7 attempts at treating rabies with milwaukee protocol (excluding index survivor)
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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
7 attempts at treating rabies with Milwaukee protocol
(excluding index survivor)• 2 “good attempts”
that fulfill assumptions and use ketamine, a benzodiazepine, amantadine and ribavirin
• Concrete mechanisms and physiology identified
0.00
0.25
0.50
0.75
1.00
0 20 40 60 80analysis time
Milw = 0 Milw = 1
Kaplan-Meier survival estimates, by Milw
p= .0037
Marburg, GermanyTransplant (+ rabies) recipient
Marburg z-score by age
z-sc
ore
BH
4, H
VA
, 5-H
IAA
-10
-5
0
5
10
15
20
Feb Mar Apr
May Jun
NO
2+N
O3
(uM
)
0
20
40
60hospitalized EEG flat
MRA low flowbrain liquefaction
5-HIAAHVABH4
NOx
BH4 as Achilles’ heel for CNS
M
M
nM
Nitric oxide synthases
Kone BC (2003) Am J Physiol Renal Physiol 285: F178
ARGBH4
O2●-
NO+ citrulline
qBH2
ONOO-
Nitric Oxide Synthase(eNOS, nNOS) in cranial
arteries• 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
Toda N (2000) Neuroscience 96: 393Pluta RM (2005) Pharmacol Ther 105: 23
Transcranial doppler ultrasound
VA
Flow = VA = kPr4
Bad Good
VmaxVminVmax
RI = (Vmax-Vmin) = 1.0 VmeanTAMMv
Indianapolis(bat strain)
• Recommended daily TCD– HD 6 normal– Vasopressors begun
• HD 10: Seizure by EEGFlat 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
TAMvMCA
0 7 14 21 28
Vel
ocity
(cm
/s)
0
100
200
300
400
Hospital Day
0 7 14 21 28
Pul
satil
ity In
dex
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Intra
cran
ial P
ress
ure
0
20
40
60
80
100
120
140
160
180
200
Vmax MCA
TAM
v
PI MCA
ICP
Hospit
aliza
tion
Transfe
rEVD
Limit c
are
Seizure
Flat E
EG
Nitroprusside
Vasopressor
MMWR (2007) 56: 361
Oakland(dog strain)
• HD 1: 2 arrests– On vasopressors– BH4 2 mg/kg/24h– Daily TCD
• HD 6: Vasospasm– Reversed by BH4
2mg/kg/8h
X Data
0 7 14 21 28
Blo
od v
eloc
ity (m
/s)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Hospit
alize
d
Arrest
x 2typ
e 1typ
e 2Hea
rt bloc
k
isopro
teren
ol
Seizure
Flat E
EG
Cerebra
l ede
ma
Hospital Day
0 7 14 21 28
Res
istiv
e In
dex
0.0
0.2
0.4
0.6
0.8
1.0
BH
4 m
g/kg
/24h
Arg
g/k
g/do
se
0
5
10
15
20
25
MMWR (2007) 56: 361
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
Oakland
• 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
X Data
0 7 14 21 28
Blo
od v
eloc
ity (m
/s)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Hospit
alize
d
Arrest
x 2typ
e 1typ
e 2Hea
rt bloc
k
isopro
teren
ol
Seizure
Flat E
EG
Cerebra
l ede
ma
Hospital Day
0 7 14 21 28
Res
istiv
e In
dex
0.0
0.2
0.4
0.6
0.8
1.0
BH
4 m
g/kg
/24h
Arg
g/k
g/do
se
0
5
10
15
20
25
TAMvMCA
0 7 14 21 28
Vel
ocity
(cm
/s)
0
100
200
300
400
Hospital Day
0 7 14 21 28
Pul
satil
ity In
dex
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Intra
cran
ial P
ress
ure
0
20
40
60
80
100
120
140
160
180
200
Vmax MCA
PI MCA
ICP
Hospit
aliza
tion
Transfe
rEVD
Limit c
are
Seizure
Flat E
EG
Nitroprusside
Vasopressor
Vm
ax
Vmax ICA
Indianapolis
• HD 17 TCD: – Sudden drop in MCA
velocity– No comparables for PI– Sudden drop in ICP
– Increase in CSF protein
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
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
0.00
0.25
0.50
0.75
1.00
0 20 40 60 80analysis time
Milw = 0 Milw = 1
Kaplan-Meier survival estimates, by Milw
[email protected]/rabies