Jose

ph F

. Ans

win

e, M

DJo

seph

F. A

nsw

ine,

MD

Sta

ff A

nest

hesi

olog

ist

Pin

nacl

e H

ealth

Hos

pita

lsH

arris

burg

, PA

Clin

ical

Ass

ocia

te P

rofe

ssor

of

Ane

sthe

siol

ogy

Pen

nsyl

vani

a S

tate

Uni

vers

ity

Hos

pita

l

Rev

ersa

l of N

euro

mus

cula

r

Rev

ersa

l of N

euro

mus

cula

r

Blo

ckad

eB

lock

ade

Def

initi

ons

Def

initi

ons

ED95

-dos

e re

quire

d to

pro

duce

95%

sup

pres

sion

of

the

first

twitc

h re

spon

se.

2xED

95–

the

ED95

mul

tiplie

d by

2 /

com

mon

ly u

sed

as th

e st

anda

rd in

tuba

ting

dose

for a

NM

BA

.T1

and

T4–

first

and

four

th tw

itch

heig

hts

(usu

ally

gi

ven

as a

% o

f the

orig

inal

twitc

h he

ight

).

Ons

et T

ime

–en

d of

inje

ctio

n of

the

NM

BA

to 9

5%

T1 s

uppr

essi

on.

Rec

over

y Ti

me

–tim

e fro

m in

duct

ion

to 2

5%

reco

very

of T

1 (N

MB

As

are

read

ily re

vers

ed w

ith

acet

ylch

olin

este

rase

inhi

bito

rs a

t thi

s po

int).

Rec

over

y In

dex

–tim

e fro

m 2

5% to

75%

T1.

Phar

mac

okin

etic

s an

d Ph

arm

acok

inet

ics

and

Phar

mac

odyn

amic

sPh

arm

acod

ynam

ics

Wha

t is

Phar

mac

okin

etic

s?Th

e pr

oces

s by

whi

ch a

dru

g is

abs

orbe

d, d

istri

bute

d,

met

abol

ized

and

elim

inat

ed b

y th

e bo

dy.

Wha

t is

Phar

mac

odyn

amic

s?Th

e st

udy

of th

e ac

tion

or e

ffect

s of

a d

rug

on li

ving

or

gani

sms.

Or,

it is

the

stud

y of

the

bioc

hem

ical

and

ph

ysio

logi

cal e

ffect

s of

dru

gs.

For e

xam

ple;

rocu

roni

um re

vers

ibly

bin

ds to

the

post

syn

aptic

en

dpla

te, t

here

by, i

nhib

iting

the

bind

ing

of

acet

ylch

olin

e.

Stru

ctur

al C

lass

es o

f St

ruct

ural

Cla

sses

of

Non

depo

lariz

ing

Rel

axan

tsN

onde

pola

rizin

g R

elax

ants

Ster

oids

: roc

uron

ium

bro

mid

e, v

ecur

oniu

m b

rom

ide,

pa

ncur

oniu

m b

rom

ide,

pip

ecur

oniu

m b

rom

ide.

Ben

zylis

oqui

nolin

ium

s: a

tracu

rium

bes

ylat

e,

miv

acur

ium

chl

orid

e, d

oxac

uriu

m c

hlor

ide,

ci

satra

curiu

m b

esyl

ate

Isoq

uino

lone

s: c

urar

e, m

etoc

urin

e

Ons

et o

f par

alys

is is

affe

cted

by:

Ons

et o

f par

alys

is is

affe

cted

by:

Dos

e(r

elat

ive

to E

D95

)Po

tenc

y(n

umbe

r of m

olec

ules

)K

EO(p

lasm

a eq

uilib

rium

con

stan

t -ch

emis

try/b

lood

flow

) —

dete

rmin

ed b

y fa

ctor

s th

at m

odify

acc

ess

to th

e ne

urom

uscu

lar j

unct

ion

such

as

card

iac

outp

ut, d

ista

nce

of th

e m

uscl

e fro

m th

e he

art,

and

mus

cle

bloo

d flo

w

(pha

rmac

okin

etic

var

iabl

es).

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.

