Double Blind Study of Hypertonic Saline vs Mannitol in the Management of Increased Intracranial Pressure (ICP).

Overview

The study goal is to compare the management of increased intra-cranial pressure (ICP) using 3% hypertonic saline vs. mannitol (given in same osmolar loads). Primary hypothesis: 1. Hypertonic saline will be non-inferior to mannitol in decreasing elevated ICP. Secondary hypotheses: 1. Hypertonic saline therapy will result with fewer complications than mannitol 2. ICP reduction duration will be longer using hypertonic saline when compared with mannitol

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: January 2014

Detailed Description

There is growing evidence in the literature indicating that ICP and Cerebral Perfusion Pressure measurements may not be sufficient in the management of elevated ICP. Based on this evidence, monitoring of partial brain tissue oxygenation has gain acceptance among neurosurgeons and neurointensivists, and has become a standard of care monitor in some centers across the country. There is, however, insufficient information in the literature describing the effects of hyperosmolar medications on regional brain tissue oxygenation. We intend to undertake this non-inferiority, prospective, randomized double-blind study to answer very important clinical questions not yet answered in the literature: Will hypertonic saline therapy, given at equiosmolar load, be non-inferior to mannitol in reducing elevated ICP?

Interventions

  • Drug: hypertonic saline
    • 3% hypertonic saline, dosed by ideal patient weight
  • Drug: Mannitol
    • Mannitol 20% intravenous solution, dosed by patient’s ideal body weight

Arms, Groups and Cohorts

  • Active Comparator: hypertonic saline
    • 3% hypertonic saline, dosed by ideal patient weight
  • Active Comparator: Mannitol
    • 20% mannitol, dosed by patient’s ideal body weight

Clinical Trial Outcome Measures

Primary Measures

  • Percent reduction of ICP from baseline
    • Time Frame: 30 minutes from completion of medication administration

Secondary Measures

  • Time from study drug administration completion to ICP < 25 mmHg
    • Time Frame: First 72 hours
  • Cumulative duration of ICP below 25 mmHg
    • Time Frame: First 24 hours
  • Cumulative duration of ICP below 25 mmHg
    • Time Frame: First 72 hours
  • Cumulative duration of cerebral perfusion pressure (CPP) above 60 mmHg
    • Time Frame: First 24 hours
  • Cumulative duration of cerebral perfusion pressure (CPP) above 60 mmHg
    • Time Frame: First 72 hours
  • Cumulative duration of regional oxygen partial pressure (pbtO2) > 20%
    • Time Frame: two hours following each dose administration during the first 24 hours
  • Total dose of medications given
    • Time Frame: First 24 hours; also over 3 days
  • Frequency of treatment failure
    • Time Frame: First 72 hours
    • Treatment failure defined as ICP > 30 mmHg for > 30 minutes
  • Frequency of rebound intracranial hypertension
    • Time Frame: First 72 hours
    • Rebound intracranial hypertension defined as ICP > 25 mmHg for more than 10 minutes following ICP stabilization
  • Frequency of composite Major Adverse Events
    • Time Frame: 3 days
    • acute kidney injury as defined by an increase in creatinine x 2 or GFR decrease > 50% or urine output < 0.5 ml/kg/h for 12 hours, compared to baseline, as per RIFLE criteria hypotensive episodes (SBP < 90 mmHg for more than 10 minutes) hemodynamic instability as measured by decrease of cardiac output by more than 15% within two hours following medication administration pulmonary edema as defined by ELWI I> 10
  • Difference in inflammatory response
    • Time Frame: Regular intervals over first 3 days
    • Determined by analysis of cytokine and inflammatory biomarkers.
  • Difference in average pre-discharge stroke scale score
    • Time Frame: hospital discharge (or 30 days if not discharged)

Participating in This Clinical Trial

Inclusion Criteria

  • Age ≥ 18 years – elevated ICP requiring ICP monitoring – ICP ≥ 25 mmHg 5 min after ICP bolt or EVD placement Exclusion Criteria:

  • Requiring decompressive craniotomy or post decompressive craniotomy – Hyponatremia (sodium level < 125 mEq/L) – Hypernatremia (sodium > 155 mmol/L) – Serum osmolality ≤ 250 mOsm/kg – Serum osmolality ≥ 320 mOsm/kg – Physical exam compatible with brain death – Patients on hemodialysis with end-stage renal disease

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Beth Israel Deaconess Medical Center
  • Provider of Information About this Clinical Study
    • Principal Investigator: Achikam Orin-Grinberg, Assistant Professor of Anaesthesia – Beth Israel Deaconess Medical Center
  • Overall Official(s)
    • Achikam Oren-Grinberg, MD, Principal Investigator, Beth Israel Deaconess Medical Center

References

Shackford SR, Bourguignon PR, Wald SL, Rogers FB, Osler TM, Clark DE. Hypertonic saline resuscitation of patients with head injury: a prospective, randomized clinical trial. J Trauma. 1998 Jan;44(1):50-8. doi: 10.1097/00005373-199801000-00004.

BARRY KG, BERMAN AR. Mannitol infusion. III. The acute effect of the intravenous infusion of mannitol on blood and plasma volumes. N Engl J Med. 1961 May 25;264:1085-8. doi: 10.1056/NEJM196105252642105. No abstract available.

Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS; Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, Manley GT, Nemecek A, Newell DW, Rosenthal G, Schouten J, Shutter L, Timmons SD, Ullman JS, Videtta W, Wilberger JE, Wright DW. Guidelines for the management of severe traumatic brain injury. II. Hyperosmolar therapy. J Neurotrauma. 2007;24 Suppl 1:S14-20. doi: 10.1089/neu.2007.9994. No abstract available. Erratum In: J Neurotrauma. 2008 Mar;25(3):276-8. multiple author names added.

The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Use of mannitol. J Neurotrauma. 2000 Jun-Jul;17(6-7):521-5. doi: 10.1089/neu.2000.17.521.

Bereczki D, Liu M, Prado GF, Fekete I. Cochrane report: A systematic review of mannitol therapy for acute ischemic stroke and cerebral parenchymal hemorrhage. Stroke. 2000 Nov;31(11):2719-22. doi: 10.1161/01.str.31.11.2719.

Qureshi AI, Suarez JI, Bhardwaj A, Mirski M, Schnitzer MS, Hanley DF, Ulatowski JA. Use of hypertonic (3%) saline/acetate infusion in the treatment of cerebral edema: Effect on intracranial pressure and lateral displacement of the brain. Crit Care Med. 1998 Mar;26(3):440-6. doi: 10.1097/00003246-199803000-00011.

Huang SJ, Chang L, Han YY, Lee YC, Tu YK. Efficacy and safety of hypertonic saline solutions in the treatment of severe head injury. Surg Neurol. 2006 Jun;65(6):539-46; discussion 546. doi: 10.1016/j.surneu.2005.11.019.

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