Hypertonic saline versus other intracranial pressure–lowering agents for people with acute traumatic brain injury

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To compare the effects of HTS solutions versus those of other ICP-lowering agents in reducing mortality, disability and elevated ICP in people with acute TBI. To quantify potential side effects resulting from the use of HTS solutions.


Hypertonic saline (HTS) solutions have been shown to reliably and safely reduce raised intracranial pressure (ICP) in patients with acute traumatic brain injury (TBI) (Fisher 1992; Härtl 1997). HTS solutions even lowered ICP in patients who were refractory to standard therapeutic approaches (Horn 1999; Kerwin 2009; Khanna 2000; Worthley 1988). Whether HTS solutions may be superior to other ICP-lowering agents for individuals with acute TBI remains a controversial issue.

Description of the condition

TBI is a major cause of death and disability worldwide (Corrigan 2010). Intracranial hypertension secondary to TBI is well known to have a profound influence on outcome, and severe intracranial hypertension was associated with higher morbidity in patients with TBI (Miller 1977). In a review of studies of the value of ICP in predicting outcomes in TBI, the rate of death was 18.4% for participants with ICP less than 20 mmHg and 24.8% for participants with ICP between 20 mmHg and 40 mmHg but 55.6% for those with ICP greater than 40 mmHg (Treggiari 2007). Achieving a sustained reduction in ICP remains a focus of neurocritical care.

Description of the intervention

Currently available medical treatments for raised ICP include hyperosmolar therapy, sedation and paralysis, hyperventilation, barbiturate coma, hypothermia, steroids and surgical intervention (Rangel-Castillo 2008). Hyperosmolar therapy is the cornerstone of pharmaceutical treatment for intracranial hypertension. Hyperosmolar therapy can be defined broadly as the use of hypertonic solutions to reduce accumulated fluid in the brain. Reported concentrations of HTS for clinical use range from 2% to 23.5%. HTS solutions are often used when elevated ICP is resistant to other intracranial pressure–lowering agents, especially in patients with head trauma or postoperative cerebral oedema (Ziai 2007).

How the intervention might work

The ICP-lowering mechanisms of HTS solutions are believed to be due to their effects on microcirculation and osmotic action (Ziai 2007). HTS solutions decrease serum viscosity and hematocrit, leading to an increase in cerebral perfusion and causing cerebral arteriole vasoconstriction that reduces cerebral blood volume (CBV) and ICP. Water always flows from body compartments with low osmolality to those with higher osmolality. HTS solutions increase plasma osmolarity after administration, thus promoting gradual movement of water from tissues into the circulation. As fluid moves into the vascular space and is carried away by the blood, the brain shrinks and ICP is reduced.

Why it is important to do this review

Increasing evidence shows that HTS solutions should be considered gold standard medical therapy for ICP (Marko 2012). This review will be undertaken to enable improved understanding of the efficacy and potential side effects of HTS solutions for people with acute TBI.


To compare the effects of HTS solutions versus those of other ICP-lowering agents in reducing mortality, disability and elevated ICP in people with acute TBI. To quantify potential side effects resulting from the use of HTS solutions.


Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) with a parallel design.

Types of participants

We will include participants with acute clinically defined TBI of any severity.

Types of interventions

Any HTS in any dosage for any duration, given at any time within eight weeks following injury. HTS is compared with another ICP-lowering agent, such as mannitol or barbiturates or steroids.

Types of outcome measures

Primary outcomes
  • Death at final follow-up.

Secondary outcomes
  • Death or disability at final follow-up (as measured by the Glasgow Outcome Scale (GOS)). The GOS score will be converted into a dichotomous outcome. ‘Death or disability’ will mean death, persistent vegetative state and severe disability; a ‘good outcome’ will include moderate disability and good recovery.

  • Uncontrolled ICP during treatment.

  • A rebound phenomenon during treatment (a subsequent rise of ICP above pretreatment levels after repeated administration of osmotic agents).

  • Pulmonary oedema during treatment.

  • Acute renal failure during treatment.

474 patients are required to have a 90% chance of detecting, as significant at the 5% level, a decrease in death from 27% in the control group to 15% in the experimental group (Lu 2005).

Search methods for identification of studies

Searches will not be restricted by date, language or publication status.

Electronic searches

The Cochrane Injuries Group Trials Search Co-ordinator will search the following.

  • Cochrane Injuries Group specialised register (present version).

  • Cochrane Central Register of Controlled Trials (CENTRAL, latest issue).

  • PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) (present).

  • EMBASE Classic + EMBASE (Ovid SP) (1947 to present).

  • ISI Web of Science: Science Citation Index-Expanded (SCI-EXPANDED) (1970 to present).

  • ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (1990 to present).

The PubMed search strategy (Appendix 1) will be adapted as necessary for each of the other databases.

Shuang Yang Liu, from the Department of Documentation and Retrieval, Xiangya Medical College, Central South University, will search the following Chinese databases.

  • ChinaBiologyMedicinedisc (CBMdisc).

