmap to improve treatment, but also as a template plementation of a clinical pathway for severe traumatic
from which to generate high quality research for future brain injury. J Trauma 2001;51:369–375.
use. The primary marker of the success of the 3rd edition 7. Vukic L, Negovetic D, Kovac D, et al. The effect of im-
of these Guidelines will be a sufficient body of Class I plementation of guidelines for the management of severe
and II studies for Level I and II recommendations in the head injury on patient treatment and outcomes. Acta Neu-
4th edition. rochir 1999;141:1203–1208.
The BTF maintains and revises several TBI Guidelines 8. Bullock R, Chesnut R, Clifton G et al. Guidelines for the
on an annual basis resulting in a 5-year cycle, approxi- management of severe head injury. Brain Trauma Founda-
mately, for each Guideline: tion, American Association of Neurological Surgeons Joint
Section on Neurotrauma and Critical Care. J Neurotrauma
• Guidelines for Prehospital Management of Trau- 1996;13:641–734.
matic Brain Injury 9. Bullock RM, Chesnut RM, Clifton GL et al. Guidelines for
• Guidelines for the Management of Severe Traumatic the management of severe traumatic brain injury. J Neuro-
Brain Injury trauma 2000;17:449–554.
• Guidelines for the Surgical Management of Trau- 10. Harris RP, Helfand M, Woolf SH, et al. Current methods
matic Brain Injury of the third U.S. Preventive Services Task Force. Am J Pre-
• Prognosis of Severe Traumatic Brain Injury vent Med 2001;20:21–35.
11. Anonymous. Undertaking systematic reviews of research
These BTF Guidelines are developed and maintained on effectiveness: CRD’s guidance for those carrying out or
in a collaborative agreement with the American Associ- commissioning reviews. CRD Report Number 4 (2nd edi-
ation of Neurological Surgeons (AANS) and the Con- tion). York, UK: NHS Centre for Reviews and Dissemi-
gress of Neurological Surgeons (CNS), and in collabo- nation; 2001. 4 (2nd edition).
ration with the AANS/CNS Joint Section on 12. Mulrow CD, Oxman AD. How to conduct a Cochrane sys-
Neurotrauma and Critical Care, European Brain Injury tematic review. Version 3.0.2. Paper presented at: Cochrane
Consortium, other stakeholders in TBI patient outcome. Collaboration, 1997; San Antonio, TX.
IV. DATA ABSTRACTION V. QUALITY ASSESSMENT
AND SYNTHESIS AND CLASSIFICATION OF EVIDENCE
FOR TREATMENT TOPICS
Two authors independently abstracted data from each
publication using an evidence table template (see Ap- In April of 2004, the Brain Trauma Foundation estab-
pendix E). They compared results of their data abstrac- lished a collaboration with the Evidence-Based Practice
tion and through consensus finalized the data tables. Due Center (EPC) from Oregon Health & Science University
to methodological heterogeneity of studies within topics, (OHSU). Center staff worked with two EPC epidemiolo-
and to the lack of literature of adequate quality, data were gists to develop criteria and procedures for the quality as-
not combined quantitatively for all but one topic. The ex- sessment of the literature. Criteria for classification of evi-
ception was Prophylactic Hypothermia, for which a meta- dence based on study design and quality are in Table 1, and
analysis was performed. are derived from criteria developed by the U.S. Preventive
Authors drafted manuscripts for each topic. The entire Services Task Force,1 the National Health Service Centre
team gathered for a 2-day work session to discuss the lit- for Reviews and Dissemination (U.K.),2 and the Cochrane
erature base and to achieve consensus on classification Collaboration.3 These criteria were used to assess the liter-
of evidence and level of recommendations. Some topics, ature for all topics except ICP Monitoring Technology.
while considered important, were eliminated due to lack Quality criteria specific to technology assessment were used
of a literature base (e.g., At-Risk Non-Comatose Patient, to assess the ICP Monitoring Technology topic.
