Skip to main content
NCBI home page
Journal of Cerebral Blood Flow & Metabolism logoLink to Journal of Cerebral Blood Flow & Metabolism
. 2012 Apr 25;32(9):1645–1658. doi: 10.1038/jcbfm.2012.57

Pharmacologic reduction of angiographic vasospasm in experimental subarachnoid hemorrhage: systematic review and meta-analysis

Tommaso Zoerle 1, Don C Ilodigwe 1, Hoyee Wan 1, Katarina Lakovic 2, Mohammed Sabri 2, Jinglu Ai 1, R Loch Macdonald 1,3,*
PMCID: PMC3437599  PMID: 22534672

Abstract

Animal models have been developed to simulate angiographic vasospasm secondary to subarachnoid hemorrhage (SAH) and to test pharmacologic treatments. Our aim was to evaluate the effect of pharmacologic treatments that have been tested in humans and in preclinical studies to determine if animal models inform results reported in humans. A systematic review and meta-analysis of SAH studies was performed. We investigated predictors of translation from animals to humans with multivariate logistic regression. Pharmacologic reduction of vasospasm was effective in mice, rats, rabbits, dogs, nonhuman primates (standard mean difference of −1.74; 95% confidence interval −2.04 to −1.44) and humans. Animal studies were generally of poor methodologic quality and there was evidence of publication bias. Subgroup analysis by drug and species showed that statins, tissue plasminogen activator, erythropoietin, endothelin receptor antagonists, calcium channel antagonists, fasudil, and tirilazad were effective whereas magnesium was not. Only evaluation of vasospasm >3 days after SAH was independently associated with successful translation. We conclude that reduction of vasospasm is effective in animals and humans and that evaluation of vasospasm >3 days after SAH may be preferable for preclinical models.

Keywords: animal model, pharmacologic reduction, subarachnoid hemorrhage, translation, vasospasm

Introduction

Outcome from aneurysmal subarachnoid hemorrhage (SAH) has improved. Mortality declined 0.4% per year, after adjustment for age, between 1973 and 2002 (Nieuwkamp et al, 2009). The main changes in management that have occurred are improvements in intensive care, early securing of the ruptured aneurysm, and use of nimodipine. Many other drugs have been tested in animal models but none has proven effective in high-quality clinical trials. Most of these studies tested drugs directed at reducing angiographic vasospasm. This was based on the hypothesis that since angiographic vasospasm is strongly correlated with cerebral infarction (Crowley et al, 2011) and cerebral infarction is correlated with unfavorable clinical outcome on the Glasgow outcome scale (Fergusen and Macdonald, 2007) then reducing vasospasm should improve clinical outcome.

There are many possible reasons for lack of translation of reducing angiographic vasospasm in animal models to improving outcome in humans, including clinical trial design, whether the animal model reproduces the disease and methodological flaws in experimental studies (van der Worp et al, 2010).

Preclinical SAH studies for pharmaceutical reduction of vasospasm differ in terms of animal used, induction of SAH, time course and severity of angiographic vasospasm (Megyesi et al, 2000; Titova et al, 2009) as well in quality of design (i.e., randomization, blinding). All these characteristics could impact the results of experimental treatment and perhaps the chance of translation, but to our knowledge there is no evidence that one model of SAH is better than any other for the purposes of predicting whether the findings in the animal study of a drug in relation to angiographic vasospasm are the same as what is found for its effects on angiographic vasospasm in human clinical trials. A meta-analysis of human clinical trials of drugs to decrease vasospasm showed that some, but obviously not all drugs tested did reduce vasospasm in randomized clinical trials (Etminan et al, 2011). Thus, the primary hypothesis tested here was that some specific animal model or characteristic of one predicts the findings in clinical trials. The idea was that if, for example, one specific species or method of induction of SAH or some such characteristic of an animal model was more likely to be associated with successful translation to prevention of angiographic vasospasm in humans, then maybe that characteristic should be used for preclinical studies. The study of Etminan et al (2011) reported that in the clinical trials, angiographic vasospasm was reduced but there was no significant effect on clinical outcome. Thus, another hypothesis that could be tested would be what animal models or characteristics of them correlate with clinical outcome in humans. The present analysis focuses on angiographic vasospasm.

Materials and methods

We conducted this systematic review and meta-analysis according to the methods recommended for assessing health technologies and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Higgins and Green, 2008; Liberati et al, 2009; Mignini and Khan, 2006; Moher et al, 2009). No language restrictions were used and two reviewers assessed each reference and determined study eligibility.

Criteria for Included Animal Studies

Type of studies

We included preclinical studies in vivo where SAH was simulated by endovascular puncture of a cerebral artery, subarachnoid clot placement, or injection of blood, hemolyzed blood or other purported vasospastic substances into the subarachnoid space.

Type of intervention

We included studies of prophylactic treatment of angiographic vasospasm with any drug tested in both experimental and clinical trials for the same purpose. Intervention was defined as treatment for the purposes of this study if drug administration was started before or under the same anesthetic time as when the SAH was induced in the animal model or within 24 hours of the last injection of blood into the subarachnoid space. We did not include studies where drugs were administered to reverse established angiographic vasospasm. For selecting drugs, we considered a systematic review of drug treatments for humans with SAH and included all drugs tested in randomized, blinded clinical trials (Etminan et al, 2011).

Type of outcome

The primary outcome was cerebral vasospasm evaluated by catheter, CT (computed tomographic), or magnetic resonance angiography or by histological methods.

Search Methods for Identification of Studies

Pubmed and Embase were searched from 1966 to November 2010, using the following terms: (subarachnoid hemorrhage) AND ((statin) OR (tissue plasminogen activator) OR (ticlopidine) OR (erythropoietin) OR (clazosentan) OR (nimodipine) OR (nicardipine) OR (fasudil) OR (tirilazad)) AND (animal OR experimental). The same search was performed for magnesium, endothelin converting enzyme, and endothelin receptor antagonist. The reference lists of the papers were checked to identify other studies not found in the initial search.

Data Collection

For every included study, we extracted data on the species and sex of animals, method of induction of SAH, drug tested, timing and method of delivery of the drug, time and method for outcome assessment, randomization, blinding, sample size estimation, inclusion and exclusion criteria and physiological variables that were measured. Data on the number of animals and degree of vasospasm in treatment and control groups were extracted. If in the same study different doses or delivery way were used, data on the effect of the intervention were extracted for every group and the most effective regimen was used for the analysis, although for assessment of heterogeneity and publication bias, results for the best as well as all (114 comparisons) are provided. If in the same study different drugs were tested, data on the effect of each drug were extracted and analyzed separately. Vasospasm was expressed as the percent reduction in cerebral artery diameter from baseline (in the studies where angiographic evaluation was performed) or compared with control values (in the studies were histological evaluation was performed). If the degree of vasospasm was expressed as reduction in artery cross sectional area, the diameter was calculated using the formula: diameter = 2 × √(area/π). If data were presented only in figures, then values were estimated using digital ruler software.

Methodologic quality of the animal studies was assessed by two reviewers by extracting data on study design, allocation concealment, blinding, number of animals randomized, age of animals, recording of physiologic variables, and inclusion of controls. We did not include funding source since this was not always reported, and we did not use a checklist and a score to assess study quality. This was because according to van der Worp et al (2010), and other sources, use of these is controversial and it is not clear that any particular characteristics are better than any others. We also did not extract data on other variables reported in some other systematic reviews (such as the neuroprotective effect of anesthesia) because in most papers there were insufficient data provided.

To assess the effect of each drug in human trials, the data were obtained from Etminan et al (2011). The outcome measure was radiographic vasospasm, which was defined as a focal or generalized reduction of cerebral arterial caliber on catheter cerebral angiography, or increased cerebral blood flow velocities on transcranial Doppler ultrasound. The included studies used various definitions of angiographic and transcranial Doppler vasospasm, so we used the definitions reported by the investigators of the original studies. If the investigators categorized angiographic vasospasm into no/mild, moderate, and severe vasospasm, we used the number of patients that had moderate-to-severe vasospasm as an outcome event. Transcranial Doppler vasospasm was defined as flow velocity of at least 120 cm/s or peak flow velocity of >200 cm/s. If studies reported angiographic and transcranial Doppler vasospasm, the data on angiographic vasospasm were used (Etminan et al, 2011).

Statistical Analysis

To test which species may reflect more accurately the effect of drug treatment on reducing vasospasm in humans, we analyzed the concordance between the drug effect in human and in the different animals. The drug effect in humans was defined as focal or generalized reduction in cerebral artery diameter on catheter angiography, or increased cerebral blood flow velocities on transcranial Doppler ultrasound, as reported previously (Etminan et al, 2011). If studies reported both catheter angiography and Doppler ultrasound, angiography results were used, and the outcome event was number of patients with moderate or severe vasospasm. The effects were defined as concordant if the drug showed evidence of positive effect in humans as well as in animals or no evidence of effect in humans as well as in animals. Drug effect was defined as discordant if the drug showed evidence of efficacy in animals but not in humans or vice versa.

A random effect standardized meta-analysis was used to assess the effect of pharmacologic reduction of vasospasm in animal studies. Effect sizes were expressed as pooled standard mean difference. Subgroup analyses by drug and animal species were performed. We used meta-regression to analyze the source of heterogeneity, if any. Factors included in the meta-regression were species and sex of animals, method of induction of SAH, drug tested, route of drug delivery, treatment start time (before or after SAH), time and method of outcome assessment, randomization, blinding (for outcome assessment and whether animals belonged to treatment or control groups before surgery), monitoring of physiological variables (temperature, blood pressure, heart rate, oxygenation, intracranial pressure), and monitoring of CO2 (Table 1).

Table 1. Characteristics of animal studies.

