Han Chen1, Zhi Song1, Jane A Dennis2. 1. Third Xiangya Hospital, Central South University, Department of Neurology, 138 Tongzipo Road, Yulu District, Chang Sha, China, 410013. 2. University of Bristol, Musculoskeletal Research Unit, School of Clinical Sciences, Learning and Research Building [Level 1], Southmead Hospital, Bristol, UK, BS10 5NB.
Abstract
BACKGROUND: Increased intracranial pressure (ICP) has been shown to be strongly associated with poor neurological outcomes and mortality for patients with acute traumatic brain injury (TBI). Currently, most efforts to treat these injuries focus on controlling the ICP. Hypertonic saline (HTS) is a hyperosmolar therapy that is used in traumatic brain injury to reduce intracranial pressure. The effectiveness of HTS compared with other ICP-lowering agents in the management of acute TBI is still debated, both in the short and the long term. OBJECTIVES: To assess the comparative efficacy and safety of hypertonic saline versus other ICP-lowering agents in the management of acute TBI. SEARCH METHODS: We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library, PubMed, Embase Classic+Embase (OvidSP), 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 using four major Chinese databases on 19 September 2018. We also checked bibliographies, and contacted study authors to identify additional studies. SELECTION CRITERIA: We sought to identify all randomised controlled trials (RCTs) of HTS versus other intracranial pressure-lowering agents for people with acute TBI of any severity. We excluded cross-over trials as incompatible with assessing long term outcomes. DATA COLLECTION AND ANALYSIS: 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 ICP (defined as failure to decrease the ICP to target and/or requiring additional intervention); and adverse events (AEs) (e.g. rebound phenomena; pulmonary oedema; acute renal failure during treatment). MAIN RESULTS: Six trials, involving data from 295 people, met the inclusion criteria. The majority of participants (89%) had a diagnosis of severe TBI. 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 TBI and in one trial, there were concerns about missing data for important outcomes. The original protocol was available for only one study 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 studies. Synthesis of long-term outcomes was inhibited by the fact that two ceased data collection within two hours of a single bolus dose of an ICP-lowering agent and one at discharge from ICU. Only three studies collected data after release from hospital. Due to variation in modes of drug administration, follow-up times, and ways of reporting changes in ICP, as well as no uniform definition of 'uncontrolled ICP', 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 ICP but that HTS had increased benefits, usually adding that pretreatment factors need to be considered (e.g. serum sodium and both system and brain hemodynamics). No trial provided data for our other outcomes of interest. Evidence for all outcomes is considered very low, as assessed by GRADE. All conclusions were downgraded due to imprecision (small sample size), indirectness (due to choice of measurement and/or selection of patients without TBI), and in some cases, risk of bias and inconsistency. Only one of the included trials reported data on adverse effects (AEs) - a rebound phenomenon, which was present only in the comparator group (mannitol). No data were reported on pulmonary oedema or acute renal failure during treatment. On the whole, investigators do not seem to have rigorously sought to collect data on AEs. AUTHORS' CONCLUSIONS: This review set out to find trials comparing HTS to a potential range of other ICP-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 HTS is no better than mannitol in efficacy and safety in the long-term management of acute TBI. Future research should be comprised of large, multi-site trials, prospectively registered, reported in accordance with current best practice. Issues such as the type of TBI suffered by participants and concentration of infusion and length of time over which the infusion is given should be investigated.
BACKGROUND: Increased intracranial pressure (ICP) has been shown to be strongly associated with poor neurological outcomes and mortality for patients with acute traumatic brain injury (TBI). Currently, most efforts to treat these injuries focus on controlling the ICP. Hypertonic saline (HTS) is a hyperosmolar therapy that is used in traumatic brain injury to reduce intracranial pressure. The effectiveness of HTS compared with other ICP-lowering agents in the management of acute TBI is still debated, both in the short and the long term. OBJECTIVES: To assess the comparative efficacy and safety of hypertonic saline versus other ICP-lowering agents in the management of acute TBI. SEARCH METHODS: We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library, PubMed, Embase Classic+Embase (OvidSP), 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 using four major Chinese databases on 19 September 2018. We also checked bibliographies, and contacted study authors to identify additional studies. SELECTION CRITERIA: We sought to identify all randomised controlled trials (RCTs) of HTS versus other intracranial pressure-lowering agents for people with acute TBI of any severity. We excluded cross-over trials as incompatible with assessing long term outcomes. DATA COLLECTION AND ANALYSIS: 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 ICP (defined as failure to decrease the ICP to target and/or requiring additional intervention); and adverse events (AEs) (e.g. rebound phenomena; pulmonary oedema; acute renal failure during treatment). MAIN RESULTS: Six trials, involving data from 295 people, met the inclusion criteria. The majority of participants (89%) had a diagnosis of severe TBI. 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 TBI and in one trial, there were concerns about missing data for important outcomes. The original protocol was available for only one study 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 studies. Synthesis of long-term outcomes was inhibited by the fact that two ceased data collection within two hours of a single bolus dose of an ICP-lowering agent and one at discharge from ICU. Only three studies collected data after release from hospital. Due to variation in modes of drug administration, follow-up times, and ways of reporting changes in ICP, as well as no uniform definition of 'uncontrolled ICP', 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 ICP but that HTS had increased benefits, usually adding that pretreatment factors need to be considered (e.g. serum sodium and both system and brain hemodynamics). No trial provided data for our other outcomes of interest. Evidence for all outcomes is considered very low, as assessed by GRADE. All conclusions were downgraded due to imprecision (small sample size), indirectness (due to choice of measurement and/or selection of patients without TBI), and in some cases, risk of bias and inconsistency. Only one of the included trials reported data on adverse effects (AEs) - a rebound phenomenon, which was present only in the comparator group (mannitol). No data were reported on pulmonary oedema or acute renal failure during treatment. On the whole, investigators do not seem to have rigorously sought to collect data on AEs. AUTHORS' CONCLUSIONS: This review set out to find trials comparing HTS to a potential range of other ICP-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 HTS is no better than mannitol in efficacy and safety in the long-term management of acute TBI. Future research should be comprised of large, multi-site trials, prospectively registered, reported in accordance with current best practice. Issues such as the type of TBI suffered by participants and concentration of infusion and length of time over which the infusion is given should be investigated.
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