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Hypertonic Saline for Increased Intracranial Pressure After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review
Accepted Manuscript Hypertonic Saline for Raised Intracranial Pressure Following Aneurysmal Subarachnoid Hemorrhage: A Systematic Review Christopher R. Pasarikovski, MD, Naif M. Alotaibi, MD, Fawaz Al-Mufti, MD, R. Loch Macdonald, MD, PhD PII:
S1878-8750(17)30784-2
DOI:
10.1016/j.wneu.2017.05.085
Reference:
WNEU 5779
To appear in:
World Neurosurgery
Received Date: 21 April 2017 Accepted Date: 14 May 2017
Please cite this article as: Pasarikovski CR, Alotaibi NM, Al-Mufti F, Macdonald RL, Hypertonic Saline for Raised Intracranial Pressure Following Aneurysmal Subarachnoid Hemorrhage: A Systematic Review, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.05.085. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Hypertonic Saline for Raised Intracranial Pressure Following Aneurysmal
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Subarachnoid Hemorrhage: A Systematic Review
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Authors: Christopher R. Pasarikovski, MD 1, Naif M. Alotaibi, MD 1,2, Fawaz Al-Mufti,
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MD 3, R. Loch Macdonald, MD, PhD 1,2, 4
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Affiliations:
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Canada; 2 Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto,
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Ontario, Canada; 3 Endovascular Surgical Neuroradiology Program, Rutgers University-New
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Jersey Medical School, Newark, NJ, USA, and 4 Division of Neurosurgery, St. Michael’s
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Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan
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Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department
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of Surgery, University of Toronto, Canada.
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Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario,
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Keywords: Aneurysm – Brain - Cerebral – Subarachnoid Hemorrhage – SAH – 3% -
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Hypertonic – Saline – Intracranial Pressure – ICP
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Corresponding Author:
Naif M. Alotaibi, M.D. Division of Neurosurgery, University of Toronto 399 Bathurst St., WW 4-427 Toronto, ON M5T 2S8
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Tel: (416) 603-5800 ext. 5503 Fax: (416) 603-5298
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Email : [email protected]
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Manuscript word count: 2258
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Title character count: 116
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Figures: 1
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Tables: 4
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Author contributions
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Study concept and design: Alotaibi, Pasarikovski
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Acquisition, analysis, or interpretation of data: All authors
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Drafting the article: Pasarikovski, Alotaibi.
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Critically revising the article: Al-Mufti, Macdonald.
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Administrative, technical, or material support: Alotaibi.
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Statistical analysis: Not applicable
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Study supervision: Alotaibi.
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Conflict of interest: Dr. Macdonald receives grant support from the Brain Aneurysm
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Foundation, Canadian Institutes for Health Research and the Heart and Stroke Foundation of
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Canada; and is an employee and Chief Scientific Officer of Edge Therapeutics, Inc. The other
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authors declare that they have no competing interests.
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Funding: This research did not receive any specific grant from funding agencies in the
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public, commercial, or not-for-profit sectors.
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ACCEPTED MANUSCRIPT ABSTRACT
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Background: The use of hyperosmolar agents such as mannitol or hypertonic saline (HTS) to
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control high intracranial pressure (ICP) in traumatic brain injury patients has been well
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studied. However, the role of HTS in the management of aneurysmal subarachnoid
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hemorrhage (aSAH)-associated raised ICP is still unclear.
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Methods: We performed a systematic review in accordance with the Preferred Reporting
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Items for Systematic Reviews and Meta-Analyses guidelines. The primary outcome of this
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review is to quantify ICP reduction produced by HTS and its effect on clinical outcomes
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defined by any standardized functional score. Secondary outcomes included: HTS vs.
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mannitol in ICP reduction, HTS effects on cerebral vasospasm, and HTS dose concentration,
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infusion rate, infusion volume, frequency of re-dosing, and serum sodium/osmolality limits
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for repeat dosing.
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Results: Five studies were included in the review encompassing 175 patients. Studies on
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aSAH included mostly poor-grade patients (defined as World Federation of Neurosurgical
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Societies grade 4 and 5). HTS concentrations ranged from 3% to 23.5%. Most studies found
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that HTS decreased ICP when compared to either baseline or placebo. The mean decrease in
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ICP from HTS administration was 8.9 mm Hg [range: 3.3-12.1]. Only one study showed
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possible improvement in poor-grade aSAH outcomes.
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Conclusions: The current evidence suggests that HTS is as effective as mannitol at reducing
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raised ICP in aSAH. However, there is not enough data to recommend the optimal and safest
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dose concentration or whether HTS significantly improves outcomes in aSAH.
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INTRODUCTION The use of hyperosmolar agents such as mannitol or hypertonic saline (HTS) for
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intracranial hypertension in traumatic brain injury (TBI) patients has been well documented.1,
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from any cause.3 Raised intracranial pressure (ICP) is common in acute aneurysmal
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subarachnoid hemorrhage (aSAH), particularity in patients with poor grade aSAH.4 The
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underlying pathophysiology between TBI and aSAH induced raised ICP is likely different,
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and hyperosmolar agents and doses used in TBI cannot necessarily be used in aSAH
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patients.5 Marginal literature on the use of HTS in aSAH induced raised ICP exist.6 The
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indication to use HTS over mannitol, HTS concentration, and bolus infusion rate is even
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more undefined.
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HTS has gained popularity among physicians treating patients for intracranial hypertension
The primary goal of this study was to conduct a systematic review on the use of HTS to lower raised ICP in aSAH patients and examine the current evidence of HTS effects on
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aSAH outcomes. Secondarily, we sought to clarify HTS concentration, infusion rates,
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volume, frequency of re-dosing, and serum sodium/osmolality restrictions in aSAH.
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METHODS
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Search Strategy and Study Eligibility
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Peer-reviewed articles were collected through MEDLINE, Embase, Scopus, and
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Cochrane Central Register of Controlled Trials (CENTRAL) searches according to the
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Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)7
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guidelines. The keywords used in combination included: “hypertonic saline”, “intracranial
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pressure”, and “subarachnoid hemorrhage.” There were no restrictions on publications’
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language, type or dates. One reviewer conducted the search (C.R.P) and then the search was
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verified by another reviewer (N.M.A). We included all studies on human subjects who had
ACCEPTED MANUSCRIPT aSAH and the use of HTS. This included the use of HTS to increase/improve cerebral
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perfusion, decrease ICP, and comparisons to mannitol. All HTS dose concentrations and
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infusion rates were included. All studies needed to be peer-reviewed, conducted on human
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subjects, and have ICP recorded with either intraparenchymal monitors or external ventricular
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drains (EVD). Case reports and case series with <65% aSAH patients were not included.