  • Wanfang Data.

  • China National Knowledge Infrastructure (CNKI).

  • VIP Database for Chinese Technical Periodicals.

The CBMdisc search strategy (Appendix 2) will be adapted as necessary for each of the other databases.

Searching other resources

We will also search the following clinical trial registers.

The reference lists of all identified relevant articles will be checked. We will contact the first authors of all included trials to ask whether they are aware of any ongoing studies.

Data collection and analysis

Selection of studies

The two review authors will independently screen the search results and will meet to discuss the trials eligible for inclusion. Disagreement about inclusion of studies will be resolved by seeking the advice of a clinical expert in neurosurgery. We will examine each potential title. If titles are ambiguous, we will read the abstracts.

Data extraction and management

Two review authors will independently extract and record the data on specially designed forms and subsequently will cross-check the data. Multiple reports of the same study will be grouped together under a single included study reference, and we will consider all study reports for data extraction.

We will collect the following data from the study reports: study design, participant characteristics, intervention characteristics, outcomes and adverse effects. Participant characteristics include age, sex and TBI severity. Intervention characteristics include concentration, dosage, timing of administration and duration of intervention. Outcome measures include ICP, cerebral perfusion pressure (CPP), mortality and morbidity according to GOS score (Jennett 1975). Dichotomous outcomes will be entered into Review Manager as the number of events by the same review authors independently.

Assessment of risk of bias in included studies

Both review authors will independently assess the risk of bias for each included study using The Cochrane Collaboration risk of bias tool (Higgins 2011). We will contact study authors to ask for clarification of study methods and to request the study protocols.

Measures of treatment effect

We will calculate risk ratios with corresponding 95% confidence intervals.

Unit of analysis issues

The unit of analysis is the participant.

Dealing with missing data

If data are missing from trial reports, we will attempt to contact trial authors. We will use intention-to-treat (ITT) analysis.

Assessment of heterogeneity

The Chi2 test will be used to assess whether differences between studies would be expected by chance. The Chi2 test is underpowered for small studies, and a significance level of P value 0.10 will be used. The I2 statistic will be used to quantify the amount of heterogeneity. An I2 test value greater than 50% will indicate substantial statistical heterogeneity.

Assessment of reporting biases

We will try to contact the study authors to ask for the original protocols and will assess reporting biases with a funnel plot if at least 10 studies are available for the meta-analysis.

Data synthesis

A Mantel-Haenszel fixed-effect model will be used.

Subgroup analysis and investigation of heterogeneity

When the data allow, subgroup analyses may be done for subsets of participants (children and adults) or for subsets of interventions (e.g. different dosage and different duration, with or without a colloid).

Sensitivity analysis

A sensitivity analysis will be performed for allocation concealment (adequate vs unclear or not done).


The review authors would like to thank the Cochrane Injuries Group for helping to draft the search strategy in English for this review.


Appendix 1. PubMed search strategy

PubMed [http://www.ncbi.nlm.nih.gov/pubmed/]

((((((((((fluid management[Title/Abstract]) OR sodium[Title/Abstract] OR fluid therapy*[Title/Abstract]) OR hypertonic saline resuscitation[Title/Abstract]) OR maintenance fluid*[Title/Abstract]) OR "hts"[Title/Abstract]) OR hypertonic saline infusion*[Title/Abstract]) OR hypertonic sodium chloride solution*[Title/Abstract])) OR ((((("Saline Solution, Hypertonic"[Mesh]) OR "Hypertonic Solutions"[Mesh:NoExp]) OR "Fluid Therapy"[Mesh]) OR "Sodium"[Mesh]) OR "Sodium Chloride"[Mesh]))) AND ((((((((("Comparative Study"[Publication Type]) OR "Randomized Controlled Trial"[Publication Type]) OR "Controlled Clinical Trial"[Publication Type])) OR (((((((randomized[Title/Abstract]) OR randomised[Title/Abstract]) OR placebo[Title/Abstract]) OR randomly[Title/Abstract]) OR trial[Title/Abstract]) OR groups[Title/Abstract]) OR group[Title/Abstract]))) NOT (("Animals"[Mesh]) NOT ("Animals"[Mesh] AND "Humans"[Mesh])))) AND (((((((((((((("Craniocerebral Trauma"[Mesh])) OR "Brain Edema"[Mesh]) OR "Glasgow Coma Scale"[Mesh]) OR "Glasgow Outcome Scale"[Mesh]) OR "Unconsciousness"[Mesh]) OR "Cerebrovascular Trauma"[Mesh])) OR ((((((((haematoma*[Title/Abstract]) OR hematoma*[Title/Abstract]) OR haemorrhag*[Title/Abstract]) OR hemorrhage*[Title/Abstract]) OR bleed*[Title/Abstract]) OR pressure[Title/Abstract])) AND ((((((head[Title/Abstract]) OR cranial[Title/Abstract]) OR cerebral[Title/Abstract]) OR brain*[Title/Abstract]) OR intra-cranial[Title/Abstract]) OR inter-cranial[Title/Abstract]))) OR (((((diffuse axonal injury[Title/Abstract]) OR diffuse axonal injuries[Title/Abstract]) OR persistent vegetative state[Title/Abstract]) OR glasgow outcome scale[Title/Abstract]) OR glasgow coma scale[Title/Abstract])) OR ((((((((((((((((injury*[Title/Abstract]) OR injuries[Title/Abstract]) OR trauma[Title/Abstract]) OR damage[Title/Abstract]) OR damaged[Title/Abstract]) OR wound*[Title/Abstract]) OR fracture*[Title/Abstract]) OR contusion*[Title/Abstract]) OR haematoma*[Title/Abstract]) OR hematoma*[Title/Abstract]) OR Haemorrhag*[Title/Abstract]) OR hemorrhag*[Title/Abstract]) OR bleed*[Title/Abstract]) OR pressure[Title/Abstract])) AND (((unconscious*[Title/Abstract]) OR coma*[Title/Abstract]) OR concuss*[Title/Abstract]))))))

