Brain Injury, May 2010; 24(5): 706–721

REVIEW

Acute management of acquired brain injury part II:

An evidence-based review of pharmacological interventions

MATTHEW J. MEYER1, JOSEPH MEGYESI2,3, JAY MEYTHALER4,5,

MANUEL MURIE-FERNANDEZ6, JO-ANNE AUBUT1, NORINE FOLEY1,
KATHERINE SALTER1, MARK BAYLEY7,8, SHAWN MARSHALL9,10, &
ROBERT TEASELL1,6,11
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1
Aging, Rehabilitation and Geriatric Care Program, Lawson Health Research Institute, London, Ontario, Canada,
2
Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada, 3London
Health Sciences Centre, University Hospital, London, Ontario, Canada, 4Department of Physical Medicine and
Rehabilitation, Wayne State University School of Medicine, Detroit, MI, USA, 5Rehabilitation Institute of Michigan,
Detroit, MI, USA, 6Department of Physical Medicine and Rehabilitation, St Joseph’s Health Care, London, Ontario,
Canda, 7Division of Physical Medicine and Rehabilitation, University of Toronto, Toronto, Ontario, Canada,
8
Toronto Rehabilitation Institute, Toronto, Ontario, Canada, 9The Ottawa Hospital Rehabilitation Centre, Ottawa,
Ontario, Canada, 10Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Cananda, and 11Department of
For personal use only.

Physical Medicine and Rehabilitation, Schulich School of Medicine and Dentistry, University of Western Ontario,
London, Ontario, Canada

(Received 22 July 2009; accepted 8 February 2010)

Abstract
Primary objective: To review the research literature on pharmacological interventions used in the acute phase of acquired
brain injury (ABI) to manage ICP and improve neural recovery.
Main outcomes: A literature search of multiple databases (CINAHL, EMBASE, MEDLINE and PSYCHINFO) and hand
searched articles covering the years 1980–2008 was performed. Peer reviewed articles were assessed for methodological
quality using the PEDro scoring system for randomized controlled trials (RCTs) and the Downs and Black tool for RCTs
and non-randomized trials. Levels of evidence were assigned and recommendations were made.
Results: In total, 11 pharmacological interventions used in the acute management of ABI were evaluated. These included
propofol, barbiturates, opioids, midazolam, mannitol, hypertonic saline, corticosteroids, progesterone, bradykinin
antagonists, dimethyl sulphoxide and cannabinoids. Of these interventions, corticosteroids were found to be contra-
indicated and cannabinoids were reported as ineffective. The other nine interventions demonstrated some benefit for
treatment of acute ABI. However, rarely did these benefits result in improved long-term patient outcomes.
Conclusions: Substantial research has been devoted to evaluating the use of pharmacological interventions in the acute
management of ABI. However, much of this research has focused on the application of individual interventions in small
single-site trials. Future research will need to establish larger patient samples to evaluate the benefits of combined
interventions within specific patient populations.

Keywords: Brain injury, acute, pharmacological management

Correspondence: Robert Teasell, Parkwood Hospital, 801 Commissioners Rd East, London, Ontario, Canada N6C 5J1. Tel: 519-685-4559. Fax: 519-685-
4023. E-mail: robert.teasell@sjhc.london.on.ca
ISSN 0269–9052 print/ISSN 1362–301X online ß 2010 Informa Healthcare Ltd.
DOI: 10.3109/02699051003692126
 Acute ABI: Pharmacological 707

Introduction ABI [3]. Stated case definitions deemed to constitute

an ABI included TBI, head injury, brain injury,
Immediately following a serious brain injury, there is
anoxia, drug or alcohol induced toxicity and infec-
a variable degree of irreversible damage to the central
tion. Case definitions of cerebrovascular accident,
nervous system, commonly known as the primary
malignant/metastatic tumours, congenital or devel-
injury. Subsequently, a chain of events often leads to
opmental problems (e.g. cerebral palsy, autism) or
ongoing neural injury caused by oedema, inflamma-
progressive degenerative diseases (e.g. Alzheimer’s,
tion, hypoxia, ischemia, release of toxic amounts
Parkinson’s) were not included [4].
of excitatory neurotransmitters and impaired ionic
Relevant studies cited in review articles,
homeostasis across neuronal cell membranes [1].
meta-analyses, systematic reviews or in selected
Treatment of acute brain injury focuses on prevent-
study articles but not identified through the original
ing or minimizing the extent of secondary injury by
literature search were hand searched and included.
controlling intracranial hypertension, maintaining
Studies published before 1980 that held significant
adequate cerebral oxygenation and promoting ionic
clinical importance were also included.
homeostasis.
Studies were assessed for methodological quality
Pharmacological strategies for the management of
using the Physiotherapy Evidence Database
intracranial hypertension generally fall under one
(PEDro) [5] scoring system for randomized con-
of three types: osmotic agents (diuretics), analgesics
trolled trials (RCTs) and the Downs and Black [6]
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or sedatives. Osmotic agents draw fluid from the

tool for both RCTs and non-randomized trials. The
cranial cavity, thereby reducing increased intracra-
PEDro scale is comprised of 11 yes or no quality
nial pressure. Analgesics and sedatives reduce
items; 10 of which are used to calculate the final
the metabolic demands placed on injured or at risk
PEDro score (0–10). The Downs and Black scale
neurons by limiting nociceptive stimulation and
consists of 27 one-point questions and one two-point
reducing overall brain activity.
question (scored from 0–2) resulting in a final score
ranging from 0–28. For both tools, higher scores are
For personal use only.

indicative of greater methodological quality. Levels

Methods
This review is the second in a series of three articles
and is also a component of a larger review process.
Detailed methods have been published separately
[2]. An exploratory search of multiple databases
(CINAHL, EMBASE, MEDLINE and PsycINFO)
was performed to identify pharmacological interven-
tions commonly used in acute ABI management.
Interventions used to lower elevated intracranial
pressure (ICP) and/or preserve neural functioning
in the acute stages following an acquired brain injury
(ABI) were considered. Interventions reported as
standard practice or indicated as having potential
future benefits were selected for review. Extensive
literature reviews were then performed for each
intervention individually using the same databases
covering the years 1980–2008.
Title and keyword searches were performed using
the name (or names) of the intervention in combi-
nation with ‘head injury’, ‘brain injury’ or ‘cranio-
cerebral injury’. Studies were considered for
inclusion if at least 50% of the patient population
consisted of patients with ABI, n  5, and the study
evaluated a targeted intervention with measurable
outcomes.
For the purpose of this review, the Toronto
Acquired Brain Injury Network definition of ABI
was adopted [2]. This was chosen to reflect local care
practices, to allow for inclusion of a large number of
pertinent trials and to coincide with definitions used
in reviews of other pharmacological interventions for
of evidence were generated based on methodological
scores, which were then used to summarize the study
results [4]:
(1) Level 1 evidence: Findings supported by the
results of one or more RCT of at least good
quality (PEDro score  6).
(2) Level 2 evidence: Findings supported by a single
RCT of at least fair quality (PEDro score < 6).
(3) Level 3 evidence: Findings supported by at least
one case-control study.
(4) Level 4 evidence: Findings supported by at least
one:
(a) Pre–post test: A prospective trail with a
baseline measure and a post intervention
measure in a single group of subjects;
(b) Post-test: A prospective study using a post
intervention measure only (no pre-test or
baseline measurement with one or more
groups); or
(c) Case series: A retrospective study, usually a
chart audit.
(5) Conflicting evidence: Findings in direct contra-
diction in at least two studies of similar meth-
odological quality.
Interventions were evaluated individually. Each
section contains a brief background regarding the
intervention, a table summarizing the details of each
study and a general overview. Bibliographical infor-
mation, methodology and outcome information are
 708 M. J. Meyer et al.