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Studies focused only on correction of hyponatremia using HTS were also excluded.
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Data Extraction
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Data on World Federation of Neurosurgical Societies (WFNS), Hunt and Hess (H&H), and Fisher Grades (FG) were collected from each study. Method of ICP monitoring
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was included, which was either intraparenchymal monitor or EVD. Other variables extracted
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from each study included study type, year of publication, country of origin, ICP reduction
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rate, functional outcomes reported, HTS dose concentration, clinical indication, infusion
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method (i.e. via central or peripheral vein) and rate, repeat dosing, comparision of HTS with
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other hyperosmolar agents.
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Quality Evaluation
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One author (N.M.A.) evaluated all included studies for their quality using the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence8. In this
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framework, the lowest level of evidence for a study is given to a specialist opinion and non-
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human studies (level 5) and the highest is for a systematic review of randomised controlled
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trials (level 1). Risk of bias assessment was not performed because of significant
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heterogeneity in study methodologies.
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Study Outcomes and Analysis The primary outcome of this review is to quantify ICP reduction produced by HTS
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and its effect on clinical outcomes defined by any standardized functional score [modified
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Rankin scale (mRS), Glasgow outcome score (GOS), or Extended-GOS). Secondary
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outcomes included: (1). HTS vs. mannitol or other agents in reducing ICP; (2). HTS effects
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on cerebral vasospasm as measured by neuroimaging changes or clinical decline; and (3).
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HTS dose concentration, infusion rate, infusion volume, frequency of re-dosing, and serum
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sodium/osmolality limits for repeat dosing.
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We intended to perform meta-analyses using random effects modelling with 95% confidence limits for all estimates but we were not able to pool the results of the all studies
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due to disparity in study designs and outcome measures. Accordingly, we present and
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summarize the results of the studies narratively.
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RESULTS
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Search Results
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The number of articles retained at each stage of data acquisition is illustrated in a
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PRISMA flowchart (Figure 1). A total of 438 non-duplicate articles were initially found.
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The vast majority (390) of articles were found using the keywords “hypertonic saline and
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intracranial pressure” as the TBI literature with respect to raised ICP is extensive. After
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removing all duplicate articles and those pertaining only to TBI, central nervous system
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tumours, or the perioperative use of hyperosmolar agents, 15 studies remained. One study
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needed to be translated to English.9 One study was removed as they examined repeat HTS
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bolus in only one patient.10 Five further studies were removed as they contained <65% aSAH
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patients.11-15 Four further studies were removed because they were pilot studies and contained
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duplicate cases, with the final manuscripts included in our systematic review.16-19 The list of
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all excluded articles with justifications is provided in Table 1. A total of five studies were
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included in the systematic review.
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Study Characteristics The features and characteristics of all included studies are presented in Table 2. We
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found no dedicated randomized control trials examining the effects of HTS on reducing
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raised ICP in aSAH. Of the five studies, two studies were randomized (randomized
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alternating treatment plan and single blind randomized control trial).9, 20 The remaining three
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were prospective/retrospective cohort studies. One study was not comprised of entirely aSAH
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patients.21 The total number of patients across all studies was 175. The aSAH severity
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grading systems were evenly divided among WFNS and H&H when reported. WFNS grades
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ranged from 4-5 and H&H grades from 2-5. Only two studies reported the Fisher grade.
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Two studies were considered as level 2 as per the OCEBM framework.9, 20 The other studies were rated as level 4, as they were unmatched cohort investigations.
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Quality Evaluation of Individual Studies
Effect of HTS on ICP and Functional Outcomes
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Most studies compared baseline ICP with values after administration of HTS (Table
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3). Four of the five studies reported the ICP differences using the mean.9, 20-22 The mean
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reduction across all four studies was 8.85 mmHg (range: 3.3-12.1).
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One study examined patient functional outcomes. Al-Rawi et al22 defined favorable
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outcome, as assessed by the mRS at the 12-month mark, as mRS ≤3. Patients in the
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favourable outcome group had ICP reduction of 71.4% ±15 at 30 minutes after HTS
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administration compared with ICP reduction of 63.6% ±24.2 in the unfavourable outcome
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group, which was statistically significant.22
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HTS versus Mannitol for Raised ICP HTS was compared to mannitol in one study. In 2015, Huang et al9 conducted a
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randomized alternating treatment protocol examining the effects of mannitol and HTS in
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decreasing raised ICP (≥20 mmHg) in aSAH (H&H grade 4-5) patients. They found no
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difference between mannitol and 3% HTS (p>0.05) in reducing ICP. Both hyperosmolar
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agents decreased ICP adequately.
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HTS for Vasospasm
Only one study was dedicated to the effects of HTS on symptomatic vasospasm. Suarez et al23, retrospectively reported their experience with 3% HTS in hyponatreimc aSAH
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patients who developed symptomatic vasospasm. Among 29 patients with Na <135 mEq/L,
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3% HTS infusion resulted in rapid volume expansion and transient clinical improvement.
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However, there were no significant changes in mean cerebral blood flow velocities, which
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were measured with transcranial Doppler ultrasound (TCD) following HTS treatment for
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vasospasm. The lack of effects on flow velocities was possibly related to, as suggested by the
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authors, the operator-dependent nature of using TCDs or the lack of TCD-continues
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monitoring.
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Concentration, Administration, Infusion Volume and Electrolyte Monitoring Primary HTS concentrations in all studies ranged from 3% to 23.5% (Table 4). All
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administrations were via central venous access. Infusion rates ranged from 5-30 min
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depending on the HTS concentrations. The infusion volumes varied significantly. Three
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studies used weight bases volumes. The most common dose concentration used in three
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studies was 23% (either 23.4% or 23.5%).
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When reported, the serum sodium limits for exclusion were <120 mEq and >155-160 mEq, with a serum osmolality limit of >320 mEq. Lewandowski21 et al. used equimolar
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doses of either 23.5% or 14.6% and found no correlation between repeat HTS doses and
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increased serum sodium concentrations. Al-Rawi22 et al and Bentsen20 et al found that HTS
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administration increased serum sodium by 11.2 mEq (no significance reported), and 3.3 mEq
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(p<0.001), respectively.
