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Traumatic brain injury (TBI) is a major cause of death and severe disability throughout the world with an estimated global pooled incidence of 349 per 100,000 person years.1 Across Europe it is estimated that each TBI related death results in on average 24 years of life lost, amounting to 1.3 million years of life lost annually across Europe due to TBI.2

In the United Kingdom, approximately 1.4 million people attend emergency departments in England and Wales annually following a head injury of which 3,500 patients have moderate to severe TBI requiring treatment in intensive care.3 Resource use is high with an average length of stay in an ICU following TBI of 9 days.3 Long term outcomes are also poor – the HTA Risk Adjustment In Neurocritical care (RAIN) study (n=3636)4 reported 26% mortality in patients with TBI at 6 months, and amongst survivors 44% had severe disability, 30% had moderate disability, and only 26% had made a good recovery. 70% of patients with TBI reported problems performing usual activities, 60% reported problems with pain or discomfort and anxiety or depression. Furthermore, 50% of patients experienced problems with mobility and 35% reporting problems with self-care.4


  1. Nguyen R, Fiest KM, McChesney J, et al. The International Incidence of Traumatic Brain Injury: A Systematic Review and Meta-Analysis. Can J Neurol Sci 2016;43:774-85.
  2. Majdan M, Plancikova D, Maas A, et al. Years of life lost due to traumatic brain injury in Europe: A cross-sectional analysis of 16 countries. PLoS Med 2017;14:e1002331.
  3. Lawrence T, Helmy A, Bouamra O, Woodford M, Lecky F, Hutchinson PJ. Traumatic brain injury in England and Wales: prospective audit of epidemiology, complications and standardised mortality. BMJ open 2016;6:e012197.
  4. Harrison DA, Prabhu G, Grieve R, et al. Risk Adjustment In Neurocritical care (RAIN)--prospective validation of risk prediction models for adult patients with acute traumatic brain injury to use to evaluate the optimum location and comparative costs of neurocritical care: a cohort study. Health Technol Assess 2013;17:vii-viii, 1-350.


A rise in intracranial pressure (ICP) is a secondary insult that can result from either the primary traumatic injury or other resulting pathologies such as cerebral oedema or obstruction to cerebrospinal fluid (CSF) flow. A number of studies have shown an association between raised ICP and poor neurological outcomes.5,6 As a result, the treatment of elevated ICP has been a central focus of both the medical and surgical management of patients with severe TBI on the ICU.

ICP monitoring is undertaken in intensive care in the presence of an abnormal CT scan and Glasgow Coma Scale (GCS) <8 or if 2 or more of age >40 years, unilateral or bilateral motor posturing, or episodes of systolic blood pressure (BP) <90 mmHg.7

A recent UK wide survey (Rowland et al., in preparation) indicates that most UK clinicians would initiate treatment for raised ICP if it increased to >20mmHg for at least 5 minutes with no reversible cause. This is consistent with the threshold used in previous trials (see Table 1) and similar to the Brain Trauma Foundation threshold (>22 mmHg)7 and a recent consensus recommendation from the European Society of Intensive Care Medicine (>25mmHg).8

Table 1. Thresholds for ICP in previous trials


>20mmHg for at least 5 minutes with no reversible cause


>20mmHg for more than 15 minutes (continuously or intermittently) within a 1-hour period


>25mmHg for 1-12 hours [Note higher threshold as the trial aimed to assess craniectomy as a last-tier intervention]


>20mmHg for more than 5 minutes

The intensive care management of patients with severe TBI and raised ICP usually takes a stepwise approach. Initial treatment focuses on treatment of immediate surgical pathology (e.g. haematoma or hydrocephalus) and the optimisation of so called “stage 1” ICU interventions (e.g. sedation, ventilation, blood pressure, temperature and positioning). If ICP remains high following this, “stage 2” interventions normally include the use of neuromuscular blockade and hyperosmolar therapy. Finally, “stage 3” measures include surgical decompressive craniectomy or barbiturate coma.

