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Treatment of intracerebral hemorrhage in animal models Metaanalysis

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					                                                            ORIGINAL ARTICLE




   Treatment of Intracerebral Hemorrhage
      in Animal Models: Meta-Analysis
               Joseph Frantzias, BSc, Emily S. Sena, PhD, Malcolm R. Macleod, PhD,
                                        and Rustam Al-Shahi Salman, MA, PhD

Objective: Interventions that improve functional outcome after acute intracerebral hemorrhage (ICH) in animals
might benefit humans. Therefore, we systematically reviewed the literature to find studies of nonsurgical treatments
tested in animal models of ICH.
Methods: In July 2009 we searched Ovid Medline (from 1950), Embase (from 1980), and ISI Web of Knowledge
(from 1969) for controlled animal studies of nonsurgical interventions given after the induction of ICH that reported
neurobehavioral outcome. We assessed study quality and performed meta-analysis using a weighted mean
difference random effects model.
Results: Of 13,343 publications, 88 controlled studies described the effects of 64 different medical interventions
(given a median of 2 hours after ICH induction) on 38 different neurobehavioral scales in 2,616 treated or control
animals (median 14 rodents per study). Twenty-seven (31%) studies randomized treatment allocation, and 7 (8%)
reported allocation concealment; these studies had significantly smaller effect sizes than those without these
attributes (p < 0.001). Of 64 interventions stem cells, calcium channel blockers, anti-inflammatory drugs, iron
chelators, and estrogens improved both structural outcomes and neurobehavioral scores in >1 study. Meta-
regression revealed that together, structural outcome and the intervention used accounted for 65% of the observed
heterogeneity in neurobehavioral score (p < 0.001, adjusted r2 ¼ 0.65).
Interpretation: Further animal studies of the interventions that we found to improve both functional and structural
outcomes in animals, using better experimental designs, could target efforts to translate effective treatments for ICH
in animals into randomized controlled trials in humans.
                                                                                                                  ANN NEUROL 2011;69:389–399



T    he global burden of acute spontaneous (nontrau-
     matic) intracerebral hemorrhage (ICH) and its out-
come appear unchanged over the past quarter century,1,2
                                                                              models of ICH reporting neurobehavioral outcomes, to
                                                                              explore their methodological quality, and to perform a
                                                                              meta-analysis of the effects of each class of intervention.
despite the improvements in outcome that can be
achieved by organized stroke unit care and neurosurgical                      Subjects and Methods
hematoma evacuation.3–6 The quest for other effective
                                                                              Eligibility Criteria
therapies has been fuelled by the recent failures of
                                                                              We sought controlled studies, regardless of their language of
recombinant activated factor VII and the neuroprotectant                      publication, of nonsurgical interventions given to wild-type
drug NXY-059 to improve outcome after acute ICH in                            (nontransgenic) animals after the induction of ICH using auto-
humans.7,8 Randomized controlled trials of medical                            logous blood or collagenase injection11 that reported neuro-
therapies such as blood pressure lowering are ongoing,9                       behavioral outcome.
but the search for other candidate interventions may best
start with methodologically robust laboratory research in                     Information Sources
animal models that accurately mimic human ICH.10                              In July 2009, we searched Ovid Medline (from 1950), Ovid
      Therefore, we aimed to undertake a systematic review                    Embase (from 1980), and ISI Web of Knowledge (from 1969)
of nonsurgical interventions in controlled studies of animal                  using comprehensive electronic search strategies (Supporting

                                     View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22243

                          Received Jun 22, 2010, and in revised form Aug 2, 0000. Accepted for publication Aug 27, 2010.

Address correspondence to Dr Salman, Bramwell Dott Building, Division of Clinical Neurosciences, Western General Hospital, Crewe Road, Edinburgh
                                         EH4 2XU, United Kingdom. E-mail: Rustam.Al-Shahi@ed.ac.uk

        From the Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

                                Additional supporting information can be found in the online version of this article.



