Naloxone for Severe Traumatic Brain Injury: A Meta-Analysis
Editor: Binu Tharakan, Texas A&M University
Health Science Center College of Medicine &
Baylor Scott and White Health, United States of
Naloxone for Severe Traumatic Brain Injury: A Meta-Analysis
Hengzhu Zhang 0
Xiaodong Wang 0
Yuping Li 0
Renfei Du 1
Enxi Xu 2
Lun Dong 0
Xingdong Wang 0
Zhengcun Yan 0
Lujun Pang 0
Min Wei 0
Lei She 0
0 Department of Neurosurgery, Clinical Medical College of Yang Zhou University , Yangzhou, Jiangsu Province , China,
1 Department of Neurosurgery, Chifeng Hospital , Chifeng, Neimenggu Province , China,
2 Department of Neurosurgery, The First People's Hospital of Zhenjiang , Zhenjiang, Jiangsu Province , China
Objective: The efficiency of naloxone for the management of secondary brain injury after severe traumatic brain injury (sTBI) remains undefined. The aim of this study is to evaluate the current evidence regarding the clinical efficiency and safety of naloxone as a treatment for sTBI in mainland China. Methodology/Principal Findings: A systematic search of the China Biology Medicine disc (CBM), China Science and Technology Journal Database (VIP), China National Knowledge Internet (CNKI), and Wan Fang Database was performed to identify randomized controlled trials (RCTs) of naloxone treatment for patients with sTBI in mainland China. The quality of the included trials was assessed, and the RevMan 5.1 software was employed to conduct this metaanalysis. Nineteen RCTs including 2332 patients were included in this study. The odds ratio (OR) showed statistically significant differences between the naloxone group and the control group (placebo) in terms of mortality at 18 months after treatment (OR, 0.51, 95%CI: 0.38-0.67; p,0.00001), prevalence of abnormal heart rates (OR, 0.30, 95%CI: 0.21-0.43; p,0.00001), abnormal breathing rate (OR, 0.25, 95%CI: 0.17-0.36; p,0.00001) at discharge, the level of intracranial pressure at discharge (OR, 2.00, 95%CI: 1.41-2.83; p50.0001), verbal or physical dysfunction rate (OR, 0.65, 95%CI: 0.43-0.98; p50.04), and severe disability rate (OR, 0.47, 95%CI: 0.30-0.73; p50.0001) at 18 months after the treatment. The mean difference (MD) showed statistically significant differences in awakening time at discharge (MD, 24.81, 95%CI: 25.49 to 24.12; p,0.00001), and GCS at 3 days (MD, 1.00, 95%CI: 0.70-1.30; p,0.00001) and 10 days (MD, 1.76, 95%CI: 1.551.97; p,0.00001) after treatment comparing naloxone with placebo group.
Conclusions/Significance: This study indicated that applying naloxone in the
early stage for sTBI patients might effectively reduce mortality, control intracranial
pressure (ICP), and significantly improve the prognosis.
Severe traumatic brain injury (sTBI) occurs mainly in the young population and
results in high morbidity and mortality. In China, more than 1/1000 people
suffered from traumatic brain injury per year and the number has shown a
substantial upward trend . Although the treatment strategy for sTBI has been
developed significantly in the past three decades, the mortality remains high (20%
to 50%), which is commonly caused by brain swelling, cerebral infarction, delayed
hematomas and cerebral hernia [2, 3]. Furthermore, the compression of brain
blood vessels caused by diffuse brain swelling, cerebral contusion, and brain tissue
hypoperfusion may lead to severe intracranial hypertension and even result in
death. To prevent the secondary damage caused by uncontrollable intracranial
hypertension, early decompressive craniotomy is a major strategy for sTBI and is
widely used in China. A systematic review of retrospective case-control studies
indicated that decompressive craniectomy could effectively reduce intracranial
pressure. However, the results still needed to be evaluated by prospective
randomized trials . Some clinical trials suggested that after decompressive
craniectomy, cerebral vascular perfusion pressure increased rapidly, which might
aggravate cerebral edema and secondary brain injury . Therefore, the current
evidence suggested that adequate cerebral perfusion pressure was necessary to
perform intracranial pressure control therapy. The American Trauma
Foundations recommended that the ideal cerebral perfusion pressure for sTBI be
between 5070 mmHg .
