MANNITOL AND
HYPERTONIC SALINE
IN SUBDURAL HEMATOMA
February 11, 2015
Briana
Santaniello, MBA
PharmD
Candidate 2015
OBJECTIVES
After reviewing the patient case, the audience should be able
to:
 Recognize the treatment options for a subdural hematoma
 Describe the mechanisms of action of these agents
 Analyze available literature comparing the ef fectiveness of
these treatments
 Determine if current guidelines should be updated to reflect
recent literature suggestive of dose change
MEET THE PATIENT: MD
 CC: Unresponsive s/p witnessed fall with subsequent emesis
 HPI:
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
83 yo F
Sustained witnessed fall
Found vomiting by son-in-law
Felt unwell & requested to lay down
Progressively more somnolent
Son-in-law called 9-11.
 PMH/PSH: sick sinus syndrome s/p pacemaker, HTN, HLD,
osteoporosis, hypothyroidism
MEET THE PATIENT: MD (CONTINUED)
 FH: unavailable
 SH: lives with husband who has dementia; babysitter of 3 year
old grandchild; has 3 children
 Allergies: midazolam
 Reaction – not specified
 Home medications (doses unknown):
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warfarin
amlodipine
levothyroxine
simvastatin
MEET THE PATIENT: MD (CONTINUED)
 Physical examination/presentation to ED:


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Somnolent
Contusion/laceration to R side of face & bridge of nose
Pupils equal and sluggishly reactive (3 mm bilaterally)
Vomitus and blood obstructing airway
Presents to ED:
GCS 9
Decompensation
ensued & left
pupil became
fixed & dilated:
GCS 7
Intubation
VITAL SIGNS AND PERTINENT
INFORMATION
Upon Arrival
Decompensation
150/84
200/88
O2 sat
97%
88%
Pulse (bpm)
105
80
RR (breaths/min)
22
20
POC (mg/dL)
161
------
INR
------
2.3
BP (mmHg)
ADDITIONAL INFORMATION
 Height: 162 cm
 Weight: 66.8 kg
 Serum creatinine: 0.9 mg/dL
 Round to 1 based on age > 65 years old
 Creatinine clearance: 40.9 mL/min
MEDICATIONS GIVEN IN ED
Decision to
intubate
•fentanyl 100 mcg IV
•etomidate & rocuronium
•propofol
Signs of
impending
herniation
•Contusion to head
•Pupil blown
•Decerebrate posturing
Suspected
subdural
hematoma
•mannitol 100 g IV
•Sent for CT scan
RESULTS OF CT SCAN
 Massive holohemispheric subdural hematoma: Left
TREATMENT OF SUBDURAL HEMATOMA
Surgical
hematoma
evacuation
Craniotomy
Burr hole trepanation/trephination
Decompressive craniectomy
Nonpharmacologic
Pharmacologic
Head elevation at 30° angle
Osmotic diuretics/Hyperosmolar therapy
-Brain Trauma Foundation’s 2007 Guidelines for the Management of Severe Traumatic Brain Injury
-Wilkins RH, Rengachary SS. Neurosurgery. 2nd ed. New York:. McGraw Hill;1996:2603-2720
URGENT SURGICAL PROCEDURES IN
ANTICOAGULATED PATIENTS
 Reversal of anticoagulant is necessary
 Immediate cessation of anticoagulants & antiplatelets
+
 vitamin K 10 mg by slow IV infusion
or
 recombinant human factor VIIa (rFVIIa)
or
 fresh frozen plasma (FFP)
or
 prothrombin complex concentrate (PCC)
PHARMACOLOGICAL OPTIONS
 MANNITOL
 Mechanism of action:
 HYPERTONIC SALINE
 Mechanism of action
osmotic gradient between
CSF and subarachnoid space
osmotic gradient: intracellular
fluid moves extracellularly
↓ subarachnoid space
pressure
↑ intravascular blood volume
↑ plasma sodium
↓ICP
↓ brain water
Fink ME. Osmotherapy for Intracranial Hypertension: Mannitol Versus Hypertonic Saline. Continuum Lifelong Learning Neurol
20012;18(3):640-654.
MANNITOL IN SUBDURAL HEMATOMA
 Available formulations:
 20% solution
 25% in vials
 Dose:
 0.5 to 1 g/kg
 Doses < 0.5 g/kg: less efficacious, shorter DOA
 Administration
 IV bolus over 20 minutes
 Requires filter
 crystallization
Fink ME. Osmotherapy for Intracranial Hypertension: Mannitol Versus Hypertonic Saline. Continuum Lifelong Learning Neurol
20012;18(3):640-654.