summarized in Tables I–XI. Levels of evidence and
conclusions are presented in Table XII.
Main outcomes and results
Propofol
Propofol is a powerful, fast-acting, short-duration
sedative that provides potentially neuroprotective
effects through decreases in peripheral vascular
tension. Several in vivo and in vitro animal studies
have shown positive effects on cerebral physiology
following an ABI including reductions in cerebral
blood flow, cerebral oxygen metabolism, EEG
activity and ICP [7]. One RCT and two
non-RCTs examining propofol use in patients with
brain injuries were evaluated (Table I).
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blocking agents, benzodiazepines, pentobarbital and
CSF drainage when compared to patients receiving
morphine alone (Table XII). However, there were
no significant between-group differences reported in
mortality rates or GOS scores at 6-month follow-up.
The administration of morphine in conjunction with
propofol infusion made conclusions regarding pro-
pofol alone problematic. The other two studies also
suggested propofol was a safe and effective sedative
agent but resulted in little or no effect on ICP or
CPP [9, 10]. Based on the results of this review,
there was strong (level 1) evidence that propofol only
reduces elevated ICP and the need for other ICP and
sedative interventions when used in conjunction with
morphine (Table XII).
Anecdotally, it has been reported that administra-
tion of high dose propofol can result in propofol

In the only RCT identified, Kelly et al. [8] infusion syndrome, characterized by severe meta-
compared propofol sedation to morphine for safety bolic acidosis, rhabdomyolosis, cardiac dysrhythmias
and efficacy. Propofol, in combination with mor- and potential cardiovascular collapse [11]; espe-
phine, reduced ICP and the need for neuromuscular cially in children [12]. In a letter to the Lancet,

Table I. Propofol for the acute management of ABI.

For personal use only.

Study n Study design PEDro D&B Interventions Results

[8] 42 RCT 8 25 Propofol & morphine vs. morphine (þ) ICP control
(ND) GOS (6M)
[10] 15 Non-RCT NS 10 Propofol vs. (þ) AVDO2
morphine/midazolam (ND) MABP, ICP, CPP, GOS (6M)
[9] 10 Case series NS 10 Propofol (þ) ICP, CPP

PEDro ¼ Physiotherapy Evidence Database rating scale score [5]; D&B ¼ Downs and Black [6] quality assessment scale score;
(þ), beneficial result; (ND), no difference; (), negative result; (NS), no score; ICP, intracranial pressure; GOS, Glasgow outcome scale;
AVDO2, arterio-venous difference oxygen; MABP, mean arterial blood pressure; CPP, cerebral perfusion pressure.

Table II. Barbiturates for the acute management of ABI.

Study n Study design PEDro D&B Interventions Results

[23] 53 RCT 6 18 Pentobarbitol vs. control (ND) Mortality, ICP, GOS

() MABP
[25] 20 RCT 5 20 Thiopental vs. pentobarbital (ND) ICP, Mortality
[24] 59 RCT 5 17 Pentobarbitol vs. mannitol () ICP, Mortality (patients with no haematoma)
[22] 73 RCT 4 18 Pentobarbitol vs. control (þ) Mortality (if ICP responded to barbiturate)
[100] 7 Non-RCT NS 17 Pentobarbitol vs. control (þ) Energy expenditure, 24 h nitrogen excretion
(ND) 3-MH excretion
[20] 40 Non-RCT NS 16 Barbiturate coma vs. control () adrenal insufficiency
[21]
52 Non-RCT NS 15 Thiopental vs. control () reversible leucopenia, granulocytopenia,
infection rate, bone marrow function
[26] 38 Non-RCT NS 15 Thiopental & hypothermia vs. (þ) GOS
control
[101] 12 Case series NS 13 Barbiturate coma (ND) ICP, MABP, CPP, PtiO2, PRx
[102] 38 Case series NS 11 Thiopentone (þ) ICP
() MAPB

PEDro ¼ Physiotherapy Evidence Database rating scale score [5]; D&B ¼ Downs and Black [6] quality assessment scale score;
(þ), beneficial result; (ND), no difference; (), negative result; (NS), no score; ICP, intracranial pressure; GOS, Glasgow Outcome Scale;
MABP, mean arterial blood pressure; 3-MH, 3-methylhistidine; CPP, cerebral perfusion pressure; PTiO2, brain tissue oxygenation;
PRx, autoregulation.
 Acute ABI: Pharmacological 709

Table III. Opioids for the acute management of ABI.

Study n Study design PEDro D&B Interventions Results

[36] 30 RCT 8 23 Morphine vs. fentanyl (ND) ICP, MABP, CPP

[35] 9 RCT 7 19 Fentanyl vs. sufentanil (ND) ICP, MABP
[40] 161 RCT 5 19 Remifentanil & propofol/midazolam if (þ) awakening for assessment
necessary vs. propofol/midazolam &
fentanyl/morphine if necessary
[38] 15 RCT 5 19 Fentanyl vs. sufentanil vs. morphine (ND) ICP
() MAP (suf vs. fen & mor)
[33] 6 Case series NS 15 Sufentanil, alfentanil or fentanyl () ICP, MABP, CPP
[39] 10 Case series NS 15 Sufentanil & sufentanil/midazolam (þ) ICP
() MABP
[34] 10 Case series NS 15 Sufentanil () ICP, MABP, CPP
[37] 20 Case series NS 14 Remifentanil (ND) ICP, CPP, CBFV
[30] 30 Case series NS 14 Sufentanil () MAP, ICP

PEDro ¼ Physiotherapy Evidence Database rating scale score [5]; D&B ¼ Downs and Black [6] quality assessment scale score;
(þ), beneficial result; (ND), no difference; (), negative result; (NS), no score; ICP; intracranial pressure; MABP, mean arterial blood
pressure; CPP, cerebral perfusion pressure; CBFV, cerebral blood flow velocity.
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Table IV. Midazolam for the acute management of ABI.

