Mannitol for acute traumatic brain injury

  • Review
  • Intervention

Authors


Abstract

Background

Mannitol is sometimes effective in reversing acute brain swelling, but its effectiveness in the ongoing management of severe head injury remains unclear. There is evidence that, in prolonged dosage, mannitol may pass from the blood into the brain, where it might cause increased intracranial pressure.

Objectives

To assess the effects of different mannitol therapy regimens, of mannitol compared to other intracranial pressure (ICP) lowering agents, and to quantify the effectiveness of mannitol administration given at other stages following acute traumatic brain injury.

Search methods

We searched the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library), MEDLINE (OvidSP), EMBASE (OvidSP), ISI Web of Science (SCI-EXPANDED & CPCI-S) and PubMed. We checked reference lists of trials and review articles, and contacted authors of trials. The search was updated on the 20th April 2009.

Selection criteria

Randomised controlled trials of mannitol, in patients with acute traumatic brain injury of any severity. The comparison group could be placebo-controlled, no drug, different dose, or different drug. We excluded cross-over trials, and trials where the intervention was started more than eight weeks after injury.

Data collection and analysis

We independently rated quality of allocation concealment and extracted the data. Relative risks (RR) and 95% confidence intervals (CI) were calculated for each trial on an intention to treat basis.

Main results

We identified four eligible randomised controlled trials. One trial compared ICP-directed therapy to 'standard care' (RR for death = 0.83; 95% CI 0.47 to 1.46). One trial compared mannitol to pentobarbital (RR for death = 0.85; 95% CI 0.52 to 1.38). One trial compared mannitol to hypertonic saline (RR for death = 1.25; 95% CI 0.47 to 3.33). One trial tested the effectiveness of pre-hospital administration of mannitol against placebo (RR for death = 1.75; 95% CI 0.48 to 6.38).

Authors' conclusions

Mannitol therapy for raised ICP may have a beneficial effect on mortality when compared to pentobarbital treatment, but may have a detrimental effect on mortality when compared to hypertonic saline. ICP-directed treatment shows a small beneficial effect compared to treatment directed by neurological signs and physiological indicators. There are insufficient data on the effectiveness of pre-hospital administration of mannitol.

摘要

甘露醇治疗急性创伤性脑损伤

研究背景

甘露醇有时可以有效地扭转急性脑水胀,但其持续治疗严重头部损伤的有效性仍不清楚。有证据表明,长时间使用甘露醇,其通过血液进入大脑可能会导致颅内压增高。

研究目的

本研究的目的是通过对比其他降低颅内压(ICP)的药剂,来评估不同甘露醇治疗方案的疗效,并量化甘露醇治疗其他阶段的急性创伤性脑损伤的疗效。

检索策略

我们检索了Cochrane图书馆损伤专业注册组,MEDLINE(期刊资源)、EMBASE(期刊资源),ISI科学数据库(SCI-EXPANDED & CPCI-S)和PubMed。我们筛查参考文献列表和文献综述,并联系试验的作者。搜索日期更新至2009年4月20日。

标准/纳入排除标准

纳入的研究为甘露醇治疗不同程度急性创伤性脑损伤的随机对照试验。对照组采用安慰剂对照、空白对照、不同剂量的甘露醇或不同的药物。我们排除交叉试验及干预措施开始于受伤后8周的试验。

数据收集与分析

研究人员独立完成分配隐藏的质量评估和资料提取。基于意向性分析计算每个试验的相对危险度(RR)和95%可信区间(CI)。

主要结果

我们纳入了四篇符合标准的随机对照试验。一项试验对比颅内压指导疗法与标准治疗(死亡危险度为 0.83,95%可信区间[0.47,1.46]。一项试验对比甘露醇与戊巴比妥(死亡危险度为0.85;95%可信区间[0.52,1.38]。一项试验对比甘露醇与高渗生理盐水(死亡相对危险度为 1.25;95%可信区间[0.47,3.33]。一项试验测试了院前急救使用甘露醇对比安慰剂的疗效差异(死亡危险度为 1.75;95%可信区间[0.48,6.38]。

作者结论

与戊巴比妥治疗相比,使用甘露醇疗法增高颅内压后可能会降低死亡率。但与高渗生理盐水相比,使用甘露醇可能会增加死亡率。对比神经症状和生理指标指导的疗法,颅内压指导的疗法具有小的疗效优势。没有足够的数据证明使用甘露醇进行院前急救的有效性。