Secondary brain injury plays a highly important role in the aggravation of sTBI.
It has been found that secondary brain injury is caused mostly by an abnormal
increase of endogenous b-opioid peptide in the traumatized brain tissue, which is
closely related to patient prognosis . As an opioid receptor antagonist,
naloxone could exert a series of effects, including improving brain
microcirculation, maintaining cerebral perfusion pressure, and preventing secondary brain
damage. Some studies have indicated that the early application of high doses of
naloxone could significantly reduce mortality in patients with acute brain injury,
promoting good neurological function recovery and improving their prognosis
[10, 11]. However, the efficacy and safety of the early usage of naloxone compared
with placebo remains controversial.
Thus, we conduct this meta-analysis to assess the efficacy of naloxone versus
placebo in treating patients with sTBI in mainland China in terms of overall
mortality, the prevalence of abnormal vital signs, the level of intracranial pressure,
awaken time, Glasgow Coma Scale (GCS), prevalence of verbal and physical
dysfunction, the severe disability rate, and treatment-related complications.
Materials and Methods
Literature Search and Study Selection
A systematic literatures search including the China Biology Medicine disc (CBM,
19782013 Oct), China Science and Technology Journal Database (VIP, 1989
2013 Oct), China National Knowledge Internet (CNKI, 19942013 Oct), and Wan
Fang Database (19972013 Oct) was performed (using the search terms
Naloxone, severe traumatic brain injury, TBI, brain injury, secondary
brain injury, and randomized controlled trial) to identify potentially relevant
RCTs published in Chinese. The computer search mode of keywords combined
with free words was adopted. All the search terms were performed the free words
and Mesh terms searching. The search strategy was determined by two
independent researchers. The search strategy of this meta-analysis is as
follows:(Naloxone[All Fields] OR Naloxone[MeSH Terms]) AND
(((((((traumatic brain injury [MeSH Terms] OR traumatic brain injury[All
Fields]) OR TBI[MeSH Terms] OR TBI[All Fields]) OR brain injury[All
Fields] OR brain injury[All Fields]) OR secondary brain injury[MeSH
Terms] OR secondary brain injury[All Fields]) AND ((((randomized
controlled trial[All Fields] OR randomized controlled trials[MeSH Terms])
OR controlled clinical trial[All Fields] OR controlled clinical trial[MeSH
Terms]) OR random allocation[All Fields] OR random allocation[MeSH
Terms]) OR double-blind method[All Fields] OR double-blind
Two independent reviewers (XD.W and YP.L) assessed the literature based on
the titles and abstracts to identify potentially relevant articles. Disagreements were
resolved through discussion. Full versions of all relevant articles were obtained
and inspected. The literature selection is presented in the PRISMA flow chart
(Fig. 1) according to the PAISMA guidelines .
The inclusion criteria were as follows: (1) randomized controlled trials (RCTs)
published in Chinese; (2) naloxone treatment applied for sTBI and compared with
placebo; (3) reports at least one of the main outcome measures of the study,
including overall mortality, prevalence of abnormal heart rates, abnormal
breathing, the level of intracranial pressure, awakening time, GCS score,
prevalence of verbal and physical dysfunction, and the severe disability rate; (4) a
minimum follow-up of 18 months; and (5) a sample size should larger than 20
patients in each group.
Fig. 1. The PRISMA flow chart of the meta-analysis.
The outcome measures included the following: (1) primary outcome measures:
overall mortality, prevalence of abnormal heart rates (Pulse rate.110 bpm, Pulse
rate ,40 bpm), abnormal breathing (Respiratory rate.26 or ,8 breaths/min
Oxygen saturation ,90% while on O2), and the level of intracranial pressure; and
(2) secondary outcome measures: awakening time, GCS score, prevalence of
verbal and physical dysfunction, and the severe disability rate.
