1. Mannitol in Head Trauma: Controversy, Data, and Implications for Evidence-Based Neurosurgery Maya Babu

2. Summary Implications for Evidence-Based Neurosurgery Four Papers Controversy Mannitol & Head Trauma

3. Head Trauma & Mannitol 1.4 million people in the US sustain traumatic brain injury annually (Langlois, 2007) –235,000 hospitalized; 50,000 die 2 types of brain insults –Primary insult: Due to trauma; irreversible –Secondary insult: Worsening ischemia due to intracranial pressure (ICP), edema, hypoxia Mannitol as a treatment following head trauma first described in the literature in 1961 (Wise and Chater) Mannitol is an osmotic diuretic (C 6 H 8 (OH) 6 ) 83% of critical care centers in the US use mannitol in >50% of their severely head-injured patients (Ghajar, 1995) Used as a treatment in moribund trauma patients

4. Controversy Three papers by Dr. Julio Cruz, et al: –Cruz J, Minoja G, Okuchi K. Improving clinical outcomes from acute subdural hematomas with emergency preoperative administration of high doses of mannitol: a randomized trial. Neurosurgery 2001;49(4):864-71. –Cruz J, Minoja G, Okuchi K. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupilary widening. Neurosurgery 2002;51(3):628-38. –Cruz J, Minoja G, Okuchi K, Facco E. Successful use of the new high-dose mannitol treatment in patients with Glasgow Coma Scores of 3 and bilateral abnormal pupillary widening: a randomized trial. Journal of Neurosurgery 2004;100(3):376-83. Co-authors unaware of the paper; had phone conversations with Cruz No evidence of patient enrollment No confirmation of Dr. Cruz’s affiliation Dr. Julio Cruz committed suicide in 2005 (2006) Cochrane Systematic Review: Reversed its position on high-dose mannitol

5. Is mannitol dangerous….or just not that effective?

6. Isovolume hypertonic solutes in the treatment of refractory posttraumatic intracranial hypertension Vialet et al, Critical Care Medicine (2003)

7. Vialet et al: Question and Methods Question How effective is mannitol compared to hypertonic saline solution (HSS) in refractory intracranial hypertension (ICH)? Methods Prospective, Randomized Trial at a French Trauma Center 20 consecutive patients with head trauma; GCS<8 All patients received an ICP monitor Interventions 2mL/kg of (1) 20% Mannitol or (2) 7.5% HSS Aim: ICP 70 mm Hg Outcome measures: (1) Number and duration of episodes of ICH daily (2) Rate of failure for each treatment Patients were monitored for 7 days

8. Results Mean number of infusions (n.s.) –Mannitol=3.7 vs. HSS = 3.3 infusions Mean number of ICH episodes daily (p<.01) –Mannitol = 13.3 vs. HSS = 6.9 episodes Rate of clinical failure (p<.01) –Mannitol = 7 vs HSS = 1 patients Conclusion Giving patients a higher osmotic load with HSS is more effective in treating ICH than mannitol Limitations Small sample size One-center Type of solute or dosing? Vialet et al: Results and Conclusions

9. Comparison of mannitol regimens in patients with severe head injury undergoing intracranial monitoring Smith et al, Journal of Neurosurgery (1986)

10. Smith et al: Question and Methods Question Does changing mannitol dose depending on ICP monitoring affect outcomes? Methods Prospective, randomized study (1980-1982) Every head injury patient presenting to North Carolina Baptist Hospital: (1) within 6h of injury (2) with a GCS ≤ 8 for 6h Exclusion criterion: Gun-shot wounds n =80 (80% male, mean age=27) All patients had ICP monitors and were intubated Random assignment to: Group I: Mannitol therapy based on ICP monitoring –ICP>25mm Hg, a 250 mL bolus –Uncontrollable ICP: 100 mL boluses (up to 1.5 g/kg*hr) Group II: Mannitol therapy based on protocol –250 mL bolus +.25 g/kg every 2h –Neurological deterioration:.75g/kg bolus and CT