Study n Study design PEDro D&B Interventions Results

[44] 59 RCT 5 17 Midazolam vs. propofol vs. (þ) Hypertrigliceridemia (mid vs. prop)
midazolam & propofol (ND) haemodynamics, ICP, CPP, SjvO2
For personal use only.

[43] 184 Chart review NS NS Midazolam () hypotension (in greater doses)
[45] 12 Case series NS 12 Midazolam (ND) ICP
() CPP, MABP

PEDro ¼ Physiotherapy Evidence Database rating scale score [5]; D&B ¼ Downs and Black [6] quality assessment scale score;
(þ), beneficial result; (ND), no difference; (), negative result; (NS), no score; ICP, intracranial pressure; CPP, cerebral perfusion
pressure; SjvO2, jugular vein O2 saturation; MABP, mean arterial blood pressure.

Table V. Mannitol for the acute management of ABI.

Study n Study design PEDro D&B Interventions Results

[60] 41 RCT 7 20 Mannitol vs. saline () Urine output

(þ) Serum sodium
(ND) BP
[57] 20 RCT 7 22 Mannitol vs. hypertonic saline () ICP clinical failure
(ND) Mortality, GOS
[59] 20 RCT 6 22 Mannitol vs. Hypertonic saline (ND) ICP
[47] 9 RCT cross-over 5 18 Mannitol vs. saline & dextran-70 () ICP
[50] 44 RCT 5 18 High dose mannitol vs. conventional-dose (þ) Papillary widening, Mortality,
mannitol GOS (6M)
[52] 141 RCT 5 18 High dose mannitol vs. conventional-dose (þ) Papillary widening, Mortality,
mannitol GOS (6M)
[51] 178 RCT 4 17 High dose mannitol vs. conventional-dose (þ) Papillary widening, Mortality,
mannitol GOS (6M)
[55] 80 RCT 4 16 Mannitol (only if ICP > 25 mmHg) vs. (ND) Mortality, ICP, neurological
mannitol outcome
[58] 13 Case series NS 10 Mannitol vs. hypertonic saline () Duration of ICP reduction
(ND) ICP
[53] 28 Case series NS 12 Mannitol 0.1 g Kg1 (100 kg patient ¼ 1.0 mmHG
ICP drop
[56] 11 Case series NS 9 Mannitol (þ) ICP, CPP (if ICP > 20 mmHg)
(ND) ICP (if < 20 mmHg)

PEDro ¼ Physiotherapy Evidence Database rating scale score [5]; D&B ¼ Downs and Black [6] quality assessment scale score;
(þ), beneficial result; (ND), no difference; (), negative result; (NS), no score; BP, blood pressure; ICP, intracranial pressure;
GOS, Glasgow outcome scale; CPP, cerebral perfusion pressure.
 710 M. J. Meyer et al.

Table VI. Hypertonic saline for the acute management of ABI.

Study n Study design PEDro D&B Interventions Results

[65] 460 RCT 10 20 Saline vs. albumin (þ) Mortality

(ND) GOS-E
[66] 229 RCT 9 23 Hypertonic saline vs. Ringer’s lactate (ND) Mortality, GOS
[57] 20 RCT 7 22 Hypertonic saline vs. mannitol (þ) ICP clinical failure
(ND) Mortality, GOS
[67] 32 RCT 6 21 Hypertonic saline vs. Ringer’s lactate (þ) ARDS, LOS, complications
[47] 9 RCT 5 18 Saline & dextran-70 vs. mannitol (þ) ICP
[64] 41 RCT 5 19 Hypertonic saline vs. Ringer’s lactate (ND) ICP, GOS
() # treatments
[62] 10 Case series NS 15 Saline (þ) ICP, CPP
[68] 14 Case series NS 12 Hypertonic saline (þ) ICP, non-contused volume
() contused hemispheric volume
[69] 10 Case series NS 12 Hypertonic saline/acetate solution (þ) ICP, lateral displacement, GCS
[61] 10 Case series NS 11 Hypertonic saline. (þ) ICP, CPP
[58] 13 Case series NS 10 Hypertonic saline vs. mannitol (þ) Duration of ICP reduction
(ND) ICP
[70] 6 Case series NS 10 Hypertonic saline (þ) ICP
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[71] 12 Case series NS 6 Hypertonic saline (þ) ICP, CPP, Pbt O2.

PEDro ¼ Physiotherapy Evidence Database rating scale score [5]; D&B ¼ Downs and Black [6] quality assessment scale score;
(þ), beneficial result; (ND), no difference; (), negative result; (NS), no score; GOS[-E], Glasgow outcome scale [extended];
ICP, intracranial pressure; ARDS, acute respiratory distress syndrome; LOS, length of stay; CPP, cerebral perfusion pressure; GCS,
Glasgow coma scale; Pbt O2, partial pressure of brain tissue O2.
For personal use only.

Table VII. Corticosteroids for the acute management of ABI.

Study n Study design PEDro D&B Interventions Results

[75] 10 008 RCT 10 27 Methylprednisolone vs. control () Mortality

[73] 396 RCT 9 19 Triamcinolone acetonide vs. placebo (þ) GOS (if GCS < 8)
[74] 76 RCT 8 19 High dose dexamethasone vs. low dose (ND) ICP, good outcomes
dexamethasone vs. placebo
[77] 88 RCT 7 20 High-dose methylprednisolone vs. low dose (ND) GOS, morbidity
methylprednisolone vs. placebo
[78] 130 RCT 4 19 Dexamethasone vs. placebo (þ) ICP (if >20 mmHg)
[79] 161 RCT 4 20 High-dose dexamethasone vs. placebo (ND) Mortality, GOS (6 Mo)
[76] 100 RCT 4 16 Methylprednisolone vs. control (ND) GOS
[80] 76 RCT 4 15 High-dose dexamethasone vs. low-dose (ND) ICP
dexamethasone vs. placebo
[81] 404 Non-RCT NS 15 Glucocorticoids vs. control () Early seizures (<2 days)

PEDro ¼ Physiotherapy Evidence Database rating scale score [5]; D&B ¼ Downs and Black [6] quality assessment scale score;
(þ), beneficial result; (ND), no difference; (), negative result; (NS), no score; GOS, Glasgow outcome scale; ICP, intracranial pressure.

Table VIII. Progesterone for the acute management of ABI.

Study n Study design PEDro D&B Interventions Results

[84] 100 RCT 10 26 IV progesterone vs. placebo (þ) Mortality (30-day), GOS-E (if GCS 9–18)
[85] 159 RCT 7 23 IV progesterone vs. placebo (þ) Mortality, GOS, mFIM,
(ND) ICP

PEDro ¼ Physiotherapy Evidence Database rating scale score [5]; D&B ¼ Downs and Black [6] quality assessment scale score;
(þ), beneficial result; (ND), no difference; (), negative result; (NS), no score; GOS-E, Glasgow outcome scale extended; GCS, Glasgow
coma scale; GOS, Glasgow outcome scale; mFIM, modified Functional Independence Measure; ICP, intracranial pressure.

