hyperosmolar therapy alexandra serafino, pharmd · hyperosmolar therapy alexandra serafino, pharmd...
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Hyperosmolar Therapy
Alexandra Serafino, PharmD Pharmacy Resident, Intermountain Medical Center, Intermountain
Healthcare; Salt Lake City, UT
Objectives: • List the more common causes of elevated intracranial pressures (ICP) • Compare and contrast the pharmacokinetics, pharmacodynamics,
and therapeutic applications of hypertonic saline and mannitol • Determine if hypertonic saline or mannitol should be used
preferentially when given a patient case
SaltyorSweet‐HowDoYouLikeYourBrain?
ALEXANDRA SERAFINO, PHARM.D.
PGY-2 CRITICAL CARE PHARMACY RESIDENT
INTERMOUNTAIN MEDICAL CENTER
MURRAY, UT
Objectives
» List the more common causes of elevated intracranial pressures (ICP)
» Compare and contrast the pharmacokinetics, therapeutic applications, and administration techniques of hypertonic saline and mannitol
» Given a patient case, determine how to appropriately administer hypertonic saline or mannitol and monitor the patient
ElevatedICP
» Increase in ICP >20 mmHg
» A neurologic emergency
» Potentially devastating
Ropper AH, et al. N Engl J Med 2012; 367:746-52.
CausesofElevatedICP
Traumatic brain injuries
Intracranial bleeding
Brain and CNS tumors
Hydrocephalus
Severe ischemic stroke
Ropper AH, et al. N Engl J Med 2012; 367:746-52.
Epidemiology
» Traumatic brain injuryo ~1.4 million sustained annually in the United States
o ~80,000 severe TBI
» Elevated ICP increases morbidity and mortalityo Mortality of 18% for ICP < 20 mmHg
o Mortality of 56% for ICP > 40 mmHg
» Long term disability is common
Treggiari MM, et al. Neurocrit Care 2007;6:104-12.Thurman DJ, et al. J Head Trauma Rehabil 1999;14:602-15.
PathophysiologyofElevatedICP
Ropper AH, et al. N Engl J Med 2012; 367:746-52.
Increased ICP• Cellular injury• Intracranial hemorrhage
Inflection point• Exponential rise in ICP• Vasoconstriction• Impaired gas exchange
Approaches arterial pressure• ICP 50-60 mmHg• Neuronal cell death
HyperosmolarTherapies
» Creates an osmolar gradient between the brain and the systemic circulationo Draws “water” from the brain into systemic
circulation
» Rapidly reduces intracranial pressureo Mitigates neuronal cell death
Ropper AH, et al. N Engl J Med 2012; 367:746-52.
PassiveDiffusion
» Brain parenchyma ~ 80% watero Increased responsiveness to changes in water
contentRopper AH, et al. N Engl J Med 2012; 367:746-52.
HyperosmolarTherapies» Should not cross the blood brain barrier (BBB)
» Reflection coefficiento Ability to create an effective gradient
» Hypertonic saline = 1
» Mannitol = 0.9
» More effective in non-injured portions of brain
Ropper AH, et al. N Engl J Med 2012; 367:746-52.Videen TO, et al. Neurology 2001;57:2120-2.
GoalsofTherapy» Decrease ICP Save brain tissue
» Direct ICP monitoring deviceso Goal ICP < 20
o Cerebral perfusion pressures (CPP) ~50-70
» No direct-pressure monitoringo Serum osmolarity
» Initial target of 300-320 mOsm/L
o Serum sodium » Initial target of 145-150 mEq/L
o Titration to effect
Ropper AH, et al. N Engl J Med 2012; 367:746-52.
Mannitol» Mechanism of action
o Osmotic diuretic
o Causes sustained hyperosmolarity via dehydration
» Possible mechanisms for reducing ICPo Intracellular removal of neuronal brain water
o Decreased production of CSF
Ropper AH, et al. N Engl J Med 2012; 367:746-52.Donato T, et al. Anesth Analg 1994; 78:58-66.
Mannitol‐ Dosing
» Suppliedo 20% (20 g mannitol/100 mL solution)
o 25% (12.5 g/50 mL solution)
» Dosingo 0.25 – 1 g/kg body weight
o 1 g/kg initial load
o 0.25-1 g/kg repeat doses q6-8h
Bullock MR, et al. Neurotrauma 2007;24:Suppl 1: S14-S20.
Mannitol‐Monitoring» Serum osmolality: daily or “trough”
» Osmole gap is a better predictor of mannitol clearance
o Recommend gap closure prior to subsequent doses regardless of serum osmolality
Bullock MR, et al. Neurotrauma 2007;24:Suppl 1: S14-S20.
Garcia-Morales EJ, et al. Crit Care Med 2004; 32(4): 986-991.
Mannitol‐ AdverseEffects» Renal failure
o Likely due to Intravascular volume depletion combined with intrarenal vasoconstriction
o > 200 g daily
» Volume contraction alkalosis» Hypokalemia» Hypochloremia» Hyperglycemic, hyperosmolar encephalopathy
o Confusion
o Seizures
Better OS, et al. Kidney Int 1997;52:886-94.Ropper AH, et al. N Engl J Med 2012; 367:746-52.