                                                                                                  V 2011 American Neurological Association 389
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Information Table 1). We also searched the proceedings of the           the latest time point after ICH induction. Prespecified second-
Society for Neuroscience and the first and second International         ary outcomes were structural measures of brain injury: either
Symposia on Cerebral Hemorrhage using the ISI Web of Knowl-             brain water content or hematoma volume. We quantified effect
edge Conference Proceedings Citation Index. We screened the             sizes with the normalized (weighted) mean difference summary
bibliographies of eligible studies for other eligible studies. We       statistic, using the summary measures of outcome provided in
contacted authors to clarify study eligibility, where necessary.        the individual comparisons in studies where sufficient data were
                                                                        available to allow this analysis (outcome reported for [1] animals
Study Selection                                                         with ICH receiving the intervention, [2] control animals with
One investigator (J.F.) screened all titles and available abstracts     ICH receiving vehicle, and [3] sham animals neither undergoing
for eligibility, and removed duplicates. Studies that appeared to       ICH nor receiving treatment). If the same group of animals was
be eligible were read in full by 2 investigators (J.F., and E.S.S. or   assessed using several neurobehavioral scores or structural out-
R.A.-S.S.), and disagreements were resolved by either discussion        comes in 1 study, we combined these using fixed effects meta-
or arbitration by a third investigator (M.R.M.). We obtained            analysis and used this pooled measure for further analysis. We
translations of studies that were not written in English.               used the DerSimonian and Laird weighted mean difference ran-
                                                                        dom effects model to aggregate the weighted summary statistic
Data Collection                                                         for each individual comparison into a pooled estimate of effect
Two investigators independently extracted data on experimental          size,14 grouping interventions by their main putative mechanism
design, study quality attributes, intervention characteristics, func-   of action as attributed by the authors of individual studies.
tional outcome (neurobehavioral score, measured on any scale),
                                                                        SENSITIVITY ANALYSES. We assessed the effect of key
and structural outcomes (brain water content, or hematoma size).
                                                                        methodological study attributes by stratifying the pooled estimate
We recorded these data in the Collaborative Approach to Meta-
                                                                        of effect in all studies by the use of randomization, allocation
Analysis and Review of Animal Data from Experimental Stroke
                                                                        concealment, and blinded assessment of outcome. For each class
(CAMARADES) Microsoft Access 2003 data manager applica-
                                                                        of intervention, we assessed whether the pooled estimate of pri-
tion. For every treatment comparison (a given dose of an inter-
                                                                        mary (neurobehavioral) outcome at the last time point of assess-
vention at a given time of administration after ICH), we
                                                                        ment was modified if we restricted analyses to outcome data pro-
extracted the number of animals in each treatment group, the
                                                                        vided at 7 6 2 days after ICH induction. In a post hoc
mean outcome score, and the standard deviation or standard error
                                                                        sensitivity analysis, we explored whether the addition of studies
of the mean. We extracted all neurobehavioral outcomes at the
                                                                        that administered interventions prior to the induction of ICH
latest time of assessment, as well as at 7 6 2 days after the induc-
                                                                        affected the pooled estimate of effect on the primary outcome.
tion of ICH (if reported) and structural outcome data at the lat-
est time when animals were culled. We extracted outcome data            ASSESSMENT OF HETEROGENEITY. We used the chi-
on untreated sham groups (in which ICH had not been induced)            square statistic to assess the significance of differences between
from experiments where these were included; in experiments that         studies (with n À 1 degrees of freedom), and used the Bonfer-
did not, we inferred sham neurobehavioral scores for functionally       roni correction to calculate significance, taking into account the
unimpaired animals, sham hematoma volumes of zero, and sham             number of comparisons performed.
brain water content values corresponding to the contralateral
brain region of the control/vehicle group. Unless outcomes were         META-REGRESSION. We identified studies describing
quantified at the relevant time points, we measured them from           functional and structural outcomes in the same group of ani-
publications’ figures (using Adobe measuring tools). We contacted       mals. We used meta-regression to explore the relationship
authors to obtain unpublished or missing data.                          between functional and structural outcome and: aspects of
                                                                        study quality; the intervention tested; the time of treatment;
Quality Assessment                                                      and the time of outcome assessment. Meta-regression extends
We assessed each study’s quality according to the CAMARADES             the random effects meta-analysis model by taking into account
10-item checklist,12 which consists of reporting of a sample size       1 or more study-level covariates and determines how much het-
calculation; use of animals with comorbidities (eg, hypertension or     erogeneity can be explained by taking into account both within-
diabetes); control of animals’ temperature; use of anesthetics other    and between-study variance.15 We performed meta-regression
than ketamine (because of its marked intrinsic neuroprotectant ac-      using STATA 10 with the linear function metareg. We built the
tivity13); randomized treatment allocation; treatment allocation        regression model in a hierarchal manner, by running the regres-
concealment; blinded assessment of outcome; publication in a            sion analysis 1 variable (or group of dummy groups) at a time.
peer-reviewed journal; statement of compliance with regulatory          The variable with the most significant change in the F ratio was
requirements; and statement of potential conflicts of interest.         the first variable to enter the model. The second variable was
                                                                        then chosen by the largest change in the F ratio in the model
Data Analysis                                                           that already contained the first variable. This process was iter-
                                                                        ated until there were no significant changes in the F ratio. The
META-ANALYSIS. The prespecified primary outcome was                     adjusted R2 value provided indicates how much residual hetero-
functional outcome as measured by neurobehavioral score at              geneity is accounted for by the covariates.