翻译注解

译者:田夏(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

Mannitol for acute traumatic brain injury

Mannitol is a sugar alcohol solution which is sometimes effective in reducing brain swelling after head injury. However, its effectiveness in the ongoing treatment of severe head injury remains unclear. There is evidence that excessive administration of mannitol may be harmful, by mannitol passing from the bloodstream into the brain, where it increases pressure within the skull and worsens brain swelling. The review authors searched the medical literature and identified four randomized controlled trials comparing mannitol to other treatment strategies for reducing brain swelling after head injury. One trial compared treatment with mannitol directed by measurement of the pressure within the skull (intracranial pressure) with ‘standard treatment’ (treatment without measurement of intracranial pressure). One trial compared treatment with mannitol to treatment with pentobarbital (a barbiturate drug). One trial compared treatment with mannitol to treatment with hypertonic saline (highly concentrated salt solution). One trial compared treatment with mannitol to treatment with placebo (an inactive ‘dummy’ solution) before arrival in the hospital (pre-hospital). The review found that treatment with mannitol for increased intracranial pressure reduced the likelihood of death when compared to treatment with pentobarbital. In contrast, it found that treatment with mannitol may increase the likelihood of death when compared to treatment with hypertonic saline. The review also found a small benefit when mannitol treatment is directed by measurement of intracranial pressure compared to ‘standard treatment.’ The review found insufficient data on the effectiveness of pre-hospital administration of mannitol.

எளியமொழிச் சுருக்கம்

கடுமையான புறவழி மூளைக் காயத்திற்கு மெனிட்டால் (mannitol)

மெனிட்டால் ஒரு சர்க்கரை ஆல்கஹால் கரைசல், அது சிலவேளைகளில் மூளைக் காயத்திற்கு பின் ஏற்படும் மூளை வீக்கத்தை திறன்பட குறைக்கும். இருப்பினும் கடும் தலைக் காயத்திற்கு திறன் வாய்ந்த சிகிச்சையா என்பது தெளிவாக தெரியவில்லை. மெனிட்டாலை அதிகப்படியாக வழங்குதல் தீங்கு விளைவிக்கலாம், அவை இரத்த நாளம் வழியாக மூளையை சென்றடைந்து தலையோடு அழுத்தத்தை அதிகரிக்கும் மற்றும் அது மூளை வீக்கத்தை மோசமாக்கும். ஆய்வு ஆசிரியர்கள், மருத்துவ ஆய்வுகளைத் தேடி தலை காயத்திற்கு பின்னர் வரும் மூளை வீக்கத்தை குறைக்க மற்ற சிகிச்சை உத்திகளுடன் மெனிட்டால் ஒப்பிட் நான்கு சமவாய்ப்பிட்டு கட்டுப்படுத்தப்பட்ட சோதனைகள் கண்டறியப்பட்டது. ஒரு ஆராய்ச்சி உள்மண்டை அழுத்தத்தைப் பொருத்து மெனிட்டால் சிகிச்சையுடன் வழக்கமான சிகிச்சையுடன் (உள்மண்டை அழுத்தத்தை அளக்காமல் சிகிச்சை அளிப்பது) ஒப்பிட்டுப்படிருந்தது. ஒரு ஆராய்ச்சி மெனிட்டால் சிகிச்சையும் பென்டோபார்பிடால்லை சிகிச்சையுடன் ஒப்பிட்டுப்படிருந்தது. ஹைபெர்டோனிக் உப்புக் கறைசல் (அதிக அடர்த்தியுடன் உப்பு கரைசல்) சிகிச்சைக்கு மெனிட்டால் கொண்டு சிகிச்சைக்கு ஒரு ஆராய்ச்சி ஒப்பிட்டுப்படிருந்தது. மருத்துவமனை வருகைக்கு முன் மருந்தற்ற குளிகையோடு (ஒரு செயலற்ற 'போலி' கறைசல்), மெனிட்டால் சிகிச்சையுடன் ஒரு ஆராய்ச்சி ஒப்பிட்டது. அதிகரித்த உள்மண்டை அழுத்ததிற்கு மெனிட்டால் சிகிச்சை, பென்டோபார்பிடால்லை சிகிச்சையுடன் ஒப்பிட்டுகையில்இறப்புக்கான சாத்தியக்கூறுகள் மெனிட்டாலில் குறைகின்றன என்று இந்த திறனாய்வில் கண்டறியப்பட்டது. இதற்கு முரணாக, மெனிட்டால் கொண்டு அளிக்கப்படும் சிகிச்சை, ஹைபெர்டோனிக் உப்புக் கரைசளுடன் ஒப்பிடுகையில் அது இறப்புக்கான சாத்தியக்கூறுகளை அதிகரிக்கின்றன என்று கண்டறியப்பட்டது. உள்மண்டை அழுத்தத்தை பொருத்து சிகிச்சை அளிக்கப்படும்போது, வழக்கமான சிகிச்சையை விட மெனிட்டால் சிகிச்சை சிறிய அளவில் நன்மை பயக்கும் என்று இந்த திறனாய்வில் அறியப்பட்டது. மருத்துவமனைக்கு வரும் முன் மெனிட்டால் அளிக்கப்படுவதின் திறனை அறிவதற்கு போதுமான தரவுகள் இல்லை என்று இந்த திறனாய்வில் அறியப்பட்டது.

