Steroids for acute spinal cord injury

  • Review
  • Intervention

Authors

  • Michael B Bracken

    Corresponding author
    1. Yale University Medical School, Department of Epidemiology & Public Health, New Haven, CT, USA
    • Michael B Bracken, Department of Epidemiology & Public Health, Yale University Medical School, Box 20834, 60 College Street, New Haven, CT, 06520-8034, USA. michael.bracken@yale.edu.

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Abstract

Background

Acute spinal cord injury is a devastating condition typically affecting young people, mostly males. Steroid treatment in the early hours after the injury is aimed at reducing the extent of permanent paralysis during the rest of the patient's life.

Objectives

To review randomized trials of steroids for human acute spinal cord injury.

Search methods

We searched the Cochrane Injuries Group's Specialised Register (searched 02 Aug 2011), The Cochrane Central Register of Controlled Trials 2011, issue 3 (The Cochrane Library), MEDLINE (Ovid) 1948 to July Week 3 2011, EMBASE (Ovid) 1974 to 2011 week 17, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to Aug 2011, ISI Web of Science: Conference Proceedings Citation Index- Science (CPCI-S) 1990 to Aug 2011 and PubMed [www.ncbi.nlm.nih.gov/sites/entrez/] (searched 04 Aug 2011) for records added to PubMed in the last 90 days). Files of the National Acute Spinal Cord Injury Study (NASCIS) were reviewed (NASCIS was founded in 1977 and has tracked trials in this area since that date). We also searched the reference lists of relevant studies and previously published reviews.

Selection criteria

All randomized controlled trials of steroid treatment for acute spinal cord injury in any language.

Data collection and analysis

One review author extracted data from trial reports. Japanese and French studies were found through NASCIS and additional data (e.g. SDs) were obtained from the original study authors.

Main results

Eight trials are included in this review, seven used methylprednisolone. Methylprednisolone sodium succinate has been shown to improve neurologic outcome up to one year post-injury if administered within eight hours of injury and in a dose regimen of: bolus 30mg/kg over 15 minutes, with maintenance infusion of 5.4 mg/kg per hour infused for 23 hours. The initial North American trial results were replicated in a Japanese trial but not in the one from France. Data was obtained from the latter studies to permit appropriate meta-analysis of all three trials. This indicated significant recovery in motor function after methylprednisolone therapy, when administration commenced within eight hours of injury. A more recent trial indicates that, if methylprednisolone therapy is given for an additional 24 hours (a total of 48 hours), additional improvement in motor neurologic function and functional status are observed. This is particularly observed if treatment cannot be started until between three to eight hours after injury. The same methylprednisolone therapy has been found effective in whiplash injuries. A modified regimen was found to improve recovery after surgery for lumbar disc disease. The risk of bias was low in the largest methyprednisolone trials. Overall, there was no evidence of significantly increased complications or mortality from the 23 or 48 hour therapy.

Authors' conclusions

High-dose methylprednisolone steroid therapy is the only pharmacologic therapy shown to have efficacy in a phase three randomized trial when administered within eight hours of injury. One trial indicates additional benefit by extending the maintenance dose from 24 to 48 hours, if start of treatment must be delayed to between three and eight hours after injury. There is an urgent need for more randomized trials of pharmacologic therapy for acute spinal cord injury.

Résumé scientifique

Stéroïdes dans les traumatismes aigus de la moelle épinière

Contexte

Les traumatismes aigus de la moelle épinière sont dévastateurs et touchent typiquement les jeunes personnes, généralement les hommes. Un traitement à base de stéroïdes administrés aux premières heures suivant le traumatisme a pour objectif de réduire le développement de l'étendue de la paralysie permanente pendant le reste de la vie du patient.

Objectifs

Évaluer des essais randomisés à base de stéroïdes pour le traitement de traumatismes aigus de la moelle épinière chez l'homme.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre des essais spécialisés du groupe Cochrane sur les blessures (recherche du 2 août 2011), le registre Cochrane des essais contrôlés 2011, numéro 3 (CENTRAL - The Cochrane Library), MEDLINE (Ovid) 1948 à la semaine 3 de juillet 2011, EMBASE (Ovid) 1974 à la semaine 17 de 2011, Web of Science de l'ISI : Science Citation Index Expanded (SCI-EXPANDED) 1970 à août 2011, Web of Science de l'ISI : Conference Proceedings Citation Index - Science (CPCI-S) 1990 à août 2011 et PubMed [www.ncbi.nlm.nih.gov/sites/entrez/] (recherche du 4 août 2011) pour les enregistrements ajoutés à PubMed au cours des 90 derniers jours). Les fichiers de la National Acute Spinal Cord Injury Study (NASCIS) ont été consultés (la NASCIS a été créée en 1977 et a permis de réaliser le suivi d'essais dans ce domaine depuis cette date). Nous avons également effectué des recherches dans les listes bibliographiques des études pertinentes et dans les revues publiées précédemment.

Critères de sélection

Tous les essais contrôlés randomisés portant sur des traitements à base de stéroïdes pour des traumatismes aigus de la moelle épinière.

Recueil et analyse des données

Un auteur de la revue a extrait des données issues de rapports d'essais. Des études japonaises et françaises ont été trouvées dans NASCIS et des données supplémentaires (par ex. des écarts types) ont été obtenues auprès des auteurs de l'étude d'origine.

Résultats principaux

Huit essais sont inclus dans cette revue, sept ont utilisé la méthylprédnisolone. Ils révèlent que le succinate de sodium de méthylprédnisolone améliore les résultats neurologiques jusqu'à un an après le traumatisme à condition d'être administré dans les huit heures suivant le traumatisme à une posologie de : bolus de 30 mg/kg pendant 15 minutes, avec une perfusion d'entretien de 5,4 mg/kg par heure pendant une durée de 23 heures. Les résultats de l'essai réalisé en Amérique du Nord ont été répliqués dans un essai japonais, mais pas dans l'essai français. Des données ont été obtenues à partir de ces études afin de réaliser une méta-analyse adéquate de ces trois essais. Elle révélait une amélioration significative de la fonction motrice après un traitement à base de méthylprédnisolone, quand son administration commence dans les huit heures suivant le traumatisme. Un essai plus récent révèle que, si le traitement à base de méthylprédnisolone est administré pendant une durée supplémentaire de 24 heures (48 heures au total), on observe une amélioration supplémentaire de la fonction neurologique motrice et de l'état fonctionnel. Ce résultat est plus particulièrement notable si le traitement ne peut pas être commencé avant trois à huit heures suivant le traumatisme. Ce même traitement s'est révélé efficace en cas de coup de fouet cervical. Un schéma posologique modifié montre qu'il favorise la guérison après l'opération chirurgicale d'une hernie discale lombaire. Les risques de biais étaient faibles dans les essais portant sur la méthylprédnisolone réalisés à grande échelle. Dans l'ensemble, aucune preuve n'a permis de démontrer une aggravation accrue du nombre de complications ou de la mortalité après un traitement de 24 ou 48 heures.

Conclusions des auteurs

Un traitement à base de méthylprédnisolone avec une posologie élevée est le seul traitement pharmacologique ayant démontré son efficacité dans trois essais randomisés lorsqu'il était administré dans les huit heures suivant le traumatisme. Un essai révèle un autre avantage en prolongeant la dose d'entretien de 24 à 48 heures, à condition que le début du traitement soit retardé de trois à huit heures suivant le traumatisme. D'avantage d'essais randomisés portant sur le traitement pharmacologique de traumatismes aigus de la moelle épinière sont nécessaires dans les meilleurs délais.

摘要

急性脊椎損傷適用的類固醇藥物

背景

急性脊椎損傷是破壞性疾病,通常影響了年輕民眾、多為男性。受傷後前幾個小時使用類固醇治療的目標在於降低病患餘生的永久性癱瘓程度 。

目的

文獻回顧類固醇藥物在急性脊椎損傷的隨機試驗。

搜尋策略

我們搜尋考科藍Injuries Group’s Specialised Register (搜尋至2011年8月2日)、考科藍Central Register of Controlled Trials2011年第3期 (考科藍圖書館)、MEDLINE (Ovid) 1948年到2011年7月年第3週、EMBASE (Ovid) 1974年到2011年17週、ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970年到2011年8月、ISI Web of Science: Conference Proceedings Citation Index- Science (CPCI-S) 19902011年8月及PubMed [www.ncbi.nlm.nih.gov/sites/entrez/] (搜尋至2011年8月4日),並取得最近90天增加到PubMed的紀錄;並搜尋國家急性脊椎損傷研究(National Acute Spinal Cord Injury Study, NASCIS) (NASCIS 於1977年成立,並自該日起追溯此領域中的試驗研究);我們也搜尋相關研究文章後面的參考文獻清單及之前所出版的文獻回顧。

選擇標準

所有類固醇治療急性脊椎損傷的隨機控制試驗,不限語言。

資料收集與分析

一位作者由試驗報告中擷取資料。在NASCIS找到日文與法文研究,原始研究作者補充相關資料(例如: SDs) 。

主要結果

8個試驗被包含於此文獻回顧中,7個使用methylprednisolone。若於受傷後8小時內給藥,Methylprednisolone sodium succinate顯示出可改善神經系統至受傷後1年,需以下列劑量處方給藥: 藥丸30mg/kg 於超過15分鐘時,加上維持期每小時5.4 mg/kg的輸液進行23 小時。初期的北美試驗結果也在日本的試驗中發現同樣結果,但卻未在法國的試驗中被發現。由法國的試驗取得研究資料,以進行所有3個試驗適當的統合分析。受傷8小時內開始給藥時,顯示在methylprednisolone治療後運動神經功能的恢復。較近期的試驗顯示,若再提供額外24小時的治療(總計48 小時),則可觀察到運動神經功能與機能性狀態更進一步的改善,此情形特別在治療無法在受傷後3到8小時開始時觀察到。相同的methylprednisolone療法曾於頸椎過度屈伸傷害中被發現有效。調整後的治療方法也被發現可提昇腰椎間盤突出疾病手術後的復原。在最大型的methyprednisolone試驗中,其偏誤風險低。整體而言,來自23或48小時的治療沒有顯著增加的併發症或死亡率的證據。

