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7 attempts at treating rabies with Milwaukee protocol (excluding index survivor)

Human rabies includes generalized cranial artery spasm that responds to tetrahydrobiopterin, L-arginine or nitroprusside. R.E. Willoughby , A. Roy-Burman, K.W. Martin, J.C. Christensen, D.F. Westenkirschner, J.D. Fleck, C. Glaser, C.E. Rupprecht and K. Hyland.

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7 attempts at treating rabies with Milwaukee protocol (excluding index survivor)

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  1. Human rabies includes generalized cranial artery spasm that responds to tetrahydrobiopterin, L-arginine or nitroprusside R.E. Willoughby, A. Roy-Burman, K.W. Martin, J.C. Christensen, D.F. Westenkirschner, J.D. Fleck, C. Glaser, C.E. Rupprecht and K. Hyland

  2. 2 “good attempts” that fulfill assumptions and use ketamine, a benzodiazepine, amantadine and ribavirin Concrete mechanisms and physiology identified 7 attempts at treating rabies with Milwaukee protocol(excluding index survivor) p= .0037

  3. Marburg, GermanyTransplant (+ rabies) recipient

  4. BH4 as Achilles’ heel for CNS mM mM nM

  5. Nitric oxide synthases O2●- NO + citrulline ONOO- ARG BH4 qBH2 Kone BC (2003) Am J Physiol Renal Physiol 285: F178

  6. NO is smooth muscle relaxant Not well known: neuronal NOS in vessel adventitia accounts for 10% of systemic vasodilator tone accounts for 50% of cranial vasodilator tone Rabies is neurotropic nNOS >> eNOS Nitric Oxide Synthase(eNOS, nNOS) in cranial arteries Toda N (2000) Neuroscience 96: 393 Pluta RM (2005) Pharmacol Ther 105: 23

  7. RI = (Vmax-Vmin) = 1.0 Vmax Vmin Vmean TAMMv Vmax Bad Good V Flow = VA = kDPr4 A Transcranial doppler ultrasound

  8. Recommended daily TCD HD 6 normal Vasopressors begun HD 10: Seizure by EEG Flat EEG HD 12 TCD: vasospasm Nitroprusside 0.2ug/kg/min HD 13: cerebral edema External ventricular drain BH4 at CNS doses HD 14: EEG responds MCA velocities remain high HD 20: increased edema Venous sinus thrombosis Indianapolis(bat strain) MMWR (2007) 56: 361

  9. HD 1: 2 arrests On vasopressors BH4 2 mg/kg/24h Daily TCD HD 6: Vasospasm Reversed by BH4 2mg/kg/8h Oakland(dog strain) MMWR (2007) 56: 361

  10. Cranial artery spasm in rabies • Seen early, hospital day 6-10 (mean HD8) • Global, including internal carotid + MCA • Transcranial doppler: high velocity, normal resistance • Responsive to 6 mg/kg/24h BH4 - OR - “low dose” 0.1-0.2 ug/kg/min nitroprusside

  11. HD 11 TCD: Decreased velocity Increased RI No cerebral edema Low opening pressure Reversed by “CNS dosing” of BH4 20mg/kg/24h + L-arginine IV 0.5g/kg/12h Increase in CSF protein Oakland

  12. HD 17 TCD: Sudden drop in MCA velocity No comparables for PI Sudden drop in ICP Increase in CSF protein Indianapolis

  13. Cranial artery spasm in rabies • Small numbers, n=3/3 when looked for • Sporadic correlations with MRA, brain scan • Associated with declines in EEG • Type 1 (high velocity, normal RI) day 6-10 • Responsive to BH4 6 mg/kg/day • Type 2 (low velocity, high RI) day 13-17 • 7 days after type 1 • Responsive (in part) to BH4 20 mg/kg/day + L-arginine 1.0 mg/kg/day given slowly • Associated with increased CSF protein

  14. Why does rabies virus kill? • BH4 and neurotransmitter deficiency • Subset of symptoms • Wasting • Cranial artery spasm • BH4 + L-arginine • Ca++ channel blockers • “Triple H” therapy • Hypercarbia rewillou@mcw.edu www.mcw.edu/rabies

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