0

060

120

180

240

300

360

420

480

Tim

e (s

ec)

% of Peak Effect

Roc

uron

ium

Vecu

roni

um

Cis

atra

curiu

mAt

racu

rium

Ons

et T

ime

of N

onde

pola

rizin

g N

MB

As

Ons

et T

ime

of N

onde

pola

rizin

g N

MB

As

Kop

man

et a

l. A

nest

h A

nalg

199

9;89

:104

6-9

Ons

et* a

nd re

cove

ry fr

om b

lock

Ons

et* a

nd re

cove

ry fr

om b

lock

Effe

cts

of a

nest

hetic

s on

clin

ical

dur

atio

n Ef

fect

s of

ane

sthe

tics

on c

linic

al d

urat

ion

of ro

curo

nium

bro

mid

e 0.

3 m

g/kg

of ro

curo

nium

bro

mid

e 0.

3 m

g/kg

Ago

ston

S. E

ur J

Ana

esth

esio

l S

uppl

. 199

4;9:

107-

11

Neu

rom

uscu

lar B

lock

ing

Age

nts:

N

euro

mus

cula

r Blo

ckin

g A

gent

s:

Dru

g In

tera

ctio

ns (a

nest

hetic

s)D

rug

Inte

ract

ions

(ane

sthe

tics)

Req

uire

men

ts fo

r NM

BA

s w

ill b

e re

duce

d by

10

% to

25%

whe

n us

ing

pote

nt in

hala

tiona

l ag

ents

suc

h as

isof

lura

ne.

Ther

e ap

pear

s to

be

no c

hang

e in

re

quire

men

ts fo

r NM

BA

s w

hen

usin

g pr

opof

ol

or o

ther

IV a

nest

hetic

s.

Pot

entia

tion

of N

on D

epol

ariz

ing

Age

nts

Pot

entia

tion

of N

on D

epol

ariz

ing

Age

nts

Aci

d-ba

se a

nd e

lect

roly

te d

istu

rban

ces

a. re

spira

tory

aci

dosi

s,b.

mag

nesi

um,

c. c

alci

um,

d. K

+D

rugs

:a.

Ane

sthe

tic in

hala

tion

agen

ts

b. A

ntib

iotic

s H

ypot

herm

iaA

ll th

e ab

ove

are

com

mon

ly p

rese

nt a

t the

end

of a

n an

esth

etic

and

in th

e re

cove

ry ro

om.

Key

Poi

nts:

Eld

erly

and

K

ey P

oint

s: E

lder

ly a

nd

Neu

rom

uscu

lar B

lock

ers

Neu

rom

uscu

lar B

lock

ers

Ther

e is

a s

light

ly s

low

er o

nset

of n

euro

mus

cula

r bl

ocka

de (l

ikel

y se

cond

ary

to s

low

er d

eliv

ery

of

rocu

roni

um to

the

neur

omus

cula

r end

plat

e (K

eo))

.Th

ere

is a

slo

wer

offs

et s

econ

dary

to a

dec

reas

ed

met

abol

ism

of r

ocur

oniu

m (d

ecre

ased

org

an m

ass

and

over

all f

unct

ion

with

nor

mal

agi

ng).

Var

iabi

lity

is m

ore

likel

y as

we

get o

lder

bec

ause

di

seas

e pr

oces

ses

affe

ctin

g th

e ph

arm

acok

inet

ics

and

phar

mac

odyn

amic

s of

NM

BA

s ar

e lik

ely

to b

e pr

esen

t.

Key

Poi

nts:

Chi

ldre

n an

d K

ey P

oint

s: C

hild

ren

and

Neu

rom

uscu

lar B

lock

ers

Neu

rom

uscu

lar B

lock

ers

Ther

e is

a fa

ster

ons

et in

neo

nate

s bu

t a d

elay

ed

offs

et.

This

is li

kely

sec

onda

ry to

an

imm

atur

e ne

urom

uscu

lar e

ndpl

ate

lead

ing

to a

qui

cker

ons

et,

and

an im

mat

ure

liver

and

kid

neys

lead

ing

to s

low

er

met

abol

ism

and

a d

elay

ed o

ffset

. In

chi

ldre

n (1

to 5

yea

rs),

the

onse

t tim

e an

d th

e du

ratio

n ap

proa

ch y

oung

adu

lts a

s or

gan

syst

ems

com

plet

e th

eir d

evel

opm

ent.