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DISCUSSION
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Raised ICP (≥20 mm Hg) is very common after poor-grade aSAH and is a wellknown predictor of morbidity and mortality.4, 24, 25 After instituting measures such as
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elevating the head of the bed, maintaining PaCO2 between 35-40, sedation, ventriculostomy
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for hydrocephalus, and evacuation of any surgical hematoma, the use of hyperosmolar agents
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is very common.26 There are no specific guidelines on which hyperosmolar agent should be
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first-line. Most ICP management protocols in aSAH are based on those developed for TBI.
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However, several differences exist between aSAH and TBI-associated raised ICP. The
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mechanical shear and stress forces causing primary brain injury in trauma are absent in
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aSAH. Other unique factors such as early hydrocephalus, volume of SAH, delayed cerebral
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ischemia (DCI), and neurocardiogenic stress cardiomyopathy should direct clinicians to treat
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aSAH-associated raised ICP as a distinct entity from TBI-associated raised ICP. A recent
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publication surveyed members of the Neurocritical Care Society and found that 90% of
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members used hyperosmolar agents for refractory raised ICP and 55% preferred HTS to
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mannitol.3 This highlights the uncertainty in clinical practice for using HTS in high ICP
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scenarios. Furthermore, the literature is even more unclear on HTS concentration, volume,
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infusion rate, repeat dosing, and acceptable levels of serum osmolality and sodium. Hyperosmolar agents such as mannitol and HTS reduce ICP by creating an osmolar
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gradient across the blood brain barrier. A fluid shift from the intracellular/interstitial space
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into the intravascular space follows, thus decreasing the volume of fluid within the brain.
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Several differences between mannitol and HTS exist. Mannitol is a potent diuretic and
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repeated doses can cause hypovolemia, hypotension, and alter blood rheology.27 HTS has
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minimal diuretic effect and can increase blood pressure. This can be clinically significant for
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aSAH patients, as current guidelines recommend euvolemia, and hypertension in patients
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with delayed cerebral ischemia.28
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There are few studies in the literature on the use of HTS to lower aSAH-associated raised ICP. Even less data is available on the concentration on HTS, infusion rates, and
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safety and efficacy of repeat infusions. Our systematic review revealed two randomized
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studies examining the effect of HTS on ICP in aSAH. Huang et al.9 2015 conducted a
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prospective randomized alternating-treatment protocol comparing HTS and mannitol, and
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each agent to baseline. They found that HTS decreased ICP by 9.9 mmHg (p<0.01)
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compared to baseline. This study was conducted in high grade aSAH (H&H 4-5) patients for
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refractory ICP ≥20 mmHg. Bentsen et al.20 2006 conducted a single-blind randomized
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control trial comparing HTS to NS on stable ventilated patients with ICP 10-20 mmHg. They
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found HTS decreased ICP by 3 mmHg (p=0.04) compared to NS. The difference between the
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above two studies is that there was no placebo controlled group in the Huang et al. study, as
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this would be unethical to allow patients with ICP ≥20 mmHg to go without hyperosmolar
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intervention and use a placebo agent. The study by Bentsen et al. was placebo controlled with
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NS; however the ICP range was only 10-20 mmHg and not refractory.
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DCI continues to be a major source of morbidity and mortality in aSAH patients. Although a significant amount of basic science research has been dedicated to identifying the
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pathogenesis of DCI in aSAH, no clear relationships have been established. The current
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consensus guidelines with respect to fluid balance in managing DCI recommend euvolemia.28
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It seems rational that improved cerebral blood flow (CBF) would decrease ischemia. Current
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data suggests that HTS boluses improve CBF which may help with DCI, however no data on
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differences in outcome is available.19, 22
There was no consistency between the five studies with respect to HTS dose
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concentration, volume of infusion, or timing of repeat dosing. It appears that HTS dose
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concentrations between 3-23.5% are safe and effective at reducing aSAH-associated raised
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ICP; however no recommendation can be made with respect to volume and repeat dosing
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with such limited and heterogeneous data. Based on the available evidence for aSAH,
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clinicians should be cautions with repeat dosing when serum sodium levels approach 155-160
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mEq or serum osmolality approaches 320 mEq. Four of the five included studies used these
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limits as cut-offs for repeat dosing.
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Moving forward, it is clear that a large multi-center RCT comparing HTS vs. mannitol in reducing aSAH-associated raised ICP patients should be undertaken. This type of
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study would provide clarity as to the most appropriate first-line hyperosmolar agent in aSAH.
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Furthermore, specific outcome measures must be standardized such as clinical outcomes
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defined by functional scores, and ICP reduction measurement. Before undertaking such a
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study, it would be advantageous to first develop a prospective clinical feasibility and safety
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study to determine the most efficacious HTS dose concentration, volume, and infusion rate.
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For example, it is not clear if a 250 cc bolus of 3% HTS better controls ICP compared to a 15
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cc bolus of 23.5% HTS in aSAH.
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ACCEPTED MANUSCRIPT The main limitation of this review was the inability to compute group statistics
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because of patient heterogeneity between the five studies. The outcome measures were
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sufficiently different and did not allow for a meta-analysis or assessment of publication bias
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for effect estimates.
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CONCLUSION
In conclusion, the current literature suggests that HTS is effective at reducing
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refractory raised ICP in aSAH patients and may improve functional outcomes. There is not
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enough data to recommend the optimal and safest concentration, volume, and infusion rate of
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HTS. Repeat boluses have been documented with safety providing serum sodium <155-160
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mEq and serum osmolality <320 mEq. Further studies should be undertaken to determine the
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optimal dose concentration and volume of HTS administered.
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with symptomatic vasospasm following subarachnoid hemorrhage. J Neurosurg
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Anesthesiol. Jul 1999;11(3):178-184.
pressure following aneurysmal subarachnoid hemorrhage: monitoring practices and
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outcome data. Neurosurgical focus. Apr 15 2003;14(4):e3.
367 368
25.
Nagel A, Graetz D, Schink T, Frieler K, Sakowitz O, Vajkoczy P, et al. Relevance of
intracranial hypertension for cerebral metabolism in aneurysmal subarachnoid
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hemorrhage. Clinical article. Journal of neurosurgery. Jul 2009;111(1):94-101.
370 371
Mack WJ, King RG, Ducruet AF, Kreiter K, Mocco J, Maghoub A, et al. Intracranial
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de Oliveira Manoel AL, Goffi A, Marotta TR, Schweizer TA, Abrahamson S,
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Macdonald RL. The critical care management of poor-grade subarachnoid
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haemorrhage. Crit Care. 2016;20(1):21.
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27.