作者結論

在受傷後8小時內給藥時,高劑量methylprednisolone類固醇療法是第三期隨機試驗中唯一顯示有效的藥物治療。若治療開始必須延後至受傷後3到8小時,其中一個試驗顯示,延伸維持的劑量由24到48小時有更進一步的益處。目前極需更多急性脊椎損傷的藥物治療隨機試驗。

摘要

类固醇治疗急性脊髓损伤

研究背景

急性脊髓损伤是一种严重破坏性的疾病,患者通常为年轻人,大部分是男性。在脊髓损伤后的最初几个小时使用类固醇治疗,是为了降低患者的永久性瘫痪的程度。

研究目的

本研究的目的是探究类固醇治疗人类急性脊髓损伤的随机试验。

检索策略

我们检索了Cochrane 损伤组专业注册网站(检索至2011年8月2号),Cochrane 随机对照试验的中心注册网站至2011,issue 3(Cochrane图书馆),MEDLINE(Ovid)1948年至2011年7月第3周,EMBASE(Ovid)1974年至2011年周17日,ISI web of science:科学引文索引扩展(SCI-EXPANDED)1970年至2011年8月,ISI web of science:网络会议论文集科学引文索引(CPCI-S)1990年至2011年8月,和PubMed (www.ncbi.nlm.nih.gov /sites/entrez/)(检索至2011年8月4日),记录将在最后90天添加到PubMed)来自国家急性脊髓损伤研究组(NASCIS)的文件已经被浏览过,(NASCIS成立于1977年,并且在试验期间一直在跟进这一领域的试验)。我们也检索了相关的参考书目中的研究,以及先前发表的文献。

标准/纳入排除标准

任何语言发表的关于类固醇治疗急性脊髓损伤的随机对照试验都被纳入。

数据收集与分析

一个作者进行了数据提取。在NASCIS中检索到来自日本和法国的文献,补充的数据(如SDs)将会从原始研究的作者那里获得。

主要结果

这篇综述共纳入了八个试验,其中七个研究用到了甲强龙。如果可以在损伤后的八小时内使用甲强龙琥珀酸钠,并按照一定的方案使用,可改善神经系统且维持长达一年。剂量方案:丸药30mg/kg,超过15分钟,每小时维护注射药物5.4mg/kg,持续23个小时。一项原始来自北美的研究结果与一项日本的研究重复,而不是来自法国的。在这两个研究当中(日本和北美),我们选择后一个版本的数据进入我们的meta分析。研究表明,在损伤后8小时内进行甲基强的松龙治疗,可以显著恢复运动功能。最近的试验表明,如果甲强龙治疗时间再多加24小时(一共48小时),运动神经功能和功能状态会更加改善。直到受伤后三到八小时之间开始治疗的患者,将会进行特别观察。我们发现,同样的疗法在治疗脑震荡时也有效果。若将治疗方案修改之后,可以用来改善腰椎椎间盘疾病手术后恢复。样本量最大的甲强龙疗法的试验,风险偏倚很低。总体来看,没有证据表明在23小时或48小时进行治疗,会显著增加并发症或导致死亡。

作者结论

一项三期随机对照试验表明,在脊髓损伤的八小时内服用大剂量甲基强的松龙类固醇治疗,是唯一有效果的药物治疗。一个试验表明,如果最初的治疗必须推迟到受伤后三至八小时后,从24到48小时内维持剂量对治疗也有好处。我们迫切需要更多的关于药物治疗急性脊髓损伤的随机对照试验。

翻译注解

译者:王聪聪(北京中医药大学循证医学中心);审校:梁宁。翻译由北京中医药大学循证医学中心组织与提供。

Plain language summary

Steroids for acute spinal cord injury

Every year, about 40 million people worldwide suffer a spinal cord injury. Most of them are young men. The results are often devastating. Various drugs have been given to patients in attempts to reduce the extent of permanent paralysis. Steroids have probably been used more for this purpose than any other type of drug. The review looked for studies that examined the effectiveness of this treatment in improving movement and reducing the death rate. Nearly all the research, seven trials, has involved just one steroid, methylprednisolone. The results show that treatment with this steroid does improve movement but it must start soon after the injury has happened, within no more than eight hours. It should be continued for 24 to 48 hours. Different dose rates of the drug have been given and the so-called high-dose rate is the most effective. The treatment does not, however, give back the patient a normal amount of movement and more research is necessary with steroids, possibly combining them with other drugs.

Résumé simplifié

Stéroïdes dans les traumatismes aigus de la moelle épinière

Chaque année, environ 40 millions de personnes dans le monde souffrent de traumatismes de la moelle épinière. Les hommes jeunes en sont les principales victimes. Les résultats sont généralement dévastateurs. Plusieurs traitements ont été administrés aux patients afin d'essayer de limiter le développement d'une paralysie permanente. La prise de stéroïdes a probablement été plus utilisée à cette fin par rapport à n'importe quel autre type de médicament. Cette revue s'est intéressée aux études ayant examiné l'efficacité de ce traitement qui consistait à améliorer la mobilité et à réduire le taux de mortalité. Presque toutes les études, sept essais, ne concernaient qu'un seul stéroïde, la méthylprédnisolone. Les résultats montrent qu'un traitement basé sur ce stéroïde améliore la mobilité, mais il doit être commencé rapidement (huit heures au maximum) après le traumatisme. Il doit être continué pendant une durée allant de 24 à 48 heures. Différentes posologies de ce médicament ont été administrées et ladite plus élevée s'est avérée la plus efficace. Toutefois, le traitement ne permet pas au patient de retrouver une mobilité normale et des recherches supplémentaires sur les stéroïdes sont nécessaires, en les combinant éventuellement à d'autres médicaments.

Notes de traduction

This translation refers to an older version of the review that has been updated or amended.

Traduit par: French Cochrane Centre 10th April, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

淺顯易懂的口語結論

急性脊椎損傷適用的類固醇藥物

每年全球約有4千萬名民眾脊髓損傷。大多數是年輕人。結果通常致殘。提供給病患不同藥物,以降低永久性癱瘓的程度。類固醇藥物可能被用在更多此類用途上,且較其他藥物為多。本文獻回顧搜尋探討此治療在改善行動能力及降低死亡率有效性的研究。在7個試驗中,幾乎所有研究都只包含一種類固醇,也就是methylprednisolone。結果顯示使用此種類固醇劑量改善行動能力,但必須在受傷發生後8小時內立刻開始治療;且治療應持續24到48小時。並提供不同藥物劑量的比率,所謂高劑量被發現最為有效。然而,治療無法讓病患回到一般的行動量,且需要更多採用類固醇藥物的研究,並可能可以測試與其他藥物組合治療的效果。

譯註

翻譯: East Asian Cochrane Alliance
翻譯補助: 台灣衛生福利部/台北醫學大學實證醫學研究中心

எளியமொழிச் சுருக்கம்

கடும் முதுகு தண்டுவடகாயத்திற்கு இயக்க ஊக்கிகள்(ஸ்டிராய்டுகள்)

உலகளவில் முதுகு தண்டு காயத்தால் ஒவ்வொரு வருடமும் சுமார் நாற்பது மில்லியன் மக்கள் பாதிக்கப்படுகிறார்கள். இதில் பெரும்பாலானோர் இளம் வயது ஆண்கள். அதன் முடிவுகளும் பெரும்பாலும் படுமோசமாக அல்லது வருத்ததிற்குரியதாய் அமைகிறது நிரந்தர வாதத்தின் அளவினை குறைக்கும் முயற்சியில் பல்வேறு மருந்துகள் நோயாளிகளுக்கு கொடுக்கப் படுகின்றன. இதில் இயக்க ஊக்கிகளின் பயன்பாடு இதர மருந்துகளை காட்டிலும் அதிகமாக இருக்கலாம். இயக்கம் மேம்படுத்தல் மற்றும் இறப்பு விகிதம் குறைத்தல் ஆகியவற்றில் இந்த சிகிச்சையின் செயல் திறன் எவ்வாறு உள்ளது என்பதனைப் பரிசோதிக்கும் ஆய்வுகளை இந்த திறனாய்வு தேடியது. ஏறத்தாழ அனைத்து ஆராய்ச்சிகளிலும், ஏழு ஆராய்ச்சிகளிலும் , மெத்தில்ப்ரிடினிசோலன் எனும் ஒரே இயக்க ஊக்கியே (steroid) ஈடுபடுத்தப்பட்டிருந்தது. இயக்க ஊக்கிகளைக்கொண்டு அளிக்கப்படும் சிகிச்சையில் இயக்கம் மேம்படுத்தபடுகின்றது என்றும், ஆனால் இதனை காயமடைந்தயுடனேயே அதாவது எட்டு மணி நேரத்திற்குள்ளாக கொடுத்தாக வேண்டும் என்றும் ஆய்வுமுடிவுகள் காட்டுகின்றன. மேலும் இந்த சிகிச்சை இருபத்திநாலு மணி முதல் நாற்பத்திஎட்டு மணி நேரம் வரை தொடரப்படவேண்டும். இம்மருந்து வெவ்வேறு அளவு விகிதத்தில் கொடுத்து சோதித்தபோது அதிக மருந்தளவு விகிதத்தில் வழங்கப்பட்ட சிகிச்சை செயல்திறம் மிக்கதாக இருந்தது. இருப்பினும் இச்சிகிச்சை இயல்பான இயக்கத்தை நோயாளிக்கு மீண்டும் தருவதில்லை. இயக்க ஊக்கிகள் மற்றும் சாத்தியமானால் இவற்றுடன் வேறு மருந்துகளும் சேர்த்து அளித்து அதிக அளவு ஆராய்ச்சிகள் செய்யப்படவேண்டியது அவசியமாகிறது.