Som

e Ph

ysio

logy

(of

Som

e Ph

ysio

logy

(of

the

Neu

rom

uscu

lar

the

Neu

rom

uscu

lar

junc

tion)

junc

tion)

Wha

t are

we

talk

ing

abou

t?W

hat a

re w

e ta

lkin

g ab

out?

The

Neu

rom

uscu

lar J

unct

ion

(NM

J)Th

e N

euro

mus

cula

r Jun

ctio

n (N

MJ)

The

NM

J is

a c

hem

ical

syn

apse

with

a n

euro

nal p

re-s

ynap

tic

term

inal

whe

re A

ch is

rele

ased

, and

a p

ost-s

ynap

tic

mem

bran

ew

here

the

chol

iner

gic

rece

ptor

s re

side

.A

ch is

syn

thes

ized

in th

e pr

e-sy

napt

ic te

rmin

al b

y ch

olin

e-O

-ac

etyl

tran

sfer

ase

from

cho

line

and

acet

ate.

Ach

is s

tore

d in

the

cyto

plas

m o

f the

pre

-syn

aptic

term

inal

and

tra

nspo

rted

into

ves

icle

s w

hich

are

mov

ed in

to p

ositi

on fo

r re

leas

e. E

ach

vesi

cle

cont

ains

app

roxi

mat

ely

5 x

10 to

the

3rd

mol

ecul

es o

f Ach

.Th

e ve

sicl

es a

re a

ligne

d ex

actly

opp

osite

the

conv

olut

ions

(w

here

nic

otin

ic re

cept

ors

are

conc

entra

ted

on th

e po

st-

junc

tiona

l mus

cle

mem

bran

e).

A

cety

lcho

lines

tera

se (A

chE

) is

pres

ent i

n th

e ar

ea o

f the

ch

olin

ergi

c re

cept

or to

dea

ctiv

ate

the

Ach

.

The

Neu

rom

uscu

lar J

unct

ion

The

Neu

rom

uscu

lar J

unct

ion

Stru

ctur

e of

the

Ace

tylc

holin

e St

ruct

ure

of th

e A

cety

lcho

line

Rec

epto

rR

ecep

tor

It is

a p

enta

mer

ic s

ite.

The

five

subu

nits

are

arr

ange

d in

a ro

sette

aro

und

a N

a-K

ioni

c ch

anne

l.E

ach

rece

ptor

has

two

Ach

rece

ptiv

e si

tes.

Two

Ach

mol

ecul

es m

ust b

ind

to th

e re

cept

or to

ope

n th

e ch

anne

l.Th

e po

tenc

y of

a N

MB

A d

epen

ds o

n ho

w w

ell t

he

agen

t fits

into

the

rece

ptor

(e. g

. cis

-atra

curiu

m [0

.1-

0.2

mg/

kg] i

s m

ore

pote

nt th

an ro

curo

nium

[0.6

m

g/kg

], th

eref

ore,

it m

ust b

e a

bette

r “fit

” with

the

re

cept

or).

The

Ace

tylc

holin

e R

ecep

tor

The

Ace

tylc

holin

e R

ecep

tor

Phys

iolo

gy o

f the

Neu

rom

uscu

lar

Phys

iolo

gy o

f the

Neu

rom

uscu

lar

Junc

tion

Junc

tion

An

actio

n po

tent

ial r

esul

ts in

rele

ase

of A

ch a

t the

pre

-syn

aptic

te

rmin

al.

AC

h in

tera

cts

with

(neu

rom

uscu

lar)

NM

rece

ptor

s at

the

end-

plat

e.D

epol

ariz

atio

n of

the

end-

plat

e m

embr

ane

resu

lts.

Mus

cle

cont

ract

ion

is in

itiat

ed.

AC

h is

inac

tivat

ed b

y ac

etyl

chol

ines

tera

se (A

ChE

).M

echa

nism

s of

Neu

rom

uscu

lar B

lock

ade

Rec

epto

r blo

ckad

e (n

on-d

epol

ariz

ing

agen

ts)

Dep

olar

izat

ion

of th

e en

d-pl

ate

(dep

olar

izin

g ag

ents

)Th

e ef

fect

of n

euro

mus

cula

r blo

ckad

e is

ske

leta

l mus

cle

para

lysi

s.