MannitolAdministration
» Peripheral or central venous catheter
» Can be given IV push
» IV filter must be usedo 0.22 micron in-line filter
» Vials must be drawn up individually and administered
MannitolPearls
» Crystallization occurs at lower temperatureso Store in heated cabinet ≤ 60°Co Allow to cool prior to administration
Crystallization
ManagingExtravasation
» Stop the infusion
» Aspirate any extravasated medication
» Elevation
» Monitor the area
» Apply compresso Warm vs. cold
Goutos I, et al. The Journal of Hand Surgery 2014;39E(8):808–818.
HypertonicSaline» Mechanism of action
o Directly increases serum osmolarity
o Osmotic mobilization of water across intact BBB
Ropper AH, et al. N Engl J Med 2012; 367:746-52.
HTS‐ DoseCalculation
» Estimated Na+ requirements
» Dosingo 1.8% NaCl = 308 mEq/L
o 3% NaCl = 513 mEq/L
o 23.4% NaCl = 4004 mEq/L
» Requires frequent sodium monitoring!
Mannitolvs.HTS
Agent Osmolarity (mOsm/L) Sodium (mEq/L)
0.9% NaCl 308 154
1.5% NaCl 513 256
1.8% NaCl 616 308
3.0% NaCl 1026 513
7.5% NaCl 2566 1026
23.4% NaCl 8008 4004
Mannitol 20% 1098 n/a
**Only ≤900 mOsm/L can be administered peripherally**
IVNaCl vs.NaCl Tablets
Agent Na+ mEq / L
0.9% NaCl 154
3.0% NaCl 513
“Salt Tablets”
1 tablet 1000 mg 17 mEq
154 mEq / 17 mEq = 9 tablets
HTS‐Monitoring
» Signs/symptoms of fluid overload
» Frequent serum Na+ or BMP lab drawso Generally every 4-6 hours
o More frequent monitoring may be necessary with continuous infusions of HTS
o Prevent rapid sodium changes
» Sodium goals may change
HTS‐ AdverseEffects
» Phlebitiso Always infuse HTS > 1.8% NaCl through a central line
» Volume overload
» Hypokalemia, hyperchloremia
» Osmotic demyelination syndromeo Alcoholism, liver disease, hypoglycemia, SIADS
o 22% of all documented cases secondary to HTS» Severe, chronic hyponatremia corrected too quickly
Ropper AH, et al. N Engl J Med 2012; 367:746-52.Kleinschmidt-Demaster BK, et al. J Neuropathol Exp Neurol 2006;65:1-11.
Phlebitis
» Preventiono Central vs. peripheral line
o “Good” peripheral» Gauge
» Location
» Management
Hypertonicsalinefortreatingraisedintracranialpressure:literaturereviewwithmeta‐analysis
Mortazavi et al, J Neurosurg 2012
Mortazavi,etalStudy Design Systematic review & Meta-analysis
Studies included HTS for elevated ICP
Studies included (#) 36
RCTs (#) 10
RCTs comparing mannitol to HTS (#)
7
Results1 RCT showed improved GOS at 1-year; 6/7 RCTssuggest improved ICP lowering with HTS vs. mannitol
Conclusions
HTS decreases ICP to a greater extent vs. mannitol, whether used as a bolus or continuous infusion, but has been not shown to improve neurologic outcomes
Mortazavi MM, et al. J Neurosurg 2012; 116:210-21
Meta‐AnalysesandReviews
» Other meta-analyses have made similar conclusionso HTS is more effective at decreasing ICP
o Limited long-term and neurologic outcome data
» Mean difference in ICP lowering is smallo ~1.5-2.5 mmHg
» Less therapeutic failures with HTS vs. mannitol
Kamel H, et al. Crit Care Med 2011; 39:554-9Hinson HE, et al. J Intensive Care Med 2013; 28(1):3-11Lazaridis C, et al. Crit Care Med 2013; 41:1353-60
Rickard AC, et al. Emerg Med J 2013
Bolusvs.ContinuousInfusion
» No recommendation can be made with regards to continuous infusion vs. bolus mannitol
» Significantly more data on bolus HTS administration
» Available data suggest bolus and continuous infusion HTS is effective at reducing ICP
Mortazavi MM, et al. J Neurosurg 2012; 116:210-21Bullock MR, et al. Neurotrauma 2007;24:Suppl 1: S14-S20.
Choices– SaltyorSweet?
» HTS vs. Mannitolo Decreases ICP to a greater extent
o Effects last longer, realized more quickly
o Lower risk of rebound ICP elevations
o Fewer adverse effects
» Clinical outcome data to support the use of one agent over the other is lacking
» Recent study of neurointensivists reports trend in increasing HTS use (55% vs. 45%)
Hays AN,. Neurocrit Care 2011, 14:222-228.
Take‐AwayPoints
» HTS over mannitol in most situations
» Either therapy will require frequent laboratory monitoringo Sodium
o Serum osmolarity
» Watch for adverse effects
» Always use a filter for mannitol
» Central vs. peripheral administration