Download Osmotherapy Indications for Osmotherapy Mannitol 20

5/6/2014
Indications for Osmotherapy
Osmotherapy
Theresa Human, PharmD, BCPS, FNCS
Pharmacy Specialist-Neurosurgery/Critical Care
Barnes Jewish Hospital
Washington University
Indication
Recommendation
Traumatic brain
injury (TBI)
Mannitol is effective for control of raised intracranial pressure
(ICP) at doses of 0.25gm/kg to 1gm/kg body weight
Intracerebral
hemorrhage (ICH)
Not mentioned in guidelines
Subarachnoid
hemorrhage (SAH)
Not mentioned in guidelines
Ischemic stroke
(CVA)
Although aggressive medical measures, including osmotherapy,
have been recommended for treatment of deteriorating patients
with malignant brain edema after large cerebral infarction, these
measures are unproven
Brain tumor
Evidence from randomized studies for a role of osmotherapy in
brain tumor edema is lacking
Bederson JB, et al. Stroke 2009; 40: 1-32.
Morgenstern LB, et al. Stroke 2010; 41: 2108-2129.
Brain Trauma Foundation. J Neurotrauma 2007; 24(1): S14-S20.
Adams HP, et al. Stroke 2007; 38: 1655-1711.
Kall ECA, et al. Curr Opin Oncol 2004; 16: 593-600.
Mannitol 20%
• Osmotic diuretic
– Non-metabolized sugar
– Filtered renally
– Minimal to no renal re-absorption
• Typical dose
– 0.25-1gm/kg every 4-6 hours
– 1.5-2gm/kg for acute herniation
Sodium Chloride
• Hypertonic crystalloid solution
– Sodium primary determinant for serum osmolarity
– Elimination exquisitely controlled by kidneys
– Variable re-absorption renally
• Typical dose
– 3%: 2.5-5ml/kg
– 23.4%: 20-30ml
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Brain Relaxation/Dehydration
• Osmotic gradient with mannitol appears to
draw intracellular fluid from brain to serum
Blood Brain
Blood Brain
H2O
Mannitol
Sodium
Blood Brain
Impact of Cerebral Autoregulation
• Immediate effect of mannitol is plasma
expansion
– Augmented blood volume increases cerebral
blood flow
– Compensatory vasoconstriction
H2O
Normal equilibrium
Mannitol infusion
H2O
Mannitol equilibrium
Normal equilibrium
Mannitol infusion
Vasoconstriction
Wu C-T, et al. Anes Analges 2010; 110: 903-907.
Rozet I, et al. Anesthes 2007; 107: 697-704.
Pharmacodynamics of Osmotherapy
Osmotherapy Agent Comparison
Osmotherapy effect
Mannitol 20%
Equi-osmolar
dose
1 gm/kg
3-4ml/kg
0.687 ml/kg
Osmolarity
1098 mOsm/L
1707 mOsm/L
7987 mOsm/L
Infusion
IVPB over 10-15min
IVPB over 10-15min
IV push over 10-15min
Central preferred
Central preferred
Peripheral x 72 hours
Central
Trough sodium levels
Trough sodium levels
Line
Vasoconstriction
Time
Sodium chloride Sodium chloride
5%
23.4%
Monitoring
Osmolar Gap trough BMP and
serum osmolality
Strict fluid ins/outs
Electrolytes
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Monitoring mannitol clearance
• Osmotic gap= measured osm - calculated osm
• Detects the presence of unmeasured osmoles
such as mannitol
• May be useful in assessing the clearance
between boluses of mannitol
• Osmolar gap of 15-20 indicates incomplete
clearance between doses
• Osmolality >320 not contraindication
Selected Reports of Rebound ICP
Study
N
Indication
Dose
Rebound rate
Node Y, et al.
65 adults
Not specified
0.5-1gm/kg
mannitol
12% of patients
Sankar T, et al.
1 adult
Meningioma
0.5gm/kg
mannitol
Accumulation
in brain by MRS
Rudehill G, et
al.
15 adults
Intracranial
tumor
1gm/kg
mannitol
Mannitol CSF
<12% serum
Palma L, et al.
21 adults
Intracranial
tumor
1gm/kg
mannitol
Mannitol brain
conc 3.5x >
plasma
Kaufmann AM,
et al.
23 cats
Cortical injury
model
0.33gm/kg
Multiple doses
inc. brain water
content 3%
Node Y, et al. Adv Neur 1990; 52: 359-363.
Sankar T, et al. J Neurosurgery 2008; 108: 1010-1013.
Rudehill A, et al. J Neurosurg Anes 1993; 5: 4-12.
Palma L, et al. J Neurosurg Sci 2006; 50: 63-66.