The

post

The

post

-- syn

aptic

term

inal

: a

syna

ptic

term

inal

: a

redu

ndan

t sys

tem

redu

ndan

t sys

tem

So, h

ow d

o w

e re

vers

e So

, how

do

we

reve

rse

neur

omus

cula

r blo

ckad

e?ne

urom

uscu

lar b

lock

ade?

Roc

uron

ium

bro

mid

e 0.

6 m

g/kg

Roc

uron

ium

bro

mid

e 0.

6 m

g/kg

reve

rsal

of b

lock

reve

rsal

of b

lock

Ther

e ar

e tw

o co

mpo

nent

s Th

ere

are

two

com

pone

nts

invo

lved

with

the

reve

rsal

of

invo

lved

with

the

reve

rsal

of

neur

omus

cula

r blo

ckad

e; re

mov

al

neur

omus

cula

r blo

ckad

e; re

mov

al

of th

e N

MB

A fr

om th

e of

the

NM

BA

from

the

neur

omus

cula

r jun

ctio

n by

ne

urom

uscu

lar j

unct

ion

by

redi

strib

utio

n an

d m

etab

olis

m,

redi

strib

utio

n an

d m

etab

olis

m,

and

chem

ical

reve

rsal

with

Ach

E an

d ch

emic

al re

vers

al w

ith A

chE

inhi

bito

rs.

in

hibi

tors

.

Ace

tylc

holin

este

rase

(Ach

E) In

hibi

tors

A

cety

lcho

lines

tera

se (A

chE)

Inhi

bito

rs

Neo

stig

min

e (p

rost

igm

in),

edro

phon

ium

(ten

silo

n),

pyrid

ostig

min

e (m

estin

on) a

re m

ost c

omm

only

use

d as

reve

rsal

ag

ents

.Th

eir p

rimar

y m

ode

of a

ctio

n is

the

inhi

bitio

n of

Ach

E (th

eref

ore

allo

win

g th

e ne

urot

rans

mitt

er a

cety

lcho

line

to b

e pr

esen

t at t

hene

urom

uscu

lar j

unct

ion

long

er).

Ons

et o

f act

ion:

Edr

opho

nium

(1-2

min

), N

eost

igm

ine

(7-1

1 m

in),

pyrid

ostig

min

e (1

6 m

in)

The

reas

on fo

r the

rapi

d on

set o

f edr

opho

nium

as

com

pare

d to

th

e ot

her t

wo

is n

ot c

lear

. A

ll th

ree

inhi

bit A

chE

as

soon

as

they

bi

nd w

ith th

e en

zym

e.

Neo

stig

min

e an

d py

ridos

tigm

ine

are

hydr

olyz

ed b

y Ac

hE.

The

enzy

me

is c

arba

myl

ated

in th

e pr

oces

s re

duci

ng it

s ab

ility

to

hydr

olyz

e ac

etyl

chol

ine.

Edr

opho

nium

is n

ot b

roke

n do

wn

by A

chE.

The

inte

ract

ion

is

com

petit

ive

and

reve

rsib

le.

The

actu

al d

urat

ion

of a

ctio

n of

all

thre

e is

1-2

hou

rs.

We

neve

r se

e it

clin

ical

ly in

the

OR

bec

ause

the

neur

omus

cula

r blo

ckin

g ag

ents

are

usu

ally

met

abol

ized

fast

er.

Dos

ing

of A

chE

Inhi

bito

rsD

osin

g of

Ach

E In

hibi

tors

Edr

opho

nium

–0.

5 –

1.0

mg/

kg

(M

ax. e

ffect

1 m

inut

e)N

eost

igm

ine

-0.

03 –

0.06

mg/

kg

(Max

. effe

ct 7

min

utes

)P

yrid

ostig

min

e –

0.25

mg/

kg

(Max

. effe

ct 1

0-13

min

utes

)

The

dura

tion

of a

ctio

n fo

r all

thre

e ag

ents

is a

bout

1-2

ho

urs.