Hyperacute Rehabilitation, ICP in the Elderly, and De- Two investigators independently read the studies in-
compressive Therapies). Manuscripts were revised. Vir- cluded in the Evidence Tables (both new studies and
tual meetings were held with a subset of the co-authors those maintained from the previous edition) and classi-
to complete the editing and consensus processes. The fi- fied them as Class I, II, or III, based on the design and
nal draft manuscript was circulated to the peer review quality criteria in Table 1. Discrepancies were resolved
panel. through consensus, or through a third person’s review.
TABLE 1. CRITERIA FOR CLASSIFICATION OF EVIDENCE
Class of evidence Study design Quality criteria
I Good quality Adequate random assignment method
randomized Allocation concealment
controlled trial Groups similar at baseline
(RCT) Outcome assessors blinded
Adequate sample size
Follow-up rate 85%
No differential loss to follow-up
Maintenance of comparable groups
II Moderate quality Violation of one or more of the criteria for a good quality RCTa
II Good quality Blind or independent assessment in a prospective study, or use
cohort of reliableb data in a retrospective study
Follow-up rate 85%
Adequate sample size
Statistical analysis of potential confoundersc
II Good quality Accurate ascertainment of cases
case-control Nonbiased selection of cases/controls with exclusion criteria
applied equally to both
Adequate response rate
Appropriate attention to potential confounding variables
III Poor quality Major violations of the criteria for a good or moderate quality
III Moderate or poor Violation of one or more criteria for a good quality cohorta
III Moderate or poor Violation of one or more criteria for a good quality case-
quality case- controla
III Case Series,
needs to make a judgment about whether one or more violations are sufficient to downgrade the class of study, based
upon the topic, the seriousness of the violation(s), their potential impact on the results, and other aspects of the study. Two or three
violations do not necessarily constitute a major flaw. The assessor needs to make a coherent argument why the violation(s) either do,
or do not, warrant a downgrade.
bReliable data are concrete data such as mortality or re-operation.
cPublication authors must provide a description of important baseline characteristics, and control for those that are unequally
distributed between treatment groups.
Class I Evidence is derived from randomized controlled VI. QUALITY ASSESSMENT
trials. However, some may be poorly designed, lack suffi- AND CLASSIFICATION OF EVIDENCE
cient patient numbers, or suffer from other methodological FOR ICP MONITORING TECHNOLOGY
inadequacies that render them Class II or III.
Class II Evidence is derived from clinical studies in Quality criteria typically used for literature about tech-
which data were collected prospectively, and retrospec- nology assessment are presented in Table 2, and are de-
tive analyses that were based on reliable data. Compari- rived from criteria developed by the U.S. Preventive Ser-
son of two or more groups must be clearly distinguished. vices Task Force.1 As indicated in Table 2, a key criterion
Types of studies include observational, cohort, preva- for establishing Class I evidence for technology assess-
lence, and case control. Class II evidence may also be ment is the application of the device in patients with and
derived from flawed RCTs. without the disease. Thus, the ability to use these crite-
Class III Evidence is derived from prospectively col- ria in evaluating ICP monitoring technology is limited,
lected data that is observational, and retrospectively col- in that it would not be ethical to test the monitors in peo-
lected data. Types of studies include case series, data- ple without probable elevated ICP. Criteria were applied
bases or registries, case reports, and expert opinion. Class when feasible to estimate the reliability of the findings
III evidence may also be derived from flawed RCTs, co- from each study included for this topic; however, levels
hort, or case-control studies. of recommendation were not applied.
TABLE 2. QUALITY ASSESSMENT OF DIAGNOSTIC STUDIES
Screening test relevant, available, adequately described
Study uses credible reference standard, performed regardless of test results
Reference standard interpreted independently of screening test
Handles indeterminate results in a reasonable manner
Spectrum of patients included in the study
Adequate sample size
Administration of reliable screening test
Class of evidence based on above criteria
Class I:II Evaluates relevant available screening test; uses a credible reference standard; interprets reference standard
independently of screening test; reliability of test assessed; has few or handles indeterminate results in a
reasonable manner; includes large number (more than 100) broad-spectrum patients with and without disease.