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                                                                                       Frantzias et al: ICH Animal Models




                                           FIGURE 1: Summary of study selection.


Results                                                         given at a median interval after ICH induction of 2
Our searches identified 98 potentially eligible studies of      hours (interquartile range, 20 minutes to 6 hours). The
the effect of nonsurgical interventions on neurobehavioral      included studies reported outcome using 38 different
outcome (Fig 1). We excluded 10 studies because ICH             neurobehavioral scales (see Supporting Information Table
was not induced using collagenase or autologous blood           1), most often the forelimb placing test (10%), neurolog-
injection,16–18 outcome data could not be extracted or          ical severity score (10%),114 corner turn test (9%), and
obtained,19 variance values of zero precluded meta-analy-       modified limb-placing test (9%). Brain water content
sis,20,21 or interventions were administered before the         was the most frequently reported structural outcome (38
induction of ICH22–25 (although we included 3 of these          [43%] studies, most of which [89%] used wet and dry
studies in a post hoc sensitivity analysis24–26). After cor-    brain weights to quantify it), and hematoma volume was
responding authors clarified the data in 2 studies,27,28 we     reported in 30 (34%) studies (and was measured by sev-
included 88 studies reporting 151 different treatment           eral techniques including a variety of histological meth-
comparisons (87 of which had sham groups) that                  ods, spectrophotometry, or magnetic resonance imaging).
described the effects of nonsurgical interventions on neu-
robehavioral outcome in 2,616 treated or control rodents        Risk of Bias of Included Studies
with ICH (Supporting Information Table 1).26–113                The median study quality score was 4/10 (interquartile
                                                                range, 3–5). Of 88 publications, 27 (31%) reported ran-
Study Characteristics                                           dom allocation to group, 7 (8%) reported allocation con-
The most frequently used animal model of ICH was col-           cealment, and 43 (49%) reported the blinded assessment
lagenase injection (53 [60%] studies; see Supporting Infor-     of outcome. No study reported a sample size calculation,
mation Table 1), and ICH was induced in the striatum in         only 1 study reported the use of animals with comorbid-
all but 1 study (99%).51 The median number of treated or        ities, and 28 (32%) used ketamine, which is an anes-
control animals used in each study was 14 (interquartile        thetic agent with intrinsic neuroprotective properties.13
range, 12–21; full range, 6–100). Only 2 studies                For neurobehavioral score, studies that did not report
reported deaths prior to the planned time of culling: 7 of      random allocation to group were associated with larger
63 animals died during ICH induction in 1 study, and 5          effect sizes (32%; 95% confidence interval [CI], 26–39;
of 18 died during another (representing a case fatality         n ¼ 107) compared to those that did (21%; 95% CI,
rate of 15%).86,94 Sixty-four different interventions were      13–29; n ¼ 42; chi-square ¼ 437; df ¼ 1; p < 0.0001).