Thongrong C, Kong N, Govindarajan B, Allen D, Mendel E, Bergese SD. Current
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purpose and practice of hypertonic saline in neurosurgery: a review of the literature.
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World neurosurgery. Dec 2014;82(6):1307-1318.
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28.
Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a
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guideline for healthcare professionals from the American Heart Association/american
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Stroke Association. Stroke. Jun 2012;43(6):1711-1737.
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Figure Legends
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Figure 1. PRISMA study flow chart showing the exclusion porocess in our review.
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Table 1: Excluded studies from our systematic review.
Design
Hauer11 (2011)
Germany
100
Prospective Cohort
Froelich15 (2009)
Sweden
187
Retrospective Cohort
Valentino10 (2008)
United States
1
Case report
Tseng19 (2007)
United Kingdom
35
Harutjunyan12 (2005)
Germany
40
Battison14 (2005)
United Kingdom
Al Rawi17(2005)
United Kingdom
19 aSAH patients (19%)
91 aSAH patients (48%)
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Only a case report on repeat dosing for one patient
Prospective Cohort
Contain duplicate patients from a final study included in our review
Prospective randomized controlled
4 aSAH patients (10%)
9
Randomized Controlled Crossover Study
3 aSAH patients (33%)
14
Prospective Cohort
Pilot study, with final study included in review
7
Prospective Cohort
Pilot study, with final study included in our review
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Bentsen18 (2004)
Reason for Exclusion
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Patients no.
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Country
First author (Year)
Tsang16 (2003)
United Kingdom
10
Prospective Cohort
Pilot study, with final study included in our review
Horn13 (1999)
Germany
10
Prospective Cohort
4 aSAH patients (40%)
Abbreviations: WFNS (World Federation of Neurosurgical Societies), H&H (Hunt and Hess Grade), FG (Fisher Grade), HTS (Hypertonic Saline)
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Table 2: Study features and characteristics included on our review.
Country
Patients no.
WFNS/H&H/FG
Design
Primary Outcome
Randomized Alternating Treatment Protocol
Comparing efficacy of HTS to mannitol in decreasing ICP
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China
25
H&H 4-5 (range)
Lewandowski21 (2013)
United States
55 with 38 aSAH (69%)
FG II-IV (range)
Retrospective Cohort
Safety of repeated does of HTS
United Kingdom
44
WFNS 4-5 (range)
Prospective Cohort
Effect of HTS on cerebral perfusion
Comparing HTS to NS in decreasing ICP
Effect of HTS on symptomatic vasospasm
23
Norway
United States
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Suarez (1999)
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Bentsen20 (2006)
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Huang Xue-cai9 (2015)
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H&H 2-5(range)
Randomized Single Blind
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H&H 1(median) FG 3 (median)
Retrospective Cohort
Abbreviations: WFNS (World Federation of Neurosurgical Societies), H&H (Hunt and Hess Grade), FG (Fisher Grade), HTS (Hypertonic Saline).
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Effect on ICP
Huang Xue-cai9 (2015)
Continuous EVD
HTS decreased ICP from 22.9±4.3 mmHg to 13.0±3.7 mmHg (p<0.01). Average reduction of 9.9
Not recorded
Lewandowski21 (2013)
Continuous but method not indicated
HTS decreased ICP from 20.4±20.3 mmHg to 10.3±13.3 mmHg (p< 0.0001). Average reduction 10.1
Not recorded
None
HTS decreased ICP from 17.5±9.1 mmHg to 5.4±4.2 mmHg (p<0.05). Average reduction 12.1
Patients with mRS ≤3 showed greater decrease in ICP after HTS
None
HTS decreased ICP from 15.1±2.9 mmHg to 11.8±2.6 mmHg (p=0.04) Average reduction 3.3
Not recorded
Normal Saline
Continuous intraparenchymal
Continuous intraparenchymal
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Al-Rawi22 (2010)
Functional Outcomes
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Table 3: The effect of HTS on ICP, functional outcome, and comparison to mannitol.
HTS vs. Other Agents
HTS vs. Mannitol with no difference in ICP reduction (p>0.5)
Abbreviations; ICP (Intracranial Pressure), mRS (modified Rankin Score), HTS (Hypertonic Saline)
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Table 4: HTS dose concentrations, infusion rates and site, and method of ICP monitoring among studies. Serum Sodium/Osmolality Restrictions
Infusion Site
Frequency of repeat HTS bolus
Huang Xue-cai9 (2015)
160 mL 3% HTS over 15-20 min
<120 Na >160
Deep Vein
Not recorded
Lewandowski21 (2013)
15-30 mL 23.4% HTS over 20 min or 24-48 mL of 14.6% HTS
None (inconsistent documentation of serum osmolality)
Central Line
Al-Rawi22 (2010)
2 mL/Kg 23.5% over 10-30 min
Na >155 and Osm >320
Central Line
No repeats
Bentsen20 (2006)
2mL/Kg 7.2% HTS in 6% hydroxyethyl starch over 30 min
Na < 160
Central Line
No repeats
Suarez23 (1999)
100-200 mL 3% HTS over 60 min
Central Line
Continuous
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Volume, concentration and Rate
First author (Year)
Na < 160
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Average 8.9 HTS repeat bolus per patient
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Full text articles assessed for eligibility (n = 15)
Records excluded (n = 424) due to: 1) Duplicate 2) Dedicated only to TBI or tumors
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Records after duplicate, title and abstract screening (n = 15)
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Records identified through database searching MEDLINE, EMBASE, Scopus, CENTRAL (n = 438)
Studies included in qualitative syntheses (n = 5)
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Screening
Identification
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Studies included in quantitative meta-analysis (n = 0)
Full articles excluded (n= 10) based on: 1) Case report (n = 1) 2) Less <65% aSAH patients (n = 5) 3) Pilot study/ or study with duplicate patients (n = 4)
ACCEPTED MANUSCRIPT Abbreviations:
Hypertonic saline (HTS)
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Traumatic brain injury (TBI)
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Intracranial pressure (ICP)
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Aneurysmal subarachnoid hemorrhage (asah)
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External ventricular drains (EVD)
•
World Federation of Neurosurgical Societies (WFNS)
•
Hunt and Hess (H&H)
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Fisher Grades (FG)
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Oxford Centre for Evidence-Based Medicine (OCEBM)
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Modified Rankin scale (mRS)
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Preferred Reporting Items for Systematic Reviews and Meta-Analyses
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(PRISMA)
Transcranial Doppler ultrasound (TCD)
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Delayed cerebral ischemia (DCI)
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S1878-8750(17)30784-2
DOI:
10.1016/j.wneu.2017.05.085
Reference:
WNEU 5779
To appear in:
World Neurosurgery
Received Date: 21 April 2017 Accepted Date: 14 May 2017
Please cite this article as: Pasarikovski CR, Alotaibi NM, Al-Mufti F, Macdonald RL, Hypertonic Saline for Raised Intracranial Pressure Following Aneurysmal Subarachnoid Hemorrhage: A Systematic Review, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.05.085. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Hypertonic Saline for Raised Intracranial Pressure Following Aneurysmal
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Subarachnoid Hemorrhage: A Systematic Review
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Authors: Christopher R. Pasarikovski, MD 1, Naif M. Alotaibi, MD 1,2, Fawaz Al-Mufti,
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MD 3, R. Loch Macdonald, MD, PhD 1,2, 4
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Affiliations:
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1
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Canada; 2 Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto,
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Ontario, Canada; 3 Endovascular Surgical Neuroradiology Program, Rutgers University-New
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Jersey Medical School, Newark, NJ, USA, and 4 Division of Neurosurgery, St. Michael’s
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Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan
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Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department
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of Surgery, University of Toronto, Canada.