Literature screening and qualitative assessment
Two researchers (XD.W and YP.L) independently read the titles and abstracts of
potential studies and requested the full texts to identify eligible research (meeting
the inclusion criteria). The methodological quality was assessed according to the
RCT evaluation criteria in Cochrane Reviewers Handbook 5.0.0 , including
the following: whether the randomization method was correct; whether allocation
concealment was performed; whether a blinding method was conducted; and
whether there were losses or exits from follow-up.
The meta-analysis was performed using the statistical software RevMan5.1 (The
Cochrane Collaboration). The odds ratio (OR) with 95% confidence interval (CI)
was used as the effect indicator for the dichotomous variables, and the weighted
mean difference (MD) was used for the measurement data. The heterogeneity
assumption checked by the x2-based Q test was used to test the clinical indicators.
P.0.05 for the Q test indicates a lack of heterogeneity among the studies, and in
such cases, the OR or MD estimate was calculated using the fixed-effects model
(the Mantel-Haenszel method). Otherwise, the random-effects model (the
DerSimonian and Laird method) was used. Sensitivity analysis was conducted to
check the stability of results in each study, and the impact of different
interventions was evaluated.
Description of the Studies
Fig. 1 shows a flow chart of the study selection and inclusion process. The primary
search yielded 137 potentially relevant articles (Fig. 1). Of these articles, 90 were
excluded after reading the title and abstract. Then, the full text of the remaining 35
articles was read by 2 independent reviewers (YP.L and HZ.Z). Sixteen studies
were further excluded because of insufficient clinical data (naloxone not
compared with a placebo, 11 articles; data could not be extracted, 5 articles).
Based on the inclusion criteria, 19 RCTs including 2332 patients with sTBI were
included in the meta-analysis . The characteristics of the included studies
are listed in Table 1. The sample size of the trials ranged from 40 to 512. All
included studies were published in Chinese an described as RCT. There are 1122
sTBI patients in the naloxone group (48.11%) and 1200 patients in the placebo
group. Five studies [14, 16, 18, 30, 31] were double blind, and the other studies did
not report blinding.
Mortality (time frame)
Eleven studies [14, 16, 17, 2225, 27, 2931] reported the mortality of sTBI
patients at 18 months follow-up end point. The test of heterogeneity showed no
significant differences among the studies (I250); therefore, we applied the
fixedeffects model. The mortality was 14.38% in the naloxone group compared with
24.64% in the placebo group. The pooled OR was 0.51 (95%CI: 0.38, 0.67;
p,0.00001) (Fig. 2).
NR: not report; Y: yes.
Prevalence of abnormal heart rates and abnormal breathing
Six studies [15, 16, 1921, 26] presented data on the prevalence of abnormal heart
rates and abnormal breathing in sTBI patients who underwent naloxone or
Fig. 2. Meta-analysis of mortality of included studies.
placebo treatment at discharge. The fixed-effects model was adopted because the
heterogeneity analysis did not show a significant difference. The results showed
that the prevalences of abnormal vital signs in the naloxone groups were
significantly lower than in the placebo groups, and the pooled OR values for the
prevalence of abnormal heart rates and the prevalence of abnormal breathing were
0.30 (95%CI: 0.210.43; p,0.00001) and 0.25 (95%CI: 0.170.36; p,0.00001),
respectively. (Fig. 3)
Intracranial pressure (time frame)
Five studies [13, 15, 20, 21, 28] reported results on intracranial pressure at
discharge. Naloxone more likely lowers the intracranial pressure of sTBI patients
than placebo. The pooled OR was 2.00 (95%CI: 1.412.83; p50.0001) for low
level ICP (,200 mmH2O), as shown in Fig. 4.
