急性脑梗死降颅压药治疗疗效及安全性的系统评价
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摘要
背景:脑梗死是人类常见疾病及多发病,具有较高的致死率和致残率,其早期的死亡主要与脑梗死后脑水肿相关。减轻脑水肿,降低颅内压是降低脑梗死早期死亡率,减少神经功能损害的主要措施之一。甘露醇、甘油果糖、速尿及七叶皂苷钠作为降颅压药被广泛应用于临床上,且存在滥用药现象,而目前它们的疗效及安全性尚不明确。
目的:评价甘露醇、甘油果糖、速尿及七叶皂苷钠分别应用于急性脑梗死的疗效及安全性。
方法:采用cochrane系统评价手册的检索策略原则制定检索策略,计算机检索PUBMED、EMBASE、VIP、CBM等数据库及手工检索《中华神经科杂志》、《临床神经病学杂志》等获取相关的文献。根据纳入及排除标准对文献进行筛查,纳入最终符合标准的研究,并对研究进行质量评价,提取数据。使用Revman5.0软件进行数据的处理和分析。
结果:甘露醇应用于急性脑梗死疗效及安全性的系统评价,共检索出742篇相关的文献,经过筛选,最终纳入8个RCT,包括689名患者。所有纳入研究的方法学质量均比较低,都没有进行随访,也没有报道患者死亡率及残疾率。有6个研究采用评分量表对神经功能缺损改善情况进行评价,其中5个研究疗效评价标准相同,进行Meta分析,提示甘露醇组疗效优于对照组,各研究间无异质性(4篇可提取二分类数据,相应RR= 1.20, 95%CI 1.10-1.32,P=0.93, I2=0%;2篇为计量资料,MD=-4.64,95%CI-6.55～-2.73 ,P=0.12, I2=58%)。Sergio santambrogio的研究疗效评价标准与上述不同,单独进行统计学分析RR=0.98,95%CI(0.52~1.83),甘露醇治疗组和对照组在改善患者神经功能缺损上无明显差异。有2个研究对患者临床症状体征改善情况直接进行评价,汇总分析RR=1.33, 95% CI 0.81-2.18,提示甘露醇组和对照组疗效相当,但异质性检验P=0.0008,I 2=91%提示这2个研究具有高度异质性。有6个研究对不良反应进行了分析,其中4个研究甘露醇治疗组及对照组均无不良反应出现,有1篇报道甘露醇组出现电解质紊乱(17.5%)、心力衰竭(5%)、肾衰竭(10%)、脑水肿加重(5%)及反跳现象(32.5%)。另1篇甘露醇组出现轻微的低钠血症,发生率为13.3%。
甘油果糖应用于急性脑梗死疗效及安全性的系统评价,共检索出66篇相关文献,经过筛选,最终没有符合要求的RCT。
速尿应用于急性脑梗死疗效及安全性的系统评价,共检索出67篇相关文献,没有符合标准的RCT纳入。
七叶皂苷钠应用于急性脑梗死疗效及安全性的系统评价,总共纳入1篇涉及116例患者的研究,分析结果显示七叶皂苷钠治疗组在改善急性脑梗死神经功能缺损上疗效优于对照组(X2=8.39,P<0.05),但未进行随访观察,无死亡例数及相关不良反应报道。
结论:1.甘露醇在短时间内对急性脑梗死患者神经功能缺损的改善可能有一定的疗效,但纳入研究质量偏低,各个研究的样本量偏小,可能存在发表偏倚,远期效益及安全性亦不明确,因此尚不好推荐甘露醇作为急性脑梗死患者的常规治疗用药。2.目前没有可靠的证据证明甘油果糖及速尿单独应用于急性脑梗死是有效和安全的。3.七叶皂苷钠治疗急性脑梗死疗效及安全性仍不能肯定,有待更多的临床高质量研究进一步证实。4.以后的研究应该开展多中心、大样本及与安慰剂对照的临床随机双盲试验,所采用的随机方法、分配隐藏及盲法应予具体描述,且应该进行长时间随访,疗效评价指标应该包括死亡率、致残率及不良反应发生率。
Background: Cerebral infarction is a common desease with high mortality and morbidity. And the brain edema is a major cause of early death after cerebral infarction. So management of reducing brain edema and controling elevated intracranial pressure (ICP) of these patients is currently being changed to an earlier and more aggressive treatment regimen. Mannitol, glycerin fructose, furosemide and sodium aescinate are claimed to reduce brain oedema and are widely used clinically, but the efficacy and safety of them used in acute ischemic stroke are not clear.