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பு:ந. தீபாமோகன்பாபு சி.இ.பி.என்.அர் குழு

概要

类固醇治疗急性脊髓损伤

每年,全世界大约有4000万人患有脊髓损伤病。大部分患者为年轻男性。脊柱损伤的结果往往很不乐观。患有脊柱损伤的患者会服用各种药物来试图减少永久性瘫痪的程度。在这些药物当中,类固醇可能比其他类型的药物更加常用。这篇综述检索了类固醇改善运动和减少死亡率疗效的相关研究。在几乎所有的研究中,七个研究都用到一种类固醇,即甲强龙。结果表明,用这种类固醇治疗脊柱损伤,是可以改善运动情况的。但它必须在脊髓损伤发生后不久使用,不超过8小时。并持续使用24到48小时。患者服用了不同剂量率的药物,而所谓的高剂量率是最有效的。然而,这些治疗并没有恢复患者的正常运动。类固醇与其他药物合并使用的效果,还需要更多的研究来证明。

翻译注解

译者:王聪聪(北京中医药大学循证医学中心);审校:梁宁。翻译由北京中医药大学循证医学中心组织与提供。

Background

It is estimated that acute spinal cord injury affects some 40 per million people each year (Bracken 1981), although estimates of incidence may vary considerably between countries. In all countries this is an injury affecting primarily young males, typically aged 20 to 35. (A 4:1 male to female ratio is common.) The permanent paralysis that follows leads to major disability, a shorter life expectancy and significant economic cost (Berkowitz 1992). Animal experimentation with pharmacologic therapy for acute spinal cord injury started in the late 1960s (Ducker 1969), became more common in the 1970s and led, in the USA, to the first National Acute Spinal Cord Injury Study (NASCIS 1) started in 1979 and completed in 1984 (Bracken 1984/85). As far as can be ascertained, this was the first randomized trial of any therapeutic modality for all aspects of spinal cord injury. The second National Acute Spinal Cord Injury Study followed (Bracken 1990/93). A multicenter trial from Japan (Otani 1994) and a single center trial from France (Petitjean 1998) both evaluated one of the treatment arms of NASCIS 2 which represents the first replication of a trial in this area. The third NASCIS trial has been reported (Bracken 1997/98).

Objectives

To assess the effects of steroids for acute spinal cord injury.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials.

Types of participants

Patients admitted to medical centers with a diagnosis of acute spinal cord injury. This review includes trials of patients with whiplash injury and those being treated for lumbar disc disease, because of the possibility of spinal cord injury with these conditions. Different trials impose their own eligibility restrictions: for example, excluding patients of young age, with gunshot injuries or with severe co-morbidity − particularly severe head trauma. Most acute spinal cord injury trials exclude patients with only nerve root damage or cauda equina.

Types of interventions

The review is restricted to treatment with steroids.

Types of outcome measures

Neurologic recovery of motor function at six weeks, six months and one year, mortality and incidence of infections form the primary outcome measures. Recovery of pinprick and light touch sensation or other sensory measures are not formally evaluated in this review.

Search methods for identification of studies

The search for trials was not restricted by language, date or publication status (i.e. published or unpublished).

Electronic searches

We searched the following electronic databases;

  • Cochrane Injuries Group Specialised Register (searched 02 Aug 2011);

  • Cochrane Central Register of Controlled Trials 2011, issue 3 (The Cochrane Library);

  • MEDLINE (Ovid) 1948 to July Week 3 2011;

  • EMBASE (Ovid)1974 to 2011 week 17;

  • ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to Aug 2011;

  • ISI Web of Science: Conference Proceedings Citation Index- Science (CPCI-S) 1990 to Aug 2011;

  • PubMed [www.ncbi.nlm.nih.gov/sites/entrez/] (searched 04 Aug 2011: records added to PubMed in the last 90 days).

The full search strategies can be found in Appendix 1.

Searching other resources

We checked the reference lists of all included studies and previously published relevant reviews. We contacted trial authors in the field for information on any further studies they may be aware of, whether published, unpublished or ongoing. The National Acute Spinal Cord Injury Study (NASCIS) was also consulted for relevant trials, the organization was founded in 1977 and has tracked trials in this area to the present date.

Data collection and analysis

The Injuries Group Trials Search Co-ordinator ran the searches. Search results were then transferred to the author who assessed them for eligibility and extracted data where appropriate.

The quality of trials was assessed using methodology developed by the Cochrane Neonatal Review Group. This considers whether the intervention was blinded, whether people evaluating outcome are blinded, how many patients were followed up and the quality of the randomization process. More details can be found in Sinclair 1992.

Mortality and more prevalent clinical sequelae have been reported for each trial in the present review. The different treatment arms under study, as well as variation in the definition of sequelae, preclude any analysis across different trials, except for a comparison of 180-day mortality in the two trials using very-high-dose methylprednisolone.

In the French trial (Petitjean 1998), additional information provided by the trial author has permitted calculation of bilateral neurologic improvement scores for motor function, and pinprick and touch sensation at one year. Standard deviations for the change scores were imputed using the method described in the Cochrane Handbook 3.02 (1997, pp 213-7) (Follmann 1992). Additional information has also been obtained for the Japanese trial (Otani 1994) to permit calculation of motor function improvement, data from the right side are used. Data from the NASCIS trials (Bracken 1984/85; Bracken 1990/93; Bracken 1997/98) uses neurologic improvement scores from the right side of the body, which is also adjusted for each patient's baseline neurologic function, and so is identical to the change scores reported in the original publications. In the NASCIS trials, when right-side data was unavailable (due to casts or amputation) the left-side score for that data point was substituted. The standard deviations for the subgroup analyses were derived from the total change score for the same parameter at the same follow-up period.

The weighted mean difference of neurologic improvement scores was computed with 95% confidence intervals (CIs). For mortality and morbidity, the relative risk (RR) and 95% CIs were computed. A fixed-effect model was assumed. The heterogeneity test was examined to assist in decisions whether or not to produce typical estimates of effect.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

All trials were randomized double-blind placebo or active drug controlled trials, except Otani 1994 and Petitjean 1998, which used a randomized control group of patients who did not receive methylprednisolone.

The NASCIS and Japanese trials used an improvement score reflecting neurologic status at follow-up, as changed from the same status measured in the emergency department. The French trial used the final bilateral total ASIA score which is very similar to NASCIS scoring (which has one additional segment) but did not compute a change score. The primary parameters were motor function and pinprick and light touch sensation. This review focuses on motor recovery scores. In the NASCIS 3 trial the functional independence measure (FIM) was also evaluated. Morbidity and mortality were examined in most trials. NASCIS used data from the right side of the body to evaluate neurologic outcomes in all trials and this review used right side data from Otani 1994 for comparison. The trial of whiplash injury used measures of disability, sick days and a sick-leave profile. The trial of lumbar disc disease measured relief of back and radicular pain and length of hospital stay.

A small trial by Matsumoto 2001 only assessed complications after methylprednisolone therapy and no efficacy data were produced.

Methlyprednisolone sodium succinate (MPSS) is the most widely studied therapy and formed at least one arm in all three NASCIS studies. It is the only therapy to have been replicated in more than one trial. All trials have imposed some therapeutic window between injury and starting administration of treatment. This window has been shortened to initiating therapy within eight hours in the more recent trials, as evidence has accumulated that pharmacologic therapies appear to require rapid administration if they are to be effective.

Trials are described in more detail in the 'Characteristics of included studies' table.

Risk of bias in included studies

Random sequence generation (selection bias)

Six studies generated the randomisation sequence adequately and were at low risk of bias; in two studies the method for generating the randomisation sequence was unclear because it was not described.

Allocation

Six studies had adequate concealment of the randomisation sequence and are at low risk of bias; in two studies it was unclear if the allocation was concealed.

Blinding

Five studies had adequate performance and detection blinding but three were at high risk due to being unblinded.

Incomplete outcome data

Six studies were at low risk of bias and two were unclear.

Selective reporting

Four studies had adequate reporting and four were unclear.

Other potential sources of bias

Three studies had low risk of other reporting biases and four were unclear.

Effects of interventions

Moderate versus low-dose methylprednisolone, 10-day regimen (Comparison 01)
One trial considered this therapeutic regimen (Bracken 1984/85). When the overall results for this trial are considered, there is no difference in the neurologic outcome scores at six weeks, six months or one year (Outcomes 01, 03, 05). Because of subsequent interest in the eight hour therapeutic window for commencing therapy, an ex-post-facto analysis of patients who initiated therapy within this time window is examined in this review (Outcomes 02, 04 ,06). There is a trend for patients treated with the high-dose regimen to recover more than those on the low-dose regimen at all three follow-up periods and on all three neurologic parameters. None of these changes reached the nominal P < 0.05 level of statistical significance.

All-cause mortality, wound infection, GI hemorrhage and sepsis were examined. Only wound infection was elevated in the high-dose regimen (RR = 3.50, 95% CI 1.18 to 10.41) (Outcomes 07 to 10).

High-dose methylprednisolone versus placebo or none, 24-hour regimen (Comparison 02)
Three trials are examined for this comparison (Bracken 1990/93, Otani 1994, Petitjean 1998). When the overall results are considered for motor function (Outcome 01) there is no effect of methylprednisolone. For the NASCIS 2 trial (Bracken 1990/93) an a-priori hypothesis was proposed to examine patients treated early versus late. The eight hour window was established based on it being close to the median time to treatment. The other two trials restricted patient eligibility to entry within eight hours of injury. When the analysis is restricted to patients treated within the eight hour window (Outcome 02), high-dose methylprednisolone resulted in greater motor function recovery at six weeks, six months and the final outcome (which differed among the trials as being 6 months or one year) (WMD = 4.06, 95% CI 0.58 to 7.55).