Hyperosmolar therapies used to control ICP include mannitol and hypertonic saline. Mannitol is a sugar alcohol which exerts its ICP-lowering effects via two mechanisms—an immediate non-osmotic effect because of plasma expansion and a slightly delayed effect related to its osmotic action. The early plasma expansion reduces blood viscosity and this in turn improves regional cerebral microvascular flow and oxygenation. It also increases intravascular volume and therefore cardiac output. Together, these effects result in an increase in regional cerebral blood flow and compensatory cerebral vasoconstriction in brain regions where autoregulation is intact, resulting in a reduction in ICP. Mannitol also establishes an osmotic gradient between plasma and brain cells, drawing water from the cerebral extracellular space into the vasculature, thereby reducing cerebral oedema.

Hypertonic saline administration produces an osmotic gradient between the intravascular and intracellular/interstitial compartments, leading to shrinkage of brain tissue (where blood brain barrier is intact) and therefore a reduction in ICP. Hypertonic saline also augments volume resuscitation and increases circulating blood volume, mean arterial blood pressure and cerebral perfusion pressure. Other suggested beneficial effects of hypertonic saline include restoration of the neuronal membrane potential, maintenance of the blood brain barrier integrity, and modulation of the inflammatory response by reducing adhesion of leukocytes to endothelium.

  1. Sorrentino E, Diedler J, Kasprowicz M, et al. Critical thresholds for cerebrovascular reactivity after traumatic brain injury. Neurocrit Care 2012;16:258-66.
  2. Marmarou A, Anderson RL, Ward JD, et al. Impact of ICP instability and hypotension on outcome in patients with severe head trauma. Special Supplements 1991;75:S59-S66.
  3. Carney N, Totten AM, O'Reilly C, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery 2017;80:6-15.
  4. Oddo M, Poole D, Helbok R, et al. Fluid therapy in neurointensive care patients: ESICM consensus and clinical practice recommendations. Intensive Care Med 2018;44:449-63.

Trial Title

“Sugar or Salt (SOS) Trial: Hyperosmolar Therapy in Traumatic Brain Injury”

Research Question

Does hyperosmolar therapy (mannitol or hypertonic saline) in traumatic brain injury (TBI) improve neurological function clinically and cost-effectively at 6 months?

Trial Design


Multi-centre, open label, randomised controlled clinical and cost effectiveness trial with an internal pilot


Intensive Care Units (ICUs) within NHS hospitals treating patients with TBI

Target Population


Adult patients (aged >16 years) with severe TBI and raised intracranial pressure (ICP)

Inclusion Criteria

1) Adult aged >16 years old

2) Admission to ICU following TBI

3) ICP >20mmHg for more than 5 mins despite stage 1 procedures

4) <10 days from initial primary head injury

5) Abnormal CT scan consistent with TBI

Exclusion Criteria

1) Devastating brain injury with withdrawal of treatment anticipated in the next 24 hours

2) Pregnancy

3) Severe hypernatraemia (serum Na > 155 mmol/L)

4) 2 or more prior doses of hyperosmolar therapy given on ICU

Planned sample size

319 per group (638 in total)

Health Technology being Assessed

2ml/kg 20% mannitol intravenous bolus (or equivalent osmolar dose)

2ml/kg bolus 2.7% hypertonic saline (or equivalent osmolar dose)

Measurement of Outcomes and Costs

Primary outcome

1. Extended Glasgow Outcome Scale (GOS-E) measured at 6 months after randomisation

Secondary outcomes

1. ICP control (during period of monitoring on ICU)

2. Progression to stage 3 therapies

3. Which stage 3 therapies were required

4. Organ support requirements during ICU

5. Critical care length of stay

6. Hospital length of stay

7. Modified Oxford Handicap Score (mOHS) at hospital discharge

8. GOS-E at 12 months

9. Survival at hospital discharge, 3 months, 6 months and 12 months

10. Quality of life (EQ-5D-5L) at hospital discharge, 3 months, 6 months and 12 months

11. Serious Adverse Events (SAEs)

Health economic outcomes

Costs and within-trial and lifetime cost-effectiveness from an NHS and Personal Social Services (PSS) perspective.

Follow-up Duration

Up to 12 months post-randomisation

Planned Trial Period

From 01/06/2019 to 28/02/2026 (total of 68 months)

SOS logo


If you have any questions about the SOS trial, please contact the trial team who will be happy to answer them.

Trial Manager: Hannah Noordali

Tel: 024 761 50478



SOS Trial

Warwick Clinical Trials Unit

Warwick Medical School

University of Warwick