Characteristic Number (%) References
Species
 Monkey 16 (22) Espinosa et al (1984); Findlay et al (1988, 1989, 1990); Hariton et al (1993); Hino et al (1995); Kanamaru et al (1990, 1991); Kim et al (1996); Lewis et al (1988); Macdonald et al (2004); Nosko et al (1985); Steinke et al (1989); Suzuki et al (1998, 1999)
 Dog 23 (31) Bulsara et al (2006); Chung and Lee (1993); Cosentino et al (1993); Itoh et al (1993, 1994); Kawashima et al (2000); Kim et al (2000); Kita et al (1998); Macdonald et al (1998a, 1998b); Matsui and Asano (1994); Matsumura et al (1991); Nirei et al (1993); Ohkuma et al (1999); Roux et al (1997); Satoh et al (1992); Seifert et al (1989); Shigeno et al (1995); Takanashi et al (2001b); Willette et al (1994); Zabramski et al (1986); Zimmermann et al (1996)
 Rabbit 24 (32) Bilginer et al (2009); Caner et al (1996); Chen et al (2009); Grasso et al (2002); Kawada et al (1999); Kwan et al (1997, 2001, 2006); Laslo et al (2006); Lin et al (2007); Marbacher et al (2008); McGirt et al (2006); Murphy et al (2008); Pasqualin et al (1991); Santhanam et al (2005); Tang et al (2008); Vollmer et al (1989); Wanebo et al (1997, 1998); Zuccarello et al (1989, 1996, 1998)
 Rat 9 (12) Chang et al (2010); Cheng et al (2009); Gul et al (2010); Hanggi et al (2009); Josko et al (2000); Sugawara et al (2008); Takanashi et al (2001a); Turowski et al (2007); Wang et al (2010)
 Mouse 2 (2) McGirt et al (2002); Mesis et al (2006); Takanashi et al (2001a); Turowski et al (2007); Wang et al (2010)
     
Sex
 Male 27 (36) Bilginer et al (2009); Chang et al (2010); Cheng et al (2009); Grasso et al (2002); Hanggi et al (2009); Josko et al (2000); Kwan et al (1997, 2001, 2006); Lin et al (2007); McGirt et al (2002, 2006); Mesis et al (2006); Murphy et al (2008); Nirei et al (1993); Pasqualin et al (1991); Santhanam et al (2005); Sugawara et al (2008); Takanashi et al (2001a); Tang et al (2008); Turowski et al (2007); Wanebo et al (1998); Wanebo et al (1997); Wang et al (2010); Willette et al (1994); Zuccarello et al (1996, 1998)
 Female 11 (14) Espinosa et al (1984); Findlay et al (1988, 1989, 1990); Gul et al (2010); Kanamaru et al (1990, 1991); Lewis et al (1988); Nosko et al (1985); Steinke et al (1989)
 Male/female 36 (49) Bulsara et al (2006); Caner et al (1996); Chen et al (2009); Chung and Lee (1993); Cosentino et al (1993); Hariton et al (1993); Hino et al (1995); Itoh et al (1993, 1994); Kawashima et al (2000); Kim et al (1996, 2000); Kita et al (1998); Laslo et al (2006); Macdonald et al (1998a, 1998b, 2004); Marbacher et al (2008); Matsui and Asano (1994); Matsumura et al (1991); McGirt et al (2006); Ohkuma et al (1999); Roux et al (1997); Satoh et al (1992); Seifert et al (1989); Shigeno et al (1995); Suzuki et al (1998, 1999); Takanashi et al (2001b); Vollmer et al (1989); Zabramski et al (1986); Zimmermann et al (1996); Zuccarello et al (1998)
     
Method of induction of SAH
 Clot placement 17 (23) Espinosa et al (1984); Findlay et al (1988, 1989, 1990); Hariton et al (1993); Hino et al (1995); Kanamaru et al (1990, 1991, 2000); Kim et al (1996); Lewis et al (1988); Macdonald et al (2004); Nosko et al (1985); Steinke et al (1989); Suzuki et al (1998, 1999)
 2 Injections cisterna magna 29 (39) Bulsara et al (2006); Chung and Lee (1993); Cosentino et al (1993); Itoh et al (1993, 1994); Kim et al (2000); Kita et al (1998); Macdonald et al (1998a, 1998b); Matsui and Asano (1994); Matsumura et al (1991); Nirei et al (1993); Ohkuma et al (1999); Roux et al (1997); Satoh et al (1992); Seifert et al (1989); Shigeno et al (1995); Takanashi et al (2001b); Willette et al (1994); Zimmermann et al (1996); Chang et al (2010); Chen et al (2009); Hanggi et al (2009); Takanashi et al (2001a); Zuccarello et al (1996, 1998)
 One injection cisterna magna 21 (28) Bilginer et al (2009); Caner et al (1996); Grasso et al (2002); Kawada et al (1999); Kwan et al (1997, 2001, 2006); Laslo et al (2006); Lin et al (2007); Marbacher et al (2008); McGirt et al (2006); Murphy et al (2008); Pasqualin et al (1991); Santhanam et al (2005); Vollmer et al (1989); Wanebo et al (1997, 1998); Zuccarello et al (1989); Gul et al (2010); Josko et al (2000); Turowski et al (2007)
 Endovascular perforation 4 (5) Cheng et al (2009); McGirt et al (2002); Mesis et al (2006); Sugawara et al (2008)
 Othera 3 (4) Tang et al (2008); Wang et al (2010); Zabramski et al (1986)
     
Severity of vasospasm in control group
 Mild 16 (22) Bulsara et al (2006); Chung and Lee (1993); Gul et al (2010); Hariton et al (1993); Itoh et al (1994); Josko et al (2000); Laslo et al (2006); Marbacher et al (2008); Mesis et al (2006); Murphy et al (2008); Sugawara et al (2008); Tang et al (2008); Turowski et al (2007); Zimmermann et al (1996); Zuccarello et al (1998)
 Moderate 55 (74) Caner et al (1996); Chang et al (2010); Chen et al (2009); Cheng et al (2009); Cosentino et al (1993); Espinosa et al (1984); Findlay et al (1989, 1988); Grasso et al (2002); Hanggi et al (2009); Hino et al (1995); Itoh et al (1993); Kanamaru et al (1990, 1991); Kawada et al (1999); Kawashima et al (2000); Kim et al (1996, 2000); Kita et al (1998); Kwan et al (1997, 2001, 2006); Lewis et al (1988); Lin et al (2007); Macdonald et al (1998a, 1998b, 2004); Matsui and Asano (1994); Matsumura et al (1991); McGirt et al (2002, 2006); Nirei et al (1993); Nosko et al (1985); Ohkuma et al (1999); Pasqualin et al (1991); Roux et al (1997); Santhanam et al (2005); Satoh et al (1992); Seifert et al (1989); Shigeno et al (1995); Steinke et al (1989); Suzuki et al (1998, 1999); Takanashi et al (2001a, 2001b); Vollmer et al (1989); Wanebo et al (1997, 1998; Wang et al (2010); Willette et al (1994); Zuccarello et al (1989, 1996)
 Severe 3 (4) Bilginer et al (2009); Findlay et al (1990); Zabramski et al (1986)
     
Evaluation of vasospasm
 Angiography 52 (70) Bulsara et al (2006); Chung and Lee (1993); Cosentino et al (1993); Espinosa et al (1984); Findlay et al (1988, 1989, 1990); Hanggi et al (2009); Hariton et al (1993); Hino et al (1995); Itoh et al (1993, 1994); Kanamaru et al (1990, 1991); Kawada et al (1999); Kawashima et al (2000); Kim et al (1996, 2000); Kita et al (1998); Laslo et al (2006); Lewis et al (1988); Macdonald et al (1998a, 1998b, 2004); Marbacher et al (2008); Matsui and Asano (1994); Matsumura et al (1991); Murphy et al (2008); Nirei et al (1993); Nosko et al (1985); Ohkuma et al (1999); Roux et al (1997); Santhanam et al (2005); Satoh et al (1992); Seifert et al (1989); Shigeno et al (1995); Steinke et al (1989); Suzuki et al (1998); Suzuki et al (1999); Takanashi et al (2001b); Tang et al (2008); Turowski et al (2007); Willette et al (1994); Zabramski et al (1986); Zimmermann et al (1996); Zuccarello et al (1989, 1996, 1998)
 Histology 22 (30) Bilginer et al (2009); Caner et al (1996); Chang et al (2010); Chen et al (2009); Cheng et al (2009); Grasso et al (2002); Gul et al (2010); Josko et al (2000); Kwan et al (1997, 2001, 2006); Lin et al (2007); McGirt et al (2002, 2006); Mesis et al (2006); Pasqualin et al (1991); Sugawara et al (2008); Takanashi et al (2001a); Vollmer et al (1989); Wanebo et al (1998, 1997); Wang et al (2010)
     
Day of evaluation of vasospasm
 3 days 21 (28) Bilginer et al (2009); Caner et al (1996); Chen et al (2009); Grasso et al (2002); Gul et al (2010); Josko et al (2000); Kwan et al (1997, 2001, 2006); Lin et al (2007); McGirt et al (2002, 2006); Mesis et al (2006); Pasqualin et al (1991); Santhanam et al (2005); Sugawara et al (2008); Tang et al (2008); Vollmer et al (1989); Wanebo et al (1997, 1998); Zuccarello et al (1989)
 >3 days 53 (72) Bulsara et al (2006); Chang et al (2010); Chen et al (2009); Chung and Lee (1993); Cosentino et al (1993); Espinosa et al (1984); Findlay et al (1988, 1989, 1990); Hanggi et al (2009); Hariton et al (1993); Hino et al (1995); Itoh et al (1993, 1994); Kanamaru et al (1990, 1991); Kawada et al (1999); Kawashima et al (2000); Kim et al (1996, 2000); Kita et al (1998); Laslo et al (2006); Lewis et al (1988); Macdonald et al (1998a, 1998b, 2004); Marbacher et al (2008); Matsui and Asano (1994); Matsumura et al (1991); Murphy et al (2008); Nirei et al (1993); Nosko et al (1985); Ohkuma et al (1999); Roux et al (1997); Satoh et al (1992); Seifert et al (1989); Shigeno et al (1995); Steinke et al (1989); Suzuki et al (1998 1999); Takanashi et al (2001a, 2001b); Turowski et al (2007); Wang et al (2010); Willette et al (1994); Zabramski et al (1986); Zimmermann et al (1996); Zuccarello et al (1989, 1996)
     