11. Smith et al: Results Results Rates of mortality (n.s.): Group I: 35% and II: 42.5% Mean highest ICP for survivors (p<.05): Group I: 35.2 mm Hg and Group II: 29.7 mm Hg Mean highest ICP for non-survivors (p<.001): Group I: 46.2 mm Hg and Group II: 40.7 mm Hg

12. Conclusions ICP guided mannitol administration does not influence mortality Limitations Threshold of 25 mm Hg ICP before mannitol bolus may be too high Mortality decreased from 46% to 28% after treating at 15 mm Hg (Saul & Ducker, 1982) Some influence of cross-over effects from Group II Smith et al: Conclusions and Limitations

13. Out-of-hospital administration of mannitol does not change systolic blood pressure Sayre et al, Academic Emergency Medicine (1996)

14. Sayre et al: Question and Methods Question Does out-of-hospital administration of mannitol affect systolic blood pressure adversely in a head trauma patient? Methods Prospective, randomized, double-blind placebo controlled trial Patients transported via university-based medical helicopter to a Level I Trauma Center 1991-1992: Intubated head trauma victims with a GCS<12 evaluated within 6h of injury Exclusions: (1) <18 (2) already received mannitol/other diuretic (3) women < 50 years old (4) receiving CPR n=41 Interventions: (1) 5mL/kg of.9% saline (2) 5mL/kg 20% Mannitol Primary endpoint: Change in systolic blood pressure over 2h

15. Results Mortality (n.s.): –Mannitol (25%) vs. Control (14%) Mean systolic BP (p<.01): –Mannitol (116 mm Hg) vs. Control (142 mmHg) Urine output (p<.001): –Mannitol (1351 mL) vs. Control (634 mL) Serum Na + on hospital arrival (p<.00001): –Mannitol (130.6) vs. Placebo ( 139.1) Blinded physician’s guess as to the intervention: –Resident: Correct in 11 of 13 cases –Investigator: Correct in 13 of 14 cases Sayre et al: Results

16. Conclusion Mannitol administered outside the hospital in this sample of patients did not lead to permanent morbidity Limitations Diastolic blood pressure more sensitive than systolic Included blunt and penetrating head trauma Not all outcomes seemingly positive Sayre et al: Conclusions and Limitations

17. The University of Toronto Head Injury Treatment Study: A Prospective, Randomized Comparison of Pentobarbital and Mannitol Schwartz et al, The Canadian Journal of Neurological Sciences (1984)

18. Schwartz et al: Question and Methods Question How does treatment of ICH due to head trauma with mannitol compare to pentobarbital? Methods (1980-1982): Prospective, Randomized Trial Patients with elevated ICP (≥25 mm Hg) & GCS ≤7 Some patients were randomized after hematoma evacuation; all patients received an ICP monitor N=59 (80% male) Interventions to maintain ICP < 20 mm Hg (1) 20% Mannitol 1g/kg; 350mL as needed within serum osmolality of 320mOs/L (2) Pentobarbital bolus up to 10mg/kg; continuous infusion of.5-3 mg/kg/hr provided that CPP >50 mm Hg Cross-over after treatment failure occurred

19. Schwartz et al: Results and Conclusions Results Mortality rates for Evacuated Hematoma Patients (n.s.): –Pentobarbital: 40% and Mannitol: 43% Mortality rates for Patients without Hematoma (p<.05): –Pentobarbital: 77% and Mannitol: 41% Twice as many pentobarbital patients had treatment failure (p<.0001) Conclusion Pentobarbital is no better than mannitol for the treatment of ICH, and may in fact be harmful Limitations Hematoma removal and intracranial hypertension May be evaluating CPP

20. What do these papers tell us? StudyStudy Intervention Mortality, Relative Risk (95% CI) Schwartz et al, 1984Mannitol vs. Phenobarbital.85 (.52-1.38) Vialet et al, 2003Manitol vs. HSS1.25 (.47-3.33) Smith et al, 1986ICP-guided vs. Protocol.83 (.47-1.46) Sayre et al, 1996Mannitol vs. Saline1.75 (.48-6.38) Dosing, Timing, and Appropriateness of Mannitol are in Doubt

21. Guidelines from AANS and CNS Guidelines for the management of severe traumatic brain injury (Level II/III): –Mannitol is effective for control of raised intracranial pressure (ICP) at doses of 0.25 g/kg to 1 g/kg body weight –Arterial hypotension (systolic blood pressure <90 mm Hg) should be avoided –Restrict mannitol use prior to ICP monitoring to patients with signs of transtentorial herniation or progressive neurological deterioration not attributable to extracranial causes Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons. Guidelines for the management of severe traumatic brain injury. Hyperosmolar therapy. J Neurotrauma 2007;24(Suppl 1):S14-S20.