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Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario,
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Keywords: Aneurysm – Brain - Cerebral – Subarachnoid Hemorrhage – SAH – 3% -
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Hypertonic – Saline – Intracranial Pressure – ICP
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Corresponding Author:
Naif M. Alotaibi, M.D. Division of Neurosurgery, University of Toronto 399 Bathurst St., WW 4-427 Toronto, ON M5T 2S8
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Tel: (416) 603-5800 ext. 5503 Fax: (416) 603-5298
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Email : [email protected]
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Manuscript word count: 2258
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Title character count: 116
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Figures: 1
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Tables: 4
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Author contributions
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Study concept and design: Alotaibi, Pasarikovski
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Acquisition, analysis, or interpretation of data: All authors
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Drafting the article: Pasarikovski, Alotaibi.
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Critically revising the article: Al-Mufti, Macdonald.
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Administrative, technical, or material support: Alotaibi.
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Statistical analysis: Not applicable
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Study supervision: Alotaibi.
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Conflict of interest: Dr. Macdonald receives grant support from the Brain Aneurysm
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Foundation, Canadian Institutes for Health Research and the Heart and Stroke Foundation of
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Canada; and is an employee and Chief Scientific Officer of Edge Therapeutics, Inc. The other
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authors declare that they have no competing interests.
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Funding: This research did not receive any specific grant from funding agencies in the
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public, commercial, or not-for-profit sectors.
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ACCEPTED MANUSCRIPT ABSTRACT
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Background: The use of hyperosmolar agents such as mannitol or hypertonic saline (HTS) to
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control high intracranial pressure (ICP) in traumatic brain injury patients has been well
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studied. However, the role of HTS in the management of aneurysmal subarachnoid
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hemorrhage (aSAH)-associated raised ICP is still unclear.
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Methods: We performed a systematic review in accordance with the Preferred Reporting
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Items for Systematic Reviews and Meta-Analyses guidelines. The primary outcome of this
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review is to quantify ICP reduction produced by HTS and its effect on clinical outcomes
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defined by any standardized functional score. Secondary outcomes included: HTS vs.
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mannitol in ICP reduction, HTS effects on cerebral vasospasm, and HTS dose concentration,
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infusion rate, infusion volume, frequency of re-dosing, and serum sodium/osmolality limits
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for repeat dosing.
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Results: Five studies were included in the review encompassing 175 patients. Studies on
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aSAH included mostly poor-grade patients (defined as World Federation of Neurosurgical
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Societies grade 4 and 5). HTS concentrations ranged from 3% to 23.5%. Most studies found
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that HTS decreased ICP when compared to either baseline or placebo. The mean decrease in
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ICP from HTS administration was 8.9 mm Hg [range: 3.3-12.1]. Only one study showed
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possible improvement in poor-grade aSAH outcomes.
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Conclusions: The current evidence suggests that HTS is as effective as mannitol at reducing
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raised ICP in aSAH. However, there is not enough data to recommend the optimal and safest
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dose concentration or whether HTS significantly improves outcomes in aSAH.
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INTRODUCTION The use of hyperosmolar agents such as mannitol or hypertonic saline (HTS) for
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intracranial hypertension in traumatic brain injury (TBI) patients has been well documented.1,
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2
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from any cause.3 Raised intracranial pressure (ICP) is common in acute aneurysmal
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subarachnoid hemorrhage (aSAH), particularity in patients with poor grade aSAH.4 The
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underlying pathophysiology between TBI and aSAH induced raised ICP is likely different,
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and hyperosmolar agents and doses used in TBI cannot necessarily be used in aSAH
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patients.5 Marginal literature on the use of HTS in aSAH induced raised ICP exist.6 The
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indication to use HTS over mannitol, HTS concentration, and bolus infusion rate is even
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more undefined.
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HTS has gained popularity among physicians treating patients for intracranial hypertension
The primary goal of this study was to conduct a systematic review on the use of HTS to lower raised ICP in aSAH patients and examine the current evidence of HTS effects on
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aSAH outcomes. Secondarily, we sought to clarify HTS concentration, infusion rates,
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volume, frequency of re-dosing, and serum sodium/osmolality restrictions in aSAH.
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METHODS
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Search Strategy and Study Eligibility
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Peer-reviewed articles were collected through MEDLINE, Embase, Scopus, and
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Cochrane Central Register of Controlled Trials (CENTRAL) searches according to the
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Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)7
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guidelines. The keywords used in combination included: “hypertonic saline”, “intracranial
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pressure”, and “subarachnoid hemorrhage.” There were no restrictions on publications’
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language, type or dates. One reviewer conducted the search (C.R.P) and then the search was
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verified by another reviewer (N.M.A). We included all studies on human subjects who had
ACCEPTED MANUSCRIPT aSAH and the use of HTS. This included the use of HTS to increase/improve cerebral
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perfusion, decrease ICP, and comparisons to mannitol. All HTS dose concentrations and
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infusion rates were included. All studies needed to be peer-reviewed, conducted on human
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subjects, and have ICP recorded with either intraparenchymal monitors or external ventricular
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drains (EVD). Case reports and case series with <65% aSAH patients were not included.
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Studies focused only on correction of hyponatremia using HTS were also excluded.