Drug
 Tirilazad 8 (11) Kanamaru et al (1990, 1991); Macdonald et al (1998a); Matsui and Asano (1994); Steinke et al (1989); Suzuki et al (1999); Vollmer et al (1989); Zuccarello et al (1989)
 Calcium antagonist 14 (19) Bilginer et al (2009); Espinosa et al (1984); Gul et al (2010); Hanggi et al (2009); Kawashima et al (2000); Laslo et al (2006); Lewis et al (1988); Marbacher et al (2008); Mesis et al (2006); Nosko et al (1985); Pasqualin et al (1991); Tang et al (2008); Turowski et al (2007); Zabramski et al (1986)
 Erythropoietin 4 (5) Chen et al (2009); Grasso et al (2002); Murphy et al (2008); Santhanam et al (2005)
 Statins 7 (9) Bulsara et al (2006); Chang et al (2010); Cheng et al (2009); McGirt et al (2002, 2006); Sugawara et al (2008); Wang et al (2010)
 Endothelin antagonist/endothelin converting enzyme inhibitor 26 (35) Caner et al (1996); Cosentino et al (1993); Hino et al (1995); Itoh et al (1993, 1994); Josko et al (2000); Kita et al (1998); Kwan et al (1997, 2001, 2006); Lin et al (2007); Macdonald et al (1998b); Matsumura et al (1991); Nirei et al (1993); Roux et al (1997); Shigeno et al (1995); Wanebo et al (1997, 1998); Willette et al (1994); Zimmermann et al (1996); Zuccarello et al (1996, 1998)
 Fasudil 4 (5) Kim et al (2000); Satoh et al (1992); Takanashi et al (2001a, 2001b)
 Tissue plasminogen activator 9 (12) Chung and Lee (1993); Findlay et al (1988, 1989, 1990); Hariton et al (1993); Kawada et al (1999); Ohkuma et al (1999); Seifert et al (1989); Suzuki et al (1998)
 Magnesium 1 (1.5) Macdonald et al (2004)
 Otherb 1 (1.5) Kim et al (1996)
     
Route of drug delivery
 Intracranial 30 (40) Chung and Lee (1993); Cosentino et al (1993); Findlay et al (1988, 1989, 1990); Hanggi et al (2009); Hariton et al (1993); Hino et al (1995); Itoh et al (1994); Josko et al (2000); Kawada et al (1999); Kawashima et al (2000); Kim et al (1996); Kita et al (1998); Lewis et al (1988); Marbacher et al (2008); Matsumura et al (1991); Nirei et al (1993); Ohkuma et al (1999); Santhanam et al (2005); Seifert et al (1989); Suzuki et al (1998); Takanashi et al (2001a, 2001b); Turowski et al (2007); Willette et al (1994); Zuccarello et al (1998)
 Systemic 44 (60) Bilginer et al (2009); Bulsara et al (2006); Caner et al (1996); Chang et al (2010); Chen et al (2009); Cheng et al (2009); Espinosa et al (1984); Grasso et al (2002); Gul et al (2010); Itoh et al (1993); Kanamaru et al (1990, 1991); Kim et al (2000); Kwan et al (1997, 2001, 2006); Laslo et al (2006); Lin et al (2007); Macdonald et al (1998a, 1998b, 2004); Matsui and Asano (1994); McGirt et al (2002, 2006); Mesis et al (2006); Murphy et al (2008); Nosko et al (1985); Pasqualin et al (1991); Roux et al (1997); Satoh et al (1992); Shigeno et al (1995); Steinke et al (1989); Sugawara et al (2008); Suzuki et al (1999); Tang et al (2008); Vollmer et al (1989); Wanebo et al (1997, 1998); Wang et al (2010); Zabramski et al (1986); Zimmermann et al (1996); Zuccarello et al (1989, 1996)
     
Pretreatment
 Before induction of SAH 7 (9) Caner et al (1996); Chang et al (2010); Cheng et al (2009); Itoh et al (1993, 1994); McGirt et al (2002); Vollmer et al (1989)
 After induction of SAH 67 (91) Bilginer et al (2009); Bulsara et al (2006); Chen et al (2009); Chung and Lee (1993); Cosentino et al (1993); Espinosa et al (1984); Findlay et al (1988, 1989, 1990); Grasso et al (2002); Gul et al (2010); Hanggi et al (2009); Hariton et al (1993); Hino et al (1995); Josko et al (2000); Kanamaru et al (1990, 1991); Kawada et al (1999); Kawashima et al (2000); Kim et al (1996, 2000); Kita et al (1998); Kwan et al (1997, 2001, 2006); Laslo et al (2006); Lewis et al (1988); Lin et al (2007); Macdonald et al (1998a, 1998b, 2004); Marbacher et al (2008); Matsui and Asano (1994); Matsumura et al (1991); McGirt et al (2006); Mesis et al (2006); Murphy et al (2008); Nirei et al (1993); Nosko et al (1985); Ohkuma et al (1999); Pasqualin et al (1991); Roux et al (1997); Santhanam et al (2005); Satoh et al (1992); Seifert et al (1989); Shigeno et al (1995); Steinke et al (1989); Sugawara et al (2008); Suzuki et al (1998, 1999); Takanashi et al (2001a, 2001b); Tang et al (2008); Turowski et al (2007); Wanebo et al (1997, 1998); Wang et al (2010); Willette et al (1994); Zabramski et al (1986); Zimmermann et al (1996); Zuccarello et al (1998, 1989, 1996)
     
Blinding of outcome
 No 29 (40) Chen et al (2009); Cosentino et al (1993); Gul et al (2010); Itoh et al (1993, 1994); Josko et al (2000); Kim et al (2000); Kita et al (1998); Laslo et al (2006); Matsui and Asano (1994); Matsumura et al (1991); McGirt et al (2006); Murphy et al (2008); Ohkuma et al (1999); Pasqualin et al (1991); Roux et al (1997); Santhanam et al (2005); Satoh et al (1992); Seifert et al (1989); Shigeno et al (1995); Takanashi et al (2001a); Tang et al (2008); Turowski et al (2007); Vollmer et al (1989); Wanebo et al (1997); Wang et al (2010); Willette et al (1994); Zabramski et al (1986); Zimmermann et al (1996); Zuccarello et al (1989, 1998)
 Yes 45 (60) Bilginer et al (2009); Bulsara et al (2006); Caner et al (1996); Chang et al (2010); Cheng et al (2009); Chung and Lee (1993); Espinosa et al (1984); Findlay et al (1988, 1989, 1990; Grasso et al (2002); Hanggi et al (2009); Hariton et al (1993); Hino et al (1995); Kanamaru et al (1990, 1991); Kawada et al (1999); Kawashima et al (2000); Kim et al (1996); Kwan et al (1997, 2001, 2006); Lewis et al (1988); Lin et al (2007); Macdonald et al (1998a, 1998b, 2004); Marbacher et al (2008); McGirt et al (2002); Mesis et al (2006); Nirei et al (1993); Nosko et al (1985); Steinke et al (1989); Sugawara et al (2008); Suzuki et al (1998, 1999); Takanashi et al (2001a, 2001b); Turowski et al (2007); Wanebo et al (1997, 1998); Wang et al (2010); Zuccarello et al (1996)
     
Blinding to induction of SAH versus saline/sham surgery
 No 59 (80) Bulsara et al (2006); Caner et al (1996); Chang et al (2010); Chen et al (2009); Cheng et al (2009); Chung and Lee (1993); Cosentino et al (1993); Espinosa et al (1984); Findlay et al (1989, 1990); Grasso et al (2002); Gul et al (2010); Hanggi et al (2009); Itoh et al (1993, 1994); Josko et al (2000); Kanamaru et al (1990, 1991); Kawada et al (1999); Kim et al (2000); Kita et al (1998); Kwan et al (1997); Kwan et al (2001, 2006); Laslo et al (2006); Lewis et al (1988); Lin et al (2007); Marbacher et al (2008); Matsui and Asano (1994); Matsumura et al (1991); McGirt et al (2002, 2006); Mesis et al (2006); Murphy et al (2008); Nirei et al (1993); Ohkuma et al (1999); Pasqualin et al (1991); Roux et al (1997); Santhanam et al (2005); Satoh et al (1992); Seifert et al (1989); Shigeno et al (1995); Sugawara et al (2008); Suzuki et al (1998, 1999); Takanashi et al (2001a); Tang et al (2008); Turowski et al (2007); Vollmer et al (1989); Wanebo et al (1998, 1997); Wang et al (2010); Willette et al (1994); Zabramski et al (1986); Zimmermann et al (1996); Zuccarello et al (1989, 1996, 1998)
 Yes 15 (20) Bilginer et al (2009); Findlay et al (1988); Hariton et al (1993); Hino et al (1995); Kawashima et al (2000); Kim et al (1996); Macdonald et al (1998a, 1998b, 2004); Nosko et al (1985); Steinke et al (1989); Takanashi et al (2001a, 2001b)
     
Inclusion and exclusion criteria
 No 65 (88) Bilginer et al (2009); Bulsara et al (2006); Chen et al (2009); Cosentino et al (1993); Espinosa et al (1984); Findlay et al (1988, 1989, 1990); Grasso et al (2002); Gul et al (2010); Hanggi et al (2009); Hariton et al (1993); Hino et al (1995); Itoh et al (1993, 1994); Josko et al (2000); Kanamaru et al (1990, 1991); Kawada et al (1999); Kawashima et al (2000); Kim et al (1996); Kim et al (2000); Kita et al (1998); Kwan et al (2001, 2006); Laslo et al (2006); Lewis et al (1988); Lin et al (2007); Macdonald et al (1998a, 1998b, 2004); Marbacher et al (2008); Matsui and Asano (1994); Matsumura et al (1991); McGirt et al (2006); Mesis et al (2006); Murphy et al (2008); Nirei et al (1993); Nosko et al (1985); Ohkuma et al (1999); Pasqualin et al (1991); Roux et al (1997); Santhanam et al (2005); Satoh et al (1992); Seifert et al (1989); Shigeno et al (1995); Steinke et al (1989); Suzuki et al (1998, 1999); Takanashi et al (2001a, 2001b); Tang et al (2008); Turowski et al (2007); Vollmer et al (1989); Wang et al (2010); Willette et al (1994); Zabramski et al (1986); Zimmermann et al (1996); Zuccarello et al (1989, 1996, 1998)
 Yes 9 (12) Caner et al (1996); Chang et al (2010); Cheng et al (2009); Chung and Lee (1993); Kwan et al (1997); McGirt et al (2002); Sugawara et al (2008); Wanebo et al (1997, 1998)
     