Class II:I Evaluates relevant available screening test; uses reasonable although not best standard; interprets reference
standard independent of screening test; moderate sample size (50–100 subjects) and with a “medium” spectrum
of patients. A study may be Class II with fewer than 50 patients if it meets all of the other criteria for Class II.
Class III: Has fatal flaw such as: uses inappropriate reference standard; screening test improperly administered; biased
ascertainment of reference standard; very small sample size of very narrow selected spectrum of patients.
VII. LEVEL OF RECOMMENDATION Thus, a meta-analysis containing only Class II studies
may be used to make a Level III recommendation if the
Levels of recommendation are Level I, II, and III, answers to the above questions render uncertainty in the
derived from Class I, II, and III evidence, respectively. confidence of the overall findings.
Level I recommendations are based on the strongest ev-
idence for effectiveness, and represent principles of pa-
tient management that reflect a high degree of clinical VIII. REFERENCES
certainty. Level II recommendations reflect a moderate
degree of clinical certainty. For Level III recommen- 1. Harris RP, Helfand M, Woolf SH, et al. Current methods of
dations, the degree of clinical certainty is not estab- the third U.S. Preventive Services Task Force. Am J Prevent
lished. Med 2001;20:21–35.
To determine the recommendation level derived from 2. Anonymous. Undertaking systematic reviews of research on
a meta-analysis, three criteria are considered: effectiveness: CRD’s guidance for those carrying out or
commissioning reviews. CRD Report Number 4 (2nd edi-
• Are all included studies of the same quality class? tion). York, UK: NHS Centre for Reviews and Dissemina-
• Are the findings of the studies in the same or con- tion; 2001. 4 (2nd edition).
tradictory directions? 3. Mulrow CD, Oxman AD. How to conduct a Cochrane sys-
• What are the results of analyses that examine po- tematic review. Version 3.0.2. Paper presented at: Cochrane
tential confounding factors? Collaboration, 1997; San Antonio, TX.
I. BLOOD PRESSURE AND OXYGENATION
mission GCS motor score, intracranial diagnosis, and of cerebral perfusion pressure (CPP) on outcome, it is
pupillary status. A single episode of hypotension was as- possible that systolic pressures higher than 90 mm Hg
sociated with increased morbidity and a doubling of mor- would be desirable during the prehospital and resuscita-
tality as compared with a matched group of patients with- tion phase, but no studies have been performed thus far
out hypotension.2 These data validate similar to corroborate this. The importance of mean arterial pres-
retrospectively analyzed Class III5,6,7,9,12–17,19 reports sure, as opposed to systolic pressure, should also be
published previously. stressed, not only because of its role in calculating CPP,
Several studies analyzed the association of inhospital but because the lack of a consistent relationship between
hypotension with unfavorable outcomes. Manley et al. systolic and mean pressures makes calculations based on
reported a non-significant trend toward increased mor- systolic values unreliable. It may be valuable to maintain
tality in patients with GCS 13 experiencing a single mean arterial pressures considerably above those repre-
inhospital event of hypotension (SBP 90) (relative risk sented by systolic pressures of 90 mm Hg throughout the
2.05, 95% CI 0.67–6.23).10 The relative risk increased to patient’s course, but currently there are no data to sup-
8.1 (95% CI 1.63–39.9) for those with two or more port this. As such, 90 mm Hg should be considered a
episodes. Thus repeated episodes of hypotension in the threshold to avoid; the actual values to target remain un-
hospital may have a strong effect on mortality. Jones et clear.