MANNITOL IN SUBDURAL HEMATOMA
(CONTINUED)
 Adverse Ef fects
 Electrolyte abnormalities (hypernatremia, hypokalemia, metabolic
acidosis)
 Hypotension
 Monitoring
 ICP
 Serum osmolarity
 DNE 320 mOsm/L
 Osmotic gradient: ideally ≥ 10 mOsm
Fink ME. Osmotherapy for Intracranial Hypertension: Mannitol Versus Hypertonic Saline. Continuum Lifelong Learning Neurol 2012;18(3):640-654.
Mannitol. Package Insert. Baxter Health Care. 2011. Old Toongabbie, NSW.
MANNITOL IN SUBDURAL HEMATOMA
(CONTINUED)
 Complications
 CHF with pulmonary edema
 Acute renal failure
 Rebound hypertension with cessation of therapy
 Contraindications
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Hypersensitivity
Anuria from severe renal disease
Severe pulmonary edema, HF
Hyperosmolarity prior to initial dose
Severe dehydration
Metabolic edema
Progressive renal disease
Fink ME. Osmotherapy for Intracranial Hypertension: Mannitol Versus Hypertonic Saline. Continuum Lifelong Learning Neurol 2012;18(3):640-654.
Mannitol. Package Insert. Baxter Health Care. 2011. Old Toongabbie, NSW.
HYPERTONIC SALINE IN SUBDURAL
HEMATOMA
 Available formulations: 2%, 3%, 5%, 7%, 23.4%
 Less potent diuretic than mannitol
 ↔ intravascular volume
 ↑ blood pressure, CO, cerebral blood flow
 Dose: 5-6 mL/kg bolus dose of 3% administered over 30 minutes
 Can vary depending on hospital’s protocol
 Administration
 IV bolus
 Preferably administered via central line
 high concentration
 Can be administered peripherally in trauma room
 Maximum of 100 mL/hr for up to 5 hours per site
Fink ME. Osmotherapy for Intracranial Hypertension: Mannitol Versus Hypertonic Saline. Continuum Lifelong Learning Neurol
20012;18(3):640-654.
HYPERTONIC SALINE IN SUBDURAL
HEMATOMA (CONTINUED)
 Side Ef fects
 Hypokalemia
 supplemental potassium
 Dehydration
 Monitoring
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serum Na+ (ideally < 160 mEq/L or < 180 mEq/L in refractory cases)
serum osmolarity (target < 320 mOsmol/L)
fluid status (intake/output)
body weight
CXR (pulmonary edema)
Fink ME. Osmotherapy for Intracranial Hypertension: Mannitol Versus Hypertonic Saline. Continuum Lifelong Learning Neurol
20012;18(3):640-654.
HYPERTONIC SALINE IN SUBDURAL
HEMATOMA (CONTINUED)
 Complications
 hyperchloremic acidosis
 With repeated doses or continuous infusion
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Central pontine myelinolysis (CPM)
Renal failure
Cardiac arrhythmias
Hemolysis
CHF with pulmonary edema
 Contraindications
 Chronic hyponatremia (i.e. SIADH) due to risk of CPM
Fink ME. Osmotherapy for Intracranial Hypertension: Mannitol Versus Hypertonic Saline. Continuum Lifelong Learning Neurol
20012;18(3):640-654.