Randomization
 No 36 (49) Bilginer et al (2009); Caner et al (1996); Cheng et al (2009); Chung and Lee (1993); Cosentino et al (1993); Grasso et al (2002); Gul et al (2010); Itoh et al (1993, 1994); Josko et al (2000); Kawada et al (1999); Kim et al (2000); Kwan et al (1997, 2001, 2006); Lin et al (2007); Matsui and Asano (1994); Matsumura et al (1991); Murphy et al (2008); Nirei et al (1993); Ohkuma et al (1999); Pasqualin et al (1991); Santhanam et al (2005); Satoh et al (1992); Seifert et al (1989); Suzuki et al (1998); Takanashi et al (2001a); Turowski et al (2007); Wang et al (2010); Willette et al (1994); Zabramski et al (1986); Zimmermann et al (1996); Zuccarello et al (1998, 1989, 1996)
 Yes 38 (51) Bulsara et al (2006); Chang et al (2010); Chen et al (2009); Espinosa et al (1984); Findlay et al (1988, 1989, 1990); Hanggi et al (2009); Hariton et al (1993); Hino et al (1995); Kanamaru et al (1990, 1991); Kawashima et al (2000); Kim et al (1996); Kita et al (1998); Laslo et al (2006); Lewis et al (1988); Macdonald et al (1998a, 1998b, 2004); Marbacher et al (2008); McGirt et al (2002, 2006); Mesis et al (2006); Nosko et al (1985); Roux et al (1997); Shigeno et al (1995); Steinke et al (1989); Sugawara et al (2008); Suzuki et al (1999); Takanashi et al (2001a, 2001b); Tang et al (2008); Vollmer et al (1989); Wanebo et al (1997, 1998); Wang et al (2010)
     
Monitoring of physiologic variables
 No 15 (20) Chang et al (2010); Cosentino et al (1993); Gul et al (2010); Itoh et al (1993, 1994); Josko et al (2000); Kawada et al (1999); Kim et al (2000); Kita et al (1998); Matsumura et al (1991); McGirt et al (2006); Ohkuma et al (1999); Seifert et al (1989); Turowski et al (2007)
 Yes 59 (80) Bilginer et al (2009); Bulsara et al (2006); Caner et al (1996); Chen et al (2009); Cheng et al (2009); Chung and Lee (1993); Espinosa et al (1984); Findlay et al (1988, 1989, 1990); Grasso et al (2002); Hanggi et al (2009); Hariton et al (1993); Hino et al (1995); Kanamaru et al (1990, 1991); Kawashima et al (2000); Kim et al (1996); Kwan et al (1997, 2001, 2006); Laslo et al (2006); Lewis et al (1988); Lin et al (2007); Macdonald et al (1998a, 1998b, 2004); Marbacher et al (2008); Matsui and Asano (1994); McGirt et al (2002); Mesis et al (2006); Murphy et al (2008); Nirei et al (1993); Nosko et al (1985); Pasqualin et al (1991); Roux et al (1997); Santhanam et al (2005); Satoh et al (1992); Shigeno et al (1995); Steinke et al (1989); Sugawara et al (2008); Suzuki et al (1998, 1999); Takanashi et al (2001a, 2001b); Tang et al (2008); Vollmer et al (1989); Wanebo et al (1997, 1998); Wang et al (2010); Willette et al (1994); Zabramski et al (1986); Zimmermann et al (1996); Zuccarello et al (1989, 1996, 1998)
     
Monitoring CO2
 No 16 (22) Bulsara et al (2006); Cosentino et al (1993); Kim et al (2000); Matsumura et al (1991); Ohkuma et al (1999)
 Yes 58 (78) Chang et al (2010); Cheng et al (2009); Gul et al (2010); Hanggi et al (2009); Josko et al (2000); Kawada et al (1999); McGirt et al (2006); Mesis et al (2006); Takanashi et al (2001a); Turowski et al (2007); Wang et al (2010)
Open in a new tab

SAH, subarachnoid hemorrhage.

a

Modified cisterna magna injection and prechiasmatic cistern injection.

b

Tissue plasminogen activator plus endothelin antagonist.

Publication bias was investigated using Begg's and Egger's tests; Begg's funnel plots are shown. For human studies, effect sizes were expressed in pooled risk ratio estimates. To assess predictors of translation from animal to human, univariable and multivariable logistic regressions were used with the dependent variable being concordance/discordance of the drug. Variables entered in the regressions were the same as the variables used for meta-regression. Bonferroni correction was used for multiple comparisons. P<0.05 was considered significant.

Results

A total of 453 studies were identified. Three hundred nineteen studies were excluded after review of the title and abstract showed the study was a review article, clinical studies with no single treatment, in-vitro study or test of a treatment to reverse established angiographic vasospasm. An additional 64 studies were excluded after reading the full text because they did not completely fulfill the inclusion criteria or they reported preliminary or incomplete data. Data from 70 papers were then extracted (Bilginer et al, 2009; Bulsara et al, 2006; Caner et al, 1996; Chang et al, 2010; Chen et al, 2009; Cheng et al, 2009; Chung and Lee, 1993; Cosentino et al, 1993; Espinosa et al, 1984; Findlay et al, 1988, 1989, 1990; Grasso et al, 2002; Gul et al, 2010; Hanggi et al, 2009; Hariton et al, 1993; Hino et al, 1995; Itoh et al, 1993, 1994; Josko et al, 2000; Kanamaru et al, 1990, 1991; Kawada et al, 1999; Kawashima et al, 2000; Kim et al, 1996, 2000; Kita et al, 1998; Kwan et al, 1997, 2001, 2006; Laslo et al, 2006; Lewis et al, 1988; Lin et al, 2007; Macdonald et al, 1998a, 1998b, 2004; Marbacher et al, 2008; Matsui and Asano, 1994; Matsumura et al, 1991; McGirt et al, 2002, 2006; Mesis et al, 2006; Murphy et al, 2008; Nirei et al, 1993; Nosko et al, 1985; Ohkuma et al, 1999; Pasqualin et al, 1991; Roux et al, 1997; Santhanam et al, 2005; Satoh et al, 1992; Seifert et al, 1989; Shigeno et al, 1995; Steinke et al, 1989; Sugawara et al, 2008; Suzuki et al, 1998, 1999; Takanashi et al, 2001a, 2001b; Tang et al, 2008; Turowski et al, 2007; Vollmer et al, 1989; Wanebo et al, 1998; Wanebo et al, 1997; Wang et al, 2010; Willette et al, 1994; Zabramski et al, 1986; Zimmermann et al, 1996; Zuccarello et al, 1989, 1996, 1998). In four papers, two drugs were tested, leading to a total of 74 comparisons for analysis (Cosentino et al, 1993; Hino et al, 1995; Zuccarello et al, 1996, 1998). There were 556 animals assigned to treatment groups and 664 to control groups.

Characteristics of the Studies

Investigators used monkeys (Macaca species), dogs (mongrel or beagles), rabbits (Japanese or New Zealand species), rats (Sprague Dawley or Wistar species) and mice (Table 1; Supplementary Table 1). The most used methods to simulate SAH were two injections of blood into the cisterna magna (dog, rabbit, and rat studies), a single injection of blood into the cisterna magna (rabbit and rat studies) and craniotomy followed by clot placement around the cerebral arteries (all monkey and one dog studies). In the other studies, endovascular perforation (rat and mouse studies), prechiasmatic cistern blood injection (one rat study) (Wang et al, 2010) or modified versions of cisterna magna injection (one rat (Tang et al, 2008) and one dog study) (Zabramski et al, 1986) were used. No studies injected hemolyzed blood or other substances into the subarachnoid space. In 48 studies (52 experiments), vasospasm was assessed using catheter or CT angiography while 22 used histology. In 49 studies (53 experiments), vasospasm was evaluated >3 days after SAH and in 21 experiments evaluation was performed before or on day 3. The degree of vasospasm in the control group was mild (<33%) in 16 experiments, moderate (33 to 66%) in 55 and severe (>66%) in three.

Drugs tested included tirilazad, tissue plasminogen activator, calcium channel antagonists (nimodipine or nicardipine), erythropoietin, statins, fasudil, endothelin antagonists, or endothelin converting enzyme inhibitors, magnesium, and in one study, tissue plasminogen activator plus an endothelin antagonist. There were no experimental studies of ticlopidine. Drugs were administered intracranially in 30 experiments and systemically in 44 (intravenous, oral, or intraperitoneal). In seven cases, treatment was started before the induction of SAH (pretreatment).

Regarding the quality of the studies, none clearly reported a sample size calculation. Only 12% described inclusion and exclusion criteria, 51% used randomization, 20% reported blinding of whether animals belonged to treatment or control group before surgery, and 60% reported blinding of assessment of outcome. Two or more of five physiological variables (heart rate, blood pressure, body temperature, intracranial pressure, oxygenation) were monitored in 80% of studies and blood or end-tidal CO2 was monitored in 78%.

Overall Treatment Effect

The pooled effect size expressed as standard mean difference showed that pharmacologic treatments significantly reduced cerebral vasospasm in the experimental studies (standard mean difference of −1.74;. 95% CI (confidence interval) −2.04 to −1.44; Figure 1). Substantial and significant heterogeneity was detected (heterogeneity χ2 statistic=340.60 (degrees of freedom=73), P=0.0001). In univariate meta-regression including all characteristics reported in Table 1, only the use of calcium antagonists (nicardipine or nimodipine) showed a significant association with the pooled effect size. Blinding induction of SAH revealed a marginal association (P=0.052). In the multivariate meta-regression including study factors with P≤0.15, treatment with calcium antagonists remained significantly associated with the pooled effect size (Supplementary Table 1).

Figure 1.

Figure 1

Open in a new tab

Effect size of 74 animal studies of pharmacologic reduction of vasospasm included in meta-analysis. Gray band represents overall effect with 95% confidence intervals (* and ** are effect of different drugs in the same publication).

Subgroup Analysis by Drug

Subgroup analysis by drug showed that every drug except magnesium was effective for reducing vasospasm. Heterogeneity was detected for every subgroup except for fasudil (Figure 2). Meta-regression was conducted for drug type versus variables significantly (P<0.05) associated in univariate analysis. This showed that the effect of erythropoietin and statins were associated with the method of induction of SAH, while calcium antagonist effect was related to the use of monkeys and mice (Table 2). This means that the effect of erythropoietin and statins are different (higher for statins, smaller for erythropoietin) in studies where cisterna magna double injection model was used compared with studies where cisterna magna single injection was used and that effect of calcium channel antagonists were different in studies where monkeys (smaller effect) or mice (higher effect) where used compared with the other studies.

Figure 2.

Figure 2

Open in a new tab

Effect size of the 74 included studies grouped by animal and drug. Gray band represents overall effect with 95% confidence interval. The size of the circle reflects the number of animals included in the different subgroups (ET antagonist: endothelin antagonist and endothelin converting enzyme inhibitor, MgSO4: magnesium).

