A previously well 6-year-old boy is brought into the emergency department at a major trauma centre via HEMS following a road traffic accident, in which he was hit by a car while crossing the road.
A full primary survey is carried out. Imaging is performed, including a CT Head. He is diagnosed with a traumatic brain injury and a fracture to his right tibia and fibula.
As the resuscitation continues, his heart rate falls, his respiratory effort becomes increasingly irregular and his systolic blood pressure rises. You identify these signs as Cushing’s Triad, secondary to rising intracranial pressure.
Following intubation, the decision is made to give a bolus of a hyperosmolar fluid. Both hypertonic saline and mannitol are available in your department. Which should be your first line choice?
What is a Traumatic Brain Injury?
Traumatic brain injury (TBI) is a major cause of paediatric morbidity and mortality worldwide. Severe TBI is broadly defined as a Glasgow Coma Score (GCS) of less than 8 following a traumatic event.
The pathophysiology behind a traumatic brain injury can be broadly divided into two categories [1]:
- Primary injury – the result of direct trauma to the brain
- Secondary injury – the range of pathophysiological responses – due to hypoxia, hypotension, hypoglycaemia, pyrexia and brain swelling – following the initial injury. This causes further damage to the brain, occurring in the hours to days following the initial trauma
B) Secondary injury – Evolving injury to the brain over hours to days due to responses following the initial trauma
A variety of pathophysiological changes occur following a TBI, including:
- Intracranial haemorrhage
- Increased cerebral blood flow due to loss of cerebral blood vessel autoregulation
- Cerebral oedema due to shift of fluid out of capillaries and cells
- Vasodilation secondary to hypercapnia or hypoxia
- Blockage of CSF drainage due to subarachnoid haemorrhage or herniation of the brain
Think of the skull as a closed system made of brain matter, CSF, and intracranial blood, with a constant combined volume.
To maintain a constant ICP, an increase in one of these components—e.g., CSF volume due to a blockage secondary to a TBI—there is a decrease in the others, such as intracranial blood flow. This is known as the Monro-Kellie hypothesis [2]. Eventually, this compensatory mechanism is overwhelmed. After this point, any further increase in one of these components leads to significant increases in ICP, resulting in reduced cerebral perfusion and, finally, brain herniation.
Rising ICP has a significant effect on cerebral perfusion pressure (CPP). Ordinarily, the mean arterial blood pressure (MAP) is higher than the ICP, enabling blood flow to the brain. This difference between the MAP and ICP is the CPP. When the ICP rises, this pressure gradient falls, reducing blood flow to the brain.
Cerebral Perfusion Pressure (CPP) = Mean Arterial Pressure (MAP) – Intracranial Pressure (ICP)
It is generally accepted that controlling ICP to minimise further swelling of the brain – and thereby maintaining cerebral perfusion pressure – is key to minimising secondary brain injury. Hyperosmolar agents are the cornerstone therapies for achieving this.
Hyperosmolar fluids have been used to reduce ICP since 1919 [3]. Mannitol and hypertonic saline are the preferred agents, with hypertonic saline being used most often.
The Brain Trauma Foundation publishes evidence-based guidelines to improve the care of children with brain injuries [4]. They cover many aspects of injury care, including hyperosmolar fluid use. Moderate-quality evidence is available for bolus administration of hypertonic saline, while only low-quality evidence supports continuous administration. No studies involving mannitol administration met the foundation’s inclusion criteria.
Given the lack of high-quality studies – particularly for mannitol – there is s need for further research in hyperosmolar therapy.
Enter P. Kochanek et al…
Kochanek PM, Tasker RC, Carney N, Totten AM, Adelson PD, Selden NR, et al. Guidelines for the management of pediatric severe traumatic brain injury, third edition: Update of the brain trauma foundation guidelines. Pediatric Critical Care Medicine. 2019 Mar;20(3S)
The Question
Which hyperosmolar agent – 3% Hypertonic Saline or Mannitol – is more effective at reducing intracranial pressure (ICP) and increasing cerebral perfusion pressure (CPP) in paediatric traumatic brain injury (TBI)?
How
This study was an observational, comparative effectiveness study comparing 3% hypertonic saline with mannitol rather than to a control. It uses data obtained as part of the larger Approaches and Decisions for Acute Paediatric TBI Trial (ADAPT).
Inclusion criteria included:
- A diagnosis of TBI
- Age birth to 18 years
- ICP monitor used as part of care
- Glasgow Coma Scale (GCS) score of 8 or lower at time of ICP monitor placement
While the exclusion criteria were:
- Pregnancy
- ICP monitor placed at different site
- Receiving boluses of both mannitol AND hypertonic saline within the same hour
518 patients at sites worldwide were included. They received 2494 boluses of either mannitol or 3% hypertonic saline. Intracranial pressure and cerebral perfusion pressure were recorded an hour before and after the bolus was administered.