MANNITOL VS. HYPERTONIC SALINE
 Double Blind Study of Hypertonic Saline vs Mannitol in the
Management of Increased Intracranial Pressure (ICP)
 Study withdrawn prior to enrollment
 Unfeasible timeline to consent prior to intervention
 No Class I evidence supporting use of one agent over the
other
 Mortazavi et al: literature review with meta -analysis
comparing hypertonic saline to mannitol
MANNITOL VS. HYPERTONIC SALINE
 Mortazavi et al: PubMed literature search of all clinical
studies in which HTS was used for elevated ICP
 12 compared hypertonic saline with mannitol
 7 RCTs, 1 prospective non-randomized study, 4 retrospective studies
 Results:
 3: hypertonic saline not clinically superior to mannitol for ICP
reduction/outcome
 9: suggested hypertonic saline is clinically superior to mannitol for ICP
reduction
Mortazavi MM, Romeo AK, Deep A, et al. Hypertonic saline for treating raised intracranial pressure: literature review with metaanalysis. J Neurosurg 2012;116:210-221
MANNITOL VS. HYPERTONIC SALINE
 Among the 9 trials supporting use of hypertonic saline over
mannitol:
 Total of 236 subjects among the 9 trials
 Different concentrations of hypertonic saline used in each trial
 Some trials used continuous infusion; others used bolus dose
 Conflicting results on mortality in hypertonic saline groups
HYPERTONIC SALINE IN SUBDURAL
HEMATOMA (CONTINUED)
 Neurocritical Care Society practice patterns survey
 mannitol: 45.1%
 More comfortable with agent, no central venous access required, more
effective
 hypertonic saline: 54.9%
 Fewer side effects, better long-term benefits, less of a rebound effect,
easier titration, less associated with renal failure
Mortazavi MM, Romeo AK, Deep A, et al. Hypertonic saline for treating raised intracranial pressure: literature review with metaanalysis. J Neurosurg 2012;116:210-221
HIGH-DOSE MANNITOL
 Randomized trial in 178 comatose adult patients diagnosed with acute
traumatic subdural hematoma over 4 year period
 Randomly assigned to 1 of 2 groups:
 High-dose mannitol group: 91 patients
 Conventional-dose mannitol group: 87 patients
 All were administered 0.6-0.7g/kg mannitol as fast IV infusion, followed by
normal saline solution administered via rapid IV infusion at 6-7 mL/kg
 25 to 30 minutes later, high-dose mannitol group received additional 0.6-0.7g/kg dose of
mannitol when pupillary widening was still observed
Cruz J, Minoja G, Okuchi G. Improving Clinical Outcomes from Acute Subdural Hematomas with the Emergency Preoperative
Administration of High Doses of Mannitol: A Randomized Trial. Neurosurgery 2001;49(4):864-871.
HIGH-DOSE MANNITOL
 All underwent standard craniotomies with clot removal, received fentanyl
and propofol, and had head elevation 30° post-craniotomy
 Monitored via ECG, pulse oximetry, expired PCO 2 , ICP, MAP
 Results:
 6 months after acute traumatic brain injury, mortality rates were as follows:
 High-dose mannitol: 14.3% (13 patients)
 Conventional-dose mannitol: 25.3% (22 patients)
 P < 0.01
 Overall clinical outcomes significantly better in patients who received high -dose
mannitol (p < 0.01)
Cruz J, Minoja G, Okuchi G. Improving Clinical Outcomes from Acute Subdural Hematomas with the Emergency Preoperative
Administration of High Doses of Mannitol: A Randomized Trial. Neurosurgery 2001;49(4):864-871.
MANNITOL FOR MD
 MD weighs 66.8 kg
 1 g/kg x 66.8 kg = 66.8 g
 MD given 100 g
???
THOUGHTS ON APPROPRIATE DOSE
 Traditionally dosed 1g/kg
 CrCl: 40.9 mL/minute
 Poor prognosis
 Potential for renal harm balanced with potential for better ICP
reduction
TAKE HOME POINTS
REFERENCES
1 . B r a i n Tr a u m a F o u n d a t i o n ’ s 2 0 0 7 G u i d e l i n e s f o r t h e M a n a g e m e n t o f S e v e r e Tr a u m a t i c B r a i n
Injury
2 . W i l k i n s R H , R e n g a c h a r y S S . N e u r o s u r g e r y. 2 n d e d . N e w Yo r k : . M c G r a w H i l l ; 1 9 9 6 : 2 6 0 3 - 27 2 0
3 . F i n k M E . O s m o t h e r a p y f o r I n t r a c r a n i a l H y p e r t e n s i o n : M a n n i t o l Ve r s u s H y p e r t o n i c S a l i n e .
Continuum Lifelong Learning Neurol 20012;18(3):640 -654.
4 . M a n n i t o l . P a c k a g e I n s e r t . B a x t e r H e a l t h C a r e . 2 0 1 1 . O l d To o n g a b b i e , N S W.
5. Mor tazavi MM, Romeo AK, Deep A , et al. Hyper tonic saline for treating raised intracranial
p r e s s u r e : l i t e r a t u r e r e v i e w w i t h m e t a - a n a l y s i s . J N e u r o s u r g 2 0 1 2 ; 1 1 6 : 2 1 0 - 2 21
6. Cruz J, Minoja G, Okuchi G. Improving Clinical Outcomes from Acute Subdural Hematomas with
t h e E m e r g e n c y P r e o p e r a t i v e A d m i n i s t r a t i o n o f H i g h D o s e s o f M a n n i t o l : A R a n d o m i z e d Tr i a l .
N e u r o s u r g e r y 2 0 0 1 ; 4 9 ( 4 ) : 8 6 4 - 8 71
.
QUESTIONS?
Thank You!