In one trial, pinprick sensation was significantly improved in all patients at six months (WMD = 3.37, 95% CI 0.74 to 6.00) but not at one year (Outcome 03). Among patients treated within eight hours these differences were enhanced at six months but were not different at one year (Outcome 04). Light touch sensation showed a similar pattern of results as pinprick (Outcomes 05 and 06).

All cause mortality (3 trials), wound infection (1 trial) and GI hemorrhage (2 trials) did not differ between the two comparison groups (Outcomes 07 to 09).

High-dose methylprednisolone for 48 versus 24 hours (Comparison 03)
One trial contributed to this analysis (Bracken 1997/98). There was a trend for greater motor function improvement in the 48-hour treated patients (Outcome 01) but at none of the follow-up periods did these differences reach statistical significance. In this trial, an a priori hypothesis proposed to examine patients initiating therapy early versus late within the overall eight hour window of eligibility. The median of three hours was selected for a cut-off point. Patients treated within three hours after injury did not differ in their recovery from 24 or 48-hour methylprednisolone (Bracken 1997/98). Patients treated within 3 to 8 hours improved more motor function if treated with 48-hour methylprednisolone (Outcome 02). No meaningful differences were observed for pinprick or touch sensation in the full analysis or in those treated at 3 to 8 hours at any of the follow-up periods (Outcomes 03 to 06).

Severe pneumonia and severe sepsis tended to be elevated in the 48-hour treated patients but overall mortality at one year was not (Outcomes 07 to 09).

High-dose methylprednisolone for 23 hours versus nimodipine for seven days (Comparison 04)
One trial contributed to this analysis (Petitjean 1998). No meaningful observations could be made from these comparisons because of very high variability in the data (Outcomes 01 to 03).

Other trials
In the whiplash trial (Pettersson 1998), the identical regimen of methylprednisolone to that administered in NASCIS 2 was found to result in fewer disabling symptoms (P = 0.047), fewer sick days (P = 0.01) and a healthier sick leave profile (P = 0.003) at six months post injury.

For patients treated with methylprednisolone at the time of their discectomy for lumbar disc disease, their hospital stay was significantly shorter than patients not so treated (1.4 versus 4.0 days, P = 0.0004) (Glasser 1993).

Discussion

Trials of steroid therapy for acute spinal cord injury are rare. Only eight trials were found in the literature, seven of methylprednisolone. Clearly, there is a critical need for more randomized trials to evaluate many aspects of management for this injury. The relatively low incidence of spinal cord injury may explain why trials have lagged behind many other clinical specialties but the fact that two large multi-center trials were concurrently underway in the US during the early 1990s indicates that there has been, and will continue to be, opportunities for more trials in this area.

The first NASCIS trial (Bracken 1984/85) did not find any beneficial effect of methylprednisolone given at 1g per day for 10 days. In analyses completed for this review, which stratify the patients according to those treated within 8 hours, there is some modest evidence of potential benefit in patients treated early.

The second NASCIS trial (Bracken 1990/93) found significantly increased neurologic recovery among patients treated with very-high-dose methylprednisolone within eight hours of injury. This treatment has become a standard therapy in many countries. As shown by this review, additional trials (Otani 1994; Petitjean 1998) have only slightly moderated the conclusion that this regimen offers some neurologic benefit to some patients. This treatment regimen does not appear to be related to any significant increased risk of medical complication. A third NASCIS trial (Bracken 1997/98) contrasted the NASCIS 2 treatment with methylprednisolone with an extended 48-hour regimen which was shown to further improve motor function and functional outcomes (not examined in this review), particularly if initiation of therapy could not start until three to eight hours post injury. The pharmacologic rationale for the effect of methylprednisolone and a review of the animal literature has been provided by Hall 1992.

The additional trials of Glasser 1993 and Pettersson 1998 provide some supportive evidence for a role for methylprednisolone in recovery from acute spinal cord injury, although it is likely that much of the recovery in those trials was due to nerve root function rather than spinal cord improvement per se.

A systematic review of almost 2500 patients in 51 trials of the use of high-dose methylprednisolone versus placebo or nothing by Sauerland 2000 provides further reassurance of safety. High-dose methylprednisolone was defined as any intravenous dose exceeding 15 mg/kg or 1g MPSS given as a single or repeated dose within a maximum of three days and discontinued afterwards. The trials included trauma and elective spine surgery. No evidence was found for any increased risk of gastro-intestinal bleeding (RD = 0.3%, P = 0.4), wound complication (RD = 1%, P = 0.2), pulmonary complications (for which MPSS was significantly protective RD = -3.5%, P = 0.003) or death (also moderately protective RD = -0.9%, P = 0.10). No evidence of harm was found when spine surgery alone was considered. These results are discussed more in Bracken 2001. In another study long-term follow-up of avascular necrosis after high-dose MPSS for acute spinal cord injury, diagnosed by MRI of femoral and humeral heads assessed blind to therapy, failed to find any increased risk (Wing 1998).

Only some of the analyses in this review have been adjusted for any potential imbalances in baseline factors observed at randomization, even though some imbalances were reported. However, none of the results reported in this review for any of the individual trials appear to be inconsistent with the data reported in the original trial reports.

Authors' conclusions

Implications for practice

Methylprednisolone sodium succinate has been shown to enhance sustained neurologic recovery in a phase three randomized trial, and to have been replicated in a second trial. Therapy must be started within eight hours of injury using an initial bolus of 30 mg/kg by IV for 15 minutes followed 45 minutes later by a continuous infusion of 5.4mg/kg/hour for 24 hours. Further improvement in motor function recovery has been shown to occur when the maintenance therapy is extended for 48 hours. This is particularly evident when the initial bolus dose could only be administered three to eight hours after injury.

Implications for research

Methylprednisolone treatment improves neurologic recovery but is unlikely to bring a return to normal function unless there is minimal initial deficit. More research is needed to examine whether different MPSS protocols would achieve even more recovery. It is likely that future trials will be able to examine concurrent pharmacologic therapies (sometimes called drug cocktails) or sequential therapies which operate on different aspects of the secondary injury processes ranging from early neuron protection to nerve regeneration in the chronic patient.

Acknowledgements

Thanks to Peter Smith for his help with translating the Petitjean paper and Frances Bunn for technical assistance. Thanks to Dr Petitjean for providing additional information about the French trial.

Data and analyses

Download statistical data

Comparison 1. Moderate vs low-dose MPSS, 10-day regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Motor function at six weeks, six months and one year: all patients1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Motor function at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 Motor function at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 Motor function at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Motor function at six weeks, six months and one year: <8 hours to treatment1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Motor function at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 Motor function at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2.3 Motor function at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Pinprick sensation at six weeks, six months and one year: all patients1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 Pinprick sensation at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Pinprick sensation at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 Pinprick sensation at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Pinprick sensation at six weeks, six months and one year: <8 hours to treatment1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Pinprick sensation at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Pinprick sensation at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 Pinprick sensation at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Touch sensation at six weeks, six months and one year: all patients1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Touch sensation at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 Touch sensation at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.3 Touch sensation at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Touch sensation at six weeks, six months and one year: <8 hours to treatment1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 Touch sensation at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 Touch sensation at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 Touch sensation at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 All-cause mortality, <210 days1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
8 Wound infection at six weeks1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
9 GI haemorrhage at six weeks1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
10 Sepsis at six weeks1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 Moderate vs low-dose MPSS, 10-day regimen, Outcome 1 Motor function at six weeks, six months and one year: all patients.

Analysis 1.2.

Comparison 1 Moderate vs low-dose MPSS, 10-day regimen, Outcome 2 Motor function at six weeks, six months and one year: <8 hours to treatment.

Analysis 1.3.

Comparison 1 Moderate vs low-dose MPSS, 10-day regimen, Outcome 3 Pinprick sensation at six weeks, six months and one year: all patients.

Analysis 1.4.

Comparison 1 Moderate vs low-dose MPSS, 10-day regimen, Outcome 4 Pinprick sensation at six weeks, six months and one year: <8 hours to treatment.

Analysis 1.5.

Comparison 1 Moderate vs low-dose MPSS, 10-day regimen, Outcome 5 Touch sensation at six weeks, six months and one year: all patients.

Analysis 1.6.

Comparison 1 Moderate vs low-dose MPSS, 10-day regimen, Outcome 6 Touch sensation at six weeks, six months and one year: <8 hours to treatment.

Analysis 1.7.

Comparison 1 Moderate vs low-dose MPSS, 10-day regimen, Outcome 7 All-cause mortality, <210 days.

Analysis 1.8.

Comparison 1 Moderate vs low-dose MPSS, 10-day regimen, Outcome 8 Wound infection at six weeks.

Analysis 1.9.

Comparison 1 Moderate vs low-dose MPSS, 10-day regimen, Outcome 9 GI haemorrhage at six weeks.

Analysis 1.10.

Comparison 1 Moderate vs low-dose MPSS, 10-day regimen, Outcome 10 Sepsis at six weeks.

