hypertonic saline versus Mannitol, the unresolved question

Comparison of Intracranial Pressure Measurements Before and After Hypertonic Saline or Mannitol Treatment in Children With Severe Traumatic Brain Injury

Patrick M. Kochanek, MD; P. David Adelson, MD; Bedda L. Rosario, PhD; James Hutchison, MD; Nikki Miller Ferguson, MD; Peter Ferrazzano, MD; Nicole O’Brien, MD;

John Beca, MD; Ajit Sarnaik, MD; Kerri LaRovere, MD; Tellen D. Bennett, MD, MS; Akash Deep, MD; Deepak Gupta, MCH, PhD; F. Anthony Willyerd, MD; Shiyao Gao, PhD;

Stephen R. Wisniewski, PhD; Michael J. Bell, MD; for the ADAPT Investigators

March 10, 2022

 Hyperosmolar agents are cornerstone therapies for paediatric severe traumatic brain injury. Guideline recommendations for 3% hypertonic saline (HTS) are based on limited numbers of patients, and no study to date has supported a recommendation for mannitol.



  • >77% of the study population received hyperosmolar therapies (Mannitol or HTS) during the ICP treatment phase of their care.
  • Hypertonic Saline was associated with lower intracranial pressure (ICP) and a higher cerebral perfusion pressure (CPP).
  • Mannitol was associated only with higher CPP.


Bottom line

  • Administration of hypertonic saline was associated with superior ICP and CPP outcomes in children with severe traumatic brain injury
  • During ICP crises, HTS was associated with better performance than Mannitol.
  • Remaining lack of evidence of superiority of one or the other agents, this study will not change of practice in our eyes


What this paper is about

  • This comparative effectiveness study examined how commonly hyperosmolar therapies are used in the management of severe traumatic head injury in children.
  • It assessed which agent – mannitol or hypertonic saline was associated with greater decreases in intracranial pressure (ICP) and/or increases in cerebral perfusion pressure (CPP)


Study Design and outcome measures

  • Observational comparative effectiveness research study conducted from February 1 2014, to September 31 2017 at 44 clinical sites in 8 countries, with follow up for 1 week after injury.
  • Boluses of HTS and mannitol were administered
  • Data on ICP and CPP were collected before and after medication administration
  • Statistical methods included linear mixed models and corrections for potential confounding variables to compare the 2 treatments.

Study Population and Characteristics

  • Inclusion criteria was age <18 years at time of injury, a diagnosis of traumatic brain injury, ICP monitor used as part of standard of care and GCS score of 8 or lower at time of monitor placement
  • Exclusion criteria were pregnancy and ICP monitor placement at an institution other than the clinical site.
  • 1018 children were screened and 18 were excluded: 787 children received some form of hyperosmolar therapy, with 521 receiving a bolus. (3 were excluded)
  • 336 (64.9%) were male; Participants mean GCS score was 5.2


Patient selection flowchart



  • Bolus HTS was observed to decrease ICP and increase CPP mean ICP 6.77mmHg; p<.001; mean CPP 12.47 mmHg, whereas mannitol was observed to increase CPP mean 11.43mmHg p=.009.
  • In the primary outcome, HTS was associated with a greater reduction in ICP compared with mannitol, but after adjustments for confounders, no differences in CPP were observed.


Study Weaknesses/Limitations;

  • Significant practice variability in the use of hyperosmolar therapies (infusion, combination therapy and concentrations) made it necessary to focus only on bolus administration of medications and only 3% HTS. This limited their ability to compare the various preparations used.
  • 2 centres contributed approximately 40% of the data on mannitol boluses which could introduce bias.
  • Although it included valuable data on patients with abusive head trauma and penetrating TBI, these factors might alter the association between hyperosmolar therapy and ICP and CPP. Additional studies of these subgroups are warranted.