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பு: க.வேணு வேந்தன் மற்றும் சி.இ.பி.என்.அர் குழு

概要

甘露醇治疗急性创伤性脑损伤

甘露醇是一种糖醇溶液,有时可以有效地减少头部受伤后形成的脑水肿。然而,其治疗重度颅脑损伤的疗效仍不明确。有证据表明,过度使用甘露醇可能对人体造成伤害。因为甘露醇从血液进入大脑后,会增加颅内压, 从而加重脑水胀。本篇综述作者检索医学文献,并确认纳入四篇甘露醇对比其他治疗措施用于减轻头部受伤后脑水胀的随机对照试验。一篇试验,采用测量颅内压指导甘露醇的用量,对比常规治疗(治疗不含颅内压测量)。一篇试验对比甘露醇与戊巴比妥(巴比妥酸盐药物)的效果。一篇试验对比甘露醇与高渗盐水(高度浓缩盐溶液)的疗效。一篇试验对比患者在到达医院之前(院前),使用甘露醇与安慰剂(不含有效成分的仿制品)的疗效。系统评价发现,相较于戊巴比妥,选用甘露醇治疗颅内压增加可以降低死亡的可能性。相反,研究发现相较于高渗盐水,甘露醇可能会增加死亡的可能性。研究还发现与常规治疗相比,颅内压测量指导下使用甘露醇疗法的一个小优势。回顾发现缺乏院前使用甘露醇疗效的数据。

翻译注解

译者:田夏(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

Mannitol is widely used in the control of raised intracranial pressure following brain injury. A 1995 survey of the critical care management of head-injured patients in the United States showed that 83% of centres used osmotic diuretics in more than half of severely head-injured patients (Ghajar 1995). A survey in the United Kingdom showed that 100% of neurosurgical centres used mannitol in the treatment of raised intracranial pressure (Jeevaratnam 1996; Matta 1996). The effectiveness of mannitol for head-injured patients in a critical condition is considered to be well established, without the need for randomised controlled trials.

For other patients, the Brain Trauma Foundation Guidelines Task Force of the American Association of Neurological Surgeons and Joint Section in Neurotrauma and Critical Care (Task Force 1995) recommend that mannitol be used only if the patient has signs of raised intracranial pressure (ICP) or deteriorating neurological status. In these circumstances, any adverse effects are most likely to be outweighed by therapeutic benefit. Nevertheless, the guidelines acknowledge that this is an area of considerable clinical uncertainty. There is uncertainty over the optimal treatment regimen, over the effectiveness of mannitol as compared to other ICP-lowering agents and over the usefulness of mannitol given at other stages following head injury, for example in the pre-hospital setting, prior to volume resuscitation.

We conducted a systematic review of randomised controlled trials that compared different mannitol treatment regimens, or compared mannitol to alternative interventions or placebo, at any stage in the acute management of head injury.

Objectives

1. To compare the effectiveness of mannitol therapy when given in different doses and for different durations.
2. To quantify the effectiveness of mannitol compared to other ICP-lowering agents.
3. To quantify the effectiveness of mannitol administration given at other stages following head injury.

Methods

Criteria for considering studies for this review

Types of studies

Controlled trials in which subjects were assigned to treatment or control groups (placebo-controlled, no drug, different drug or different mannitol regimen) on the basis of random or quasi-random allocation. We excluded trials with a cross-over design.

Types of participants

Participants had a clinically defined acute traumatic brain injury of any severity.

Types of interventions

The treatment group received mannitol in any dose for any duration, at any time within eight weeks following injury. The control group received any of the following: mannitol in a different dose from the treatment group, another ICP-lowering agent such as barbiturates or placebo or standard care only.

Types of outcome measures

We aimed to extract from each trial the number of patients originally allocated to each group. Within each group, we aimed to extract the number of participants who died from any cause during the follow-up period or who were dead, in a vegetative state or severely disabled, compared to moderate or good recovery (according to Glasgow Coma Scale [GCS] criteria).

Search methods for identification of studies

The search was limited by date, language or publication type.

Electronic searches

The Cochrane Injuries Group Trials Search Co-ordinator searched the following:

  1. Cochrane Injuries Group Specialised Register (20th April 2009);

  2. CENTRAL (The Cochrane Library 2009, Issue 2);

  3. MEDLINE (OvidSP) (1950 to April 2009);

  4. EMBASE (OvidSP) (1980 to April 2009);

  5. ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to April 2009;

  6. Conference Proceedings Citation Index- Science (CPCI-S) 1990 to April 2009;

  7. PubMed (added in last 6 months; searched 21 April 2009).

Search strategies are listed in Appendix 1.

Searching other resources

The reference lists of all relevant articles identified were checked. A letter was sent to the first author of reports to ask for further information on the published report and asking them to assist in identifying any further trials which may have been conducted by them, or other investigators. Eligibility was determined by reading the reports of possible trials.