Objectives: To test the efficacy and safety of the treatment with mannitol, glycerin fructose, furosemide or sodium aescinate after acute ischaemic stroke.
Methods: The standard search strategy was made according to the Cochrane systematic review handbook and the trails were searched in the databank MEDLINE, EMBASE, VIP, CBM and so on. The Chinese Journal of Neurology and Journal of Clinical Neurology were also checked. Then study selection was performed base on included and excluded criterion. Two of the reviewers independently extracted data from the trials. Data synthesis and analysis was performed with the use of the Cochrane Review Manager software (RevMan version 5.0).
Results: Mannitol for acute cerebral infarction, 742 studies were searched and 8 RCTs involving 689 participants were eligible according to included and excluded criterions. All the trials were assessed of poor methodological quality. Case fatality, the proportion of dependent patients at the end of the follow-up were not reported. Pooled analysis of 5 trials showed mannitol was associated with a significant improvement of the neurological deficit (RR= 1.20, 95%CI 1.10-1.32 for the dichotomous data ; MD=-4.64, 95%CI-6.55~-2.73 for the continuous data ) . But another trail showed no difference between mannitol-treated and control groups in improving the neurological deficit (RR=0.98,95%CI 0.52~1.83).2 trials evaluated the improvement of the neurological symptom and signs. The pooled analysis indicated that there is no difference for mannitol in improving neurological symptom and signs after cerebral infarction between mannitol-treated and control groups.6 trials reported the side effects and 4 of which showed no appearance of side effects.2 trial reported that the patients who were treated with mannitol have complications of electrolytes disturbance(17.5%), heart failure(5%), renal failure(10%), aggravation of cerebral edema (5%)and rebound phenomenon(32.5%). Hyponatremia was reported in the other trial with the incident rate 13.3%.
Glycerin fructose for acute cerebral infarction: 66 studies were searched and no trials were eligible.
Furosemide for acute cerebral infarction: 67 studies were searched and no trials were eligible.
Sodium aescinate for acute cerebral infarction:1 trial involving 116 participants was included and the analysis showed that sodium aescinate have positive effect in improving the neurological deficit(X2=8.39,P<0.05),but the case fatality, the proportion of dependent patients, and side effects were not reported.
Conclusions: (1) This systematic review suggests a favourable effect of mannitol treatment on the improvement of neurological deficit after cerebral infarction, but the methodological quality was poor and the number of patients is relatively small. In addition, the evidence of benefit in long term survival and dependency are not supported. So the efficacy and safety of mannitol treatment in cerebral infarction have not been yet confirmed. (2) As a result of lack of appropriate randomized trials, currently no conclusion can be drawn on the effects and safety of glycerin fructose and furosemide in acute cerebral infarction.(3) The effect of sodium aescinate on improvement of neurological deficit after cerebral infarction is uncertain. (4) To prove the efficacy and safety of mannitol, glycerin fructose , furosemide and sodium aescinate, placebo-controlled, unconfounded, properly randomized clinical studies should be designed and performed.
目的:评价甘露醇、甘油果糖、速尿及七叶皂苷钠分别应用于急性脑梗死的疗效及安全性。
方法:采用cochrane系统评价手册的检索策略原则制定检索策略,计算机检索PUBMED、EMBASE、VIP、CBM等数据库及手工检索《中华神经科杂志》、《临床神经病学杂志》等获取相关的文献。根据纳入及排除标准对文献进行筛查,纳入最终符合标准的研究,并对研究进行质量评价,提取数据。使用Revman5.0软件进行数据的处理和分析。