Comparison 2. High-dose MPSS vs none, 24-hour regimen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Motor function at six weeks, six months and one year: all patients3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.1 Motor function at six weeks1306Mean Difference (IV, Fixed, 95% CI)1.23 [-1.08, 3.54]
1.2 Motor function at six months2414Mean Difference (IV, Fixed, 95% CI)0.85 [-1.79, 3.49]
1.3 Motor function at one year2335Mean Difference (IV, Fixed, 95% CI)-1.17 [-4.80, 2.47]
2 Motor function at six weeks, six months, and one year: <8 hours to treatment3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 Motor function at six weeks1136Mean Difference (IV, Fixed, 95% CI)3.47 [0.02, 6.92]
2.2 Motor function at six months2250Mean Difference (IV, Fixed, 95% CI)4.44 [0.96, 7.93]
2.3 Motor function at one year2177Mean Difference (IV, Fixed, 95% CI)4.17 [-0.27, 8.61]
2.4 Motor function at final (six-month or one-year) outcome3294Mean Difference (IV, Fixed, 95% CI)4.06 [0.58, 7.55]
3 Pinprick sensation at six weeks, six months and one year: all patients2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 Pinprick sensation at six weeks1301Mean Difference (IV, Fixed, 95% CI)1.88 [-0.23, 3.99]
3.2 Pinprick sensation at six months1295Mean Difference (IV, Fixed, 95% CI)3.37 [0.74, 6.00]
3.3 Pinprick sensation at one year2334Mean Difference (IV, Fixed, 95% CI)0.18 [-2.66, 3.02]
4 Pinprick sensation at six weeks, six months and one year: <8 hours to treatment2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
4.1 Pinprick at Six Weeks1136Mean Difference (IV, Fixed, 95% CI)3.02 [-0.14, 6.18]
4.2 Pinprick at Six Months1133Mean Difference (IV, Fixed, 95% CI)4.82 [0.91, 8.73]
4.3 Pinprick at One Year2177Mean Difference (IV, Fixed, 95% CI)2.32 [-1.73, 6.37]
5 Touch sensation at six weeks, six months and one year: All patients1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Touch Sensation at Six Weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 Touch Sensation at Six Months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.3 Touch Sensation at One Year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Touch sensation at six weeks, six months and one year: <8 hours to treatment2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
6.1 Touch Sensation at Six Weeks1136Mean Difference (IV, Fixed, 95% CI)3.79 [0.28, 7.30]
6.2 Touch Sensation at Six Months1133Mean Difference (IV, Fixed, 95% CI)4.59 [0.43, 8.75]
6.3 Touch Sensation at One Year2177Mean Difference (IV, Fixed, 95% CI)3.35 [-0.82, 7.53]
7 All-cause mortality <180 days3530Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.24, 1.25]
8 Wound infection at 6 weeks1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
9 GI haemorrhage at 6 weeks2379Risk Ratio (M-H, Fixed, 95% CI)2.18 [0.80, 5.93]
Analysis 2.1.

Comparison 2 High-dose MPSS vs none, 24-hour regimen, Outcome 1 Motor function at six weeks, six months and one year: all patients.

Analysis 2.2.

Comparison 2 High-dose MPSS vs none, 24-hour regimen, Outcome 2 Motor function at six weeks, six months, and one year: <8 hours to treatment.

Analysis 2.3.

Comparison 2 High-dose MPSS vs none, 24-hour regimen, Outcome 3 Pinprick sensation at six weeks, six months and one year: all patients.

Analysis 2.4.

Comparison 2 High-dose MPSS vs none, 24-hour regimen, Outcome 4 Pinprick sensation at six weeks, six months and one year: <8 hours to treatment.

Analysis 2.5.

Comparison 2 High-dose MPSS vs none, 24-hour regimen, Outcome 5 Touch sensation at six weeks, six months and one year: All patients.

Analysis 2.6.

Comparison 2 High-dose MPSS vs none, 24-hour regimen, Outcome 6 Touch sensation at six weeks, six months and one year: <8 hours to treatment.

Analysis 2.7.

Comparison 2 High-dose MPSS vs none, 24-hour regimen, Outcome 7 All-cause mortality <180 days.

Analysis 2.8.

Comparison 2 High-dose MPSS vs none, 24-hour regimen, Outcome 8 Wound infection at 6 weeks.

Analysis 2.9.

Comparison 2 High-dose MPSS vs none, 24-hour regimen, Outcome 9 GI haemorrhage at 6 weeks.

Comparison 3. High-dose MPSS for 48 hours vs 24 hours
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Motor function at six weeks, six months and one year: all patients1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Motor function at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 Motor function at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 Motor function at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Motor function at six weeks, six months and one year: 3-8 hours to treatment1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Motor function at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 Motor function at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2.3 Motor function at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Pinprick sensation at six weeks, six months and one year: all patients1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3.1 Pinprick sensation at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Pinprick sensation at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 Pinprick sensation at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Pinprick sensation at six weeks, six months and one year: 3-8 hours to treatment1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4.1 Pinprick sensation at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Pinprick sensation at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 Pinprick sensation at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Touch sensation at six weeks, six months and one year: all patients1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Touch sensation at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 Touch sensation at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.3 Touch sensation at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Touch sensation at six weeks, six months and one year: 3-8 hours to treatment1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6.1 Touch sensation at six weeks1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 Touch sensation at six months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 Touch sensation at one year1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
7 Severe pneumonia at 6 weeks1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
8 Severe sepsis at 6 weeks1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
9 Mortality at 1 year1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 3.1.

Comparison 3 High-dose MPSS for 48 hours vs 24 hours, Outcome 1 Motor function at six weeks, six months and one year: all patients.

Analysis 3.2.

Comparison 3 High-dose MPSS for 48 hours vs 24 hours, Outcome 2 Motor function at six weeks, six months and one year: 3-8 hours to treatment.

Analysis 3.3.

Comparison 3 High-dose MPSS for 48 hours vs 24 hours, Outcome 3 Pinprick sensation at six weeks, six months and one year: all patients.

Analysis 3.4.

Comparison 3 High-dose MPSS for 48 hours vs 24 hours, Outcome 4 Pinprick sensation at six weeks, six months and one year: 3-8 hours to treatment.

Analysis 3.5.

Comparison 3 High-dose MPSS for 48 hours vs 24 hours, Outcome 5 Touch sensation at six weeks, six months and one year: all patients.

Analysis 3.6.

Comparison 3 High-dose MPSS for 48 hours vs 24 hours, Outcome 6 Touch sensation at six weeks, six months and one year: 3-8 hours to treatment.

Analysis 3.7.

Comparison 3 High-dose MPSS for 48 hours vs 24 hours, Outcome 7 Severe pneumonia at 6 weeks.

Analysis 3.8.

Comparison 3 High-dose MPSS for 48 hours vs 24 hours, Outcome 8 Severe sepsis at 6 weeks.

Analysis 3.9.

Comparison 3 High-dose MPSS for 48 hours vs 24 hours, Outcome 9 Mortality at 1 year.

Comparison 4. Methylprednisolone for 23 hours and nimodipine for 7 days
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 One-year motor function improvement score1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2 One-year pinprick sensation improvement score1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3 One-year touch sensation improvement score1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
Analysis 4.1.

Comparison 4 Methylprednisolone for 23 hours and nimodipine for 7 days, Outcome 1 One-year motor function improvement score.

Analysis 4.2.

Comparison 4 Methylprednisolone for 23 hours and nimodipine for 7 days, Outcome 2 One-year pinprick sensation improvement score.

Analysis 4.3.

Comparison 4 Methylprednisolone for 23 hours and nimodipine for 7 days, Outcome 3 One-year touch sensation improvement score.

Appendices

Appendix 1. Search strategy

Cochrane Injuries Group Specialised Register (searched 02 August 2011)
#1 (“spinal cord” or spinal-cord* or spine or spinal) and (Broken or break* or fractur* or wound* or trauma* or injur* or damag* or lesion* or contusion* or laceration* or trauma or ischemi*))
#2 paraplegi* or paraparesis or qadriplegi* or quadriparesi* or tetraplegi* or tetraplagi* or tetraparesis
#3 central cord injury syndrome
#4 (myelopathy and (traumatic or post-traumatic))
#5 (steroid* or glucocorticoid* or prednisolone* or betamethasone* or cortisone* or dexamethasone* or hydrocortisone* or methylprednisolone* or prednisone* or triamcinolone* or corticosteroid*)
#6 #1 and #2

Cochrane Central Register of Controlled Trials 2011, issue 3 (The Cochrane Library)
#1 paraplegi* or paraparesis
#2 qadriplegi* or quadriparesi*
#3 tetraplegi* or tetraplagi* or tetraparesis
#4 (spine or spinal) near3 (Broken or break* or fracture* or wound* or trauma* or injur* or damag*)
#5 (spinal cord) near3 (contusion or laceration or trauma or injur* or ischemi*)
#6 (central cord injury syndrome)
#7 (myelopathy near3 (traumatic or post-traumatic))
#8 MeSH descriptor Central Cord Syndrome explode all trees
#9 MeSH descriptor Spinal Cord Ischemia explode all trees
#10 MeSH descriptor Spinal Fractures explode all trees
#11 MeSH descriptor Spinal Cord Injuries explode all trees
#12 MeSH descriptor Paraplegia explode all trees
#13 MeSH descriptor Quadriplegia explode all trees
#14 MeSH descriptor Spinal Cord explode all trees with qualifiers: SU,TH
#15 MeSH descriptor Cervical Vertebrae explode all trees with qualifier: IN
#16 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15)
#17 MeSH descriptor Glucocorticoids explode all trees
#18 MeSH descriptor Steroids explode all trees
#19 steroid* or glucocorticoid* or prednisolone* or betamethasone* or cortisone* or dexamethasone* or hydrocortisone* or methylprednisolone* or prednisone* or triamcinolone* or corticosteroid*
#20 (#17 OR #18 OR #19)
#21 (#16 AND #20)