Cremer et al. [13] assessed all patients treated in their they identified a crude odds ratio of 1.93 (95% CI
facility from 1996–1999 retrospectively and identi- 1.12–3.32, p ¼ 0.018) for developing propofol infu-
fied seven patients who died of apparent propofol sion syndrome per unit (mg kg1 h1) increase in
infusion syndrome. Using logistic regression analysis, propofol dose. Similarly, Otterspoor et al. [14]
 Acute ABI: Pharmacological 711

Table IX. Bradykinin antagonist for the acute management of ABI.

Study n Study design PEDro D&B Interventions Results

[86] 139 RCT 8 22 BradycorTM vs. placebo (þ) ICP (days 4 & 5), mortality
(ND) GOS
[87] 20 RCT 6 21 BradycorTM vs. Ringer’s lactate (þ) ICP, GCS
[90] 25 RCT 4 17 Anatibant vs. placebo (þ) GOS (3, 6 Mo)

PEDro ¼ Physiotherapy Evidence Database rating scale score [5]; D&B ¼ Downs and Black [6] quality assessment scale score;
(þ), beneficial result; (ND), no difference; (), negative result; (NS), no score; ICP, intracranial pressure; GOS, Glasgow outcome scale;
GCS, Glasgow coma scale.

Table X. DMSO for the acute management of ABI.

Study n Study design PEDro D&B Interventions Results

[92] 10 Case series NS 10 DMSO (þ) ICP (30 min)

[91] 10 Case series NS 8 DMSO (if ICP  25 mmHg) (þ) ICP, CPP (short term)
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[93] 5 Case studies NS NS DMSO (þ) ICP (15 min)

() hypernaetremia

PEDro ¼ Physiotherapy Evidence Database rating scale score [5]; D&B ¼ Downs and Black [6] quality assessment scale score;
(þ), beneficial result; (ND), no difference; (), negative result; (NS), no score; ICP, intracranial pressure; CPP, cerebral perfusion
pressure.

Table XI. Cannabinoids for the acute management of ABI.

For personal use only.

Study n Study design PEDro D&B Interventions Results

[99] 861 RCT 10 25 Dexanabinol vs. placebo (ND) Mortality, GOS, ICP, CPP, BI, SF36, CIQ
[98] 67 RCT 8 22 Dexanabinol vs. placebo (þ) ICP, CPP, GOS (1 Mo), DRS

PEDro ¼ Physiotherapy Evidence Database rating scale score [5]; D&B ¼ Downs and Black [6] quality assessment scale score;
(þ), beneficial result; (ND), no difference; (), negative result; (NS), no score; ICP, intracranial pressure; CPP, cerebral perfusion
pressure; DRS, disability rating scale; BI, Barthel index; SF36, short form 36; CIQ, community reintegration questionnaire.

reviewed case reports to assess risk factors associated
with propofol infusion syndrome. They identified
large cumulative doses, young age, acute neurological
injury, low carbohydrate intake, high fat intake,
catecholamine infusion, corticosteroid infusion, crit-
ical illness and inborn errors of mitochondrial fatty
acid oxidation as potential risk factors. They recom-
mended that until further research is conducted,
propofol infusion should not exceed 4 mg kg1 h1 in
patients with any of the above risk factors and that
infusion of 5 mg kg1 h1 should never be exceeded.
Barbiturates
Barbiturates have long been used in the management
of elevated ICP. It is believed that barbiturates
reduce increased ICP through the suppression
of cerebral metabolism, thereby reducing meta-
bolic demands and cerebral blood volume [15].
Barbiturates are also utilized to prevent the devel-
opment of seizures in acute ABI, despite conflicting
claims regarding their efficacy [16]. Early reports
supported the therapeutic benefit of barbiturate use
in patients with ABI [17, 18] and suggested
barbiturates reduced elevated ICP, even in patients
unresponsive to other ICP management interven-
tions (mannitol and hyperventilation) [19].
However, most early investigations were uncon-
trolled comparisons of small patient cohorts.
More recent studies have suggested barbiturate-
induced coma may result in adverse effects including
adrenal insufficiency [20] and bone marrow sup-
pression [21]. Four RCTs and six non-RCTs
evaluating barbiturate use in ABI were found
(Table II).
Conflicting evidence has been reported regarding
many aspects of barbiturate use in patients with ABI.
Eisenberg et al. [22] reported high dose pentobarbi-
tal was an effective adjunctive therapy for the
management of elevated ICP refractory to conven-
tional therapeutic measures and supported the use
of high dose barbiturates for a small sub-group of
severe ABI patients (GCS  7). In contrast, Ward
et al. [23] reported pentobarbital was no better
than conventional ICP management measures
in a similar group of patients (GCS  7), while
 712 M. J. Meyer et al.

Table XII. Recommendations regarding pharmacological interventions for acute ABI management.

Treatment Conclusion Level of Evidence

Propofol  Propofol reduces ICP and the need for other ICP and sedative interventions when 1
used in conjunction with morphine
Barbiturates  There is no difference between thiopental and pentobarbital for control of elevated 1
ICP
 Pentobarbital is less effective than mannitol for control of elevated ICP 2
 Barbiturate therapy may cause reversible leukopenia, granulocytopenia and 3
systemic hypotension
 A combination barbiturate therapy and hypothermia may result in improved 3
clinical outcomes up to 1 year post-injury
 Pentobarbital is more effective than conventional ICP management measures Conflicting
Opioids  Bolus opioid administration results in elevated ICP 1
 Remifentanil results in faster arousal compared to hypnotic-based sedation 2
regimens
 Infusion of opioids results in elevations in ICP Conflicting
Midazolam  Midazolam has no effect on ICP in brain injured patients 2
 Midazolam negatively affects CPP and MAP Conflicting
Mannitol  Higher dose mannitol is superior to conventional mannitol in improving mortality 1
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rates and clinical outcomes

 Mannitol is less effective than hypertonic saline for reducing ICP 1
 Out-of-hospital administration of mannitol does not adversely affect blood pressure 1
compared to treatment with saline
 Prophylactic mannitol does not result in decreased ICP Conflicting
Hypertonic saline  Hypertonic saline improves ICP and CPP in brain injured patients 1
 Hypertonic saline reduces ICP more effectively than mannitol 1
 Hypertonic saline results in similar improvements in ICP and GOS outcomes 1
compared with Ringer’s lactate solution
For personal use only.