Three studies [27, 28, 30] reported the awakening time of sTBI patients at
discharge. The meta-analysis showed that naloxone promoted awakening better
than placebo with statistical significance (MD, 24.81, 95%CI: 25.49 to 24.12;
p,0.00001). (Fig. 5)
The GCS scores
Nine studies [1619, 22, 2426, 31] reported the GCS scores of patients on the day
of admission and 3 days and 10 days after treatment. All the patients GCS scores
on the day of admission had a similar baseline without significant differences. The
patients in the naloxone groups had significantly higher GCS scores than the
placebo groups at 3 days (MD, 1.00, 95%CI: 0.701.30; p,0.00001) and 10 days
(MD, 1.76, 95%CI: 1.551.97; p,0.00001) after treatment. (Fig. 6)
Prevalence of verbal and physical dysfunction
Seven studies [17, 21, 24, 25, 27, 29, 30] reported the prevalence of verbal and
physical dysfunction (corresponding to a GOS of 4), and the severe disability rate
(corresponding to a GOS of 2 and 3) of sTBI patients at 18 months after
treatment. The test of heterogeneity showed no significant differences between the
two groups, and therefore we applied the fixed-effects model. The results showed
that naloxone could improve the patients prognosis significantly compared with
the placebo group. The pooled OR of the prevalence of verbal and physical
dysfunction was 0.65 (95%CI: 0.430.98; p50.04), and the pooled OR for severe
disability was 0.47 (95%CI: 0.300.73; p50.0001) (Fig.7).
Fig. 3. Meta-analysis of the prevalence of abnormal heart rates and breathing rate of naloxone for sTBI.
Qualitative Assessment and Publication Bias
The quality of the studies included in this meta-analysis is shown in Table 1.
There were 5 studies conforming to grade A, while the other studies belonged to
grade B according to the methodological quality assessment. It can be observed
from the funnel plot that the publication bias was low regarding mortality (Fig. 8)
and prevalence of abnormal heart rates and abnormal breathing (S1 Fig.), mediate
regarding the level of intracranial pressure, GCS, and prevalence of verbal and
Fig. 4. Meta-analysis of the level of intracerebral pressure of included studies.
physical dysfunction (S2, S4, and S5 Figs.), and high regarding awakening time
Fig. 7. Meta-analysis of Prevalence of verbal and physical dysfunction in sTBI patients.
Subgroup analysis of different doses and treatment durations
Dose and treatment duration may impact the mortality and prognosis of sTBI
patients; therefore, a subgroup analysis was applied to determine the effect of dose
and duration between the naloxone and placebo groups (Table 2). The subgroup
analysis included two comparisons as follows: high-dose group (.0.3 mg/kg)
versus low-dose group (,8 mg/d) and short duration (710 d) versus long
duration (.14 d). The results showed no significant difference with P values in
mortality of 0.58 and 0.99, GCS of 0.76 and 0.42, the preravence of verbal and
physical dysfunction of 0.26 and 0.32, and severe disability of 0.97 and 0.68,
respectively (test for subgroup differences).
Fig. 8. Funnel plot of included studies regarding morality.
We performed the sensitivity analysis on each study of this meta-analysis by
deleting each individual data set to evaluate its influence on the pooled ORs. The
results showed that no individual study significantly influence the pooled ORs.
TBI is a common severe disease that primarily occurs in patients below 45 years of
age, with poor prognosis and a series of social problems. Because primary brain
injury can cause several secondary complications, the mortality of sTBI patients is
higher than for other traumatic injuries. Therefore, the prevention of secondary
brain injury has become crucially important in clinical practice . At present,
the standard treatments of secondary brain injury in China are: 1) maintain
airway patency, 2) early application of calcium antagonists, 3) mannitol, 4)
neurotrophic drugs, 5) barbiturates, 6) high-dose corticosteroids, 7) Vitamin C,
8) hypothermia, and 9) surgery. The doctors apply the treatments according to the
patients condition. Xis  study confirmed that patients in the naloxone group
achieved reversed disturbance of consciousness and relieved respiratory
depression more quickly than the placebo group (P,0.05). According to several studies
focusing on the mechanism of secondary brain injury, a large quantity of
endogenous endorphins have been found in TBI patients cerebrospinal fluid,
which might participate in the secondary brain injury procedure and be closely
related to the prognosis of sTBI patients. Several studies have indicated that
GCS(10 days after treatment)
verbal and physical dysfunction
P,0.05, show statistically significant differences.
