We reviewed the evidence for the effectiveness and safety of infusions (where a substance is given through a vein) of hypertonic saline (concentrated salt (sodium chloride) solution) compared with other types of infusion for lowering intracranial pressure (pressure in and around the brain) in the management of acute traumatic brain injury.
Acute traumatic brain injury (sudden and severe injury to the brain, often due to accidents) is a leading cause of death and disability worldwide, especially in children and young people. Intracranial hypertension (the build-up of high pressure within and around the brain) is common after damage to the brain. This is because the skull is a rigid compartment that contains three parts: soft brain tissue, blood, and cerebrospinal fluid. If an increase occurs in the volume of one component, such as hematomas (collections of blood) within the brain's soft tissue, the volume of one or more of the other components must decrease - otherwise intracranial pressure will rise. If intracranial pressure increases beyond certain limits, there is an imbalance, and blood flow to the brain becomes dangerously low. This high intracranial pressure can cause serious effects that include brain damage and death. Hyperosmolar therapy is an important treatment for raised intracranial pressure. One kind of hyperosmolar therapy involves an infusion of concentrated (hypertonic) saline (table salt/sodium chloride) solution into the blood; other treatments including mannitol (a form of sugar) can also be used. Such treatments may lower intracranial pressure by reducing water volume inside and between brain cells.
In December 2019, the authors of this review searched for randomised trials comparing the effects and safety of hypertonic saline with other fluid infusions that are used to lower intracranial pressure in people with acute traumatic brain injury. The review authors searched a wide variety of medical databases and identified six relevant trials, with data from a total of 287 participants. The trials were all randomised controlled trials, which produce the most reliable evidence. Three trials took place in India, one each in France and Germany, and one included people from both France and Israel. Most people in the trials (91%) had traumatic brain injury. Trials compared various concentrations of hypertonic saline with either mannitol or mannitol in combination with glycerol.
Based on limited data of these six trials, there is no clear evidence to support the use of hypertonic saline infusion over mannitol infusion for people with acute traumatic brain injury. Adverse effects of the treatments were not routinely measured.
More research is needed. Future trials should be larger and better reported. Potential points for research include investigating whether there is a particular concentration of infusion, or length of time over which the infusion is given, that benefits people with raised intracranial pressure after traumatic brain injury.
This review set out to find trials comparing hypertonic saline to a potential range of other intracranial pressure-lowering agents, but only identified trials comparing it with mannitol or mannitol in combination with glycerol. Based on limited data, there is weak evidence to suggest that hypertonic saline is no better than mannitol in efficacy and safety in the long-term management of acute traumatic brain injury. Future research should be comprised of large, multi-site trials, prospectively registered, reported in accordance with current best practice. Trials should investigate issues such as the type of traumatic brain injury suffered by participants and concentration of infusion and length of time over which the infusion is given.
Increased intracranial pressure has been shown to be strongly associated with poor neurological outcomes and mortality for patients with acute traumatic brain injury. Currently, most efforts to treat these injuries focus on controlling the intracranial pressure. Hypertonic saline is a hyperosmolar therapy that is used in traumatic brain injury to reduce intracranial pressure. The effectiveness of hypertonic saline compared with other intracranial pressure-lowering agents in the management of acute traumatic brain injury is still debated, both in the short and the long term.
To assess the comparative efficacy and safety of hypertonic saline versus other intracranial pressure-lowering agents in the management of acute traumatic brain injury.
We searched Cochrane Injuries' Specialised Register, CENTRAL, PubMed, Embase Classic+Embase, ISI Web of Science: Science Citation Index and Conference Proceedings Citation Index-Science, as well as trials registers, on 11 December 2019. We supplemented these searches with searches of four major Chinese databases on 19 September 2018. We also checked bibliographies, and contacted trial authors to identify additional trials.
We sought to identify all randomised controlled trials (RCTs) of hypertonic saline versus other intracranial pressure-lowering agents for people with acute traumatic brain injury of any severity. We excluded cross-over trials as incompatible with assessing long-term outcomes.
Two review authors independently screened search results to identify potentially eligible trials and extracted data using a standard data extraction form. Outcome measures included: mortality at end of follow-up (all-cause); death or disability (as measured by the Glasgow Outcome Scale (GOS)); uncontrolled intracranial pressure (defined as failure to decrease the intracranial pressure to target and/or requiring additional intervention); and adverse events e.g. rebound phenomena; pulmonary oedema; acute renal failure during treatment).
Six trials, involving data from 287 people, met the inclusion criteria. The majority of participants (91%) had a diagnosis of severe traumatic brain injury. We had concerns about particular domains of risk of bias in each trial, as physicians were not reliably blinded to allocation, two trials contained participants with conditions other than traumatic brain injury and in one trial, we had concerns about missing data for important outcomes. The original protocol was available for only one trial and other trials (where registered) were registered retrospectively.
Meta-analysis for both the primary outcome (mortality at final follow-up) and for 'poor outcome' as per conventionally dichotomised GOS criteria, was only possible for two trials. Synthesis of long-term outcomes was inhibited by the fact that two trials ceased data collection within two hours of a single bolus dose of an intracranial pressure-lowering agent and one at discharge from the intensive care unit (ICU). Only three trials collected data after participants were released from hospital, one of which did not report mortality and reported a 'poor outcome' by GOS criteria in an unconventional way. Substantial missing data in a key trial meant that in meta-analysis we report 'best-case' and 'worst-case' estimates alongside available case analysis. In no scenario did we discern a clear difference between treatments for either mortality or poor neurological outcome.
Due to variation in modes of drug administration (including whether it followed or did not follow cerebrospinal fluid (CSF) drainage, as well as different follow-up times and ways of reporting changes in intracranial pressure, as well as no uniform definition of 'uncontrolled intracranial pressure', we did not perform meta-analysis for this outcome and report results narratively, by individual trial. Trials tended to report both treatments to be effective in reducing elevated intracranial pressure but that hypertonic saline had increased benefits, usually adding that pretreatment factors need to be considered (e.g. serum sodium and both system and brain haemodynamics). No trial provided data for our other outcomes of interest. We consider evidence quality for all outcomes to be very low, as assessed by GRADE; we downgraded all conclusions due to imprecision (small sample size), indirectness (due to choice of measurement and/or selection of participants without traumatic brain injury), and in some cases, risk of bias and inconsistency.
Only one of the included trials reported data on adverse effects; a rebound phenomenon, which was present only in the comparator group (mannitol). None of the trials reported data on pulmonary oedema or acute renal failure during treatment. On the whole, trial authors do not seem to have rigorously sought to collect data on adverse events.