The Results
The average decrease in ICP for hypertonic saline boluses was 1.03 mmHg (p <0.001) while the average for mannitol was 0.20 mmHg (p = 0.44 – i.e. statistically insignificant).
A greater decrease in ICP was noted with hypertonic saline than mannitol.
These results held even when adjusted for confounding factors including gender, GCS, cause of injury and presence of an epidural haematoma.
No statistically significant difference was noted in CPP improvement between both fluids.
Study Strengths
As highlighted in the Brain Trauma Foundation Guidelines, there is a lack of large, high-quality trials concerning hyperosmolar fluids in the management of raised ICP, particularly for mannitol. This study recruited a large and diverse range of patients from eight different countries.
The paper also included TBIs secondary to penetrating injuries and abuse, which are often excluded from other studies, despite being a significant cause of injuries in children.
Limitations
The paper notes significant variation in practice in the use of hypertonic saline; 27 different concentrations were identified. For this study, the authors decided to only collect data on 3% hypertonic saline.
While hypertonic saline is often given as an infusion to help manage raised ICP, this paper only covers bolus administration. As such, these findings may not apply to the treatment algorithms and approaches used by many clinical centres.
The study additionally only measures ICP one hour after bolus administration. This study will have missed any sustained change in the ICP beyond this.
Significantly, it should be noted that the study does not cover long-term outcomes, including survival. This will be of greater importance to both clinicians and patients than which fluid causes a greater decrease in ICP.
Lastly, the authors note that 40% of the data from mannitol administration came from 2 centres – which may introduce bias to the results.
What Other Research Is There On The Topic?
There was also a meta-analysis on this topic in the adult population by Schwimmbeck et al [6] in 2021. Here is a quick summary of this study:
Population: RCTs, quasi-randomised, cross-over and unblinded trials comparing hypertonic saline to mannitol in patients with severe traumatic brain injuries, with a total of 21 studies included following screening.
Interventions and Control: RCT protocols varied on dosing and bolus vs infusion but used mannitol or hypertonic saline (or Hartmanns solution) as either the control or the intervention.
Outcomes: Six studies reported mortality as primary outcome and six reported functional outcome at the end of study follow-up as their primary outcome.
Results: The pooled data showed no statistical difference in survival or neurological outcomes. However, they felt one study had a bias towards mannitol in the category of patients chosen. Once this study was excluded, there was, in fact, a statistically significant decrease in mortality and neurological impacts with hypertonic saline.
The Bottom Line
Boluses of 3% hypertonic saline are superior to mannitol in reducing intracranial pressure for paediatric traumatic brain injuries.
Future research should focus on long-term outcomes following mannitol or hypertonic saline use to determine the optimal hyperosmolar fluid of choice for traumatic brain injury.
References
- Vavilala M, Tasker R. Severe traumatic brain injury (TBI) in children: Initial evaluation and management [Internet]. 2023 [cited 2024 Apr 10]. Available from: https://www.uptodate.com/contents/severe-traumatic-brain-injury-tbi-in-children-initial-evaluation-and-management
- Tasker R. Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis [Internet]. 2024 [cited 2024 Apr 14]. Available from: https://www.uptodate.com/contents/elevated-intracranial-pressure-icp-in-children-clinical-manifestations-and-diagnosis
- Weed LH, McKibben PS. Pressure changes in the cerebro-spinal fluid following intravenous injection of solutions of various concentrations. American Journal of Physiology-Legacy Content. 1919 May 1;48(4):512–30. doi:10.1152/ajplegacy.1919.48.4.512
- Kochanek PM, Tasker RC, Carney N, Totten AM, Adelson PD, Selden NR, et al. Guidelines for the management of pediatric severe traumatic brain injury, third edition: Update of the brain trauma foundation guidelines. Pediatric Critical Care Medicine. 2019 Mar;20(3S). doi:10.1097/pcc.0000000000001735
- Kochanek PM, Adelson PD, Rosario BL, Hutchison J, Miller Ferguson N, Ferrazzano P, et al. Comparison of intracranial pressure measurements before and after hypertonic saline or mannitol treatment in children with severe traumatic brain injury. JAMA Network Open. 2022 Mar 10;5(3). doi:10.1001/jamanetworkopen.2022.0891
- Schwimmbeck, F., Voellger, B., Chappell, D. and Eberhart, L. (2019). Hypertonic Saline Versus Mannitol for Traumatic Brain Injury. Journal of Neurosurgical Anesthesiology, p.1. doi:https://doi.org/10.1097/ana.0000000000000644.