22. Future Directions Mannitol versus other solutions –More effective infusions with a higher osmotic load? Potential pitfalls of mannitol (Kaufmann & Cardoso, 1992) Research in trauma settings –Challenging to limit the influence of intervention cross- over

23. Mannitol Controversy: Conclusions Evidence-based neurosurgery: an analytic approach Health reform shaped by “evidence-based medicine” –Stimulus included $1.1 B for Comparative Effectiveness Research –Food & Drug Administration approvals –Reimbursement guidance 1 (1) Dhruva et al, New England Journal of Medicine, 2009

24. "Half of what you'll learn in medical school will be shown to be either dead wrong or out of date within five years of your graduation; the trouble is that nobody can tell you which half -- so the most important thing to learn is how to learn on your own…" -Dr. David Sackett, evidence-based medicine pioneer Evidence-Based Medicine

25. “Human beings are not uniform in their biology. Rather than rigidity, flexibility is appropriate in applying evidence from clinical trials. A good doctor exercises sound clinical judgment by consulting expert guidelines and assessing ongoing research….but then decides what is quality care for the individual patient. And what is best sometimes deviates from the norms.” -Jerome Groopman & Pamela Hartzband, Wall Street Journal, 2009

26. Acknowledgements Dr. Clark Chen

27. Thank you!

28. References Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons. Guidelines for the management of severe traumatic brain injury. Hyperosmolar therapy. J Neurotrauma 2007;24(Suppl 1):S14-S20. Ghajar J,Hariri RJ,Narayan RK, et al.Survey of critical caremanagement of comatose, head-injured patients in the United States. Critical Care Medicine 1995;23(3):560–7. Wise BL, Chater N: Effect of mannitol on cerebrospinal fluid pressure: The actions of hypertonic mannitol solutions and of urea compared. Arch Neurol 4:200-202, 1961. Kaufmann AM, Cardoso ER. Aggravation of vasogenic cerebral edema by multiple-dose mannitol. J Neurosurg. 1992 Oct;77(4):584-9 Vialet R, Albanese J, Thomachot L, Antonini F, Bourgouin A, Alliez B, et al.Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 mL/kg 7.5% saline is more effective than 2 mL/kg 20% mannitol. CriticalCareMedicine 2003;31(6):1683–7. Smith HP, Kelly DL Jr, McWhorter JM, et al.Comparison of mannitol egimens in patients with severe head injury undergoing intracranial monitoring. Journal of Neurosurgery 1986;65(6):820–4. Sayre MR, Daily SW, Stern SA, Storer DL, van Loveren HR, Hurst JD. Out-of-hospital administration ofmannitol does not change systolic blood pressure. Academic Emergency Medicine 1996;3(9):840–8. Schwartz ML, Tator CH, Rowed DW, Reid SR, Meguro K, Andrews DF. The University of Toronto head injury treatment study: a prospective, randomized comparison of pentobarbital and mannitol. Cruz J, Minoja G, Okuchi K. Improving clinical outcomes from acute subdural hematomas with emergency preoperative administration of high doses of mannitol: a randomized trial. Neurosurgery 2001;49(4):864-71. Cruz J, Minoja G, Okuchi K. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupilary widening. Neurosurgery 2002;51(3):628-38. Cruz J, Minoja G, Okuchi K, Facco E. Successful use of the new high-dose mannitol treatment in patients with Glasgow Coma Scores of 3 and bilateral abnormal pupillary widening: a randomized trial. Journal of Neurosurgery 2004;100(3):376-83. Wakai A, Roberts I, Schierhout G. Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD001049. Roberts I, Smith R, Evans S. Doubts over head injury studies. BMJ 2007;334:392-394,