Data collection and analysis

We determined eligibility by reading the reports of possible trials and corresponding with the trialists. The reviewers independently rated quality of allocation concealment and independently extracted the data. We resolved disagreement by discussion. We calculated relative risks and 95% confidence intervals for each trial on an intention to treat basis. For trials which used comparable treatment regimens, we planned to calculate summary relative risks and 95% confidence intervals using a fixed effects model, and to stratify the analyses on allocation concealment.

Results

Description of studies

Four studies met the inclusion criteria.

Sayre 1996 compared the pre-hospital administration of mannitol with placebo (normal saline). Eligible patients were those with moderate and severe head injury (GCS 11 or less), above 18 years of age. Patients were excluded if they may have been pregnant, had already received a diuretic, or were receiving cardiopulmonary resuscitation. The mannitol group received 5ml/kg of 20% mannitol through a large bore IV catheter over five minutes. The placebo group was given 5ml/kg of 0.9% saline solution. Forty-four participants were randomised; three were later excluded as they were found to be ineligible. The treatment to which these three patients were allocated, as well as follow-up information were unavailable. Therefore, the analysis was based upon 20 participants in the mannitol group and 21 participants in the placebo group. Length of follow-up was for two hours after arrival at the hospital.

Schwartz 1984 compared mannitol to pentobarbital. Patients with severe head injury (GCS <8), and with raised ICP for longer than 15 minutes were eligible. Treatment allocation was stratified according to the presence of intracranial haematomas. The mannitol group received 20% mannitol solution at an initial dose of 1g per kg. Additional increments were given to maintain the intracranial pressure at less than 20 torr, within a serum osmolality of mannitol of 320mOs/litre. The pentobarbital group received pentobarbital as an intravenous (IV) bolus of up to 10mg/kg, followed by a continuous infusion at 0.5 to 3mg/kg/hr, provided that CPP remained above 50 torr. Additional increments of pentobarbital were given to maintain the intracranial pressure at less than 20 torr. For subsequent episodes of raised ICP, there was some cross-over to the alternate treatment group, but the analysis was on the original intent-to-treat. Seventy participants were randomised; 11 were later deemed ineligible and excluded. Data on the treatment to which these 11 patients were allocated and follow-up information were unavailable. Therefore, the analysis was based on 31 participants in the mannitol group and 28 participants in the pentobarbital group. Length of follow-up was one year.

Smith 1986 compared two regimens for guiding the administration of mannitol, one according to neurological signs and physiological measurements, and the other using ICP monitoring. Participants had a severe head injury (GCS 8 or less). The protocol for the first group used neurological signs, GCS, ventilatory values and arterial blood gas to guide administration of mannitol. In the second group, a 250ml bolus of mannitol (20%) was given if ICP > 25mmHg, and subsequent boluses were given incrementally. Eighty participants were randomised. Data were available for 40 participants in the first group, and 37 participants in the ICP-directed treatment group. Follow-up was one year.

Vialet 2003 compared mannitol to hypertonic saline. Eligible patients were those with severe head injury (GCS <8) who required intravenous infusions of an osmotic agent to treat episodes of intracranial hypertension resistant to standard therapy (cerebrospinal fluid drainage, volume expansion and/or inotropic support, hyperventilation). The mannitol group received 20% mannitol solution. The hypertonic saline group received 7.5% hypertonic saline. The infused volume was the same for both solutions: 2 ml/kg body weight in 20 minutes. The aim was to decrease ICP to <25 mm Hg or to increase CPP to >70 mm Hg. In case the first infusion failed, the patient received a second infusion within ten minutes after the end of the first infusion. Treatment failure was defined as the inability to decrease ICP to <35 mm Hg or to increase CPP to >70 mm Hg with two consecutive infusions of the selected osmotic solution. In that case, the protocol was stopped, and patients were followed up for mortality or 90-day neurologic status. Because 20% mannitol can crystallize at ambient temperature, injections could not be performed in a blinded manner. Twenty patients were randomised, ten to each group. Outcome was assessed at 90 days using the Glasgow Outcome Scale administered by a practitioner who was blind to acute patient care.

Risk of bias in included studies

Sayre 1996: The study was randomised and double-blind. Allocation concealment was by pharmacy-prepared blinded solutions.

Schwartz 1984: The study was randomised and single-blind. Allocation concealment was by using serially numbered sealed envelopes.

Smith 1986:The study was randomised but not reported as double-blind. Allocation concealment was by the use of sealed envelopes.

Vialet 2003: The study was randomised but allocation concealment was not described. Outcome assessment was blind to acute clinical care.

The risk of bias across the four studies is summarised in Figure 1 and Figure 2.

Figure 1.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. Four studies are included in this review.

Effects of interventions

One trial compared ICP-directed therapy to 'standard care' in which mannitol therapy was directed by neurological signs (Smith 1986). The study was randomised and allocation concealment was by the use of sealed envelopes. For ICP-directed treatment compared to treatment based on neurological signs, the RR for death was 0.83 (95% CI 0.47 to 1.46); this trial demonstrated a similar effect for death or severe disability (RR = 0.88; 95% CI 0.55 to 1.38).