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Data Extraction
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Data on World Federation of Neurosurgical Societies (WFNS), Hunt and Hess (H&H), and Fisher Grades (FG) were collected from each study. Method of ICP monitoring
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was included, which was either intraparenchymal monitor or EVD. Other variables extracted
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from each study included study type, year of publication, country of origin, ICP reduction
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rate, functional outcomes reported, HTS dose concentration, clinical indication, infusion
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method (i.e. via central or peripheral vein) and rate, repeat dosing, comparision of HTS with
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other hyperosmolar agents.
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Quality Evaluation
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One author (N.M.A.) evaluated all included studies for their quality using the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence8. In this
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framework, the lowest level of evidence for a study is given to a specialist opinion and non-
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human studies (level 5) and the highest is for a systematic review of randomised controlled
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trials (level 1). Risk of bias assessment was not performed because of significant
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heterogeneity in study methodologies.
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Study Outcomes and Analysis The primary outcome of this review is to quantify ICP reduction produced by HTS
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and its effect on clinical outcomes defined by any standardized functional score [modified
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Rankin scale (mRS), Glasgow outcome score (GOS), or Extended-GOS). Secondary
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outcomes included: (1). HTS vs. mannitol or other agents in reducing ICP; (2). HTS effects
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on cerebral vasospasm as measured by neuroimaging changes or clinical decline; and (3).
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HTS dose concentration, infusion rate, infusion volume, frequency of re-dosing, and serum
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sodium/osmolality limits for repeat dosing.
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We intended to perform meta-analyses using random effects modelling with 95% confidence limits for all estimates but we were not able to pool the results of the all studies
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due to disparity in study designs and outcome measures. Accordingly, we present and
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summarize the results of the studies narratively.
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RESULTS
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Search Results
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The number of articles retained at each stage of data acquisition is illustrated in a
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PRISMA flowchart (Figure 1). A total of 438 non-duplicate articles were initially found.
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The vast majority (390) of articles were found using the keywords “hypertonic saline and
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intracranial pressure” as the TBI literature with respect to raised ICP is extensive. After
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removing all duplicate articles and those pertaining only to TBI, central nervous system
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tumours, or the perioperative use of hyperosmolar agents, 15 studies remained. One study
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needed to be translated to English.9 One study was removed as they examined repeat HTS
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bolus in only one patient.10 Five further studies were removed as they contained <65% aSAH
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patients.11-15 Four further studies were removed because they were pilot studies and contained
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duplicate cases, with the final manuscripts included in our systematic review.16-19 The list of
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all excluded articles with justifications is provided in Table 1. A total of five studies were
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included in the systematic review.
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Study Characteristics The features and characteristics of all included studies are presented in Table 2. We
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found no dedicated randomized control trials examining the effects of HTS on reducing
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raised ICP in aSAH. Of the five studies, two studies were randomized (randomized
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alternating treatment plan and single blind randomized control trial).9, 20 The remaining three
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were prospective/retrospective cohort studies. One study was not comprised of entirely aSAH
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patients.21 The total number of patients across all studies was 175. The aSAH severity
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grading systems were evenly divided among WFNS and H&H when reported. WFNS grades
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ranged from 4-5 and H&H grades from 2-5. Only two studies reported the Fisher grade.
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Two studies were considered as level 2 as per the OCEBM framework.9, 20 The other studies were rated as level 4, as they were unmatched cohort investigations.
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Quality Evaluation of Individual Studies
Effect of HTS on ICP and Functional Outcomes
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Most studies compared baseline ICP with values after administration of HTS (Table
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3). Four of the five studies reported the ICP differences using the mean.9, 20-22 The mean
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reduction across all four studies was 8.85 mmHg (range: 3.3-12.1).
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One study examined patient functional outcomes. Al-Rawi et al22 defined favorable
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outcome, as assessed by the mRS at the 12-month mark, as mRS ≤3. Patients in the
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favourable outcome group had ICP reduction of 71.4% ±15 at 30 minutes after HTS
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administration compared with ICP reduction of 63.6% ±24.2 in the unfavourable outcome
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group, which was statistically significant.22
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HTS versus Mannitol for Raised ICP HTS was compared to mannitol in one study. In 2015, Huang et al9 conducted a
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randomized alternating treatment protocol examining the effects of mannitol and HTS in
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decreasing raised ICP (≥20 mmHg) in aSAH (H&H grade 4-5) patients. They found no
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difference between mannitol and 3% HTS (p>0.05) in reducing ICP. Both hyperosmolar
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agents decreased ICP adequately.
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HTS for Vasospasm
Only one study was dedicated to the effects of HTS on symptomatic vasospasm. Suarez et al23, retrospectively reported their experience with 3% HTS in hyponatreimc aSAH
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patients who developed symptomatic vasospasm. Among 29 patients with Na <135 mEq/L,
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3% HTS infusion resulted in rapid volume expansion and transient clinical improvement.
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However, there were no significant changes in mean cerebral blood flow velocities, which
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were measured with transcranial Doppler ultrasound (TCD) following HTS treatment for
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vasospasm. The lack of effects on flow velocities was possibly related to, as suggested by the
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authors, the operator-dependent nature of using TCDs or the lack of TCD-continues
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monitoring.
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Concentration, Administration, Infusion Volume and Electrolyte Monitoring Primary HTS concentrations in all studies ranged from 3% to 23.5% (Table 4). All
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administrations were via central venous access. Infusion rates ranged from 5-30 min
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depending on the HTS concentrations. The infusion volumes varied significantly. Three
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studies used weight bases volumes. The most common dose concentration used in three
203
studies was 23% (either 23.4% or 23.5%).
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When reported, the serum sodium limits for exclusion were <120 mEq and >155-160 mEq, with a serum osmolality limit of >320 mEq. Lewandowski21 et al. used equimolar
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doses of either 23.5% or 14.6% and found no correlation between repeat HTS doses and
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increased serum sodium concentrations. Al-Rawi22 et al and Bentsen20 et al found that HTS
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administration increased serum sodium by 11.2 mEq (no significance reported), and 3.3 mEq
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(p<0.001), respectively.
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DISCUSSION
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Raised ICP (≥20 mm Hg) is very common after poor-grade aSAH and is a wellknown predictor of morbidity and mortality.4, 24, 25 After instituting measures such as
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elevating the head of the bed, maintaining PaCO2 between 35-40, sedation, ventriculostomy
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for hydrocephalus, and evacuation of any surgical hematoma, the use of hyperosmolar agents
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is very common.26 There are no specific guidelines on which hyperosmolar agent should be
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first-line. Most ICP management protocols in aSAH are based on those developed for TBI.