结果:甘露醇应用于急性脑梗死疗效及安全性的系统评价,共检索出742篇相关的文献,经过筛选,最终纳入8个RCT,包括689名患者。所有纳入研究的方法学质量均比较低,都没有进行随访,也没有报道患者死亡率及残疾率。有6个研究采用评分量表对神经功能缺损改善情况进行评价,其中5个研究疗效评价标准相同,进行Meta分析,提示甘露醇组疗效优于对照组,各研究间无异质性(4篇可提取二分类数据,相应RR= 1.20, 95%CI 1.10-1.32,P=0.93, I2=0%;2篇为计量资料,MD=-4.64,95%CI-6.55～-2.73 ,P=0.12, I2=58%)。Sergio santambrogio的研究疗效评价标准与上述不同,单独进行统计学分析RR=0.98,95%CI(0.52~1.83),甘露醇治疗组和对照组在改善患者神经功能缺损上无明显差异。有2个研究对患者临床症状体征改善情况直接进行评价,汇总分析RR=1.33, 95% CI 0.81-2.18,提示甘露醇组和对照组疗效相当,但异质性检验P=0.0008,I 2=91%提示这2个研究具有高度异质性。有6个研究对不良反应进行了分析,其中4个研究甘露醇治疗组及对照组均无不良反应出现,有1篇报道甘露醇组出现电解质紊乱(17.5%)、心力衰竭(5%)、肾衰竭(10%)、脑水肿加重(5%)及反跳现象(32.5%)。另1篇甘露醇组出现轻微的低钠血症,发生率为13.3%。
甘油果糖应用于急性脑梗死疗效及安全性的系统评价,共检索出66篇相关文献,经过筛选,最终没有符合要求的RCT。
速尿应用于急性脑梗死疗效及安全性的系统评价,共检索出67篇相关文献,没有符合标准的RCT纳入。
七叶皂苷钠应用于急性脑梗死疗效及安全性的系统评价,总共纳入1篇涉及116例患者的研究,分析结果显示七叶皂苷钠治疗组在改善急性脑梗死神经功能缺损上疗效优于对照组(X2=8.39,P<0.05),但未进行随访观察,无死亡例数及相关不良反应报道。
结论:1.甘露醇在短时间内对急性脑梗死患者神经功能缺损的改善可能有一定的疗效,但纳入研究质量偏低,各个研究的样本量偏小,可能存在发表偏倚,远期效益及安全性亦不明确,因此尚不好推荐甘露醇作为急性脑梗死患者的常规治疗用药。2.目前没有可靠的证据证明甘油果糖及速尿单独应用于急性脑梗死是有效和安全的。3.七叶皂苷钠治疗急性脑梗死疗效及安全性仍不能肯定,有待更多的临床高质量研究进一步证实。4.以后的研究应该开展多中心、大样本及与安慰剂对照的临床随机双盲试验,所采用的随机方法、分配隐藏及盲法应予具体描述,且应该进行长时间随访,疗效评价指标应该包括死亡率、致残率及不良反应发生率。
Background: Cerebral infarction is a common desease with high mortality and morbidity. And the brain edema is a major cause of early death after cerebral infarction. So management of reducing brain edema and controling elevated intracranial pressure (ICP) of these patients is currently being changed to an earlier and more aggressive treatment regimen. Mannitol, glycerin fructose, furosemide and sodium aescinate are claimed to reduce brain oedema and are widely used clinically, but the efficacy and safety of them used in acute ischemic stroke are not clear.
Objectives: To test the efficacy and safety of the treatment with mannitol, glycerin fructose, furosemide or sodium aescinate after acute ischaemic stroke.
Methods: The standard search strategy was made according to the Cochrane systematic review handbook and the trails were searched in the databank MEDLINE, EMBASE, VIP, CBM and so on. The Chinese Journal of Neurology and Journal of Clinical Neurology were also checked. Then study selection was performed base on included and excluded criterion. Two of the reviewers independently extracted data from the trials. Data synthesis and analysis was performed with the use of the Cochrane Review Manager software (RevMan version 5.0).
Results: Mannitol for acute cerebral infarction, 742 studies were searched and 8 RCTs involving 689 participants were eligible according to included and excluded criterions. All the trials were assessed of poor methodological quality. Case fatality, the proportion of dependent patients at the end of the follow-up were not reported. Pooled analysis of 5 trials showed mannitol was associated with a significant improvement of the neurological deficit (RR= 1.20, 95%CI 1.10-1.32 for the dichotomous data ; MD=-4.64, 95%CI-6.55~-2.73 for the continuous data ) . But another trail showed no difference between mannitol-treated and control groups in improving the neurological deficit (RR=0.98,95%CI 0.52~1.83).2 trials evaluated the improvement of the neurological symptom and signs. The pooled analysis indicated that there is no difference for mannitol in improving neurological symptom and signs after cerebral infarction between mannitol-treated and control groups.6 trials reported the side effects and 4 of which showed no appearance of side effects.2 trial reported that the patients who were treated with mannitol have complications of electrolytes disturbance(17.5%), heart failure(5%), renal failure(10%), aggravation of cerebral edema (5%)and rebound phenomenon(32.5%). Hyponatremia was reported in the other trial with the incident rate 13.3%.