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Similarly, studies that did not report allocation conceal-       anti-inflammatory drugs, iron chelators, estrogens, micro-
ment were associated with larger estimates of effect             glial inhibitors, propofol, and an angiotensin II receptor
(31%; 95% CI, 26–37; n ¼ 132) compared to studies                blocker. Of these 8 interventions, the angiotensin II re-
that did (20%; 95% CI, 6–33; n ¼ 17; chi-square ¼ 33,            ceptor blocker (81%; 95% CI, 68–94) and anti-inflam-
df ¼ 1, p < 0.0001). The reporting of blinded assess-            matory drugs (19%; 95% CI, 0.5–38) also reduced he-
ment of outcome accounts for a significant proportion of         matoma volume. There was neither an improvement in
between-study heterogeneity (chi-square ¼ 43, df ¼ 1,            neurobehavioral outcome nor a reduction in brain water
p < 0.001), but there was no difference in effect sizes          content for antioxidant drugs, glutamate receptor antago-
between studies that did blind outcome assessment and            nists, hypothermia, and gap junction inhibitors. The
those that did not (29%; 95% CI, 22–36 vs 30%; 95%               effects of the remaining 11 interventions on functional
CI, 21–38).                                                      and structural outcomes were discordant.

Neurobehavioral Outcomes                                         Meta-Regression of Structural and
Stem cells, calcium channel blockers, anti-inflammatory          Neurobehavioral Outcomes
drugs, iron chelators, growth factors, thrombin inhibi-          Fifty-three comparisons reported both a functional and a
tors, and peroxisome proliferator-activated receptor             structural outcome in the same group of animals. Struc-
gamma agonists improved neurobehavioral scores at the            tural outcome explained 38% of the observed heteroge-
last time point of assessment, although there was signifi-       neity in functional outcome (s2 ¼ 816, adjusted r2 ¼
cant between-study heterogeneity in several of these             0.38, Fig 4). In a multivariate model, structural outcome
classes of intervention (Fig 2). In a sensitivity analysis re-   and the intervention used accounted for 65% of the
stricted to studies reporting neurobehavioral outcome at         observed heterogeneity in neurobehavioral score (F15, 37
7 6 2 days after interventions delivered within 24 hours         ¼ 5.31, p < 0.001, df ¼ 52, s2 ¼ 286, adjusted r2 ¼
of ICH (using 44% of the data used to evaluate the pri-          0.65). Relative to structural benefit, additional functional
mary outcome), the improvement of neurobehavioral                benefit was observed when animals were treated with
outcome became statistically significant for some inter-         anti-inflammatory drugs (30%; 95% CI, 8–51), antia-
ventions (anti-oxidants, glutamate receptor antagonists,         poptotic drugs (38%; 95% CI, 11–65), and albumin
heme oxygenase inhibitors, and minocycline) and insig-           (67%; 95% CI, 22–112) compared to antioxidants as
nificant for others (calcium channel blockers, thrombin          the reference group (chosen because this group contained
inhibitors, and tumor necrosis factor (TNF)-a inhibitor          the largest quantity of data). Gap junction inhibitors
antisense oligonucleotide). In a post hoc sensitivity analy-     reduced functional benefit (À30%; 95% CI, À54 to
sis of the primary outcome in studies of interventions al-       À7). These findings were not affected by whether the
ready included in the meta-analysis, also including stud-        structural outcome reported was hematoma volume or
ies that treated animals prior to ICH induction had no           brain water content. Study quality had no effect on the
significant impact on the pooled estimate for the 3 inter-       relationship between structural and functional outcome.
vention groups (antioxidants, estrogens, and TNF-a in-
hibitor antisense oligonucleotides) reporting both pre-
and post-ICH delivery of intervention (see Fig 2).24–26          Discussion
We did not further analyze data from 2 studies that              In a systematic review and meta-analysis of 88 controlled
treated animals prior to the induction ICH with agents           studies describing the effects of 64 different nonsurgical
that had not also been administered after ICH                    interventions on 38 different neurobehavioral scales in
induction.22,23                                                  2,616 rodents, interventions that improved both neuro-
                                                                 behavioral score and structural outcome(s) in 2 or more
Structural Outcomes                                              animal studies (albeit with some between-study heteroge-
In the studies that reported brain water content in addi-        neity) included stem cells, calcium channel blockers,
tion to neurobehavioral scores (Fig 3), the pooled reduc-        anti-inflammatory drugs, estrogens, and iron chelators.
tion of brain water content was 34% (95% CI, 25–43)                    We benefited from comprehensive search strategies
in 78 comparisons involving 867 animals, with substan-           without language bias, prespecified outcomes and analytic
tial heterogeneity between studies (chi-square ¼ 956, p <        approaches, sensitivity analyses, and correction of statisti-
0.0001). Among 19 classes of intervention, 12 (63%)              cal tests for multiple comparisons. Other reviews have
significantly reduced brain water content (see Fig 3), and       not meta-analyzed existing data.11,115 Nevertheless, publi-
8 of these also significantly improved neurobehavioral           cation bias is known to result in an overestimation of
scores (see Fig 2): stem cells, calcium channel blockers,        effect sizes in animal models,116 and may have affected