Table 2. Subgroup analysis by drug and species.

Drug Variable Regression coefficient (95% confidence interval) P-value
Erythropoietin Single versus double    
  Cisterna magna injection 5.31 (2.50 to 8.13) 0.000
       
Calcium channel antagonists Monkeys 0.78 (0.14 to 1.42) 0.017
  Mice −2.78 (−4.26 to −1.29) 0.000
       
Statin Single versus double    
  Cisterna magna injection 4.38 (−1.55 to −7.21) 0.002
 
  
  
  
Species
 Variable
 Regression coefficient (95% confidence interval)
 P-value
Dog Tissue plasminogen    
  Activator −2.06 (−3.66 to −0.46) 0.012
       
Monkey Tirilazad −1.85 (−3.39 to −0.30) 0.019
  Vasospasm severity −2.22 (−4.20 to −0.23) 0.029
       
Rat Single versus double    
  Cisterna magna injection 4.17 (0.76 to 7.59) 0.017
Open in a new tab

Subgroup Analysis by Species

Subgroup analysis by species showed that pharmacologic treatment was effective in all species (Figure 2). Again, heterogeneity was detected and meta-regression showed that the pooled effect in rats was associated with the method of induction of SAH, in dogs with use of tissue plasminogen activator, and in monkeys with tirilazad and severity of vasospasm (Table 2). The heterogeneity means that in rats, treatment effect was higher when cisterna magna models were used, that in dogs, tissue plasminogen activator was more effective than other drugs, and that in monkeys, tirilizad was more effective compared with other drugs and that treatment effect was higher when drugs where tested against severe vasospasm.

Publication Bias

Both the Begg's (z-score continuity corrected 6.68, P=0.000) and Egger's test (bias coefficient −4.83; 95% CI −5.96 to −3.69; P=0.000) of heterogeneity in the 74 most effective doses in the pooled studies returned strong evidence of heterogeneity. The results were similar when including all 114 dose regimens tested (Begg's z-score continuity corrected 8.18, P=0.000 and Egger's test bias coefficient −4.79; 95% CI −5.75 to −3.84; P=0.000). Furthermore, Begg's funnel plot showing asymmetric orientation of the data points for both analyses (Figure 3).

Figure 3.

Figure 3

Open in a new tab

Begg's funnel plots with pseudo 95% confidence limits for 74 (upper) or 114 (lower) dose regimen comparisons.

Treatment Effect of Different Drugs in Different Species and Translation

Considering separately the effect of the different drugs in the different species, it is interesting to note that calcium antagonists and endothelin antagonists showed no significant effect in monkeys, statins had no significant effect in dogs, and endothelin antagonists had no significant effects in rats (Table 3). Therefore, the argument that all drugs are effective in animal models is not correct. We next considered data in a systematic review of the effect of pharmaceutical reduction of radiographic vasospasm with different drugs in human clinical trials (Etminan et al, 2011). Drug effects were classified as concordant or discordant based simply on whether or not the study or group of studies demonstrated a statistically significant effect on vasospasm. If, for example, the drug reduced vasospasm in dogs and in humans, or did not do so in either, then it was concordant. Any other result was discordant. Fasudil, endothelin antagonists (clazosentan), and tissue plasminogen activator showed a beneficial effect on angiographic vasospasm in humans while calcium antagonists (nimodipine and nicardipine), erythropoietin, statins, and tirilizad showed no significant effect (Table 3). Since no data were available on the effects of magnesium and tissue plasminogen activator plus endothelin antagonists, experiments using these treatments were excluded from further analysis.

Table 3. Treatment effect of different drugs in different species.

Species Calcium channel antagonist Statins Erythropoietin Tissue plasminogen activator Tirilazad Fasudil Endothelin antagonist/enzyme inhibitor
Human 0.85 0.85 0.85 0.54 0.92 0.62 0.60
Risk ratio (95% CI) 0.66; 1.08 0.55; 1.31 0.51; 1.41 0.33; 0.88 0.76; 1.11 0.46; 0.83 0.50; 0.73
Monkey −0.25 Not tested Not tested −1.77 −2.90 Not tested −0.26
Standard mean difference (95% CI) −0.77; 0.28 Not tested Not tested −3.21; −0.34 −4.60; −1.19 Not tested −2.23; 1.71
Dog −1.62 −0.97 Not tested −5.30 −2.54 −3.10 −1.66
Standard mean difference (95% CI) −2.58; −0.65 −2.38; 0.44 Not tested −8.43; −2.18 −3.58; −1.51 −4.73; −1.47 −2.17; −1.14
Rabbit −0.89 −4.99 −2.29 −2.04 −2.21 Not tested −2.20
Standard mean difference (95% CI) −1.58; −0.19 −7.73; 2.25 −3.91; −0.67 −3.84; −0.24 −3.38; −1.05 Not tested −3.22; −1.18
Rat −1.08 −3.51 Not tested Not tested Not tested −2.67 −0.42
Standard mean difference (95% CI) −1.72; −0.45 −6.21; −0.80 Not tested Not tested Not tested −3.91; −1.43 −1.35; 0.52
Mouse −3.80 −1.46 Not tested Not tested Not tested Not tested Not tested
Standard mean difference (95% CI) −5.24; −2.36 −2.51; −0.40 Not tested Not tested Not tested Not tested Not tested
Open in a new tab

CI, confidence interval.

Two of the four drugs (50%) tested in monkeys presented results concordant with clinical trials (calcium channel antagonists had no significant effects in either, tissue plasminogen activator was significantly effective in both). In dogs, four (statins had no significant effects whereas fasudil, tissue plasminogen activator, and endothelin antagonists/endothelin converting enzyme inhibitors had significant effects) of six drugs (67%) were concordant and in rabbits, two (tissue plasminogen activator and endothelin antagonists had significant effects) of six (33%). One drug (fasudil had significant effect) of four (25%) was concordant in rats while in mice, none of two was concordant (Table 3). Considering animal studies individually, 55% were concordant. In multivariate logistic regression after using a Bonferroni adjustment for multiple testing, the only significant predictor of translation was the day of assessment of vasospasm (continuous or dichotomized ≤ versus > 3 days). Studies where vasospasm was evaluated after day 3 from SAH have results more concordant with human trials than others. Univariate analysis showed angiographic evaluation of vasospasm (versus histology), intracranial delivery of drug (versus other routes), use of randomization, statement of inclusion and exclusion criteria, cisternal injection procedure or fresh blood injection (versus clot placement), and blinding of assessment of outcome were associated with higher probability of translation (P<0.15; Table 4; Supplementary Figure 1).

Table 4. Results of univariate and multivariate logistic regression for predictors of translation.

Variable Univariate analysis
 Multivariate analysis
  P-value Unadjusted odds ratio (95% confidence interval) P-value Unadjusted odds ratio (95% confidence interval)
Angiography versus histology 0.0039 5.04 (1.68; 15.11) Not significant  
Fresh blood versus clot placement 0.1490 1.96 (0.65; 5.90) Not significant  
         
Day of vasospasm evaluation
 Continuous 0.0056 1.38 (1.10; 1.74) 0.0006 1.62 (1.23; 2.14)
 >3 versus #3 days 0.0019 6.22 (1.96; 19.7) 0.0002 11.2 (3.13; 40.1)
Drug delivery (intracranial versus systemic) 0.0750 2.40 (0.92; 6.29) Not significant  
Randomization 0.1007 0.46 (0.18; 1.16) Not significant  
Blinding outcome 0.1149 0.46 (0.18; 1.21) Not significant  
Inclusion/exclusion criteria 0.0578 0.20 (0.04; 1.05) Not significant  
Open in a new tab

Discussion

This systematic review found that pharmacologic treatments that are effective at reducing vasospasm in animal models of SAH are also usually effective in humans. However, publication bias was detected, suggesting that some studies remain unpublished and that the data may overestimate the true effect of the drugs. Since one of the objectives of animal experimentation is to develop new treatment for human disease, lack of publishing of negative experimental studies may contribute substantially to unsuccessful translation of results to humans (Sena et al, 2010; van der Worp et al, 2010). On the other hand, methodologic quality of many of the studies was poor, and would limit the interpretation of experimental studies showing treatment benefits, as well as of those showing no benefit. We also found significant heterogeneity and that the effect size was related to some of the study characteristics. The type of SAH model for erythropoietin and statins, animal species for calcium channel antagonists, tissue plasminogen activator for dogs, tirilizad and severity of vasospasm for monkeys were significantly different. This observation suggests that results of experimental studies are related not only to the drug tested but also to the study design and quality and that these factors should be considered when evaluating whether to test a drug in humans.

The other main objective of this work was to assess if any animal used in models of SAH more accurately reflects results of human studies. We observed that not every drug is effective in every species and that in monkey and dog studies the concordance with human studies was higher. However, in multivariate logistic regression after adjustment for multiple testing, only the day of evaluation of vasospasm (>3 days after SAH) correlated with successful translation of results to humans. These observations have practical implications for study design and model selection and it may be that in further preclinical experiments long-term drug effect evaluation should be preferred.

There are a number of limitations to this analysis. Most instances of concordance were positive, in that drugs worked in animals and humans. However, additional important confirmatory data would be studies showing that drugs that were not effective in humans also were not in animals. In studies that show no effect, drug dose, timing and route of administration would also need to be fully explored or at least shown to be equivalent between animal and human studies. There are limited data on some models, such as rats and mice. Only 11 of the 72 (15%) studies used rats or mice, and almost all recent studies use them. Given the paucity of data, we cannot exclude the possibility that these models are equal to dogs and monkeys in terms of translation of results to human. In human trials, angiographic vasospasm frequently was considered as a dichotomous variable (none/mild or moderate/severe), while in animal studies, it is expressed as a continuous variable. For this reason, it was not possible to compare exactly the effects in animals and humans. We focused on prophylactic treatments and in the human studies, drugs were administered before the onset of angiographic vasospasm. In the animal studies, however, since we included some studies where drug administration began after the second blood injection and angiography was not done, it is possible that some of these studies were also treating established vasospasm. The classification of drugs also could be questioned. We categorized magnesium separately since it has calcium antagonist and putative neuroprotective effects. Another option would be to include it in the calcium antagonist category. For calcium antagonists, we searched only for nimodipine and nicardipine since other calcium antagonists have not been studied in randomized clinical trials in humans.