MEDLINE (Ovid SP) 1948 to July Week 3 2011
1. exp Spinal Cord/su, th [Surgery, Therapy]
2. exp Spinal Cord Injuries/
3. exp Spinal Cord Ischemia/
4. exp Central Cord Syndrome/
5. (myelopathy adj3 (traumatic or post-traumatic)).ab,ti.
6. ((spine or spinal) adj3 (fracture* or wound* or trauma* or injur* or damag*)).ab,ti.
7. (spinal cord adj3 (contusion or laceration or transaction or trauma or ischemia)).ab,ti.
8. central cord injury syndrome.ab,ti.
9. central spinal cord syndrome.ab,ti.
10. exp Cervical Vertebrae/in [Injuries]
11. SCI.ab,ti.
12. exp Paraplegia/
13. exp Quadriplegia/
14. (paraplegi* or quadriplegi* or tetraplegi*).ab,ti.
15. or/1-14
16. exp Glucocorticoids/
17. exp Steroids/
18. (steroid* or glucocorticoid* or prednisolone* or betamethasone* or cortisone* or dexamethasone* or hydrocortisone* or methylprednisolone* or prednisone* or triamcinolone* or corticosteroid*).ab,ti.
19. 16 or 17 or 18
20. 15 and 19
21. randomi?ed.ab,ti.
22. randomized controlled trial.pt.
23. controlled clinical trial.pt.
24. placebo.ab.
25. clinical trials as topic.sh.
26. randomly.ab.
27. trial.ti.
28. 21 or 22 or 23 or 24 or 25 or 26 or 27
29. (animals not (humans and animals)).sh.
30. 28 not 29
31. 20 and 30

EMBASE 1974 to 2011 August (week 17)
1.exp Spinal Cord/su, th [Surgery, Therapy]
2.exp Spinal Cord Injury/
3.exp Spinal Cord Ischemia/
4.exp Central Cord Syndrome/
5.(myelopathy adj3 (traumatic or post-traumatic)).ab,ti.
6.((spine or spinal) adj3 (fracture* or wound* or trauma* or injur* or damag*)).ab,ti.
7.(spinal cord adj3 (contusion or laceration or transaction or trauma or ischemia)).ab,ti.
8.central cord injury syndrome.ab,ti.
9.central spinal cord syndrome.ab,ti.
10.exp Paraplegia/
11.exp Quadriplegia/
12.(paraplegi* or quadriplegi* or tertraplegi*).ab,ti.
13.SCI.ab,ti.
14.or/1-13
15.exp Glucocorticoid/
16.exp Steroid/
17.(steroid* or glucocorticoid* or prednisolone* or betamethasone* or cortisone* or dexamethasone* or hydrocortisone* or methylprednisolone* or prednisone* or triamcinolone* or corticosteroid*).ab,ti.
18.or/15-17
19.14 and 18
20.exp Randomized Controlled Trial/
21.exp controlled clinical trial/
22.randomi?ed.ab,ti.
23.placebo.ab.
24.*Clinical Trial/
25.randomly.ab.
26.trial.ti.
27.20 or 21 or 22 or 23 or 24 or 25 or 26
28.exp animal/ not (exp human/ and exp animal/)
29.27 not 28
30.19 and 29

ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to Aug 2011
ISI Web of Science: Conference Proceedings Citation Index- Science (CPCI-S) 1990 to Aug 2011
#1 Topic=((“spinal cord” or spinal-cord* or spine or spinal) NEAR (Broken or break* or fractur* or wound* or trauma* or injur* or damag* or lesion* or contusion* or laceration* or trauma or ischemi*)) OR Topic=(paraplegi* or paraparesis or qadriplegi* or quadriparesi* or tetraplegi* or tetraplagi* or tetraparesis) OR Topic=("central cord injury syndrome") OR Topic=((spine or spinal) NEAR (myelopathy NEAR (traumatic or post-traumatic)))
#2 Topic=((steroid* or glucocorticoid* or prednisolone* or betamethasone* or cortisone* or dexamethasone* or hydrocortisone* or methylprednisolone* or prednisone* or triamcinolone* or corticosteroid*))
#3 Topic=((clinical OR control* OR placebo OR random*) NEAR (trial* or group* or study or studies or placebo or controlled)) NOT Topic=(ANIMAL*)
#4 #1 AND #2 AND #3

PubMed [www.ncbi.nlm.nih.gov/sites/entrez/] (searched 04 August 2011: limit: added to PubMed in the last 90 days)
#1 (“spinal cord” or spinal-cord* or spine or spinal) and (Broken or break* or fractur* or wound* or trauma* or injur* or damag* or lesion* or contusion* or laceration* or trauma or ischemi*))
#2 paraplegi* or paraparesis or qadriplegi* or quadriparesi* or tetraplegi* or tetraplagi* or tetraparesis
#3 central cord injury syndrome
#4 (spine or spinal) and (myelopathy and (traumatic or post-traumatic))
#5 #1 or #2 or #3 or #4
#6 (steroid* or glucocorticoid* or prednisolone* or betamethasone* or cortisone* or dexamethasone* or hydrocortisone* or methylprednisolone* or prednisone* or triamcinolone* or corticosteroid*)
#7 #5 and #6
#8 ((randomized controlled trial[pt] OR controlled clinical trial[pt]) OR (randomized OR randomised OR randomly OR placebo[tiab]) OR (trial[ti]) OR ("Clinical Trials as Topic"[MeSH Major Topic])) NOT (("Animals"[Mesh]) NOT ("Humans"[Mesh] AND "Animals"[Mesh]))
#9 #7 and #8

Feedback

Steroids for acute spinal cord injury

Summary

Please note that this comment, and the subsequent reply from the reviewer, was originally about the first version of this review (Pharmacology in acute spinal cord injury). The review has subsequently been revised to the present version (Steroids for acute spinal cord injury).

Summary of comments and criticisms.

The author of the criticism refers to the papers by Coleman et al 2000, and Hurlbert RJ which disagree with the conclusions of this review. He would like the following points addressed (each comment has a number with a corresponding response from the reviewers in the reply section below):

1. "NASCIS II" implied that there was a positive result in the primary efficacy analysis for the entire 487 patient sample. However, this analysis was in fact negative. A positive result was only found in a secondary analysis of a small subgroup (62 + 67 patients) splitting the sample before and after 8 hours.

2. The placebo group treated before 8 hours did poorly, not only when compared with the methylprednisolone group treated before 8 hours, but even when compared with the placebo group treated after 8 hours. Thus the positive result may have been caused by a weakness in the control group rather than any strength of methylprednisolone.

3. Most of the combined improvement from all patients in the subgroup (62 + 67 patients) was due to differences in the changes in the patients with incomplete lesions. This comparison involved only 22 patients in the methylprednisolone group and 24 patients in the placebo group.

4. The NASCIS II and III reports embody specific choices of statistical methods that have strongly shaped the reporting of results but have not been adequately challenged or even explained.

5. In NASCIS III, a randomization imbalance occurred that allocated a disproportionate number of patients with no motor deficit (and therefore no chance for recovery) to the lower dose control group. When this imbalance is controlled for, much of the superiority of the higher dose group seems to disappear.

6. Perhaps one half of the NASCIS III sample may have had at most a minor deficit. Thus, we do not know whether the results of these studies reflect the severely injured population to which they have been applied.

7. The numbers, tables, and figures in the published reports are scant and are inconsistently defined, making it impossible even for professional statisticians to duplicate the analyses, to guess the effect of changes in assumptions, or to supply the missing parts of the picture.

8. Nonetheless, even 9 years after NASCIS II, the primary data have not been made public.

9. The reporting of the NASCIS studies has fallen short of the guidelines of the ICH/FDA, and of the Evidence-based Medicine Group.

10. Despite the lucrative "off label" markets for methylprednisolone in Spinal Cord Injury, no Food and Drug Association indication has been obtained, and there has been no public process of validation.

11. These shortcomings have denied physicians the chance to use confidently a drug that many were enthusiastic about and have left them in an intolerably ambiguous position in their therapeutic choices, in their legal exposure, and in their ability to perform further research to help their patients.

12. Animal studies of the effect of Methylprednisolone and the human studies are different, and little work has been done to relate them explicitly. It is simply not true that the NASCIS studies either strongly confirm or are strongly confirmed by the animal studies.

In conclusion the use of methylprednisolone administration in the treatment of acute SCI is not proven as a standard of care, nor can it be considered a recommended treatment. Evidence of the drug's efficacy and impact is weak and may only represent random events. In the strictest sense, 24-hour administration of methylprednisolone must still be considered experimental for use in clinical SCI. Forty-eight-hour therapy is not recommended. These conclusions are important to consider in the design of future trials and in the medico-legal arena.

References:
Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med. 1990 May 17;322(20):1405-11.

Bracken MB, Shepard MJ, Holford TR, et al Administration of Methylprednisolone for 24 or 48 hours or Tirilazad Mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the third national acute spinal cord injury randomized controlled trial. JAMA 1997;277:1597-1604.

Coleman WP, Benzel D, Cahill DW, Ducker T, Geisler F, Green B et al. A critical appraisal of the reporting of the National Acute Spinal Cord Injury Studies (II and III) of methylprednisolone in acute spinal cord injury. J Spinal Disord. 2000 Jun;13(3):185-99.

Hurlbert RJ. Methylprednisolone for acute spinal cord injury: an inappropriate standard of care. J Neurosurg 2000 Jul;93(1 Suppl):1-7.

Reply

Detailed responses to the comments reflected in the Criticism have been published elsewhere (1,2) and should be consulted by the interested reader.

1. The primary NASCIS 2 report (3) clearly stated that no benefit of methylprednisolone (MP) was observed in the total study group. In the a priori analysis of patients treated relatively quickly after injury (within 8 hours which was the modal time from injury to initiating therapy, and the only dichotomy analysed) patients treated with MP recovered significantly better than placebo treated patients. Examination of drug effect as a function of time to injury was a major hypothesis in the design of both NASCIS 2 and 3.

2. The comparison of placebo treated patients before versus after eight hours is not a randomized comparison and there is no reason to expect that these patients would be similar. The time taken to initiate therapy was largely a function of how quickly patients were admitted to hospital and there are many reasons why this may vary by severity of injury. The only valid comparisons for analysis are the ones reported, ie. comparisons of treatment (which was randomized) within the early and late time periods.