al. found that in patients with episodes of in-hospital hy-
potension, increased total duration of hypotensive
episodes was a significant predictor of both mortality V. SUMMARY
(p 0.0064) and morbidity (“Good” vs. “Bad” outcome,
p 0.0118).8 A significant proportion of TBI patients have hypox-
The question of the influence of hypoxia and hy- emia or hypotension in the prehospital setting as well as
potension on outcome has not been subject to manipula- inhospital. Hypotension or hypoxia increase morbidity
tive investigation, as it is unethical to assign patients to and mortality from severe TBI. At present, the defining
experimental hypotension. Therefore the large, prospec- level of hypotension is unclear. Hypotension, defined as
tively collected, observational data set from the TCDB is a single observation of an SBP of less than 90 mm Hg,
the best information on the subject that is available. This must be avoided if possible, or rapidly corrected in se-
and other studies show a strong association between hy- vere TBI patients.1,4 A similar situation applies to the de-
potension and poor outcomes. However, because of eth- finition of hypoxia as apnea cyanosis in the field, or a
ical considerations there is no Class I study of the effect PaO2 60 mm Hg. Clinical intuition suggests that cor-
of blood pressure resuscitation on outcome. recting hypotension and hypoxia improves outcomes;
In a series of studies by Vassar et al.,20–22 designed to however, clinical studies have failed to provide the sup-
determine the optimal choice of resuscitation fluid, cor- porting data.
recting hypotension was associated with improved out-
comes. One of these studies was a randomized, double-
blind, multicenter trial comparing the efficacy of VI. KEY ISSUES
administering 250 mL of hypertonic saline versus nor- FOR FUTURE INVESTIGATION
mal saline as the initial resuscitation fluid in 194 hy-
potensive trauma patients; 144 of these patients (74%) The major questions for resuscitating the severe TBI
had a severe TBI (defined as an abbreviated injury score patient are as follows:
[AIS] for the head of 4, 5, or 6). Hypertonic saline sig-
nificantly increased blood pressure and decreased over- • The level of hypoxia and hypotension that correlates
all fluid requirements. with poor outcome
• Treatment thresholds
Resuscitation End-Points • Optimal resuscitation protocols for hypoxia and hy-
The value of 90 mm Hg as a systolic pressure thresh- potension
old for hypotension has been defined by blood pressure • The impact of correcting hypoxia and hypotension
distributions for normal adults. Thus, this is more a sta- on outcome
tistical than a physiological finding. Given the influence • Specification of target values
I. BLOOD PRESSURE AND OXYGENATION
VII. EVIDENCE TABLE
EVIDENCE TABLE I. BLOOD PRESSURE AND OXYGENATION
Reference Description of study class Conclusion
Chesnut et A prospective study of 717 III Hypotension was a statistically
al., 19932 consecutive severe TBI patients independent predictor of outcome.
admitted to four centers A single episode of hypotension
investigated the effect on during this period doubled
outcome of hypotension (SBP mortality and also increased
90 mm Hg) occurring from morbidity. Patients whose
injury through resuscitation. hypotension was not corrected in
the field had a worse outcome than
those whose hypotension was
corrected by time of ED arrival.
Cooke et A prospective audit of 131 III 27% of patients were hypoxemic
al., 19953 patients with severe TBI on arrival to the ED.
evaluating the early
management of these patients in
Fearnside et A prospective study of III Hypotension (SBP
al., 19934 prehospital and inhospital 90 mm Hg) was an independent
predictors of outcome in 315 predictor of increased morbidity
consecutive severe TBI patients and mortality.
admitted to a single trauma
Gentleman A retrospective study of 600 III Improving prehospital
et al., 19925 severe TBI patients in three management decreased the
cohorts evaluating the influence incidence of hypotension but its
of hypotension on outcome and impact on outcome in patients
the effect of improved suffering hypotensive insults was
prehospital care in decreasing maintained as a statistically
its incidence and negative significant, independent predictor
impact. of poor outcome. Management
strategies that prevent or minimize
hypotension in the prehospital
phase improve outcome from
Hill et A retrospective study of III Improving the management of
al., 19936 prehospital and ED hypovolemic hypotension is a
resuscitative management potential mechanism for improving
of 40 consecutive, multitrauma the outcome from severe TBI.