Kaufmann AM, et al. J neurosurgery 1992; 77: 584-589.
Blood-Brain Barrier Penetration
• “Reflection coefficient”
– HTS = 1
– Mannitol = 0.9
• Typical blood-brain barrier penetration
– Sodium highly regulated
– Mechanisms for hexose transport
Mannitol Penetration into CSF
Plasma vs CSF
mannitol
concentrations
after a single 1
g/kg dose
Rudehill A, et al. J Neurosurg Anes
1993; 5: 4-12.
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Mannitol vs Hypertonic saline
Mannitol vs Hypertonic saline
Theoretical benefits of hypertonic saline
– Less volume (23.4%)
– Lack of diuretic effect
– Reflection coefficient (1 vs 0.9)
– Attenuation of macrophage & neutrophil
activation
• Variable immune response
Kamel H, et al. Crit Care Med 2011; 39: 554-559.
Mortazavi MM, et al. J Neurosurgery 2012; 116: 210-221.
Two meta-analyses
Study
N, population
Agents
Results
Superior agent
Affif, 2003
40, tumor
Mannitol 20%,
HTS 3%
ICP reduction for both
groups
Equal
Battison,
2005
9, TBI + SAH
Mannitol 20%,
HTS 7.5% +
dextran
ICP reduction for both
groups
Equal
Francony,
2008
20, TBI + ICH +
CVA
Mannitol 20%,
HTS 7.45%
ICP reduction for both
groups
Equal
Ichai, 2009
34, TBI
Mannitol 20%,
Sodium lactate
ICP reduction for both
groups
Equal
Schwarz,
1998
9, CVA + ICH
Mannitol 20%,
HTS 7.5% +
hetastarch
ICP reduction for both
groups
Equal
Hartujunyan,
2005
40, SAH + CVA +
TBI + TBI
Mannitol 15%,
HTS 7.2% +
hetastarch
HTS > Mannitol for ICP
reduction at 30 & 60min
after infusion
HTS > mannitol
Kamel H, et al. Crit Care Med 2011; 39: 554-559.
Mannitol vs Hypertonic saline
Mannitol vs Hypertonic saline
Kamel H, et al. Crit Care Med 2011; 39: 554-559.
Two meta-analyses
Study
N,
population
Agents
Results
Superior agent
Fisher, 1992
18, TBI,
pediatrics
HTS 3%, 0.9% NaCl
HTS reduced ICP
HTS > NS
Schwarz,
1998
9, CVA +
ICH
Mannitol 20%, HTS
7.5% + hetastarch
ICP reduction for both
groups
Equal
Vialet, 2003
20, TBI
Mannitol 20%, HTS
7.5%
Isovolemic doses, HTS >
mannitol for ICP reduction
HTS > mannitol
Big dose > small
Battison,
2005
9, TBI +
SAH
Mannitol 20%, HTS
7.5% + dextran
ICP reduction for both
groups
Equal
Hartujunyan,
2005
40, SAH +
CVA + TBI +
TBI
Mannitol 15%, HTS
7.2% + hetastarch
HTS > Mannitol for ICP
reduction at 30 & 60min
after infusion
HTS > mannitol
Bentsen, 2006 22, SAH
7.2% HTS +
hetastarch, 0.9% NaCl
ICP reduction in HTS group
HTS > NS
Francony,
2008
20, TBI +
ICH + CVA
Mannitol 20%, HTS
7.45%
ICP reduction for both
groups
Equal
Ichai, 2009
34, TBI
Mannitol 20%, Sodium ICP reduction for both
lactate
groups
Equal
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Mannitol vs Hypertonic saline
Summary
– Mannitol & HTS are essentially equivalent
• Though some evidence suggests HTS better
– Osmotherapy agents have multiple mechanisms of
action to reduce ICP
– Osmolar gap calculation is likely superior to
arbitrary serum osmolality threshold for dosing
Mortazavi MM, et al. J Neurosurgery 2012; 116: 210-221.
The Role of 4-Factor PCC
for Hemostasis
Warfarin Reversal
Theresa Human Pharm.D., BCPS, FNCS
Barnes-Jewish Hospital
Washington University
St. Louis MO
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Fresh Frozen Plasma
– Accessibility
– Inexpensive
– Large volume (15-20 mL/kg)
• Tolerability issues for patient with
cardiac/pulmonary/renal disease
– TRALI
– TACO
– Transfusion reactions
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PCC vs Plasma
Efficacy and safety of a four-factor
prothrombin complex concentrate (4F-PCC) in
patients on vitamin K antagonists presenting
with major bleeding: a randomized, plasmacontrolled, phase IIIb study.