Another issue is the analysis was restricted to evaluation of angiographic or large-artery vasospasm. Most models of SAH differ from human SAH in that animals do not develop cerebral infarctions or other delayed processes that are proposed to be important in humans, such as cortical spreading ischemia and microthromboembolism (Dreier et al, 2009; Vergouwen et al, 2008). The end points in human clinical trials are usually clinical outcome and delayed cerebral ischemia but neurological and functional examination after experimental SAH is still uncommonly used (Jeon et al, 2009; Takata et al, 2008). There is some evidence that reduction of angiographic vasospasm does not correlate with improved outcome in humans (Etminan et al, 2011; Macdonald, 2011; Macdonald et al, 2008). Unfortunately, if this is true and not due to other reasons, such as efficacy of rescue therapy in placebo groups, insensitive outcome measures, drug side-effects and such, animal models will have to be reassessed to ensure they reflect relevant human features if they are to be used to decide whether to advance drugs into clinical trials. The present analysis focused on angiographic vasospasm but subsequent analysis might examine the relation between delayed cerebral ischemia and neurological outcome in animals and humans.

In conclusion, we found evidence that animal models can inform effects of pharmacologic treatments for angiographic vasospasm in human clinical trials. Higher species, longer durations of assessment of vasospasm and injections of fresh blood may be more applicable.

RL Macdonald is a consultant for Actelion Pharmaceuticals and Chief Scientific Officer of Edge Therapeutics, Inc. Edge Therapeutics is dedicated to developing drugs to improve outcome of patients with subarachnoid hemorrhage and brain injuries.

Footnotes

Supplementary Information accompanies the paper on the Journal of Cerebral Blood Flow & Metabolism website (http://www.nature.com/jcbfm)

This study was supported by grants from the Physicians Services Incorporated Foundation and the Heart and Stroke Foundation of Ontario to RL Macdonald.

Supplementary Material

Supplementary Information
Click here for additional data file. (287KB, doc)