Glycerin fructose for acute cerebral infarction: 66 studies were searched and no trials were eligible.
Furosemide for acute cerebral infarction: 67 studies were searched and no trials were eligible.
Sodium aescinate for acute cerebral infarction:1 trial involving 116 participants was included and the analysis showed that sodium aescinate have positive effect in improving the neurological deficit(X2=8.39,P<0.05),but the case fatality, the proportion of dependent patients, and side effects were not reported.
Conclusions: (1) This systematic review suggests a favourable effect of mannitol treatment on the improvement of neurological deficit after cerebral infarction, but the methodological quality was poor and the number of patients is relatively small. In addition, the evidence of benefit in long term survival and dependency are not supported. So the efficacy and safety of mannitol treatment in cerebral infarction have not been yet confirmed. (2) As a result of lack of appropriate randomized trials, currently no conclusion can be drawn on the effects and safety of glycerin fructose and furosemide in acute cerebral infarction.(3) The effect of sodium aescinate on improvement of neurological deficit after cerebral infarction is uncertain. (4) To prove the efficacy and safety of mannitol, glycerin fructose , furosemide and sodium aescinate, placebo-controlled, unconfounded, properly randomized clinical studies should be designed and performed.
引文
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[41]王大伟.甘油果糖注射液和甘露醇注射液治疗急性脑梗死疗效比较.现代中西医结合杂志,2009; 18(8):873-874
[42]苏柱新.小剂量甘露醇加速尿治疗脑卒中.河北医学,1999; 5(8):32-33
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[44]林霞,刘宁,谷有全等.注射用七叶皂苷钠对大鼠局灶性脑缺血再灌注损伤后环氧合酶2表达的影响.中国康复医学杂志,2010; 25(8):729-732
[45]胡霞敏,曾繁典.β-七叶皂苷钠对大鼠脑缺血-再灌注损伤的保护作用.药学学报,2004; 29(6):419-423
[46]张韶华,韩文江,李晓蕾等.七叶皂苷钠对大鼠局灶性脑缺血再灌注后MMP一9和LN表达的影响.西安交通大学学报(医学版),2008; 29(6):621-624
[47]吴戈.七叶皂苷钠对大鼠大脑中动脉梗死后基质金属蛋白酶-9表达的影响.医药论坛杂志,2010; 31(5):1-6
[48]黄勤华,叶允瑞.七叶皂苷钠治疗急性脑梗死41例疗效观察.youjiang medical journal,2008; 36(3):268-269
[1]赵冬,我国人群脑卒中发病率、死亡率的流行病学研究.中华流行病学杂志, 2003. 24(3): 236-239.
[2] Mathers, C.D.D. Loncar, Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med, 2006. 3(11): e442.
[3]贾建平主编,神经病学.人民卫生出版社, 2008.
[4] Slivka.A,E.Murphy,L.Horrocks, Cerebral Edema After Temporary and Permanent Middle CerebralArtery Occlusion in the Ra,t Stroke, 1995. 26(6): 1061-1066.
[5] Wijdicks, E. F.,Diringer, M. N.middle cerebral artery territory infarction and early brain swelling:progression and effect of age on outcome. mayo clin proc 1998. 73(9): 829-836.
[6] JV Bounds, D.W., JP Whisnant , H Okazaki, Mechanisms and timing of deaths from cerebral infarction. Stroke, 1981. 12(4): 474-477.
[7] Steven Vernino, R.D.B., Jr, James J. Sejvar, JoRean D. Sicks,etc, Cause-Specific Mortality After First Cerebral Infarction. A Population-Based Study. Stroke, 2003. 34.
[8] N.Diringer, M.A. R.Zazulia, osmotic therapy:fact and fiction. Neurocritical Care, 2004. 1: 219-233.
[9] R. P. Paczynski, M., Y. Y. He, M., M. N. Diringer, etc,Multiple-Dose Mannitol Reduces Brain Water Content in a Rat Model of Cortical Infarction. Stroke, 1997. 28(7): 1437-1444.
[10]李丙选,林妍,李玉枝等,甘露醇滴速对脑梗死患者血粘度的影响中华神经科杂志, 1998. 31(003).
[11] Luvisotto, T.L., R.N. Auer, G.R. Sutherland, The effect of mannitol on experimental cerebral ischemia, revisited. Neurosurgery, 1996. 38(1): 131-138.
[12]王百怡,郭春荣,甘露醇在临床的应用.中国医学杂志, 2007. 5(012): 9-11.