392                                                                                                          Volume 69, No. 2
FIGURE 2: Weighted mean difference meta-analysis of the effects of nonsurgical interventions on neurobehavioral outcome in
controlled animal studies. Diamonds represent grouped estimates of effect (and their associated 95% confidence intervals) for
either classes of intervention or several studies of the same intervention. Effect estimates are organized by classes of
intervention followed by individual interventions, in descending order of sample size. Heterogeneity between studies within
each class of intervention is indicated in parentheses. Squares represent point estimates of effect, and horizontal lines are
their 95% confidence intervals. Details of interventions and experimental design in the individual studies are provided in
Supplementary Table 1. ATSC 5 adipose tissue-derived stromal cells; BMSC 5 bone marrow stem cells; NSC 5 nonspecific
suppressor cells; VEGF 5 vascular endothelial growth factor; MSC 5 mesenchymal stem cells; UCBC 5 umbilical cord blood
culture; GCSF 5 granulocyte colony-stimulating factor; GABA 5 gamma-aminobutyric acid; TNF 5 tumor necrosis factor.
ANNALS     of Neurology




FIGURE 3: Weighted mean difference meta-analysis of the effects of nonsurgical interventions on brain water content in
controlled animal studies. Diamonds represent grouped estimates of effect (and their associated 95% confidence intervals) for
either classes of intervention or several studies of the same intervention. Effect estimates are organized in the same order as
Figure 2. Heterogeneity between studies within each class of intervention is indicated in parentheses. Squares represent point
estimates of effect, and horizontal lines are their 95% confidence intervals. Details of interventions and experimental design in
the individual studies are provided in Supplementary Table 1.


our findings. Although the use of weighted mean differ-            ral scales, these scales measure different functions, and
ence meta-analysis allows the combination and compari-             the findings presented here represent a summary of
son of outcomes across a large number of neurobehavio-             available data.




FIGURE 4: Meta-regression of functional (neurobehavioral score) and structural (brain water content or hematoma size)
outcomes that were measured in the same groups of animals. The size of each point reflects the precision of each comparison.