 Hypertonic saline solution results in improved mortality rates but not GOS scores 1
compared to albumin
 Hypertonic saline may increase the volume of contused brain tissue 4
Corticosteroids  Methylprednisolone increases mortality rates in ABI patients and should not be 1
used
 Triamcinolone may improve outcomes in patients with a GCS < 8 and a focal 1
lesion
 Glucocorticoid administration may increase the risk of developing first late seizures 3
 Corticosteroids reduce ICP Conflicting
Progesterone  Progesterone decreases mortality rates in ABI patients and improves clinical 1
outcomes up to 6 months post-treatment
Bradykinin  Bradycor is effective in preventing acute elevations in ICP post-ABI 1
Antagonists  Bradykinin antagonists improve functional clinical outcomes Conflicting
Dimethyl sulphoxide  Dimethyl sulphoxide transiently reduces ICP elevations 4
Cannabinoids  Dexanabinol does not provide acute improvement in ICP or long-term clinical 1
benefits post-ABI

Schwartz et al. [24] suggested pentobarbital is less
effective than mannitol in the treatment of elevated
ICP. Perez-Barcena et al. [25] reported thiopental
may be superior to pentobarbital in controlling
ICP; however, Llompart-Pou et al. [20] reported
thiopental led to increased risk of developing adrenal
insufficiency compared to control.
Nordby and Nesbakken [26] reported thiopental
combined with mild hypothermia resulted in better
clinical outcomes on the Glasgow Outcome scale 1
year post-injury when compared with conventional
ICP management measures (including hyperventila-
tion, steroids and mannitol). However, because
this study used a combination of thiopental and
hypothermia, it was not possible to attribute
better clinical outcomes to thiopental alone. In a
separate meta-analysis, Roberts [15] reported
that, while barbiturates may reduce elevated ICP,
there was little evidence to link this with reductions
in mortality or disability. In the same meta-analysis,
Roberts [15] noted that barbiturate therapy was
associated with substantial hypotension that could
offset any ICP-lowering effect. Similarly, this
review located several studies linking barbiturate
use to adverse effects, including decreased cerebral
perfusion pressure due to decreased arterial pres-
sure [27] and reduced production of white blood
cells [21]. Stover and Sticker [21] noted interactions
with bone marrow suppressing antibiotics (specifi-
cally tazobactum/piperacillin) can further exacer-
bated the suppression of white blood cell
production.

In summary, there was conflicting evidence as to
whether barbiturates are more effective than other
conventional ICP management strategies and strong
(level 1) evidence of no difference between thiopen-
tal and pentobarbital for ICP control. There was
level 2 evidence that mannitol is superior to
pentobarbital for ICP control and level 3 evidence
that barbiturates may cause reversible leukopenia,
granulocytopenia and systemic hyotension. There
was also level 3 evidence that barbiturate use in
conjunction with hypothermia improves long-term
patient outcomes (Table XII).
Opioids
Opioids are substances that have morphine-like
actions. They work by binding to opioid receptors,
found principally in the central nervous system and
Brain Inj Downloaded from informahealthcare.com by HINARI on 03/21/11
the gastrointestinal tract. Each opioid has a distinct
binding affinity to group(s) of opioid receptors that
then determines its pharmacodynamic response.
Morphine has been the most commonly used
opioid following an ABI, while fentanyl and its
derivatives have gained popularity owing to their
more rapid onset and shorter duration of effect [28].
For personal use only.
Controversy persists regarding the effect of opioids
on ICP and CPP. It has been reported that opioids
can increase cerebral blood flow (CBF), which may
lead to an increase in ICP [29–32] in the presence
of intracranial pathology. This review found four
RCTs and five non-RCTs evaluating opioid use in
acute ABI management (Table III).
Analgesic sedation with opioids is commonly used
in conjunction with hypnotic agents (i.e. midazolam,
propofol) to reduce nociceptive stimulation. This
makes it difficult to evaluate the effects of opioids
in isolation. Five studies reported increases in ICP
after opioid administration [30, 33–36], while two
found no increase [37, 38] and one reported a
decrease [39]. However, mode of administration has
been suggested as a determining factor for increases
in ICP [33, 34]. In those studies where patients
received only bolus injections of opioids, significant
increases in ICP were seen [30, 35, 36]. There was
strong (level 1) evidence that bolus opioid adminis-
tration resulted in increased ICP and conflicting
evidence regarding the effects of opioid infusion on
ICP levels (Table XII).
Fentanyl and its derivatives have been suggested
as more ideally suited for sedation in patients with
brain injury due to their rapid onset and short
duration [28]. In this review, one study found
remifentanil resulted in significantly faster arousal
compared to propofol or midazolam [40]. The
authors suggested that this allowed for prompt
neurological assessment. However, patients in
the treatment group received remifentanyl as the
Acute ABI: Pharmacological 713
primary sedative agent and then a hypnotic agent,
while patients in the control groups received fentanyl
or morphine in conjunction with a hypnotic agent.
Therefore, remifentanil’s efficacy can be compared
to hypnotic-based sedation but not fentanyl or
morphine. There was level 2 evidence that remifen-
tanil results in faster arousal compared to hypnotic
based sedation (Table XII).
Midazolam
Midazolam is a fast-acting benzodiazepine with a
short half-life and inactive metabolites [41]. It is
anxiolytic and displays anti-epileptic, sedative, and
amnestic properties. It is a protein-bound, highly
lipid soluble drug which crosses the blood–brain
barrier and has a rapid onset of action within
1–5 minutes in most patients [42]. However, delayed
elimination of midazolam, resulting in prolonged
sedation, has been demonstrated in some critically
ill patients.
Studies in the operating room or intensive care
unit have demonstrated midazolam to be relatively
safe in euvolemic patients or in the presence of
continuous haemodynamic monitoring for early
detection of hypotension [43]. Midazolam has been
found to reduce cerebrospinal fluid pressure in
patients without intracranial mass lesions as well as
decrease cerebral blood flow and cerebral oxygen
consumption [42]. One RCT and two non-RCTs on
midazolam use in acute ABI management were
reviewed (Table IV).