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However, several differences exist between aSAH and TBI-associated raised ICP. The
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mechanical shear and stress forces causing primary brain injury in trauma are absent in
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aSAH. Other unique factors such as early hydrocephalus, volume of SAH, delayed cerebral
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ischemia (DCI), and neurocardiogenic stress cardiomyopathy should direct clinicians to treat
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aSAH-associated raised ICP as a distinct entity from TBI-associated raised ICP. A recent
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publication surveyed members of the Neurocritical Care Society and found that 90% of
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members used hyperosmolar agents for refractory raised ICP and 55% preferred HTS to
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mannitol.3 This highlights the uncertainty in clinical practice for using HTS in high ICP
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scenarios. Furthermore, the literature is even more unclear on HTS concentration, volume,
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infusion rate, repeat dosing, and acceptable levels of serum osmolality and sodium. Hyperosmolar agents such as mannitol and HTS reduce ICP by creating an osmolar
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gradient across the blood brain barrier. A fluid shift from the intracellular/interstitial space
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into the intravascular space follows, thus decreasing the volume of fluid within the brain.
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Several differences between mannitol and HTS exist. Mannitol is a potent diuretic and
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repeated doses can cause hypovolemia, hypotension, and alter blood rheology.27 HTS has
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minimal diuretic effect and can increase blood pressure. This can be clinically significant for
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aSAH patients, as current guidelines recommend euvolemia, and hypertension in patients
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with delayed cerebral ischemia.28
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There are few studies in the literature on the use of HTS to lower aSAH-associated raised ICP. Even less data is available on the concentration on HTS, infusion rates, and
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safety and efficacy of repeat infusions. Our systematic review revealed two randomized
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studies examining the effect of HTS on ICP in aSAH. Huang et al.9 2015 conducted a
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prospective randomized alternating-treatment protocol comparing HTS and mannitol, and
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each agent to baseline. They found that HTS decreased ICP by 9.9 mmHg (p<0.01)
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compared to baseline. This study was conducted in high grade aSAH (H&H 4-5) patients for
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refractory ICP ≥20 mmHg. Bentsen et al.20 2006 conducted a single-blind randomized
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control trial comparing HTS to NS on stable ventilated patients with ICP 10-20 mmHg. They
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found HTS decreased ICP by 3 mmHg (p=0.04) compared to NS. The difference between the
246
above two studies is that there was no placebo controlled group in the Huang et al. study, as
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this would be unethical to allow patients with ICP ≥20 mmHg to go without hyperosmolar
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intervention and use a placebo agent. The study by Bentsen et al. was placebo controlled with
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NS; however the ICP range was only 10-20 mmHg and not refractory.
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DCI continues to be a major source of morbidity and mortality in aSAH patients. Although a significant amount of basic science research has been dedicated to identifying the
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pathogenesis of DCI in aSAH, no clear relationships have been established. The current
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consensus guidelines with respect to fluid balance in managing DCI recommend euvolemia.28
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It seems rational that improved cerebral blood flow (CBF) would decrease ischemia. Current
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data suggests that HTS boluses improve CBF which may help with DCI, however no data on
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differences in outcome is available.19, 22
There was no consistency between the five studies with respect to HTS dose
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concentration, volume of infusion, or timing of repeat dosing. It appears that HTS dose
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concentrations between 3-23.5% are safe and effective at reducing aSAH-associated raised
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ICP; however no recommendation can be made with respect to volume and repeat dosing
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with such limited and heterogeneous data. Based on the available evidence for aSAH,
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clinicians should be cautions with repeat dosing when serum sodium levels approach 155-160
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mEq or serum osmolality approaches 320 mEq. Four of the five included studies used these
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limits as cut-offs for repeat dosing.
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Moving forward, it is clear that a large multi-center RCT comparing HTS vs. mannitol in reducing aSAH-associated raised ICP patients should be undertaken. This type of
267
study would provide clarity as to the most appropriate first-line hyperosmolar agent in aSAH.
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Furthermore, specific outcome measures must be standardized such as clinical outcomes
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defined by functional scores, and ICP reduction measurement. Before undertaking such a
270
study, it would be advantageous to first develop a prospective clinical feasibility and safety
271
study to determine the most efficacious HTS dose concentration, volume, and infusion rate.
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For example, it is not clear if a 250 cc bolus of 3% HTS better controls ICP compared to a 15
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cc bolus of 23.5% HTS in aSAH.
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because of patient heterogeneity between the five studies. The outcome measures were
276
sufficiently different and did not allow for a meta-analysis or assessment of publication bias
277
for effect estimates.
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CONCLUSION
In conclusion, the current literature suggests that HTS is effective at reducing
281
refractory raised ICP in aSAH patients and may improve functional outcomes. There is not
282
enough data to recommend the optimal and safest concentration, volume, and infusion rate of
283
HTS. Repeat boluses have been documented with safety providing serum sodium <155-160
284
mEq and serum osmolality <320 mEq. Further studies should be undertaken to determine the
285
optimal dose concentration and volume of HTS administered.
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Tseng MY, Al-Rawi PG, Pickard JD, Rasulo FA, Kirkpatrick PJ. Effect of hypertonic
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Tseng MY, Al-Rawi PG, Czosnyka M, Hutchinson PJ, Richards H, Pickard JD, et al. Enhancement of cerebral blood flow using systemic hypertonic saline therapy
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Bentsen G, Breivik H, Lundar T, Stubhaug A. Hypertonic saline (7.2%) in 6% hydroxyethyl starch reduces intracranial pressure and improves hemodynamics in a
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Lewandowski-Belfer JJ, Patel AV, Darracott RM, Jackson DA, Nordeen JD, Freeman WD. Safety and efficacy of repeated doses of 14.6 or 23.4 % hypertonic saline for
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Al-Rawi PG, Tseng MY, Richards HK, Nortje J, Timofeev I, Matta BF, et al.
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Suarez JI, Qureshi AI, Parekh PD, Razumovsky A, Tamargo RJ, Bhardwaj A, et al. Administration of hypertonic (3%) sodium chloride/acetate in hyponatremic patients
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Nagel A, Graetz D, Schink T, Frieler K, Sakowitz O, Vajkoczy P, et al. Relevance of
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Mack WJ, King RG, Ducruet AF, Kreiter K, Mocco J, Maghoub A, et al. Intracranial
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Macdonald RL. The critical care management of poor-grade subarachnoid
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haemorrhage. Crit Care. 2016;20(1):21.
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Thongrong C, Kong N, Govindarajan B, Allen D, Mendel E, Bergese SD. Current
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purpose and practice of hypertonic saline in neurosurgery: a review of the literature.