naloxone could effectively reduce the endogenous endorphin content and the
reaction of inflammatory mediators, improve cerebral hypoxia, inhibit the
generation of oxygen free radicals, resist lipid peroxidation, and protect the
activity of the Na+-k+-ATP enzyme on the neuronal cell membrane .
Intracranial hypertension is another important cause of secondary brain injury.
Therefore, it was necessary to monitor the patients ICP level, which also assisted
doctors in choosing the better treatment . The results of this research showed
that naloxone could effectively control intracranial pressure. However, the GCS
scores of patients after naloxone treatments were much higher than for the
placebo groups. This result indicated that early use of naloxone could help to
protect brain neurons and promote neurological recovery.
The follow-up outcomes at 18 months after treatment showed that naloxone
could reduce both mortality and the prevalence of verbal and physical
dysfunction, improving the prognosis of patients. Yangs study  showed that
naloxone could improve the conduction velocity of nerves and promote the
recovery of neurological function.
The effective dose of naloxone remains controversial. According to a recent
RCT, the usage of early high-dose naloxone achieved better efficacy than the
lowdose group (p,0.0). Naloxone can penetrate the blood-brain barrier to result in a
fast onset; however, its half-life is short. Some studies suggested that continuous
administration of high-dose naloxone is essential to remain clinical efficacy .
However, our statistical analysis of subgroups found no significant difference
between the high-dose and low-dose groups. To preclude the impact of the quality
and sample size of the included studies, further studies are needed to determine
the efficacy of different doses of naloxone for treating sTBI patients.
The included RCTs did not report the side effects of naloxone. In summary, this
study revealed that naloxone could be recommended to treat sTBI patients,
especially in the early stages. The limitations to this study were as follows: there
were only 5 studies conforming to grade A, while the other studies belonged to
grade B according to the methodological quality assessment; several RCTs needed
improvements in the implementation of allocation concealment and the blinding
method for evaluators and surveyors; the data on mortality and prognosis after 2
years have never been reported. In addition, all included clinical trials did not
evaluate the mechanism action of naloxone, which might be of value to
understand how naloxone worked in avoid secondary brain injury. These
limitations might increase the possibility of publication bias and affect the final
result of the meta-analysis. Therefore, further large multicenter RCTs are needed
to confirm this conclusion.
In summary, the results indicated that naloxone could effectively reduce the
mortality and prevalence of abnormal vital signs, control the severe intracranial
hypertension, shorten the awaken time, and improve the TBI patients prognosis.
In addition, naloxone might contribute to promoting the recovery of neurological
function and significantly improve the prognosis of patients.
S1 Fig. Funnel plot of included studies regarding prevalence of abnormal heart
rates and breathing rate.
S2 Fig. Funnel plot of included studies regarding the level of intracerebral
S3 Fig. Funnel plot of included studies regarding awakened time.
S4 Fig. Funnel plot of included studies regarding GCS in different time points.
S5 Fig. Funnel plot of included studies regarding Prevalence of verbal and
S1 Checklist. PRISMA checklist.
Conceived and designed the experiments: YPL HZZ Xiaodong Wang. Performed
the experiments: YPL LS ZCY EXX. Analyzed the data: YPL MW Xingdong Wang
LS LD. Contributed reagents/materials/analysis tools: YPL HZZ RFD Xiaodong
Wang LJP. Wrote the paper: YPL HZZ LS LJP LS. Literature search and data
extraction: HZZ YPL Xingdong Wang. Setting search strategy: RFD ZCY EXX.
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