patients. Hypotension SBP 80
mm Hg) correlated strongly
with fatal outcomes.
hemorrhagic hypovolemia was
the major etiology of
Jeffreys et A retrospective review of III Hypotension was one of the four
al., 19817 hospital records in 190 TBI most common avoidable factors
patients who died after correlated with death.
Kohi et al., A retrospective evaluation of 67 III Early hypotension increases the
19849 severe TBI patients seen over a mortality and worsens the
6-month period were correlated prognosis of survivors
with 6-month outcome. in severe TBI.
I. BLOOD PRESSURE AND OXYGENATION
EVIDENCE TABLE I. BLOOD PRESSURE AND OXYGENATION (CONT’D)
Reference Description of study class Conclusion
Marmarou From a prospectively collected III The two most critical values were
et al., 199111 database of 1,030 severe TBI the proposition of hourly ICP
patients; all 428 patients who readings greater than 20 mm Hg
met ICU monitoring criteria and the proportion of hourly SBP
were analyzed for monitoring readings less than 80 mm Hg. The
parameters that determined incidence of morbidity and
outcome and their threshold mortality resulting from severe
values. TBI is strongly related to ICP and
hypotension measured during the
course of ICP management.
Miller et al., A prospective study of 225 III Hypotension (SBP 95 mm Hg)
198212 severely head-injured patients was significantly
regarding the influence of associated with increased
secondary insults on outcome. morbidity and mortality.
Miller et One hundred consecutive III Hypotension (SBP 95 mm Hg)
al., 197813 severe TBI patients were associated with a non-significant
prospectively studied regarding trend toward worse outcome in
the influence of secondary entire cohort. This trend met
insults on outcome. Seminal statistical significance for patients
report relating early without mass lesions. Hypotension
hypotension to increased is a predictor of increased
morbidity and mortality. morbidity and mortality from
Influence of hypotension on severe TBI.
outcome not analyzed
independently from other
Narayan et Retrospective analysis of 207 III ICP control using a threshold of 20
al., 198214 consecutively admitted severe mm Hg as a part of an overall
TBI patients. Management aggressive treatment approach to
included aggressive attempts to severe TBI associated with
control ICP using a threshold of improved outcome.
20 mm Hg.
Pietropaoli A retrospective review of the III Early surgery with intraoperative
et al., 199215 impact of hypotension (SBP hypotension was significantly
90 mm Hg) on 53 otherwise correlated with increased mortality
normotensive severe TBI from severe TBI in a duration-
patients who received early dependent fashion. The mortality
surgery (within 72 h of rate was 82% in the group with
injury). hypotension and 25% in the
normotensive group (p 0.001).
The duration f intraoperative
hypotension was inversely
correlated with Glasgow Outcome
Scale score using linear regression
(R 0.30, p 0.02).
Rose et al., A retrospective review of III Hypotension is a major avoidable
197716 hospital and necropsy records cause of increased mortality in
of 116 TBI patients who were patients with moderate TBI.
known to have talked before
Seelig et A study of all patients (n 160) III Early hypotension was
al., 198617 with an ICP of 30 mm Hg significantly correlated with
I. BLOOD PRESSURE AND OXYGENATION
during the first 72 h after increased incidence and severity of
injury from a prospectively intracranial hypertension and
collected database of severe increased mortality.
TBI patients (n 348).
Stocchetti A cohort study of 50 trauma III Fifty-five percent of patients were
et al., patients transported from the hypoxic (SaO2 90%) and 24%
199618 scene by helicopter, which were hypotensive. Both hypoxemia
evaluated the incidence and and hypotension negatively
effect of hypoxemia and affected outcome, however, the
hypotension on outcome. degree to which each
independently affected the
outcome was not studied.
