Mannitol and hypertonic saline in Subdural hematoma Briana Santaniello, MBA PharmD Candidate 2015 February 11, 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 effectiveness 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: 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): warfarin amlodipine levothyroxine simvastatin

Meet the patient: MD (continued) Physical examination/presentation to ED: 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 BP (mmHg) 150/84 200/88 O2 sat 97% 88% Pulse (bpm) 105 80 RR (breaths/min) 22 20 POC (mg/dL) 161 ------ INR 2.3

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 Craniotomy Burr hole trepanation/trephination Decompressive craniectomy Head elevation at 30° angle Osmotic diuretics/Hyperosmolar therapy Surgical hematoma evacuation Non-pharmacologic *craniotomy has better outcomes (limited observational data) Pharmacologic -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) fresh frozen plasma (FFP) prothrombin complex concentrate (PCC) PCC dose calculated using initial INR and body weight

Pharmacological options MANNITOL HYPERTONIC SALINE Mechanism of action: Mechanism of action osmotic gradient between CSF and subarachnoid space ↓ subarachnoid space pressure ↓ICP osmotic gradient: intracellular fluid moves extracellularly ↑ intravascular blood volume ↑ plasma sodium ↓ brain water Mannitol is a sugar alcohol, filtered by kidney *intracellular volume inversely proportional to plasma sodium concentration* Na+ has reflection coefficient of nearly 1; with intact BBB, little Na+ crosses BBB, so Na+ can pull fluid out of interstitial space 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 *IV bolus can be given peripherally osmotic gradient tells you actual serum mannitol level and mannitol clearance 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 Effects 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 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 *theoretically can be administered as continuous infusion but time is of the essence in someone with impending herniation so the faster the better* 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 Effects Hypokalemia supplemental potassium Dehydration Monitoring 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 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 *Beth Israel Deaconess was withdrawn study*

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 meta-analysis. 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 meta-analysis. 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 PCO2, 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. Brain Trauma Foundation’s 2007 Guidelines for the Management of Severe Traumatic Brain Injury 2. Wilkins RH, Rengachary SS. Neurosurgery. 2nd ed. New York:. McGraw Hill;1996:2603-2720 3. Fink ME. Osmotherapy for Intracranial Hypertension: Mannitol Versus Hypertonic Saline. Continuum Lifelong Learning Neurol 20012;18(3):640-654. 4.Mannitol. Package Insert. Baxter Health Care. 2011. Old Toongabbie, NSW. 5. Mortazavi MM, Romeo AK, Deep A, et al. Hypertonic saline for treating raised intracranial pressure: literature review with meta-analysis. J Neurosurg 2012;116:210-221 6. 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 .

Questions? Thank You!