Infusions of midazolam or propofol were reported
to provide similar quality sedation in patients with
severe head trauma, although propofol was asso-
ciated with a high incidence of hypertriglyceridemia
[44]. In both studies evaluating midazolam and ICP,
no significant difference was seen after midazolam
administration [44, 45]. However, significant hypo-
tension related to increased doses of midazolam [43]
and decreases in MAP resulting in decreased CPP
(especially in patients with initial ICP  18 mmHg)
[45] were also reported. In summary, there was level
2 evidence that midazolam has no effect on ICP, but
conflicting evidence regarding midazolam’s effect on
MAP and CPP (Table XII). Hypotension should be
monitored as a potential side-effect based on current
research.
Mannitol
Mannitol is an osmotic agent that draws excess fluid
from the cranial cavity, thereby decreasing ICP.
However, with prolonged dosage, mannitol may
penetrate the blood–brain barrier, potentially exacer-
bating any elevation in ICP [46]. Mannitol has also
been associated with significant diuresis, acute renal
failure, hyperkalemia, hypotension and rebound
 714 M. J. Meyer et al.
increments in ICP [47, 48]. For these reasons, it has
been recommended that mannitol only be used
when signs of elevated ICP or deteriorating neuro-
logical status suggest the benefits of mannitol may
outweigh potential complications or adverse effects
[49]. Eight RCTs and three non-RCTs assessing the
efficacy of mannitol in brain injury management
were reviewed (Table V).
All of the studies reviewed reported that mannitol
reduced ICP. However, there remains considerable
uncertainty regarding how and when it should be
used. Cruz et al. [50–52] conducted three separate
RCTs in ABI patients to investigate the effects of
high dose mannitol on clinical outcomes 6 months
post-injury. All three trials indicated that high dose
mannitol (1.4 g kg1) was superior to conventional
mannitol therapy (0.7 g kg1) in improving mortality
rates and clinical outcomes. This finding was
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further supported by Sorani et al. [53] who found
a 1.0 mmHg drop in ICP for every 0.1 g Kg1
increase in mannitol dosage. However, the
American Association of Neurological Surgeons
(AANS) has recommended mannitol for ICP control
at 0.25–1 g Kg1 body weight, but that systolic BP
should not be allowed to drop below 90 mmHg [54].
For personal use only.
While improved outcomes may be obtained with
higher doses, decisions regarding mannitol adminis-
tration should be made on a case-by-case basis.
Three studies addressed the effects of timing and
ICP level on mannitol administration. In the only
RCT evaluating timing of administration, Smith
et al. [55] reported no significant difference in terms
of mortality rates or neurological outcome between
patients receiving mannitol irrespective of ICP mea-
surement and those who received mannitol only after
the onset of intracranial hypertension (>25 mmHg).
However, the lack of a non-treatment control group
makes it unclear whether or not prophylactic
mannitol was effective. Hartl et al. [56] reported
that mannitol was only effective in diminishing ICP
when initial ICP was elevated (>20 mmHg); this
was corroborated by Sorani et al. [53]. Therefore,
there appears to be conflicting evidence regarding
the benefit of prophylactic mannitol administration.
Five studies and a review were located that
assessed the efficacy of mannitol therapy relative to
other osmotic agents. Three studies reported man-
nitol resulted in poorer reductions in ICP when
compared to hypertonic saline [47, 57, 58].
Francony et al. [59] found mannitol and saline
were comparable in reducing ICP in stable patients
with intact autoregulation and Sayre et al. [60]
reported mannitol administration did not signifi-
cantly affect blood pressure relative to saline when
administered out of hospital. However, a 2008
Cochrane review concluded mannitol may have
beneficial effects on mortality when compared to
pentobarbital but detrimental effects when com-
pared to hypertonic saline [46]. The authors report
consensus agreement that mannitol is effective
in reducing ICP, but has potentially harmful side-
effects that need to be taken into consideration.
In conclusion, this review resulted in strong
(level 1) evidence that mannitol reduces elevated
ICP, but equally strong evidence that mannitol is
less effective than hypertonic saline for ICP reduc-
tion (Table XII). Given mannitol’s effectiveness in
reducing elevated ICP, further research into specific
indications for its use relative to other osmotic agents
would be beneficial.
Hypertonic saline
Hypertonic saline is an osmotic agent that has
traditionally been used as an adjunct to mannitol
or in individuals who have become tolerant to
mannitol. However, recent studies have examined
hypertonic saline as a primary measure for ICP
control [58, 61]. Hypertonic saline exerts its effect
primarily by increasing serum sodium and osmolar-
ity, thereby establishing an osmotic gradient. Water
diffuses passively from cerebral intracellular and
interstitial space into capillaries resulting in a reduc-
tion in ICP [62]. Although mannitol works similarly,
sodium chloride has a better reflection coefficient
(1.0) than mannitol (0.9) [63], making it a better
osmotic agent. Hypertonic saline may also normalize
resting membrane potential and cell volume by
restoring normal intracellular electrolyte balance in
injured cells [62]. Six RCTs and seven non-RCTs
examining the use of hypertonic saline were reviewed
(Table VI).
Based on the above studies, hypertonic saline
proved beneficial in many aspects of acute ABI
management. There was strong (level 1) evidence
hypertonic saline is effective in reducing ICP as all
of the above trials demonstrated decreases in ICP
associated with hypertonic saline administration [47,
57, 58, 61, 62, 64–71]. Three studies also reported
improvements in CPP [61, 62, 71] and one reported
improvements in cerebral oxygenation [71].
Compared to mannitol, hypertonic saline was
shown to induce a significantly greater decrease
in ICP over time [47], with fewer incidences of
persistent ICP [57]. Hypertonic saline was also
shown to decrease mortality rates in severely injured
patients (GCS 3–8) compared with albumin infu-
sions [65] and resulted in similar reductions in
ICP when compared to Ringer’s lactate solution
[64, 66].
Despite these positive findings, some limitations
to hypertonic saline use were also noted. Shackford
et al. [64] reported that more medical interventions
were required to reduce ICP with hypertonic saline