Vassar et A randomized, double-blind, II No beneficial or adverse effects of
al., 199020 clinical trial of 106 patients rapid infusion of 7.5% NaCl or
over an 8-month period. 7.5% NaCl/6% dextran 70 were
Intracranial hemorrhage was noted. There was no evidence of
present in 28 (26%) patients. potentiating intracranial bleeding.
There were no cases of central
pontine myelinolysis; however,
patients with severe pre-existing
disease were excluded from the
Vassar et A randomized, double-blind III The survival rate of severely head-
al., 199121 multicenter clinical trial of 166 injured patients to hospital
hypotensive patients over a 44-month discharge was significantly higher
month period. Fifty-three of for those who received hypertonic
these patients (32%) had a saline/dextran (HSD) (32% of
severe TBI (defined as an AIS score patients with HSD vs. 16% in
for the head of 4, 5, or 6).
Vassar et A randomized, double-blind III Raising the blood pressure in the
al., 199322 multicenter trial comparing the hypotensive, severe TBI patient
efficacy of administering 250 improves outcome in proportion to
mL of hypertonic saline versus the efficacy of the resuscitation.
normal saline as the initial Prehospital administration of 7.5%
resuscitation fluid in 194 sodium chloride to hypotensive
hypotensive trauma patients trauma patients was associated
over a 15-month period. 144 of with a significant increase in blood
these patients (74%) had a pressure compared with infusion of
severe TBI (defined as an Lactated Ringer’s (LR) solution.
abbreviated injury score [AIS] The survivors in the LR and
for the head of 4, 5, or 6). hypertonic saline (HS) groups had
significantly higher blood
pressures than the non-survivors.
Thee was no significant increase
in the overall survival of patients
with severe brain injuries,
however, the survival rate in the
HS group was higher than that in
the LR group for the cohort with a
baseline GCS score of 8 or less.
Jones et al., Prospective analysis of 124 III Mortality is best predicted by
19948 patients 14 years old admitted durations of hypotensive (p
to single center with a GCS 0.0064), hypoxemia (p 0.0244),
12, or 12 and Injury Severity and pyrexic (p 0.0137) insults.
Score 16, with clinical Morbidity (“Good” vs. “Bad”
I. BLOOD PRESSURE AND OXYGENATION
EVIDENCE TABLE I. BLOOD PRESSURE AND OXYGENATION (CONT’D)
Reference Description of study class Conclusion
indications for monitoring. outcome) was predicted by
Subgroup analysis performed hypotensive insults (p 0.0118),
on 71 patients for whom data and pupillary response on
existed for 8 potential admission (p 0.0226).
secondary insults (ICP,
CPP, hypoxemia, pyrexia,
bradycardia, tachycardia) to
identify predictors of morbidity/
Manley et Prospective cohort of 107 III Early inhospital hypotension but
al., 200110 patients with GCS 13 admitted not hypoxia is associated with
to a single center; primarily increased mortality. Odds ratio for
evaluating impact of hypoxic mortality increases from 2.1 to 8.1
and hypotensive episodes with repeated episodes of
during initial resuscitation on hypotension.
mortality. Impact of multiple
episodes of hypoxia or
Struchen et Cohort of 184 patients with III Adjusting for age and emergency
al., 200119 severe TBI admitted to a single room GCS, ICP 25 mm Hg,
level I trauma center MAP 80 mm Hg, CPP 60 mm
neurosurgical ICU who Hg, and SjO2 50% were
received continuous monitoring associated with worse outcomes.
of ICP, MAP, CPP, and jugular
venous saturation (SjO2).
Primary outcomes were GOS
and Disability Rating Scale
(DRS). Analysis included
multiple regression model
evaluating effect of physiologic
variables on outcome.
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