Question

• Is hypertonic saline a more effective therapeutic measure to reduce intracranial pressure in children with intracranial masses compared to Mannitol?

Clinical Bottom Lines

1. Although Mannitol remains the most commonly used agent for reducing ICP in the acute setting for intracranial masses, after reviewing "expert opinion" level evidence both in the literature and with our PICU attendings, it appears that hypertonic saline may be preferable based on a comparison of the adverse effect profile (less predisposition towards hemodynamic instability, less risk of renal complications, easier to track and follow with serum sodium levels).
2. Additionally, it appears that in the acute setting, using boluses of both hypertonic saline and mannitol (as was performed in the clinical scenario that stirred this investigation) are based on anecdotal evidence.

Summary of Key Evidence

1. Ethics: IRB approved; no informed consent needed
   
2. Setting: Egleston Children's Hospital (Emory University) PICU
   
3. Inclusion Criteria: Admission to PICU, Invasive intracranial monitor, Required at least one dose of HS or mannitol for increased ICP
   
4. Study Design: Retrospective Cohort (2 studies)
   Study 1
   -HS infusions only: 25 patients; outcomes evaluated prior to infusion, at 30, 60, 120 mins after infusions
   -Mannitol infusions only: 18 patients, outcomes evaluated prior to infusion, at 30, 60, 120 mins after infusions
   -Comparisons made among and between HS and Mannitol
   Study 2
   -Data reviewed separately from study 1
   -12 Patients; Individuals Received Both HS and Mannitol infusions;
   
5. Dosages used: HS: 5mL/kg dose; Mannitol 0.5g/kg dose or 1g/kg dose
   
6. Outcomes Measured: ICP, CPP, MAP, and HR prior to infusion; 30, 60, and 120 minutes after treatment
   
7. Data Collection: PICU Pharmaceutical database Dec 1993 - DEC 1995; Nurses notes and MAR for drug timing and outcome measurement
   
8. Study Results:
   Study 1: Hypertonic Saline Infusions only compared to Mannitol Infusions only
   -statistically significant difference in median GCS between group receiving HS and those receiving mannitol, higher GCS scores in HS group (p <0.02)
   -statistically significant difference in baseline ICP of mannitol group compared to HS group, higher ICP scores in Mannitol group (p<0.02)
   -significant reductions in ICP were noted at 30 , 60 and 120 minutes following the HS infusions
   -CPP increased significantly at 60 and 120 minutes after HS infusions
   -No significant change in HR or MAP
   -Significant reductions in ICP were seen at 60 and 120 minutes after mannitol infusions
   -No significant changes were noted in CPP, HR, or MAP
   Study 2: Hypertonic Saline and Mannitol Infusions both received; compared within individuals at time of administration
   -Statistically significant difference between baseline ICP prior to receiving Mannitol compared to ICP prior to receiving HS (p<0.05)
   -Significant reductions in ICP at 60 and 120 minutes for infusions of Mannitol
   -Significant reductions in ICP at 60 and 120 minutes for infusions of HS
   -Significant reductions in CPP at 30, 60 and 120 minutes for infusions of HS compared to Mannitol
   

Additional Comments

• Key flaw in the study was the baseline ICP in both studies, in both groups being analyzed, were different at baseline and found to be statistically significant; ICP was actual outcome that was being evaluated in this study; furthermore the GCS scores at baseline were also different at baseline and considered statistically significant. Thus the question posed by study could not be answered as it would not be a valid comparison; the outcomes of Mannitol could not be compared to HS and be considered valid.
• Two different dosages of Mannitol were used; they were of different osmolalities and one dose was not comparable to the osmolality of HS used; the dose that was used was not identified.
• Method of Analysis chosen for the study does not appear optimal; Kruskal Wallis often used for three or more treatment groups consisting of different individuals; a more appropriate method of statistical analysis would have be the Two Factor Repeated Measures Analysis of Variance (evaluates multiple treatments in the same individual with an acknowledgment of a baseline).
  

Citation

1. Vats A, Chambliss CR, Anand KJS, et al. Is hypertonic saline an effective alternative to mannitol in the treatment of elevated pressure in pediatric patients? Journal of Intensive Care Medicine 1999;14:184-8.
2. Wakai A, Roberts I, Schierhout G. Mannitol for acute traumatic brain injury. The Cochrane Databse of Systematic Reviews 2005, Issue 4. Art. No: CD001049.pub2 DOI: 10.1002/14651858. CD001049.pub2.
3. Rogers, Mark C. Nichols, David G; Textbook of Pediatric Intensive Care; Third Edition 1996.
4. Chapter 17. Critical pathway for the treatment of established intracranial hypertension in pediatric traumatic brain injury; Pediatric Critical Care Medicine 2003 4(3) Supplement (s65-67).
5. Chapter 11. Use of hyperosmolar therapy in the management of severe pediatric traumatic brain injury, Pediatric Critical Care Medicine 2003 4(3) Supplement (s40-44).
6. Ogden AT, Mayer SA, Connolly, ES Hyperosmolar Agents in Neurosurgical Practice: The Evolving Role of Hypertonic Saline; Neurosurgery 57(2):207-215; 2005.
7. Tommasino, C Fluids and the neurosurgical patient; Anesthesiology Clinics of North America 20(2) 329-346 2002.
8. Allen CH, Ward JD An Evidence-Based Approach to Management of Increased Intracranial Pressure Critical Care Clinics 14(3) 485-495 July 1998.
9. Mokri B. The Monro-Kellie Hypothesis: Applications in CSF volume depletion. Neurology 2001; 56; 1746-8.

CAT Author: Sandhya Sasi, MD

CAT Appraisers: Steven Park, MD

Date appraised: October 4, 2006