One trial compared mannitol to pentobarbital (Schwartz 1984). This trial was randomised and single blind. Only patients with known raised ICP were included. For mannitol compared to pentobarbital in the treatment of patients with raised ICP, the RR for death was 0.85 (95% CI 0.52 to 1.38).

One trial compared mannitol to hypertonic saline (Vialet 2003). This trial was randomised and single blind. Only patients with head injury and persistent coma who required osmotherapy to treat episodes of intracranial hypertension resistant to standard therapy were included. For mannitol compared to hypertonic saline in the treatment of refractory intracranial hypertension episodes in comatose patients with severe head injury, the RR for death was 1.25 (95% CI 0.47 to 3.33).

The effectiveness of pre-hospital administration of mannitol against placebo was investigated in Sayre 1996. This study was randomised and allocation concealment was through pharmacy prepared blinded solutions. For pre-hospital infusion of mannitol compared to placebo in patients with head injury and multiple trauma, the RR for death was 1.75 (95% CI 0.48 to 6.38).

Discussion

There were few eligible trials of mannitol therapy in head-injured patients.

ICP-directed treatment showed a small beneficial effect on mortality when compared to treatment directed according to neurological signs and physiological indicators (RR = 0.83; 95% CI 0.47 to 1.46). The method of allocation concealment in this study was adequate to prevent foreknowledge of treatment, and was unlikely to have led to bias. Owing to small patient numbers, the effect measure is imprecise. It must be noted that in this study the ICP-directed protocol initiated mannitol only when the ICP rose to above 25mmHg. Therefore these results cannot be extrapolated to ICP-directed protocols which initiate mannitol therapy at a lower level.

Mannitol therapy may have a beneficial effect on mortality when compared to pentobarbital therapy. However, the single trial which tested this (Schwartz 1984) yielded an imprecise effect measure, which also may be compatible with no difference, or a beneficial effect of pentobarbital. The trial was testing an initial treatment of mannitol compared to pentobarbital as some patients later received the alternate therapy if the allocated therapy failed to control ICP.

Mannitol therapy may have a detrimental effect on mortality when compared to hypertonic saline therapy. The single trial which compared mannitol to hypertonic saline (Vialet 2003) was too small for reliable conclusions. The trial was not designed to test the effect of these osmotic agents on neurologic recovery or death.

The single trial which compared pre-hospital administration of mannitol to placebo showed an increase in mortality amongst the mannitol-treated patients (RR = 1.75; 95% CI 0.48 to 6.38). The estimate yielded by this trial is imprecise owing to the small sample size. The effect measure also may be compatible with no difference, or a beneficial effect of pre-hospital administration of mannitol.

Authors' conclusions

Implications for practice

There is insufficient reliable evidence to make recommendations on the use of mannitol in the management of patients with traumatic brain injury.

Implications for research

There are many unanswered questions regarding the optimal use of mannitol following acute traumatic head injury. The widespread current use of mannitol, and lack of clarity regarding optimal administration, present an ideal opportunity for the conduct of randomised controlled trials.

Data and analyses

Download statistical data

Comparison 1. ICP-directed mannitol ('treatment') compared to mannitol according to neurological signs ('control')
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2 Death or severe disability1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
Analysis 1.1.

Comparison 1 ICP-directed mannitol ('treatment') compared to mannitol according to neurological signs ('control'), Outcome 1 Death.

Analysis 1.2.

Comparison 1 ICP-directed mannitol ('treatment') compared to mannitol according to neurological signs ('control'), Outcome 2 Death or severe disability.

Comparison 2. Mannitol versus pentobarbital
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
Analysis 2.1.

Comparison 2 Mannitol versus pentobarbital, Outcome 1 Death.

Comparison 3. Mannitol versus hypertonic saline
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
Analysis 3.1.

Comparison 3 Mannitol versus hypertonic saline, Outcome 1 Death.

Comparison 4. Mannitol versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
Analysis 4.1.

Comparison 4 Mannitol versus placebo, Outcome 1 Death.

Appendices

Appendix 1. Search strategies

Cochrane Injuries Group’s Specialised Register
(mannitol or Mannit or Mannite or Osmosal or Osmosteril or Resectisol or Aridol or Bronchitol or bromine or mitobronitol or dibromomannitol or myelobromol or nsc-94* or osmitrol or osmofundin or "(l)-mannitol" or "Dextro Mannitol" or D-Mannitol or (diuretic* and osmotic*)) AND (“intracranial pressure” OR “intracranial hypotension” OR “intracranial hypertension” or head* or brain*)