394                                                                                                             Volume 69, No. 2
                                                                                              Frantzias et al: ICH Animal Models


       Methodological problems known to affect animal           account. Although this provides some basis for the use of
studies were evident in the studies included in our analy-      structural outcomes in clinical trial programs, it does sug-
ses.117 Their methodological quality was generally poor         gest first that such structural outcomes capture only a
(median score, 4/10), but variation among studies               proportion of efficacy, and second that the relationship
enabled us to confirm the potent influences of random-          between structural and functional outcome—and there-
ization and allocation concealment on effect sizes. No          fore the utility of such structural outcome measures—
study reported a sample size calculation, the use of keta-      may vary substantially between different drug classes.
mine anesthesia was frequent despite its known intrinsic              Discordance has previously been reported between
neuroprotective properties,13 and every study bar 1 used        animal and human studies in other diseases,123 and we
only healthy animals, which is known to bias animal stud-       have shown that this is also the case for ICH. Of the
ies of stroke.118 Furthermore, young animals without            interventions that improved both structural outcomes
comorbidities are unrepresentative of humans who suffer         and neurobehavioral scores in animal models (see Figs 2
ICH,9 and the predominantly striatal location of ICH            and 3), anti-inflammatory drugs have not improved out-
induction in the included studies did not fully represent       come in humans.124 Similarly, recombinant activated fac-
ICH in humans, which occurs in lobar regions and the            tor VII did not improve outcome in humans, and indeed
posterior fossa, may extend into other brain compartments,      the first evidence of benefit on structural outcomes in
and often causes hydrocephalus. Studies used a diverse array    animals was reported after the start of human trials.7,125
of neurobehavioral scales, and several used only 1 scale              For progress to be made in translational ICH
when a battery of tests might have given a more complete        research, the quality of animal studies must improve.126
description of neurobehavioral outcome.119 Many of the          We have reasonable understanding of some of the patho-
scales have not been validated and rely on primarily motor      physiological processes underlying ICH in animals,3,127
tasks. Moreover, the neurobehavioral scale used should          but future research might usefully focus on understand-
relate to whether an ICH is cortical or striatal, because the   ing to what extent these mechanisms are important in
neurological impairments arising from ICH vary by the an-       humans, allowing drug development to be targeted at the
atomical location of the ICH.119 Furthermore, because           key processes. Furthermore, we need animal models of
                                                                ICH that better mimic important pathophysiologic proc-
rodents have proportionately less white matter than
                                                                esses in humans, including hematoma expansion and re-
humans,11 and may have greater neuroplasticity,115 there
                                                                currence,3,10,115 and we need these experiments to be
may be problems with the relevance of the animal models
                                                                conducted in such a way as to minimize the risk of study
to human ICH. There are differences between the 2 main
                                                                quality bias. Only then may the translational paradigm
rodent models of ICH,120 but we found no evidence that
                                                                be reliable enough for effective treatments in animal
1 was any more relevant to the human condition than the
                                                                models to be tested in randomized controlled trials in
other. There was a general shortage of external validation of
                                                                humans.
interventions that appeared to improve outcome.
       We have used meta-analysis to derive summary esti-
mates of efficacy from a collection of relatively small         Acknowledgment
studies, many of which were not sufficiently powered to         R.A.-S.S. was funded by a clinician scientist fellowship
detect modest treatment effects. Where possible, we have        from the UK Medical Research Council. M.R.M.
used weighted rather than standardized mean differences,        acknowledges the support of the MRC Trials Methodol-
because this is a more powerful statistical approach when       ogy Hub.
the size of contributing studies is small.121 The use of              We thank E. Lebedeva, A. Wong, and Dr C. Four-
meta-analysis to aggregate data for neurobehavioral out-        naris for their generous assistance with translating studies
comes described using ordinal scales is well established        for this review.
(and indeed many of the contributing studies use para-
metric statistics to analyze these data), and is justified      Potential Conflicts of Interest
because parametric analyses of nonparametric data               Nothing to report.
becomes more valid when large numbers of studies are
aggregated in this way.122
       Importantly, only 40% of the variation in treatment      References
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