• Primary Endpoint
– Hemostasis Efficacy (24 hours)
• Criteria: assessment of Hgb/Hct; visualization of
bleeding cessation; hematoma size & volume with no
expansion
• Secondary Endpoint
– INR reduction ≤ 1.3 measured at least 30 min from
the end of infusion
Sarode R et al. Circulation 2013 Aug 9
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Adverse Reactions
ALWAYS Vitamin K
Adverse Reaction
Kcentra
N (%)
FFP
N (%)
Resp distress/dyspnea/hypoxia
2 (1.9)
4 (3.7)
• Necessary for prolonged reversal of INR
• Effects are delayed
Pulmonary Edema
0
4 (3.7)
– IV – onset within 6 hours; peak 12-24 h
Fluid Overload
1 (1 )
6 (5.5)
Hypotension
5 (4.9)
3 (2.8)
Transfusion Reaction
0
4 (3.7)
MI
0
3 (2.8)
Stroke
2 (1.9)
0
Calf DVT
1 (1)
0
Fistula Clot
1 (1)
0
• Preferred for urgent/elective reversal or hepatic dysfunction
– PO – onset within 24 hours, peak 24-48 h
• SQ and IM routes – unpredictable absorption
• Higher doses may increase the need for and
duration of bridge therapy
– Vitamin K is fat soluble
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Yasaka M et al. Thrombosis Research. 2003; 108:25-30
Yasaka M et al. Thrombosis Research. 2003; 108:25-30
Coagulation Cascade
Direct Thrombin Inhibitors
& Factor Xa Inhibtors
Warfarin inhibits
II, VII, IX, X;
Protein C & S
Factor Xa Inhibitors
Direct Thrombin
Inhibitors
Am J Health-Syst Pharm. 2013;70:S12-21
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Laboratory Monitoring
Lab Test
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Comments
INR or PT
Useful;
value
increased
Potentially useful; value
increased; point of care
tests can be falsely
elevated
Potentially useful
Potentially useful
PT may be considered b/c
INR may not be calibrated
for the TSOAs; PT more
responsive to FXaI than the
DTI; limited ability do
quantify amount of drug
aPTT
Value
somewhat
increased
apTT response flattens at
higher serum drug
concentrations
Potentially
useful; value
increased
Potentially useful;
value increased
aPTT more responsive to DTI
than FXaI; limited ability to
quantify amount of drug
TT
Clinical use
limited
Sensitive at low
concentration but not
useful at higher
concentrations
Inadequate
measure
Inadequate
measure
Limited ability to quantify
amount of DTI
ECT
Clinical use
limited
Not widely available but
potential ability to
quantify amount of drug
present
Inadequate
measure
Inadequate
measure
Limited availability in US;
potential quantitative test
Dilute TT
Clinical use
limited
Potential ability to
quantify amount of drug
present
Inadequate
measure
Inadequate
measure
Lack of standardization and
potential differences among
laboratories; may have
limitations at low DTI
concentrations
Chromogenic
anti-FXa assay
Inadequate
measure
Inadequate measure
Potentially
useful; value
increased
Potentially useful;
value increased
Nonstandardized; results
may vary among labs
Factor Xa Inhibitors
• Apixaban (Eliquis®)
– Half-life 8-12 hours
• Rivaroxaban (Xarelto®)
– Half-life 5-9 hours
• Consider PCC at 50 units/kg
• Charcoal if ≤ 3 hours from last dose
Am J Health-Syst Pharm. 2013;70:1914-1929
Reversal of Rivaroxaban by
Prothrombin Complex Concentrate
• Randomized, double-blind, placebo-controlled, cross-over trial
• 12 Healthy male volunteers
PT
Direct Thrombin Inhibitor
• Dabigatran (Pradaxa®)
– Half-life 12-17 hours
– PCC does NOT appear to have reversal effect
– Recommend Acute Hemodialysis
– Charcoal if ≤ 3 hours from last dose
Rivaroxaban
Author’s conclusion: 4-Factor PCC 50 units/kg reverses the anticoagulant
effect of rivaroxaban
Eerenberg ES et.al. Circulation. 2011;124:1573-1579
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Reversal of Dabigatran by
Prothrombin Complex Concentrate
• Randomized, double-blind, placebo-controlled, cross-over trial
• 12 Healthy male volunteers
Questions?
aPTT
TT
Dabigatran
Theresa Human, PharmD, BCPS, FNCS
Pharmacy Specialist-Neurosurgery/Critical Care
Barnes Jewish Hospital
Washington University
Author’s conclusion: 4-Factor PCC 50 units/kg has no influence on the
anticoagulant action of dabigatran
Eerenberg ES et.al. Circulation. 2011;124:1573-1579
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