CENTRAL (The Cochrane Library)
#1MeSH descriptor Craniocerebral Trauma explode all trees
#2MeSH descriptor Cerebrovascular Trauma explode all trees
#3MeSH descriptor Brain Edema explode all trees
#4(brain or cerebral or intracranial) next (oedema or edema or swell*)
#5MeSH descriptor Glasgow Coma Scale explode all trees
#6MeSH descriptor Glasgow Outcome Scale explode all trees
#7MeSH descriptor Unconsciousness explode all trees
#8glasgow next (coma or outcome) next (score or scale)
#9(Unconscious* or coma* or concuss* or 'persistent vegetative state') near5 (injur* or trauma* or damag* or wound* or fracture*)
#10"Rancho Los Amigos Scale"
#11(head or crani* or cerebr* or capitis or brain* or forebrain* or skull* or hemispher* or intra-cran* or inter-cran*) near3 (injur* or trauma* or damag* or wound* or fracture* or contusion*)
#12Diffuse next axonal next injur*
#13(head or crani* or cerebr* or brain* or intra-cran* or inter-cran*) near3 (haematoma* or hematoma* or haemorrhag* or hemorrhag* or bleed* or pressure)
#14(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13)
#15MeSH descriptor Mannitol explode all trees
#16MeSH descriptor Diuretics, Osmotic explode all trees
#17(mannitol or Mannit or Mannite or Osmosal or Osmosteril or Resectisol or Aridol or Bronchitol or bromine or mitobronitol or dibromomannitol or myelobromol or nsc-94* or osmitrol or osmofundin or "(l)-mannitol" or Dextro Mannitol or D-Mannitol or (diuretic* adj5 osmotic*)).ab,ti.
#18(#15 OR #16 OR #17)
#19 (#14 and #18)


MEDLINE (OvidSP)
1.exp mannitol/
2.exp Diuretics, Osmotic/
3.(mannitol or Mannit or Mannite or Osmosal or Osmosteril or Resectisol or Aridol or Bronchitol or bromine or mitobronitol or dibromomannitol or myelobromol or nsc-94* or osmitrol or osmofundin or "(l)-mannitol" or Dextro Mannitol or D-Mannitol or (diuretic* adj5 osmotic*)).ab,ti.
4.1 or 2 or 3
5.exp Craniocerebral Trauma/
6.exp Brain Edema/
7.exp Glasgow Coma Scale/
8.exp Glasgow Outcome Scale/
9.exp Unconsciousness/
10.exp Cerebrovascular Trauma/
11.((head or crani* or cerebr* or capitis or brain* or forebrain* or skull* or hemispher* or intra-cran* or inter-cran*) adj5 (injur* or trauma* or damag* or wound* or fracture* or contusion*)).ab,ti.
12.((head or crani* or cerebr* or brain* or intra-cran* or inter-cran*) adj5 (haematoma* or hematoma* or haemorrhag* or hemorrhag* or bleed* or pressure)).ti,ab.
13.(Glasgow adj (coma or outcome) adj (scale* or score*)).ab,ti.
14."rancho los amigos scale".ti,ab.
15.("diffuse axonal injury" or "diffuse axonal injuries").ti,ab.
16.((brain or cerebral or intracranial) adj3 (oedema or edema or swell*)).ab,ti.
17.((unconscious* or coma* or concuss* or 'persistent vegetative state') adj3 (injur* or trauma* or damag* or wound* or fracture*)).ti,ab.
18.exp coma/
19.or/5-18
20.4 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
31.30 and 20

EMBASE (OvidSP)
1.exp mannitol/
2.exp Osmotic Diuretic Agent/
3.(mannitol or Mannit or Mannite or Osmosal or Osmosteril or Resectisol or Aridol or Bronchitol or bromine or mitobronitol or dibromomannitol or myelobromol or nsc-94* or osmitrol or osmofundin or "(l)-mannitol" or Dextro Mannitol or D-Mannitol or (diuretic* adj5 osmotic*)).ab,ti.
4.1 or 2 or 3
5.exp Brain Injury/
6.exp Brain Edema/
7.exp Glasgow Coma Scale/
8.exp Glasgow Outcome Scale/
9.exp Rancho Los Amigos Scale/
10.exp Unconsciousness/
11.((brain or cerebral or intracranial) adj5 (oedema or edema or swell*)).ab,ti.
12.((head or crani* or cerebr* or capitis or brain* or forebrain* or skull* or hemispher* or intra-cran* or inter-cran*) adj5 (injur* or trauma* or damag* or wound* or fracture* or contusion*)).ab,ti.
13.(Glasgow adj (coma or outcome) adj (scale* or score*)).ab,ti.
14.Rancho Los Amigos Scale.ab,ti.
15.((unconscious* or coma* or concuss* or 'persistent vegetative state') adj3 (injur* or trauma* or damag* or wound* or fracture*)).ti,ab.
16.Diffuse axonal injur*.ab,ti.
17.((head or crani* or cerebr* or brain* or intra-cran* or inter-cran*) adj3 (haematoma* or hematoma* or haemorrhag* or hemorrhag* or bleed* or pressure)).ab,ti.
18.or/5-17
19.exp Randomized Controlled Trial/
20.exp controlled clinical trial/
21.randomi?ed.ab,ti.
22.placebo.ab.
23.*Clinical Trial/
24.randomly.ab.
25.trial.ti.
26.19 or 20 or 21 or 22 or 23 or 24 or 25
27.exp animal/ not (exp human/ and exp animal/)
28.26 not 27
29.28 and 18
30.4 and 29

ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) & Conference Proceedings Citation Index- Science (CPCI-S)
1.Topic=(mannitol or Mannit or Mannite or Osmosal or Osmosteril or Resectisol or Aridol or Bronchitol or bromine or mitobronitol or dibromomannitol or myelobromol) OR Topic=(nsc-94* or osmitrol or osmofundin or "(l)-mannitol" or "Dextro Mannitol" or D-Mannitol or (diuretic* and osmotic*))
2.Topic=(intracranial pressure OR intracranial hypotension OR intracranial hypertension or head* or brain*)
3.TS=(clinical OR control* OR placebo OR random OR randomised OR randomized OR randomly OR random order OR random sequence OR random allocation OR randomly allocated OR at random) SAME TS=(trial* or group* or study or studies or placebo or controlled)
4.1 and 2 and 3

PubMed
1.(Mannitol OR Mannit OR Mannite OR Osmosal OR Osmosteril OR Resectisol OR Aridol OR Bronchitol OR Bromine OR Mitobronitol OR Dibromomannitol OR Myelobromol OR Nsc-94* OR Osmitrol OR Osmofundin OR "(l)-mannitol" OR "Dextro Mannitol" OR D-Mannitol OR (diuretic* and osmotic*))
2.(“intracranial pressure” OR “intracranial hypotension” OR “intracranial hypertension” OR head OR brain)
3.((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]))
4.#1 AND #2 AND #3

Feedback

Mannitol for acute traumatic brain injury

Summary

A. The search strategy would be clearer if the reviewer specified what additional search terms were used within the Injuries Group database to identify relevant articles (e.g., mannitol And acute brain injury). Also, the report does not specify whether any other databases, such as Medline or Embase, were searched, and if so, what search terms were used. The search should specify the total number of reports that were identified by the search strategy.

B. Would it be correct to interpret the review as demonstrating that there is no good evidence (i.e. no RCT's comparing mannitol to placebo or alternate therapies) to support our current mannitol use post-head injury? Presumably current use of mannitol by clinicians is based primarily on the pharmacological activities of mannitol, observational human studies, and animal evidence supporting its potential benefit.

Reply

A. We did not use any additional search terms in the Injuries Group database apart from 'mannitol'. No other databases, such as EMBASE, were searched separately (these searches were already included in the Injuries Group database).

B. Yes - the review concludes that there is a lack of evidence for effectiveness, which is not the same as saying there is evidence of a lack of effectiveness.

Contributors

Dr Michael Bullard

What's new

DateEventDescription
6 August 2013AmendedCopy edits made to the text.

History

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

DateEventDescription
20 April 2009New search has been performedThe search has been updated to April 2009.
20 April 2009New citation required but conclusions have not changedThe search has been updated to April 2009. No new trials were identified. The conclusions remain the same.
10 July 2008AmendedConverted to new review format.
22 November 2006AmendedNovember 2006
In response to concerns raised about the integrity of the data from the trials by Cruz et al, the Cochrane Injuries Group undertook an investigation in which attempts were made to find out where the patients were recruited and to access the original trial data for external validation. Despite considerable efforts the Group is unable to provide any reassurance about the integrity of trial data and for this reason the trials in question have been removed from the review.

Contributions of authors

AW ran the searches, screened the citations for eligibility, extracted data, entered data into RevMan and wrote the updated review.

AM screened the citations for eligibility, entered data into RevMan and helped write the updated review.

IR screened citations, extracted data, helped to write the original review.

GS designed and ran the searches, screened the citations for eligibility, contacted authors, extracted data, entered data into RevMan and wrote up the original review.

Declarations of interest

None known.

Sources of support

Internal sources

  • Department of Emergency Medicine, St. Vincent's University Hospital, Dublin 4, Ireland.

External sources

  • NHS R& D Programme: mother and child health, UK.

  • The Higher Specialist Training Scheme in Emergency Medicine, Ireland.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Sayre 1996

MethodsRandomised and double blind placebo controlled trial.
ParticipantsModerate and severe head injury (CGS 11 and less), above 18 years of age.
InterventionsMannitol received 5ml/kg of 20% mannitol through large-bore intravenous catheter over five minutes; placebo group were given5ml/kg of 0.9% saline solution.
OutcomesDeath was reported. Length of follow-up was two hours after hospital admission.
NotesTesting pre-hospital administration of mannitol.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskInformation not provided in published study.
Allocation concealment (selection bias)Low riskQuote: "The study solutions were prepared by the pharmacy department and were identified by a code number. An envelope showing the code number identified the contents of that IV bag. If the treating physicians at the receiving trauma center believed it was necessary to know whether the patient had received mannitol or placebo, the envelope could be opened".
Blinding (performance bias and detection bias)
All outcomes
Low risk

Comment: Blinding is implied but not explicitly stated.

