MANNITOL AND HYPERTONIC SALINE IN SUBDURAL HEMATOMA February

MANNITOL AND HYPERTONIC SALINE IN SUBDURAL HEMATOMA February 11, 2015 Briana Santaniello, MBA Pharm. D 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 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 150/84 200/88 O 2 sat 97% 88% Pulse (bpm) 105 80 RR (breaths/min) 22 20 POC (mg/d. L) 161 ------ INR ------ 2. 3 BP (mm. Hg)

ADDITIONAL INFORMATION Height: 162 cm Weight: 66. 8 kg Serum creatinine: 0. 9 mg/d. L § Round to 1 based on age > 65 years old Creatinine clearance: 40. 9 m. L/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. 2 nd ed. New York: . Mc. Graw 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 (r. FVIIa) 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 ↓ICP ↓ brain water ↑ plasma sodium 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 Effects § Electrolyte abnormalities (hypernatremia, hypokalemia, metabolic acidosis) § Hypotension Monitoring § ICP § Serum osmolarity § DNE 320 m. Osm/L § Osmotic gradient: ideally ≥ 10 m. Osm 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 m. L/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 m. L/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 Effects § Hypokalemia § supplemental potassium § Dehydration Monitoring § § § serum Na+ (ideally < 160 m. Eq/L or < 180 m. Eq/L in refractory cases) serum osmolarity (target < 320 m. Osmol/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

MANNITOL VS. HYPERTONIC SALINE Mortazavi et al: Pub. Med 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. 7 g/kg mannitol as fast IV infusion, followed by normal saline solution administered via rapid IV infusion at 6 -7 m. L/kg 25 to 30 minutes later, high-dose mannitol group received additional 0. 6 -0. 7 g/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 weighs 66. 8 kg § 1 g/kg x 66. 8 kg = 66. 8 g § MD given 100 g ? ? ?

THOUGHTS ON APPROPRIATE DOSE Traditionally dosed 1 g/kg Cr. Cl: 40. 9 m. L/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. 2 nd ed. New York: . Mc. Graw 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!