3. Statistically significant improvement in MP treated patients was observed and reported in both neurologically complete and incomplete patients as assessed in the emergency department.

4. The statistical procedure used to analyze NASCIS 2 and 3 was primarily analysis of covariance which is a standard form of analysis for randomized controlled trials. This methodology is described in any standard text.

5. In NASCIS 3 an imbalance at randomization was reported (4, table 2) which allocated somewhat more severely injured patients to Tiralazad mesylate. There was also a non-significant baseline difference in the two MP groups. Baseline neurological function was controlled in all statistical analyses and, as expected, the multivariate analysis of the two MP groups showed reduced improvement differences when the baseline differences were taken into account. These "controlled" analyses form the primary published results.

6. The NASCIS 3 report (4) shows severity of injury of all patients in the trial. Overall, for motor function 35.2% were quadriplegic; 31.0% paraplegic; 13.4% quadriparetic; 4.0% paraparetic and 14.4% normal although all normal motor responses had some sensory loss. After accounting for trial exclusion criteria (gunshot wounds, etc), the study population reflects the pattern of spinal injury seen in hospital emergency departments. Both NASCIS 2 and 3 showed efficacy of MP in severely injured patients, defined as having complete neurological loss below the level of injury.

7. Professional biostatisticians are among the NASCIS investigators and authors, were part of the review process at NEJM and JAMA, and sat on NIH panels overseeing the trials. Standard statistical procedures were used (item 4) and the neurological and functional definitions used are standard criteria promulgated by the American Spinal Injury Association, endorsed by the International Medical Society of Paraplegia, and widely adopted for clinical and research purposes around the world.

8. NASCIS data sets are available to recognized authoritative agencies and groups who submit a proposal describing their intended use of the data and demonstrate that they have the technical, biostatistical and clinical expertise to understand and analyse these complex data sets in an unbiased manner. Since NASCIS investigators continue to be funded by NIH for analyses of NASCIS 2 and 3, there is concern that analyses not be done which pre-empt publication of the same analyses by the initial investigators.

9. The ICH/FDA guidelines were published in 1996 but they enshrined principles and practices that have been evolving for many years. The NASCIS reports, even early ones, clearly meet both the spirit and intent of the recommendations.

10. The NASCIS studies are funded by the United States National Institute of Neurological Disease and Stroke. However, responsibility for seeking an indication for use in spinal injury from national drug regulatory agencies rests with the pharmaceutical company manufacturing the compound, Pharmacia-Upjohn Inc. NASCIS data is available for purposes of seeking regulatory approval of MP in any country. To the best of our knowledge, FDA approval has not been sought but an indication has been sought and obtained in a large number of other countries.

11. Physicians in many countries confidently use MP for spinal cord injury and have done so since 1990. The NASCIS 2 data supporting use has not changed since 1990. Nothing from the NASCIS studies prevents further research in spinal cord injury just as therapeutic discoveries in other areas of medicine do not stop research either. If MP has no benefit, comparing therapies to it should not pose a problem in demonstrating a new drug's superiority. If MP does confer benefit, comparison with it is necessary.

12. Animal studies serve two roles in developing scientific evidence. They prompt testing of therapies in humans after successful trial in animals and they provide biologic plausibility to the human evidence once it has been gathered. The weight of evidence from cat and other models using MP, which led to the initial trials, is strongly supportive of the role of MP (5). New experimental studies of MP in enhancing neuro-regeneration and playing other beneficial roles at the molecular level (6-8) provide further additional evidence of plausibility to support the human trials. This is an extraordinarily difficult but critically important area of human research and it is cause for concern that more trials of MP and other therapies are not being conducted. Currently, primary evidence of efficacy and safety from three trials, and secondary evidence from trials of related clinical conditions and animal studies, as reported in this Cochrane Review, support use of MP in the management of spinal cord injury. There is no other pharmacologic therapy with sufficient evidence to support use at this time.

References

1. Bracken MB, Aldrich EF, Herr DL et al. Clinical measurement, statistical analysis and risk benefit: controversies from trials of spinal injury. J Trauma 2000; 48:558-61.

2. Bracken MB. Methylprednisolone and spinal cord injury. J Neurosurg Spine 2000; 93:175-8.

3. Bracken MB, Shepard MJ, Collins WF et al. A randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury: results of the second national acute spinal cord injury study. New Engl J Med 1990; 322:1405-11.

4. Bracken MB, Shepard MJ, Holford TR et al. Methylprednisolone administered for 24 or 48 hours, or 48 hour tirilazad mesylate, in the treatment of acute spinal cord injury; results of the third national acute spinal cord injury randomized controlled trial. JAMA 1997; 277:1597-1604.

5. Hall ED. The neuroprotective pharmacology of methylprednisolone. J Neurosurg 1992; 76:13-22.

6. Oudega M, Vargas CA, Weber AB et al. Long-term effects of methylprednisolone following transection of adult rat spinal cord. Eur J Neurosci 1999; 11:2453-64.

7. Banik NL, Matzelle D, Terry E et al. A new mechanism of methylprednisolone and other corticoids action demonstrated in vitro: inhibition of a proteinase (calpain) prevents myelin and cytoskeletal protein degradation. Brain Res 1997; 748:205-10.

8. Xu J, Fan G, Chen S et al. Methylprednisolone inhibition of TNF-alpha expression and NF-KB activation after spinal cord injury.

Contributors

Author of comment: Peter Mikkelsen
Author of response: Michael Bracken

What's new

DateEventDescription
30 August 2012Review declared as stableThere are no ongoing RCTs in humans, and no new studies have been included in the review since 2004. The search will be updated in 2015.

History

Protocol first published: Issue 1, 1998
Review first published: Issue 1, 1998

DateEventDescription
7 December 2011New citation required but conclusions have not changed

The search was updated on 2nd August 2011.

531 (after de-duplication) articles were retrieved. Studies were selected for further examination by screening titles and (in about half of the citations) the abstract.

There were no new studies meeting the review's inclusion criteria.

The results and conclusions of the review are unchanged.

6 December 2011New search has been performedThe search for studies has been updated to 2 August 2011.
11 September 2008AmendedConverted to new review format.
1 September 2007New search has been performedSearches were last updated in September 2007.

An updated search on MEDLINE and CENTRAL was conducted in October 2004. No new studies for inclusion were found. One further excluded study (Yokota 1995) was identified.

Contributions of authors

The sole author is responsible for the review.

Declarations of interest

Professor Bracken was an occasional consultant to Pharmacia & Upjohn Inc and is an author on several of the papers included in this review.

Sources of support

Internal sources

  • Yale University School of Medicine Department of Epidemiology and Public Health, USA.

External sources

  • National Institute Neurological Diseases and Stroke, NIH, USA.

Notes

There are no ongoing RCTs in humans, and no new studies have been included in the review since 2004. The search will be updated in 2015.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bracken 1984/85

MethodsMulti-center (n=9) double-blind randomized trial. After ascertaining eligibility a 24-hour telephone number called to learn which uniquely numbered drug packet (already delivered to the hospital) should be used. Each hospital given block of 6 (3 patients in each treatment arm). Double dummy technique used to mask study drugs.
ParticipantsIn all, 330 patients randomized within 48h of injury (165 to each treatment), 24 patients excluded from analysis for specified reasons (table 2). In this review morbidity and mortality use all randomized patients in denominator but conclusions remain unchanged. This review delineates those patients treated within 8h of injury.
Interventions

Treatment arm 1: (n=165) Immediately after randomization a loading dose of 100 mg MPPS and 25 mg every six hours thereafter for 10 days.

Treatment arm 2: (n=165) As above but 1000 mg LD and 250 mg thereafter. LD administered over 10 minutes.
Maintenance doses administered using fluid administration set, either directly or through IV.

Outcomes

Neurological examinations and clinical status examined six weeks, six months and one year after injury. Neuroexam included motor function and pinprick and light touch sensation, all measured categorically and as continuous scales. All outcomes assessed blind.

Clinical outcomes included: urinary tract infection, pneumonia, decubitus, gastrointestinal hemorrhage, wound infection, sepsis, arrythmia, thrombophlebitis, pulmonary embolus, paralytic ileus, congestive heart failure, myocardial infarction, angina pectoris and death < 14 days, 15-28 days and at 1 year.