compared to Ringer’s lactate, although a lack of
baseline comparability between groups may have
biased the results. Lescot et al. [68] applied CT
technology to assess the effectiveness of hypertonic
saline on volume, weight and specific gravity of
contused and non-contused brain tissue. Three days
after TBI, the blood–brain barrier remained
semi-permeable in non-contused areas but not in
contused areas. Contused tissue increased in volume
following administration of hypertonic saline. The
authors recommended further study was needed to
assess the effects of hypertonic saline on different
tissue types so contusion site and size could be
factored into clinical decisions.
This review resulted in the following conclusions
regarding hypertonic saline use in acute ABI man-
agement. There was level 1 evidence that hypertonic
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saline improves ICP and CPP in patients with
acute brain injury, reduces ICP more effectively
than mannitol, results in similar reductions in ICP
and GOS outcomes compared with Ringer’s lactate
solution and decreases mortality rates but not GOS
scores compared to albumin. There was level 4
evidence that hypertonic saline may increase the
volume of contused brain tissue (Table XII).
For personal use only.
Corticosteroids
Corticosteroids used in brain injury care have
included dexamethasone, methylprednisolone, pre-
dnisolone, betamethasone, cortisone, hydrocorti-
sone, prednisone and triamcinolone [72]. The use
of such a broad spectrum of agents within diverse
patient groups has complicated one’s understanding
of corticosteroid efficacy in acute ABI. This problem
has been exacerbated by a lack of understanding of
the mode of steroid action in this setting. Laboratory
studies have reported reductions in wet brain weight,
facilitation of synaptic transmission, reduction of
lipid peroxidation, enhanced blood flow, preserva-
tion of electrolyte distribution and membrane stabi-
lization with corticosteroid use [73]. Research
has noted focal lesions appear to respond well to
corticosteroid therapy while diffuse intracerebral
lesions and haematomas appear less responsive [73,
74]. Nine studies (eight RCTS and one non-RCT)
on corticosteroid use in acute ABI were reviewed
(Table VII).
In what has become the definitive study of
corticosteroid use to date, Roberts et al. [75]
conducted a large, multinational, randomized con-
trolled collaborative study of early methylpredniso-
lone use after severe head injury. This study,
the Corticosteroid Randomization After Severe
Head Injury (CRASH) trial, was halted after
10 008 patients had been randomly allocated as the
reported relative risk of death was greater in the
Acute ABI: Pharmacological 715
steroid group compared to controls (1.18, 95% CI
1.09–1.27; p ¼ 0.0001). Further analysis showed
no differences in outcomes between eight CT
sub-groups or between patients with major extra-
cranial injury compared to those without. The
authors also conducted a systematic review and
meta-analysis of existing trials using corticosteroids
for head injury. Before the CRASH trial, a 0.96
(95% CI 0.85–1.08) relative risk of death was
reported in the corticosteroid group. The addition
of the CRASH trial increased the relative risk to
1.12 (95% CI 1.05–1.2). The authors concluded
that corticosteroids should not be used in head
injury care. The meta-analysis performed by Roberts
et al. [75] included all but two of the studies in this
review.
Of the studies in this review, two assessed methyl-
prednisolone use and both reported no improve-
ments in GOS outcome at 6 months [76, 77].
However, Giannotta et al. [77] reported patients less
than 40 years old demonstrated decreased mortality
rates. Four studies evaluated dexamethasone treat-
ment [74, 78–80], none of which reported significant
improvements compared with placebo.
Watson et al. [81] retrospectively evaluated
the influence of four different corticosteroids on
post-traumatic seizure rates. They noted patients
receiving glucocorticoid treatment on the first day
post-injury were at increased risk of developing a
first late seizure when compared to patients receiving
no treatment. They also saw no improvement in
patients receiving glucocorticoids after the first day.
In the only study reporting positive results,
Grumme et al. [73] found the synthetic corticoster-
oid triamcinolone improved outcomes in patients
with both a GCS < 8 and a focal lesion.
In summary, there was level 1 evidence that
methylprednisolone increases mortality and should
not be used in acute ABI management and there was
conflicting evidence regarding the effect of corticos-
teroids on ICP. There was level 1 evidence based on
one study that triamcinolone may improve outcomes
in patients with a GCS < 8 and a focal lesion,
but further study should be carried out cautiously
given the results of a larger trial. There was level 3
evidence that glucocorticoid administration may
increase the risk of developing first late seizures
(Table XII).
Progesterone
Progesterone has been identified as a potential
neuro-protective agent. Animal research suggests
progesterone modulates excito-toxicity, reconstitutes
the blood–brain barrier, reduces cerebral oedema,
regulates inflammation and decreases apoptosis
[82]. In some cases, women have been excluded
 716 M. J. Meyer et al.
from studies due to concerns that hormonal inter-
actions will improve their outcomes and bias study
results [83]. However, few clinical studies have
shown this to be true, while several epidemiological
studies have indicated that female patients may
actually do worse [83]. Only two published clinical
studies of progesterone use in ABI have been
performed to date (Table VIII).
In a phase II trial, Wright et al. [84] assessed
progesterone vs. placebo for patients acutely follow-
ing ABI. Patients in the progesterone group demon-
strated no increase in complication rates and a
decreased 30-day mortality rate. In addition, utiliz-
ing a post-hoc analysis, patients with moderate–
severe brain injury showed significantly greater
rates of moderate-to-good GOS-E scores. Despite
limitations with sample size, the authors noted that
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these results were encouraging and warranted inves-
tigation in a larger and more thorough clinical trial.
Xiao et al. [85] provided intravenous progesterone
to TBI patients with a GCS < 9. Despite no change
in ICP compared to controls, significant improve-
ments in Glasgow Outcome Scale, mortality and
modified FIM scores were reported at 3 and 6
month follow-up. Based on these trials, there was
For personal use only.
level 1 evidence that progesterone can decrease
mortality rates in ABI patients and improve clinical
outcomes (Table XII). Given these beneficial
results and the lack of complications associated
with progesterone administration, further study is
warranted.
Bradykinin antagonists
Tissue injury and subsequent cell death act as strong
triggers for the initiation of an inflammatory
response. The kinin-kallikrein pathway is one of
the components of this acute inflammatory cascade
following traumatic brain injury [86, 87]. The
generation of bradykinin leads to a detrimental
cascade of events ultimately ending in altered
vascular permeability and tissue oedema [88].
Animal research using BK2 receptor knockout mice
has demonstrated direct involvement of this receptor
in the development of inflammatory-induced sec-
ondary damage and subsequent neurological deficits
resulting from diffuse TBI [89]. These findings
suggest that specific inhibition of the BK2 receptor
could prove to be an effective therapeutic strategy
following brain injury. Three studies evaluating the
efficacy of BradycorTM and Anatibant (two bradyki-
nin antagonists) in the acute treatment of ABI were
reviewed (Table IX).
Narotam et al. [87] reported treatment with
BradycorTM resulted in significant reductions in
ICP elevation and decreased deterioration in GCS
scores over the course of the study. Furthermore, the
need for other therapeutic interventions to control
ICP was markedly lower in those treated with
BradycorTM [87]. A larger RCT conducted by
Marmarou et al. [86] reported that, compared with
those assigned to a placebo group, patients treated
with BradycorTM experienced a significant reduction
in intracranial hypertension (ICP > 15 mmHg).
However, despite trends favouring the BradycorTM
treatment, there were no significant differences
in mortality rates, improvements in GOS scores at
3 and 6 months or the intensity of therapeutic
interventions needed to control ICP [86].
In a more recent study, severe head injury patients
were randomized to receive placebo or Anatibant,
a more potent bradykinin antagonist than
BradycorTM [90]. The authors were unable to
report any conclusive evidence to support or refute
the efficacy of Anatibant in preventing brain oedema
or deteriorations in ICP and CPP, which they
attributed to a small sample size and lack of baseline
comparability between groups [90]. However, the
authors did report that those patients who received
the higher dose of this drug showed more favourable
outcomes on the GOS at 3 and 6 months compared
with the other groups [90].
In summary, there was level 1 evidence that
Bradycor is effective in preventing acute elevations
in ICP post-ABI but conflicting evidence that
bradykinin antagonists improve functional clinical
outcomes such as the GOS (Table XII).
Dimethyl sulphoxide
Dimethyl sulphoxide (DMSO) has been reported to
result in strong diuresis, protect cells from mechan-
ical damage, reduce oedema in tissue by stabilizing
cell membranes and act as a free radical scavenger
[91]. DMSO is also believed to increase tissue
perfusion, thereby improving cell oxygenation, neu-
tralizing metabolic acidosis and decreasing intracel-
lular fluid retention [91]. This study identified three
studies examining the effects of DMSO in the
management of ICP and brain swelling post ABI
(Table X).
In a study using a single group intervention
design, Kulah et al. [91] demonstrated that, for the
majority of participants, DMSO was effective in
controlling ICP elevations within minutes of injec-
tion, which was accompanied by a concomitant
increase in CPP. Unfortunately, these benefits
appear to be transient, since continuous infusions
of DMSO for up to 7 days failed to control
elevations in ICP. In a similar study, Karaca et al.
[92] reported that, although reductions in ICP were
seen within the first 30 minutes of DMSO adminis-
tration, the effect was not sustained and most
patients required maintenance doses for 2–10 days

