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

ICPInflectionPoint

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.

Sweet‐Mannitol

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.

Salty‐ HypertonicSaline

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.

HTS‐ AdverseEffects

Phlebitis

» Preventiono Central vs. peripheral line

o “Good” peripheral» Gauge

» Location

» Management

MANNITOL VS.HYPERTONIC SALINECLINICAL TRIALS

StudiesofMannitolvs.HTS

Mortazavi MM, et al. J Neurosurg 2012; 116:210-21

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

Mortazavi,etal

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

Mortazavi MM, et al. J Neurosurg 2012; 116:210-21

Bolusvs.ContinuousInfusions

Mortazavi MM, et al. J Neurosurg 2012; 116:210-21

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.

GuidelineRecommendations

Bullock MR, et al J Neurotrauma. 2007;24 Suppl 1:S14-20

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

Questions?