NotesHistorical note: This may be the first randomized controlled trial of any treatment modality for acute spinal cord injury. This trial is often referred to as NASCIS 1 (The first National Acute Spinal Cord Injury Study).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Methods
Allocation concealment (selection bias)Low riskSee Methods
Blinding of participants and personnel (performance bias)
All outcomes
Low riskpatients, caregivers and statistical analysts blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskPatients, caregivers blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk92% follow-up at 6 weeks and 65% at 6 months, 100% survival analysis
Selective reporting (reporting bias)Low riskOutcomes prespecified in protocol
Other biasLow riskSubgroups prespecified in protocol

Bracken 1990/93

MethodsMulti-center (n=10) double-blind randomized trial. Three treatment arms in blocks of 9 (3 each arm) per center. Randomized by central telephone. Double-dummy technique used to mask study drugs which were given by separate IV sites using flow rates and concentrations according to each patient's body mass.
ParticipantsEligible patients had a diagnosed spinal cord injury, gave consent, were randomized within 12 hours of injury, 13 years or older, and met other specified clinical and study criteria. In all 487 patients randomized to three arms and analysis followed intention-to-treat principle.
InterventionsTreatment arm 1: (n=162) Methylprednisolone bolus of 30 mg/kg body weight followed by 5.4 mg/kg per hour for 23 hours.
Treatment arm 2: (n=154) Naloxone bolus of 5.4 mg/kg of body weight followed by 4.0 mg/kg per hour for 23 hours.
Treatment arm 3: (n=171) Placebo given by bolus and infusion using double-dummy technique.
OutcomesNeurological function examined six weeks, six months and one year after injury using categorical and continuous scales to assess motor function, pin and light touch sensation.
Morbidity evaluated at same times and included all outcomes studied in earlier (1984) NASCIS trial. Mortality assessed to 1 year after injury. All outcomes assessed blind.
NotesThis trial is often referred to as NASCIS 2 (The second National Acute Spinal Cord Injury Study).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Methods
Allocation concealment (selection bias)Low riskSee Methods
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPatients, caregivers and statistical analysts blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskPatients and caregivers blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk98% follow-up at 6 weeks and 96% at 6 months, 100% survival analysis
Selective reporting (reporting bias)Low riskOutcomes prespecified in protocol
Other biasLow riskSubgroups prespecified in protocol

Bracken 1997/98

MethodsMulti-center (n=16) double-blind randomized trial. After ascertaining eligibility a 24-hour telephone number called to randomize. Three treatment arms in blocks of 9 (3 each arm per center). Double-dummy techniques used to mask study drug which were given by IV using infusion rates and dose schedules according to each patient's body mass.
ParticipantsEligible patients had diagnosed spinal cord injury, gave consent, were randomized within 6 hours of injury to begin treatment within 8 hours, were 13 years or older, and met other specified clinical and study criteria. In all 499 patients were randomized (485 planned) to three arms and analysis used intent-to-treat and compliers (N=461) groups.
InterventionsAll patients received an IV bolus of methylprednisolone (30 mg/kg) before randomization. Patients in 24h regimen (N=166) received methylprednisolone infusion of 5.4 mg/kg/h for 24h, those in the 48h methylprednisolone group (n=167) received an infusion of 5.4 mg/kg/h for 48h, and those in a third group (n=166) received a 2.5 mg/kg bolus infusion of tirilazad mesylate every 6h for 48h.
OutcomesMotor function change between initial presentation and at 6 weeks and 6 months after injury, and functional independence measure (FIM) assessed at 6 weeks and six months and one year. Morbidity evaluated at six weeks and six months and included all outcomes assessed in earlier (1984 and 1990) NASCIS trials. Mortality assessed at six months and at one year post injury. All outcomes assessed blind.
NotesThis trial is often referred to as NASCIS 3 (the third National Acute Spinal Cord Injury Study). Methylprednisolone is the sodium succinate preparation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Methods
Allocation concealment (selection bias)Low riskSee Methods
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPatients, caregivers and statistical analysts blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskPatients and caregivers blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk97% follow-up at 6 weeks and 94% at 6 months, 100% survival analysis
Selective reporting (reporting bias)Low riskOutcomes prespecified in protocol
Other biasLow riskSubgroups prespecified in protocol

Glasser 1993

MethodsRandomized single (patient) blind trial. Method of randomization not specified.
ParticipantsPatients undergoing lumbar discetomy presenting with radicular symptoms and radiographically confirmed herniated nucleus pulposus.
Interventions1) 160 mg IM Depo-Medrol and 250 mg MPPS at start of procedure. Macerated fat graft soaked in 80 mg Depo-Medrol placed over affected nerve root after discetomy. 30 ml 0.25% bupivacaine infiltrated to paraspinal muscles during closure (N=12).
2) Bupivacaine procedure only (N=10).
3) No corticoids or bupivacaine (N=10).
OutcomesLength of hospital stay; postpartum narcotic analgesia; back and radicular pain on post-op day 1.
NotesDepo-Medrol is methylprednisolone acetate.
MPPS is methylprednisolone sodium succinate.
This study may largely be assessing nerve roots rather than acute spinal cord injuty.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization methods not stated
Allocation concealment (selection bias)Unclear riskRandomization methods not stated
Blinding of participants and personnel (performance bias)
All outcomes
High riskThe study was not blinded
Blinding of outcome assessment (detection bias)
All outcomes
High riskThe study was not blinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk72% of patients were followed-up
Selective reporting (reporting bias)Unclear riskProtocol not seen
Other biasUnclear riskNone observed

Matsumoto 2001

MethodsSingle center randomized double blind trial. Method of randomization not specified.
ParticipantsIn all 46 patients with cervical spine injury. Exclusions were only nerve root injuries, cauda equina and gunshot victims.
InterventionsTreatment arm 1: (n=23) MPSS given according to NASCIS 2 protocol.
Treatment arm 2: (n=23) placebo (no details of placebo provided).
OutcomesEfficacy not studied. Complications assessed 8 weeks after injury.
NotesSome evidence for MPSS group to be more severely injured.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization methods not stated
Allocation concealment (selection bias)Unclear riskRandomization methods not stated
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPatients, caregivers and statistical analysts blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskPatients and caregivers blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk100% follow-up
Selective reporting (reporting bias)Unclear riskOnly selected data on complications reported
Other biasUnclear riskNone observed

Otani 1994

MethodsPatients allocated "by envelope method" and so assumed to be randomized. Blinding is not assumed since no placebo group.
ParticipantsMulticenter trial in Japan including 15 neurosurgery, 27 orthopedic and 11 emergency centers. Inclusion criteria: diagnosis of loss of motor or sensory function from spinal cord injury; could receive treatment within 8 hours of injury; 16-25 years of age; obtained informed consent; available for 6 month follow-up.
Excluded: root involvement or cauda equina only; serious co-morbidity; corticosteroid use > 100 mg MPSS or equivalent before randomization; other prespecified clinical criteria. In all 158 patients randomized (82 MPSS, 76 control) of which 81 and 70, and 70 and 47 entered the safety and efficacy analyses respectively.
Reasons for drop-out are tabulated. It appears as if largest exclusions were for control patients. Baseline differentials suggest this occurred most frequently in severely injured controls.
Interventions1. Treated group: MPSS as bolus of 30 mg/kg for 15 mins by infusion, 45 mins pause then 23 hr maintenance infusion by 5.4 mg/kg. (NB this is an exact replication of the NASCIS 2 MPSS protocol, see Bracken et al 1990). No other corticosteroid therapy.
2. Control group: standard treatment without any corticosteroid therapy. No placebo given.
NB surgery appears to have been given as necessary but this is not entirely clear from text.
OutcomesNeurological follow-up was at 24 and 48 hrs, one and six weeks, three and six months.
Motor function, pin and light touch sensation were assessed using NASCIS 2 criteria and Frankel's classification (at 6 months).
Urinary function and sphincter control were evaluated. A global improvement assessment was also used. A large number of laboratory values and vital signs were measured.
NotesA translation of this paper from the original Japanese has been provided by Pharmacia Upjohn Inc. Copies of the English translation are available from the editor of this review.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Methods
Allocation concealment (selection bias)Low riskSee Methods
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding in this study - control is conventional therapy
Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding in this study - done by attending doctor
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk74% follow-up at final six month outcome assessment
Selective reporting (reporting bias)Low riskPublished reports concur with protocol expectations (reviewer has copy of protocol)
Other biasUnclear riskUpjohn directly funded the study

Petitjean 1998

MethodsSingle center trial. Randomization methods: two numbers given each treatment and followed "table de permutation au hasard" and balanced every eight patients. Administration of intervention not masked.
ParticipantsEligible patients had a diagnosed spinal cord injury, gave consent, were hospitalized within 8h of injury, were aged 16 to 64, and met other clinical criteria.
Interventions1) Methylprednisolone bolus of 30mg/kg over 1h followed by 5.4mg/kg/h for 23h (N=27).
2) Nimodipine 0.015mg/kg/h over 2h followed by 0.03mg/kg/h for 7days if MABP > 60mgHg (N=27).
3) Both of the above treatments given concurrently (N=27).
4) No pharmacologic treatment (N=25).
OutcomesNeurological examination using ASIA criteria at admission and 1year after injury. Outcome assessed blind.
NotesA translation of this paper from the original French is available from the Cochrane Injuries review Group.
ASIA and NASCIS neurological examinations are identical except for one additional segment measured in NASCIS. Additional information obtained from author but N's slightly larger in published report.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomization methods not stated but blocked at 8
Allocation concealment (selection bias)Unclear riskRandomization methods not stated
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding in this study
Blinding of outcome assessment (detection bias)
All outcomes
High riskNo blinding in this study
Incomplete outcome data (attrition bias)
All outcomes
Low risk94% follow-up at 1 year final outcome assessment
Selective reporting (reporting bias)Unclear riskProtocol not seen
Other biasUnclear riskProtocol not seen

Pettersson 1998

MethodsRandomized double blind trial. Method of randomization not specified.
ParticipantsMen and women with whiplash injury Grade 2 and 3 by Quebec criteria and enrolled within 8 hours of injury.
Interventions(1) Methylprednisolone bolus of 30 mg/kg for 15 min, wait 45 min, then 5.4 mg/kg/h for 23h (N=20).
(2) Placebo (N=20).
OutcomesRepeated neurological examinations, VAS-scales and pain sketch form at baseline, 2 and 6 weeks and 6 months after injury. Number of sick days. Outcomes assessed blind.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomized by pharmacist
Allocation concealment (selection bias)Low riskRandomized by pharmacist
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPatients and caregivers blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskPatients and caregivers blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk100% follow-up at final 6 month assessment
Selective reporting (reporting bias)Unclear riskProtocol not seen
Other biasUnclear riskProtocol not seen

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Kiwerski 1992Patients not randomized to treatment.
Pointillart 2000Duplicate publication of Petitjean 1998. Translated into English, very minor changes to table 3 (numbers instead of per cent), and no reference in this paper to original French version. Change in first authorship.
Yokota 1995Patients not randomized to treatment. An English translation of this study is available from the Cochrane Injuries Group.

Ancillary