Appendix 2. CBMdisc search strategy

#1 "随机对照试验"[扩展全部树]/全部副主题词

#2 "随机分配"[扩展全部树]/全部副主题词

#3 "双盲法"[扩展全部树]/全部副主题词

#4 "单盲法"[扩展全部树]/全部副主题词

#5 "临床试验"[扩展全部树]/全部副主题词

#6 "临床试验"

#7 "双盲"

#8 "单盲"

#9 "安慰剂"

#10 "盲法"

#11 "随机"

#12 "研究设计"[扩展全部树]/全部副主题词

#13 CT=对比研究

#14 "评价研究"[扩展全部树]/全部副主题词

#15 "随访研究"[扩展全部树]/全部副主题词

#16 "前瞻性研究"[扩展全部树]/全部副主题词

#17 "对照"

#18 "前瞻"

#19 "志愿者"

#20 CT=动物 AND NOT(CT=人类 AND CT=动物)

#21 #1-#11/ OR 查找包括随机试验在内的所有临床实验文献)

#22 #21 AND NOT #20(排除动物试验后所有人体实验的临床实验文献)

#23 #12-#19/OR(查找所有包括评价、对比、随访及前瞻性研究的文献)

#24 #23 AND NOT #20(排除动物试验后所有包括评价、对比、随访及前瞻性研究的文献)

#25 #22 OR #24(排除动物试验后所有包括随机对照试验在内的人体临床试验及评价、对比、随访及前瞻性研究的人体试验文献)

#26 "盐水, 高渗"[不加权:扩展]

#27 "高渗溶液"[不加权:不扩展]

#28 "补液疗法"[不加权:扩展]

#29 "钠"[不加权:扩展]

#30 "氯化钠"[不加权:扩展]

#31 "高渗氯化钠溶液复苏"[常用字段:智能]

#32 ("液体疗法"[常用字段:智能]) OR "补液疗法"[常用字段:智能]

#33 "hts"[常用字段:智能]

#34 "高渗盐水"[常用字段:智能]

#35 "高渗氯化钠溶液"[常用字段:智能]

#36 #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35

#37 "颅脑损伤"[不加权:扩展]

#38 "脑水肿"[不加权:扩展]

#39 "格拉斯哥昏迷量表"[不加权:扩展]

#40 "格拉斯哥预后评分"[不加权:扩展]

#41 "意识丧失"[不加权:扩展]

#42 "脑血管损伤"[不加权:扩展]

#43 #37 OR #38 OR #39 OR #40 OR #41 OR #42

#44 "脑出血"[常用字段:智能]

#45 "脑溢血"[常用字段:智能]

#46 "脑水肿"[常用字段:智能]

#47 "脑血肿"[常用字段:智能]

#48 #44 OR #45 OR #46 OR #47

#49 "弥漫性轴索损伤"[常用字段:智能]

#50 "弥漫性轴突损伤"[常用字段:智能]

#51 "植物状态"[常用字段:智能]

#52 "格拉斯哥昏迷量表"[常用字段:智能]

#53 "格拉斯哥预后评分"[常用字段:智能]

#54 #49 OR #50 OR #51 OR #52 OR #53

#55 "创伤和损伤"[不加权:扩展]

#56 "损伤"[常用字段:智能]

#57 "创伤"[常用字段:智能]

#58 "出血"[常用字段:智能]

#59 "溢血"[常用字段:智能]

#60 "血肿"[常用字段:智能]

#61 "水肿"[常用字段:智能]

#62 #55 OR #56 OR #57 OR #58 OR #59 OR #60 OR #61

#63 "昏迷"[常用字段:智能]

#64 "震荡"[常用字段:智能]

#65 #63 OR #64

#66 #62 AND #65

#67 #43 OR #48 OR #54 OR #66

#68 #25 AND #36 AND #67

Contributions of authors

Both review authors contributed to the protocol.

Declarations of interest

None known.