to minimize fluctuations in ICP. Marshall et al. [93]
reported that rapid infusions of DMSO were effec-
tive in controlling elevated ICP in patients for whom
ICP could not be controlled by standard measures.
All three studies scored low on methodological
quality, limiting the strength of conclusions.
Therefore, there is level 4 evidence that dimethyl
sulphoxide transiently reduces ICP elevations, but
further study is required (Table XII).
Cannabinoids
Dexanabinol (HU-211) is a synthetic, non-
psychotropic cannabinoid [94] thought to act as
a non-competitive N-methyl-D-aspartate receptor
antagonist to decrease glutamate excito-toxicity
[95]. Dexanabinol is believed to possess antioxidant
properties [96] and has shown encouraging neuro-
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protective effects in animal models of TBI [97].
Two studies on cannabinoid use in humans were
reviewed (Table XI).
Knoller et al. [98] reported that the active drug
group showed significant improvements in ICP and
CPP. However, despite showing initially significant
improvements on the GOS and DRS at 1 month
For personal use only.
post-treatment, these benefits were no longer signif-
icant at 6-month follow-up. Subsequently, Maas
et al. [99] conducted a large-scale multi-centre RCT
and reported that, compared with placebo, dexana-
binol did not significantly improve outcomes
(i.e. extended GOS, mortality rates, Barthel
index or quality of life measures (SF36, CIQ)) at
6-months. Moreover, dexanabinol failed to provide
acute control of derangements in ICP or CPP [99].
These negative findings suggest that the initial
benefits reported by Knoller et al. [98] could have
been due to the small sample size in this earlier
study. Therefore, there was level 1 evidence that
dexanabinol does not result in acute improvement
in ICP or benefits in long-term outcomes
(Table XII).
Discussion
This review evaluated a total of 11 pharmacological
interventions used in the acute management of
acquired brain injury. Of these, corticosteroids
were found to be contraindicated and cannabinoids
were shown to be ineffective. Each of the other
interventions showed promise in acute ABI care.
However, limited efficacy was found for improved
long-term outcomes and specific applications for
many of the interventions require further study.
Evidence suggests that propofol sedation is safe
and effective; however, its benefit without concom-
itant morphine administration requires further inves-
tigation. There is also consensus evidence suggesting
Acute ABI: Pharmacological 717
that propofol infusion greater than 4 mg kg1 h1
may result in propofol infusion syndrome, a danger-
ous and potentially fatal adverse effect.
Barbiturate sedation remains questionable in
ABI care. There is conflicting evidence regarding
the benefits of barbiturate use in ICP management
and some indication that mannitol may be more
effective in this regard. Also, there is evidence to
suggest that barbiturate use can lead to negative
side-effects including reversible leukopenia, granu-
locytopenia and systemic hypotension. Barbiturates
have increasingly limited indication and, given
the benefits noted with use of alternate sedatives
including propofol and midazolam, it is questionable
as to whether further study into the role of
barbiturates in ABI management is appropriate.
Opioid administration leads to increases in ICP
if given via bolus injection; however, there was
conflicting evidence regarding the effects of infusion
administration on ICP levels. One study also
suggested that remifentanil may allow for more
rapid arousal relative to hypnotic-based sedation.
Given the prevalence of opioid administration in
patients with brain injury, further research into their
effect on ICP is necessary.
Midazolam was found to provide similar quality
sedation to propofol with no increase in ICP.
However, midazolam has been linked to significant
hypotension resulting in decreases in CPP that
require monitoring upon administration.
Mannitol is a common treatment for management
of elevated ICP and this review resulted in strong
evidence that mannitol is effective in reducing ICP.
However, these benefits may only be seen when
ICP is already elevated. Moreover, there was strong
evidence that mannitol was less effective than
hypertonic saline in reducing elevated ICP.
Hypertonic saline was shown to be very effective in
reducing elevated ICP and may reduce mortality
rates in severely injured patients. For this reason,
hypertonic saline may be the optimal osmotic agent
for use in acute ABI care. However, one study found
that hypertonic saline may result in greater swelling
of contused tissue. Further study into this finding
appears warranted.
Based on a large scale international trial, corticos-
teroid use in patients with ABI was found to increase
mortality rates. Similarly, this review found the
majority of studies demonstrated a lack of improve-
ment associated with corticosteroid use and evidence
that they may lead to increases in early onset
seizures. Only triamcinolone was found to improve
patient outcomes in severely injured patients with
focal lesions; however, in light of the other studies,
these findings should be interpreted cautiously. This
review supports the recommendation that corticos-
teroids should not be used in acute ABI care.
 718 M. J. Meyer et al.
Progesterone has gained interest as a possible
neuroprotective agent post-ABI. This review located
two trials into progesterone use, both of which
resulted in beneficial outcomes and decreased mor-
tality. Although one trial was a preliminary phase II
trial, there is evidence to suggest that progesterone
is safe and effective, warranting further study.
Three other less common interventions for ICP
management were also reviewed. There is an indi-
cation that the bradykinin antagonists Bradycor and
Anatibant result in transient reductions in ICP;
however, further study into their effect on long-term
outcomes is necessary. Dimethyl sulphoxide
was shown to transiently reduce ICP levels in the
short-term and may be beneficial in instances where
ICP is unresponsive to other treatments. Finally,
despite initial promise, larger studies suggest canna-
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binoids are not effective in reducing ICP or
improving outcomes post-ABI.
Pharmacological interventions will continue to
play a key role in the acute management of ABI.
Excluding corticosteroids and cannabinoids, each of
the other nine interventions showed promise in some
aspect of acute care. Given the diversity of complica-
tions associated with brain injury, treatment often
For personal use only.
requires combinations of medications that make
isolating the effect of a single intervention difficult.
Future research should aim to establish large scale
trials similar to the CRASH trial for corticosteroid
use so that stronger and more definitive conclusions
can be drawn. Also, further research into the effects
of interventions within different patient groups will
allow for more individualized treatment strategies
resulting in improved patient outcomes.
Conclusions
Substantial research has been devoted to evaluating
the use of pharmacological interventions in the acute
management of ABI. Based on the results of this
review, corticosteroids were found to be contra-
indicated and cannabinoids were reported as inef-
fective. The other nine interventions demonstrated
some benefit for treatment of acute ABI. However,
rarely did these benefits result in improved
long-term patient outcomes.
Declaration of interest: The authors report no
conflict of interest. The authors alone are responsi-
ble for the content and writing of the paper.
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