Quote: "This was a prospective, randomized, double-blind, placebo-controlled clinical trial of the effect of mannitol on systolic BP in multiply injured patients with severe head injuries".

Quote: "The study solutions were prepared by the pharmacy department and were identified by a code number. An envelope showing the code number identified the contents of that IV bag. If the treating physicians at the receiving trauma center believed it was necessary to know whether the patient had received mannitol or placebo, the envelope could be opened".

Quote: "At the conclusion of the 2-hour monitoring period, the EM resident and the investigator recording the patient data were asked to provide their guesses as to whether mannitol or placebo had been administered to the patient. For those patients actually given mannitol, the resident correctly picked mannitol in 11 of 13 cases for which a guess was given; and the investigators correctly picked mannitol in 13 of 14 cases. For those patients actually given placebo, the resident correctly picked placebo in 5 of 10 cases for which a guess was given; and the investigators correctly picked placebo for 13 of 16 cases".

Schwartz 1984

MethodsRandomised single blind trial.
ParticipantsSevere head injury (GCS<8). Participants had to have already been resuscitated and had raised ICP for more than 15 minutes.
Interventions

The mannitol group received 20% mannitol solution at an initial dose of 1g per kg. Additional increments were given to maintain the intracranial pressure at less than 20 torr, within a serum osmolarity of mannitol of 320mOs/L.

The pentobarbital group received pentobarbital as an IV bolus of up to 10mg/kg, followed by a continuous infusion at 0.5-3 mg/kg/hr, provided that CPP remained above 50 torr, Additional increments of pentobarbital were given to maintain the intracranial pressure at less than 20 torr.

OutcomesDeath reported. Follow-up to three months.
NotesFor subsequent episodes of raised ICP, cross-over between the groups was allowed.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "The starting drug was determined by a random number generator."
Allocation concealment (selection bias)Low riskQuote: "The mechanism of randomization was the opening of a serially-numbered, sealed envelope taken from one of two packages of envelopes, one for patients who had had intracranial hematomas removed and one for those who developed raised intracranial pressure from brain injury alone."
Blinding (performance bias and detection bias)
All outcomes
Unclear risk.

Smith 1986

MethodsRandomised controlled trial; not reported as double-blind.
ParticipantsSevere head injury (GCS 8 or less).
InterventionsCompared two regimens of guiding the administration of mannitol, one according to neurological signs and physiological measurements, and the other using ICP monitoring. The protocol for the first group used neurological signs, GCS, ventilatory values and arterial blood gas to guide administration. In the second group, a 250ml bolus of mannitol (20%) was given if ICP >25mmHg, and subsequent boluses were given incrementally.
OutcomesDeaths and neurological disability were reported. Follow-up was one year.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided in published study.
Allocation concealment (selection bias)Low riskQuote: "The patients were randomly assigned to one of two groups by means of sealed envelopes containing cards designating the assigned protocol: Group I (mannitol therapy based on ICP monitoring) or Group II (empirical mannitol therapy)".
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information provided in published study.

Vialet 2003

MethodsRandomised single blind trial.
ParticipantsSevere head injury (GCS<8) who required intravenous infusions of an osmotic agent to treat episodes of intracranial hypertension resistant to standard therapy.
InterventionsCompared two osmotic agents, mannitol and hypertonic saline solution. The mannitol group received 20% mannitol solution. The hypertonic saline group received 7.5% hypertonic saline. The infused volume was the same for both solutions: 2 ml/kg body weight in 20 minutes.
OutcomesDeath and neurological disability reported. Follow-up to three months.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided in published study.
Allocation concealment (selection bias)Unclear riskQuote: "After randomization, the patients received either 20% mannitol (1160 mOsm/kg/H2O) or 7.5% HSS (2400 mOsm/kg/H2O)".
Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "Because 20% mannitol can crystallize at ambient temperature, injections could not be performed in a blinded manner."

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Battison 2005Cross-over design.
Cruz 2001Concerns about the integrity of the trial data. Manuscripts does not indicate where the patients were randomised and despite an investigation by the Cochrane Injuries Group this remains open to question.
Cruz 2002Concerns about the integrity of the trial data. Manuscripts does not indicate where the patients were randomised and despite an investigation by the Cochrane Injuries Group this remains open to question.
Cruz 2004Concerns about the integrity of the trial data. Manuscripts does not indicate where the patients were randomised and despite an investigation by the Cochrane Injuries Group this remains open to question.
Fortune 1995Controlled follow up study; no means to reduce bias in the selection of the control group was used.
Francony 2008Participants were not all head-injured patients.
Gaab 1989Randomised to a diuretic, not necessarily mannitol.
Harutjunyan 2005Participants were not all head-injured patients.
Ichai 2009Cross-over design.
Levin 1979Participants were not all head injured; had a cross-over design.
Midgely 1993Cross-over design.
Smedema 1993Participants were not all head-injured patients.

Ancillary