References

  1. Bilginer B, Onal MB, Narin F, Soylemezoglu F, Ziyal IM, Ozgen T. The effects of intravenous cilostazol and nimodipine on cerebral vasospasm after subarachnoid hemorrhage in an experimental rabbit model. Turk Neurosurg. 2009;19:374–379. [PubMed] [Google Scholar]
  2. Bulsara KR, Coates JR, Agrawal VK, Eifler DM, Wagner-Mann CC, Durham HE, Fine DM, Toft K. Effect of combined simvastatin and cyclosporine compared with simvastatin alone on cerebral vasospasm after subarachnoid hemorrhage in a canine model. Neurosurg Focus. 2006;21:E11. doi: 10.3171/foc.2006.21.3.11. [DOI] [PubMed] [Google Scholar]
  3. Caner HH, Kwan AL, Arthur A, Jeng AY, Lappe RW, Kassell NF, Lee KS. Systemic administration of an inhibitor of endothelin-converting enzyme for attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage. J Neurosurg. 1996;85:917–922. doi: 10.3171/jns.1996.85.5.0917. [DOI] [PubMed] [Google Scholar]
  4. Chang CZ, Wu SC, Lin CL, Hwang SL, Howng SL, Kwan AL. Atorvastatin preconditioning attenuates the production of endothelin-1 and prevents experimental vasospasm in rats. Acta Neurochir (Wien) 2010;152:1399–1406. doi: 10.1007/s00701-010-0652-3. [DOI] [PubMed] [Google Scholar]
  5. Chen G, Zhang S, Shi J, Ai J, Hang C. Effects of recombinant human erythropoietin (rhEPO) on JAK2/STAT3 pathway and endothelial apoptosis in the rabbit basilar artery after subarachnoid hemorrhage. Cytokine. 2009;45:162–168. doi: 10.1016/j.cyto.2008.11.015. [DOI] [PubMed] [Google Scholar]
  6. Cheng G, Wei L, Zhi-Dan S, Shi-Guang Z, Xiang-Zhen L. Atorvastatin ameliorates cerebral vasospasm and early brain injury after subarachnoid hemorrhage and inhibits caspase-dependent apoptosis pathway. BMC Neurosci. 2009;10:7. doi: 10.1186/1471-2202-10-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chung WY, Lee LS. The effect of tissue plasminogen activator (t-PA) on cerebral vasospasm in canine subarachnoid hemorrhage. Chung Hua i Hsueh Tsa Chih. 1993;52:298–306. [PubMed] [Google Scholar]
  8. Cosentino F, McMahon EG, Carter JS, Katusic ZS. Effect of endothelinA-receptor antagonist BQ-123 and phosphoramidon on cerebral vasospasm. J Cardiovasc Pharmacol. 1993;22 (Suppl 8:S332–S335. doi: 10.1097/00005344-199322008-00087. [DOI] [PubMed] [Google Scholar]
  9. Crowley RW, Medel R, Dumont AS, Ilodigwe D, Kassell NF, Mayer SA, Ruefenacht D, Schmiedek P, Weidauer S, Pasqualin A, Macdonald RL. Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage. Stroke. 2011;42:919–923. doi: 10.1161/STROKEAHA.110.597005. [DOI] [PubMed] [Google Scholar]
  10. Dreier JP, Major S, Manning A, Woitzik J, Drenckhahn C, Steinbrink J, Tolias C, Oliveira-Ferreira AI, Fabricius M, Hartings JA, Vajkoczy P, Lauritzen M, Dirnagl U, Bohner G, Strong AJ. Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage. Brain. 2009;132:1866–1881. doi: 10.1093/brain/awp102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Espinosa F, Weir B, Overton T, Castor W, Grace M, Boisvert D. A randomized placebo-controlled double-blind trial of nimodipine after SAH in monkeys. Part 1: clinical and radiological findings. J Neurosurg. 1984;60:1167–1175. doi: 10.3171/jns.1984.60.6.1167. [DOI] [PubMed] [Google Scholar]
  12. Etminan N, Vergouwen MD, Ilodigwe D, Macdonald RL. Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2011;31:1443–1451. doi: 10.1038/jcbfm.2011.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fergusen S, Macdonald RL. Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery. 2007;60:658–667. doi: 10.1227/01.NEU.0000255396.23280.31. [DOI] [PubMed] [Google Scholar]
  14. Findlay JM, Weir BK, Gordon P, Grace M, Baughman R. Safety and efficacy of intrathecal thrombolytic therapy in a primate model of cerebral vasospasm. Neurosurgery. 1989;24:491–498. doi: 10.1227/00006123-198904000-00002. [DOI] [PubMed] [Google Scholar]
  15. Findlay JM, Weir BK, Kanamaru K, Grace M, Baughman R. The effect of timing of intrathecal fibrinolytic therapy on cerebral vasospasm in a primate model of subarachnoid hemorrhage. Neurosurgery. 1990;26:201–206. doi: 10.1097/00006123-199002000-00003. [DOI] [PubMed] [Google Scholar]
  16. Findlay JM, Weir BK, Steinke D, Tanabe T, Gordon P, Grace M. Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH. J Neurosurg. 1988;69:723–735. doi: 10.3171/jns.1988.69.5.0723. [DOI] [PubMed] [Google Scholar]
  17. Grasso G, Buemi M, Alafaci C, Sfacteria A, Passalacqua M, Sturiale A, Calapai G, De VG, Piedimonte G, Salpietro FM, Tomasello F. Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage. Proc Natl Acad Sci USA. 2002;99:5627–5631. doi: 10.1073/pnas.082097299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gul S, Bahadir B, Hanci V, Acikgoz S, Bektas S, Ugurbas E, Ankarali H, Kalayci M, Acikgoz B. Effects of ebselen versus nimodipine on cerebral vasospasm subsequent to experimental subarachnoid hemorrhage in rats. J Clin Neurosci. 2010;17:608–611. doi: 10.1016/j.jocn.2009.07.115. [DOI] [PubMed] [Google Scholar]
  19. Hanggi D, Eicker S, Beseoglu K, Rapp M, Perrin J, Nawatny J, Turowski B, Sommer C, Steiger HJ. Dose-related efficacy of a continuous intracisternal nimodipine treatment on cerebral vasospasm in the rat double subarachnoid hemorrhage model. Neurosurgery. 2009;64:1155–1159. doi: 10.1227/01.NEU.0000340685.06407.FD. [DOI] [PubMed] [Google Scholar]
  20. Hariton GB, Findlay JM, Weir BK, Kasuya H, Grace MG, Mielke BW. Comparison of intrathecal administration of urokinase and tissue plasminogen activator on subarachnoid clot and chronic vasospasm in a primate model. Neurosurgery. 1993;33:691–696. doi: 10.1227/00006123-199310000-00020. [DOI] [PubMed] [Google Scholar]
  21. Higgins J, Green S.2008Cochrane Handbook for Systematic Reviews of Interventions The Cochrane Collaboration; Available at http://www.cochrane-handbook.org [Google Scholar]
  22. Hino A, Weir BK, Macdonald RL, Thisted RA, Kim CJ, Johns LM. Prospective, randomized, double-blind trial of BQ-123 and bosentan for prevention of vasospasm following subarachnoid hemorrhage in monkeys. J Neurosurg. 1995;83:503–509. doi: 10.3171/jns.1995.83.3.0503. [DOI] [PubMed] [Google Scholar]
  23. Itoh S, Sasaki T, Asai A, Kuchino Y. Prevention of delayed vasospasm by an endothelin ETA receptor antagonist, BQ-123: change of ETA receptor mRNA expression in a canine subarachnoid hemorrhage model. J Neurosurg. 1994;81:759–764. doi: 10.3171/jns.1994.81.5.0759. [DOI] [PubMed] [Google Scholar]
  24. Itoh S, Sasaki T, Ide K, Ishikawa K, Nishikibe M, Yano M. A novel endothelin ETA receptor antagonist, BQ-485, and its preventive effect on experimental cerebral vasospasm in dogs. Biochem Biophys Res Comm. 1993;195:969–975. doi: 10.1006/bbrc.1993.2139. [DOI] [PubMed] [Google Scholar]
  25. Jeon H, Ai J, Sabri M, Tariq A, Shang X, Chen G, Macdonald RL. Neurological and neurobehavioral assessment of experimental subarachnoid hemorrhage. BMC Neurosci. 2009;10:103. doi: 10.1186/1471-2202-10-103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Josko J, Hendryk S, Jedrzejowska-Szypulka H, Slowinski J, Gwozdz B, Lange D, Harabin-Slowinska M. Effect of endothelin-1 receptor antagonist BQ-123 on basilar artery diameter after subarachnoid hemorrhage (SAH) in rats. J Physiol Pharmacol. 2000;51:241–249. [PubMed] [Google Scholar]
  27. Kanamaru K, Weir BK, Findlay JM, Grace M, Macdonald RL. A dosage study of the effect of the 21-aminosteroid U74006F on chronic cerebral vasospasm in a primate model. Neurosurgery. 1990;27:29–38. doi: 10.1097/00006123-199007000-00004. [DOI] [PubMed] [Google Scholar]
  28. Kanamaru K, Weir BK, Simpson I, Witbeck T, Grace M. Effect of 21-aminosteroid U-74006F on lipid peroxidation in subarachnoid clot. J Neurosurg. 1991;74:454–459. doi: 10.3171/jns.1991.74.3.0454. [DOI] [PubMed] [Google Scholar]
  29. Kawada S, Kinugasa K, Meguro T, Hirotsune N, Tokunaga K, Kamata I, Nakashima H, Ohmoto T. Experimental study of intracisternal administration of tissue-type plasminogen activator followed by cerebrospinal fluid drainage in the ultra-early stage of subarachnoid haemorrhage. Acta Neurochir. 1999;141:1331–1338. doi: 10.1007/s007010050438. [DOI] [PubMed] [Google Scholar]
  30. Kawashima A, Kasuya H, Sasahara A, Miyajima M, Izawa M, Hori T. Prevention of cerebral vasospasm by nicardipine prolonged-release implants in dogs. Neurol Res. 2000;22:634–641. doi: 10.1080/01616412.2000.11740733. [DOI] [PubMed] [Google Scholar]
  31. Kim CJ, Bassiouny M, Macdonald RL, Weir B, Johns LM. Effect of BQ-123 and tissue plasminogen activator on vasospasm after subarachnoid hemorrhage in monkeys. Stroke. 1996;27:1629–1633. doi: 10.1161/01.str.27.9.1629. [DOI] [PubMed] [Google Scholar]
  32. Kim I, Leinweber BD, Morgalla M, Butler WE, Seto M, Sasaki Y, Peterson JW, Morgan KG. Thin and thick filament regulation of contractility in experimental cerebral vasospasm. Neurosurgery. 2000;46:440–447. doi: 10.1097/00006123-200002000-00033. [DOI] [PubMed] [Google Scholar]
  33. Kita T, Kubo K, Hiramatsu K, Sakaki T, Yonetani Y, Sato S, Fujimoto M, Nakashima T. Profiles of an intravenously available endothelin A-receptor antagonist, S-0139, for preventing cerebral vasospasm in a canine two-hemorrhage model. Life Sci. 1998;63:305–315. doi: 10.1016/s0024-3205(98)00274-4. [DOI] [PubMed] [Google Scholar]
  34. Kwan AL, Bavbek M, Jeng AY, Maniara W, Toyoda T, Lappe RW, Kassell NF, Lee KS. Prevention and reversal of cerebral vasospasm by an endothelin-converting enzyme inhibitor, CGS 26303, in an experimental model of subarachnoid hemorrhage. J Neurosurg. 1997;87:281–286. doi: 10.3171/jns.1997.87.2.0281. [DOI] [PubMed] [Google Scholar]
  35. Kwan AL, Lin CL, Chang CZ, Wu HJ, Hwong SL, Jeng AY, Lee KS. Continuous intravenous infusion of CGS 26303, an endothelin-converting enzyme inhibitor, prevents and reverses cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery. 2001;49:422–427. doi: 10.1097/00006123-200108000-00029. [DOI] [PubMed] [Google Scholar]
  36. Kwan AL, Lin CL, Yen CP, Winardi W, Su YF, Winardi D, Dai ZK, Jeng AY, Kassell NF, Howng SL, Wang CJ. Prevention and reversal of vasospasm and ultrastructural changes in basilar artery by continuous infusion of CGS 35066 following subarachnoid hemorrhage. Exp Biol Med (Maywood) 2006;231:1069–1074. [PubMed] [Google Scholar]
  37. Laslo AM, Eastwood JD, Chen FX, Lee TY. Dynamic CT perfusion imaging in subarachnoid hemorrhage-related vasospasm. AJNR. 2006;27:624–631. [PMC free article] [PubMed] [Google Scholar]
  38. Lewis PJ, Weir BK, Nosko MG, Tanabe T, Grace MG. Intrathecal nimodipine therapy in a primate model of chronic cerebral vasospasm. Neurosurgery. 1988;22:492–500. doi: 10.1227/00006123-198803000-00007. [DOI] [PubMed] [Google Scholar]
  39. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. doi: 10.1136/bmj.b2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Lin CL, Kwan AL, Dumont AS, Su YF, Kassell NF, Wang CJ, Wu SC, Kuo CL, Huang CS, Jeng AY, Liu CS. Attenuation of experimental subarachnoid hemorrhage-induced increases in circulating intercellular adhesion molecule-1 and cerebral vasospasm by the endothelin-converting enzyme inhibitor CGS 26303. J Neurosurg. 2007;106:442–448. doi: 10.3171/jns.2007.106.3.442. [DOI] [PubMed] [Google Scholar]
  41. Macdonald RL. Predicting vasospasm after subarachnoid hemorrhage. World Neurosurg. 2011;75:25–26. [Google Scholar]
  42. Macdonald RL, Bassiouny M, Johns L, Sajdak M, Marton LS, Weir BK, Hall ED, Andrus PK. U74389G prevents vasospasm after subarachnoid hemorrhage in dogs. Neurosurgery. 1998a;42:1339–1345. doi: 10.1097/00006123-199806000-00089. [DOI] [PubMed] [Google Scholar]
  43. Macdonald RL, Curry DJ, Aihara Y, Zhang ZD, Jahromi BS, Yassari R. Magnesium and experimental vasospasm. J Neurosurg. 2004;100:106–110. doi: 10.3171/jns.2004.100.1.0106. [DOI] [PubMed] [Google Scholar]
  44. Macdonald RL, Johns L, Lin G, Marton LS, Hallak H, Marcoux F, Kowalczuk A. Prevention of vasospasm after subarachnoid hemorrhage in dogs by continuous intravenous infusion of PD156707. Neurologia Medico-Chirurgica. 1998b;38 (Suppl:138–145. doi: 10.2176/nmc.38.suppl_138. [DOI] [PubMed] [Google Scholar]