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Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a
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Figure Legends
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Figure 1. PRISMA study flow chart showing the exclusion porocess in our review.
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ACCEPTED MANUSCRIPT
Table 1: Excluded studies from our systematic review.
Design
Hauer11 (2011)
Germany
100
Prospective Cohort
Froelich15 (2009)
Sweden
187
Retrospective Cohort
Valentino10 (2008)
United States
1
Case report
Tseng19 (2007)
United Kingdom
35
Harutjunyan12 (2005)
Germany
40
Battison14 (2005)
United Kingdom
Al Rawi17(2005)
United Kingdom
19 aSAH patients (19%)
91 aSAH patients (48%)
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Only a case report on repeat dosing for one patient
Prospective Cohort
Contain duplicate patients from a final study included in our review
Prospective randomized controlled
4 aSAH patients (10%)
9
Randomized Controlled Crossover Study
3 aSAH patients (33%)
14
Prospective Cohort
Pilot study, with final study included in review
7
Prospective Cohort
Pilot study, with final study included in our review
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Bentsen18 (2004)
Reason for Exclusion
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Patients no.
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Country
First author (Year)
Tsang16 (2003)
United Kingdom
10
Prospective Cohort
Pilot study, with final study included in our review
Horn13 (1999)
Germany
10
Prospective Cohort
4 aSAH patients (40%)
Abbreviations: WFNS (World Federation of Neurosurgical Societies), H&H (Hunt and Hess Grade), FG (Fisher Grade), HTS (Hypertonic Saline)
ACCEPTED MANUSCRIPT
Table 2: Study features and characteristics included on our review.
Country
Patients no.
WFNS/H&H/FG
Design
Primary Outcome
Randomized Alternating Treatment Protocol
Comparing efficacy of HTS to mannitol in decreasing ICP
RI PT
First author (Year)
China
25
H&H 4-5 (range)
Lewandowski21 (2013)
United States
55 with 38 aSAH (69%)
FG II-IV (range)
Retrospective Cohort
Safety of repeated does of HTS
United Kingdom
44
WFNS 4-5 (range)
Prospective Cohort
Effect of HTS on cerebral perfusion
Comparing HTS to NS in decreasing ICP
Effect of HTS on symptomatic vasospasm
23
Norway
United States
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Suarez (1999)
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Bentsen20 (2006)
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Al-Rawi22 (2010)
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Huang Xue-cai9 (2015)
22
H&H 2-5(range)
Randomized Single Blind
29
H&H 1(median) FG 3 (median)
Retrospective Cohort
Abbreviations: WFNS (World Federation of Neurosurgical Societies), H&H (Hunt and Hess Grade), FG (Fisher Grade), HTS (Hypertonic Saline).
ACCEPTED MANUSCRIPT
Effect on ICP
Huang Xue-cai9 (2015)
Continuous EVD
HTS decreased ICP from 22.9±4.3 mmHg to 13.0±3.7 mmHg (p<0.01). Average reduction of 9.9
Not recorded
Lewandowski21 (2013)
Continuous but method not indicated
HTS decreased ICP from 20.4±20.3 mmHg to 10.3±13.3 mmHg (p< 0.0001). Average reduction 10.1
Not recorded
None
HTS decreased ICP from 17.5±9.1 mmHg to 5.4±4.2 mmHg (p<0.05). Average reduction 12.1
Patients with mRS ≤3 showed greater decrease in ICP after HTS
None
HTS decreased ICP from 15.1±2.9 mmHg to 11.8±2.6 mmHg (p=0.04) Average reduction 3.3
Not recorded
Normal Saline
Continuous intraparenchymal
Continuous intraparenchymal
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Al-Rawi22 (2010)
Functional Outcomes
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First author (Year)
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Table 3: The effect of HTS on ICP, functional outcome, and comparison to mannitol.
HTS vs. Other Agents
HTS vs. Mannitol with no difference in ICP reduction (p>0.5)
Abbreviations; ICP (Intracranial Pressure), mRS (modified Rankin Score), HTS (Hypertonic Saline)
ACCEPTED MANUSCRIPT
Table 4: HTS dose concentrations, infusion rates and site, and method of ICP monitoring among studies. Serum Sodium/Osmolality Restrictions
Infusion Site
Frequency of repeat HTS bolus
Huang Xue-cai9 (2015)
160 mL 3% HTS over 15-20 min
<120 Na >160
Deep Vein
Not recorded
Lewandowski21 (2013)
15-30 mL 23.4% HTS over 20 min or 24-48 mL of 14.6% HTS
None (inconsistent documentation of serum osmolality)
Central Line
Al-Rawi22 (2010)
2 mL/Kg 23.5% over 10-30 min
Na >155 and Osm >320
Central Line
No repeats
Bentsen20 (2006)
2mL/Kg 7.2% HTS in 6% hydroxyethyl starch over 30 min
Na < 160
Central Line
No repeats
Suarez23 (1999)
100-200 mL 3% HTS over 60 min
Central Line
Continuous
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Volume, concentration and Rate
First author (Year)
Na < 160
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Abbreviations: Na (Sodium), Osm (Osmolality), HTS (Hypertonic Saline).
Average 8.9 HTS repeat bolus per patient
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Full text articles assessed for eligibility (n = 15)
Records excluded (n = 424) due to: 1) Duplicate 2) Dedicated only to TBI or tumors
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Records after duplicate, title and abstract screening (n = 15)
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Records identified through database searching MEDLINE, EMBASE, Scopus, CENTRAL (n = 438)
Studies included in qualitative syntheses (n = 5)
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Eligibility
Screening
Identification
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Studies included in quantitative meta-analysis (n = 0)
Full articles excluded (n= 10) based on: 1) Case report (n = 1) 2) Less <65% aSAH patients (n = 5) 3) Pilot study/ or study with duplicate patients (n = 4)
ACCEPTED MANUSCRIPT Abbreviations:
Hypertonic saline (HTS)
•
Traumatic brain injury (TBI)
•
Intracranial pressure (ICP)
•
Aneurysmal subarachnoid hemorrhage (asah)
•
External ventricular drains (EVD)
•
World Federation of Neurosurgical Societies (WFNS)
•
Hunt and Hess (H&H)
•
Fisher Grades (FG)
•
Oxford Centre for Evidence-Based Medicine (OCEBM)
•
Modified Rankin scale (mRS)
•
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
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(PRISMA)
Transcranial Doppler ultrasound (TCD)
•
Delayed cerebral ischemia (DCI)
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