[13] ANTHONY M.KAUFMANN, B.S.M., M.D,ERICO R.CARDOSO, aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg, 1992. 77(4): 584-589.
[14]狄晴,徐俊,张颖冬,甘露醇治疗缺血性脑水肿的实验研究.临床神经病学杂志, 1998. 11(006): 330-333.
[15]黄钊阳,老年急性大面积脑梗塞不同剂量甘露醇治疗研究.医学信息(西安上半月), 2005. 18(008): 974-975.
[16]赖呈谋,甘露醇治疗急性脑卒中对肾功能损害观察.华夏医学, 2009(005): 847-848.
[17]张光运,曹玉红,韩军良等,不同剂量甘露醇对大面积脑梗死脑疝防治的效果. Chin J care Med, 2005. 25(3): 232.
[18]耿纪超,陈攸,早期小剂量甘露醇治疗进展性脑梗死的临床观察.中国实用医药, 2009. 4(032): 30-31.
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[44]林霞,刘宁,谷有全等.注射用七叶皂苷钠对大鼠局灶性脑缺血再灌注损伤后环氧合酶2表达的影响.中国康复医学杂志,2010; 25(8):729-732
[45]胡霞敏,曾繁典.β-七叶皂苷钠对大鼠脑缺血-再灌注损伤的保护作用.药学学报,2004; 29(6):419-423
[46]张韶华,韩文江,李晓蕾等.七叶皂苷钠对大鼠局灶性脑缺血再灌注后MMP一9和LN表达的影响.西安交通大学学报(医学版),2008; 29(6):621-624
[47]吴戈.七叶皂苷钠对大鼠大脑中动脉梗死后基质金属蛋白酶-9表达的影响.医药论坛杂志,2010; 31(5):1-6
[48]黄勤华,叶允瑞.七叶皂苷钠治疗急性脑梗死41例疗效观察.youjiang medical journal,2008; 36(3):268-269
[1]赵冬,我国人群脑卒中发病率、死亡率的流行病学研究.中华流行病学杂志, 2003. 24(3): 236-239.
[2] Mathers, C.D.D. Loncar, Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med, 2006. 3(11): e442.
[3]贾建平主编,神经病学.人民卫生出版社, 2008.
[4] Slivka.A,E.Murphy,L.Horrocks, Cerebral Edema After Temporary and Permanent Middle CerebralArtery Occlusion in the Ra,t Stroke, 1995. 26(6): 1061-1066.
[5] Wijdicks, E. F.,Diringer, M. N.middle cerebral artery territory infarction and early brain swelling:progression and effect of age on outcome. mayo clin proc 1998. 73(9): 829-836.
[6] JV Bounds, D.W., JP Whisnant , H Okazaki, Mechanisms and timing of deaths from cerebral infarction. Stroke, 1981. 12(4): 474-477.
[7] Steven Vernino, R.D.B., Jr, James J. Sejvar, JoRean D. Sicks,etc, Cause-Specific Mortality After First Cerebral Infarction. A Population-Based Study. Stroke, 2003. 34.
[8] N.Diringer, M.A. R.Zazulia, osmotic therapy:fact and fiction. Neurocritical Care, 2004. 1: 219-233.
[9] R. P. Paczynski, M., Y. Y. He, M., M. N. Diringer, etc,Multiple-Dose Mannitol Reduces Brain Water Content in a Rat Model of Cortical Infarction. Stroke, 1997. 28(7): 1437-1444.
[10]李丙选,林妍,李玉枝等,甘露醇滴速对脑梗死患者血粘度的影响中华神经科杂志, 1998. 31(003).
[11] Luvisotto, T.L., R.N. Auer, G.R. Sutherland, The effect of mannitol on experimental cerebral ischemia, revisited. Neurosurgery, 1996. 38(1): 131-138.
[12]王百怡,郭春荣,甘露醇在临床的应用.中国医学杂志, 2007. 5(012): 9-11.
[13] ANTHONY M.KAUFMANN, B.S.M., M.D,ERICO R.CARDOSO, aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg, 1992. 77(4): 584-589.
[14]狄晴,徐俊,张颖冬,甘露醇治疗缺血性脑水肿的实验研究.临床神经病学杂志, 1998. 11(006): 330-333.
[15]黄钊阳,老年急性大面积脑梗塞不同剂量甘露醇治疗研究.医学信息(西安上半月), 2005. 18(008): 974-975.
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