  45. Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, Frey A, Roux S, Pasqualin A. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39:3015–3021. doi: 10.1161/STROKEAHA.108.519942. [DOI] [PubMed] [Google Scholar]
  46. Marbacher S, Neuschmelting V, Graupner T, Jakob SM, Fandino J. Prevention of delayed cerebral vasospasm by continuous intrathecal infusion of glyceroltrinitrate and nimodipine in the rabbit model in vivo. Intensive Care Med. 2008;34:932–938. doi: 10.1007/s00134-008-0995-x. [DOI] [PubMed] [Google Scholar]
  47. Matsui T, Asano T. Effects of new 21-aminosteroid tirilazad mesylate (U74006F) on chronic cerebral vasospasm in a ″two-hemorrhage″ model of beagle dogs. Neurosurgery. 1994;34:1035–1039. doi: 10.1227/00006123-199406000-00012. [DOI] [PubMed] [Google Scholar]
  48. Matsumura Y, Ikegawa R, Suzuki Y, Takaoka M, Uchida T, Kido H, Shinyama H, Hayashi K, Watanabe M, Morimoto S. Phosphoramidon prevents cerebral vasospasm following subarachnoid hemorrhage in dogs: the relationship to endothelin-1 levels in the cerebrospinal fluid. Life Sci. 1991;49:841–848. doi: 10.1016/0024-3205(91)90249-b. [DOI] [PubMed] [Google Scholar]
  49. McGirt MJ, Lynch JR, Parra A, Sheng H, Pearlstein RD, Laskowitz DT, Pelligrino DA, Warner DS. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke. 2002;33:2950–2956. doi: 10.1161/01.str.0000038986.68044.39. [DOI] [PubMed] [Google Scholar]
  50. McGirt MJ, Pradilla G, Legnani FG, Thai QA, Recinos PF, Tamargo RJ, Clatterbuck RE. Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm. Neurosurgery. 2006;58:945–951. doi: 10.1227/01.NEU.0000210262.67628.7E. [DOI] [PubMed] [Google Scholar]
  51. Megyesi JF, Vollrath B, Cook DA, Findlay JM. In vivo animal models of cerebral vasospasm: a review. Neurosurgery. 2000;46:448–460. [PubMed] [Google Scholar]
  52. Mesis RG, Wang H, Lombard FW, Yates R, Vitek MP, Borel CO, Warner DS, Laskowitz DT. Dissociation between vasospasm and functional improvement in a murine model of subarachnoid hemorrhage. Neurosurg Focus. 2006;21:E4. doi: 10.3171/foc.2006.21.3.4. [DOI] [PubMed] [Google Scholar]
  53. Mignini LE, Khan KS. Methodological quality of systematic reviews of animal studies: a survey of reviews of basic research. BMC Med Res Methodol. 2006;6:10. doi: 10.1186/1471-2288-6-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. doi: 10.1136/bmj.b2535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Murphy AM, Xenocostas A, Pakkiri P, Lee TY. Hemodynamic effects of recombinant human erythropoietin on the central nervous system after subarachnoid hemorrhage: reduction of microcirculatory impairment and functional deficits in a rabbit model. J Neurosurg. 2008;109:1155–1164. doi: 10.3171/JNS.2008.109.12.1155. [DOI] [PubMed] [Google Scholar]
  56. Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol. 2009;8:635–642. doi: 10.1016/S1474-4422(09)70126-7. [DOI] [PubMed] [Google Scholar]
  57. Nirei H, Hamada K, Shoubo M, Sogabe K, Notsu Y, Ono T. An endothelin ETA receptor antagonist, FR139317, ameliorates cerebral vasospasm in dogs. Life Sci. 1993;52:1869–1874. doi: 10.1016/0024-3205(93)90007-p. [DOI] [PubMed] [Google Scholar]
  58. Nosko M, Weir B, Krueger C, Cook D, Norris S, Overton T, Boisvert D. Nimodipine and chronic vasospasm in monkeys: Part 1. Clinical and radiological findings. Neurosurgery. 1985;16:129–136. doi: 10.1227/00006123-198502000-00001. [DOI] [PubMed] [Google Scholar]
  59. Ohkuma H, Parney I, Megyesi J, Ghahary A, Findlay JM. Antisense preproendothelin-oligoDNA therapy for vasospasm in a canine model of subarachnoid hemorrhage. J Neurosurg. 1999;90:1105–1114. doi: 10.3171/jns.1999.90.6.1105. [DOI] [PubMed] [Google Scholar]
  60. Pasqualin A, Vollmer DG, Marron JA, Tsukahara T, Kassell NF, Torner JC. The effect of nicardipine on vasospasm in rabbit basilar artery after subarachnoid hemorrhage. Neurosurgery. 1991;29:183–188. doi: 10.1097/00006123-199108000-00003. [DOI] [PubMed] [Google Scholar]
  61. Roux S, Breu V, Giller T, Neidhart W, Ramuz H, Coassolo P, Clozel JP, Clozel M. Ro 61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm. J Pharmacol Exp Ther. 1997;283:1110–1118. [PubMed] [Google Scholar]
  62. Santhanam AV, Smith LA, Akiyama M, Rosales AG, Bailey KR, Katusic ZS. Role of endothelial NO synthase phosphorylation in cerebrovascular protective effect of recombinant erythropoietin during subarachnoid hemorrhage-induced cerebral vasospasm. Stroke. 2005;36:2731–2737. doi: 10.1161/01.STR.0000190021.85035.5b. [DOI] [PubMed] [Google Scholar]
  63. Satoh S, Suzuki Y, Harada T, Ikegaki I, Asano T, Shibuya M, Sugita K, Hidaka H. Possible prophylactic potential of HA1077, a Ca2+ channel antagonist and vasodilator, on chronic cerebral vasospasm. Eur J Pharmacol. 1992;220:243–248. doi: 10.1016/0014-2999(92)90754-r. [DOI] [PubMed] [Google Scholar]
  64. Seifert V, Eisert WG, Stolke D, Goetz C. Efficacy of single intracisternal bolus injection of recombinant tissue plasminogen activator to prevent delayed cerebral vasospasm after experimental subarachnoid hemorrhage [see comments] Neurosurgery. 1989;25:590–598. doi: 10.1097/00006123-198910000-00013. [DOI] [PubMed] [Google Scholar]
  65. Sena ES, van der Worp HB, Bath PM, Howells DW, Macleod MR. Publication bias in reports of animal stroke studies leads to major overstatement of efficacy. PLoS Biol. 2010;8:e1000344. doi: 10.1371/journal.pbio.1000344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Shigeno T, Clozel M, Sakai S, Saito A, Goto K. The effect of bosentan, a new potent endothelin receptor antagonist, on the pathogenesis of cerebral vasospasm. Neurosurgery. 1995;37:87–90. doi: 10.1227/00006123-199507000-00013. [DOI] [PubMed] [Google Scholar]
  67. Steinke DE, Weir BK, Findlay JM, Tanabe T, Grace M, Krushelnycky BW. A trial of the 21-aminosteroid U74006F in a primate model of chronic cerebral vasospasm. Neurosurgery. 1989;24:179–186. doi: 10.1227/00006123-198902000-00005. [DOI] [PubMed] [Google Scholar]
  68. Sugawara T, Ayer R, Jadhav V, Chen W, Tsubokawa T, Zhang JH. Simvastatin attenuation of cerebral vasospasm after subarachnoid hemorrhage in rats via increased phosphorylation of Akt and endothelial nitric oxide synthase. J Neurosci Res. 2008;86:3635–3643. doi: 10.1002/jnr.21807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Suzuki H, Kanamaru K, Kuroki M, Sun H, Waga S, Miyazawa T. Effects of unilateral intrathecal administrations of low dose tissue-type plasminogen activator on clot lysis, vasospasm and brain phospholipid hydroperoxidation in a primate model of bilateral subarachnoid hemorrhage. Neurol Res. 1998;20:625–631. doi: 10.1080/01616412.1998.11740574. [DOI] [PubMed] [Google Scholar]
  70. Suzuki H, Kanamaru K, Kuroki M, Sun H, Waga S, Miyazawa T. Effects of tirilazad mesylate on vasospasm and phospholipid hydroperoxides in a primate model of subarachnoid hemorrhage. Stroke. 1999;30:450–455. doi: 10.1161/01.str.30.2.450. [DOI] [PubMed] [Google Scholar]
  71. Takanashi Y, Ishida T, Meguro T, Kirchmeier MJ, Allen TM, Zhang JH. Intrathecal application with liposome-entrapped Fasudil for cerebral vasospasm following subarachnoid hemorrhage in rats. J Clin Neurosci. 2001a;8:557–561. doi: 10.1054/jocn.2001.0998. [DOI] [PubMed] [Google Scholar]
  72. Takanashi Y, Ishida T, Meguro T, Kiwada H, Zhang JH, Yamamoto I. Efficacy of intrathecal liposomal fasudil for experimental cerebral vasospasm after subarachnoid hemorrhage. Neurosurgery. 2001b;48:894–900. doi: 10.1097/00006123-200104000-00041. [DOI] [PubMed] [Google Scholar]
  73. Takata K, Sheng H, Borel CO, Laskowitz DT, Warner DS, Lombard FW. Long-term cognitive dysfunction following experimental subarachnoid hemorrhage: new perspectives. Exp Neurol. 2008;213:336–344. doi: 10.1016/j.expneurol.2008.06.009. [DOI] [PubMed] [Google Scholar]
  74. Tang WH, Chen Z, Liu Z, Zhang JH, Xi G, Feng H. The effect of ecdysterone on cerebral vasospasm following experimental subarachnoid hemorrhage in vitro and in vivo. Neurol Res. 2008;30:571–580. doi: 10.1179/174313208X297986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Titova E, Ostrowski RP, Zhang JH, Tang J. Experimental models of subarachnoid hemorrhage for studies of cerebral vasospasm. Neurol Res. 2009;31:568–581. doi: 10.1179/174313209X382412. [DOI] [PubMed] [Google Scholar]
  76. Turowski B, Hanggi D, Beck A, Aurich V, Steiger HJ, Moedder U. New angiographic measurement tool for analysis of small cerebral vessels: application to a subarachnoid haemorrhage model in the rat. Neuroradiology. 2007;49:129–137. doi: 10.1007/s00234-006-0168-y. [DOI] [PubMed] [Google Scholar]
  77. van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O'Collins V, Macleod MR. Can animal models of disease reliably inform human studies. PLoS Med. 2010;7:e1000245. doi: 10.1371/journal.pmed.1000245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Vergouwen MD, Vermeulen M, Coert BA, Stroes ES, Roos YB. Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia. J Cereb Blood Flow Metab. 2008;28:1761–1770. doi: 10.1038/jcbfm.2008.74. [DOI] [PubMed] [Google Scholar]
  79. Vollmer DG, Kassell NF, Hongo K, Ogawa H, Tsukahara T. Effect of the nonglucocorticoid 21-aminosteroid U74006F experimental cerebral vasospasm. Surg Neurol. 1989;31:190–194. doi: 10.1016/0090-3019(89)90115-8. [DOI] [PubMed] [Google Scholar]
  80. Wanebo JE, Arthur AS, Louis HG, West K, Kassell NF, Lee KS, Helm GA. Systemic administration of the endothelin-A receptor antagonist TBC 11251 attenuates cerebral vasospasm after experimental subarachnoid hemorrhage: dose study and review of endothelin-based therapies in the literature on cerebral vasospasm. Neurosurgery. 1998;43:1409–1417. [PubMed] [Google Scholar]
  81. Wanebo JE, Louis HG, Arthur AS, Zhou J, Kassell NF, Lee KS, Helm GA.1997Attenuation of cerebral vasospasm by systemic administration of an endothelin-A receptor antagonist, TBC 11251, in a rabbit model of subarachnoid hemorrhage Neurosurg Focus 3E8 [DOI] [PubMed] [Google Scholar]
  82. Wang Z, Chen G, Zhu WW, Bian JY, Shen XO, Zhou D. Influence of simvastatin on microthrombosis in the brain after subarachnoid hemorrhage in rats: a preliminary study. Ann Clin Lab Sci. 2010;40:32–42. [PubMed] [Google Scholar]
  83. Willette RN, Zhang H, Mitchell MP, Sauermelch CF, Ohlstein EH, Sulpizio AC. Nonpeptide endothelin antagonist. Cerebrovascular characterization and effects on delayed cerebral vasospasm. Stroke. 1994;25:2450–2455. doi: 10.1161/01.str.25.12.2450. [DOI] [PubMed] [Google Scholar]
  84. Zabramski J, Spetzler RF, Bonstelle C. Chronic cerebral vasospasm: effect of calcium antagonists. Neurosurgery. 1986;18:129–135. doi: 10.1227/00006123-198602000-00002. [DOI] [PubMed] [Google Scholar]
  85. Zimmermann M, Seifert V, Loffler BM, Stolke D, Stenzel W. Prevention of cerebral vasospasm after experimental subarachnoid hemorrhage by RO 47-0203, a newly developed orally active endothelin receptor antagonist. Neurosurgery. 1996;38:115–120. doi: 10.1097/00006123-199601000-00028. [DOI] [PubMed] [Google Scholar]
  86. Zuccarello M, Boccaletti R, Romano A, Rapoport RM. Endothelin B receptor antagonists attenuate subarachnoid hemorrhage-induced cerebral vasospasm. Stroke. 1998;29:1924–1929. doi: 10.1161/01.str.29.9.1924. [DOI] [PubMed] [Google Scholar]
  87. Zuccarello M, Marsch JT, Schmitt G, Woodward J, Anderson DK. Effect of the 21-aminosteroid U-74006F on cerebral vasospasm following subarachnoid hemorrhage. J Neurosurg. 1989;71:98–104. doi: 10.3171/jns.1989.71.1.0098. [DOI] [PubMed] [Google Scholar]
  88. Zuccarello M, Soattin GB, Lewis AI, Breu V, Hallak H, Rapoport RM. Prevention of subarachnoid hemorrhage-induced cerebral vasospasm by oral administration of endothelin receptor antagonists. J Neurosurg. 1996;84:503–507. doi: 10.3171/jns.1996.84.3.0503. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Information
Click here for additional data file. (287KB, doc)

Articles from Journal of Cerebral Blood Flow & Metabolism are provided here courtesy of SAGE Publications

RESOURCES