Ant

icho

liner

gic

Dru

gs (d

osin

g) w

ith 0

.5

Ant

icho

liner

gic

Dru

gs (d

osin

g) w

ith 0

.5

to 1

.0 m

g/kg

Edr

opho

nium

or 5

0 to

70

to 1

.0 m

g/kg

Edr

opho

nium

or 5

0 to

70

mic

rogr

am/k

g N

eost

igm

ine

mic

rogr

am/k

g N

eost

igm

ine

Atr

opin

e–

10 m

icro

gram

/kg

Gly

copy

rrol

ate

–5

to 1

0 m

icro

gram

/kg

(Usu

ally

giv

en o

ne m

inut

e be

fore

Ed

roph

oniu

m)

Ant

agon

ism

of r

ocur

oniu

m b

rom

ide

Ant

agon

ism

of r

ocur

oniu

m b

rom

ide

(0.6

mg/

kg)

(0.6

mg/

kg)

Ada

pted

from

: Nag

uib

et a

l Ane

sthe

siol

ogy

1993

;79:

739-

745

N =

neo

stig

min

e

E =

edro

phon

ium

chl

orid

e

Ant

agon

ism

of r

ocur

oniu

m b

rom

ide

Ant

agon

ism

of r

ocur

oniu

m b

rom

ide

(0.6

mg/

kg)

(0.6

mg/

kg)

Ada

pted

from

: Nag

uib

et a

l Ane

sthe

siol

ogy

1993

;79:

739-

745

Is th

ere

a di

ffere

nt m

echa

nism

of

Is th

ere

a di

ffere

nt m

echa

nism

of

actio

n be

twee

n A

chE

inhi

bito

rs?

Wha

t ac

tion

betw

een

Ach

E in

hibi

tors

? W

hat

do w

e kn

ow?

do w

e kn

ow?

Edr

opho

nium

and

neo

stig

min

e ar

e no

t equ

ally

ef

fect

ive

espe

cial

ly w

ith m

ore

inte

nse

leve

ls o

f bl

ocka

de.

The

onse

t of e

drop

honi

um is

fast

er th

an th

e ot

hers

ev

en th

ough

the

inhi

bitio

n of

Ach

E is

felt

to o

ccur

im

med

iate

ly u

pon

its b

indi

ng w

ith a

ll of

the

agen

ts.

Edr

opho

nium

ass

iste

d an

tago

nism

of A

chE

is k

now

n to

hav

e a

“flat

ter”

dose

-resp

onse

cur

ve th

an th

at o

f ne

ostig

min

e.

Dos

e / R

espo

nse

Cur

ves

(Ach

E D

ose

/ Res

pons

e C

urve

s (A

chE

Inhi

bito

rs)

Inhi

bito

rs)

Ace

tylc

holin

este

rase

Inhi

bito

rs:

Ace

tylc

holin

este

rase

Inhi

bito

rs:

Poss

ible

Alte

rnat

ive

Mec

hani

sms

of

Poss

ible

Alte

rnat

ive

Mec

hani

sms

of

Act

ion

Act

ion

Pre

syna

ptic

effe

cts

(eith

er b

y di

rect

ly

bind

ing

to, o

r by

havi

ng a

n in

crea

sed

amou

nt o

f Ach

pre

sent

at t

he

pres

ynap

tic re

cept

or)

Dire

ct a

ctio

n (b

indi

ng) a

t the

po

stsy

napt

ic a

cety

lcho

line

rece

ptor

Cei

ling

Effe

ct o

f Ace

tylc

holin

este

rase

C

eilin

g Ef

fect

of A

cety

lcho

lines

tera

se

Inhi

bito

rsIn

hibi

tors

Side

Effe

cts

of A

chE

Inhi

bito

rsSi

de E

ffect

s of

Ach

E In

hibi

tors

card

iac

arrh

ythm

ias

(esp

ecia

lly

brad

ycar

dia)

bron

choc

onst

rictio

nin

crea

sed

saliv

atio

n?

incr

ease

d in

cide

nce

of n

ause

a an

d vo

miti

ng (m

any

stud

ies

disa

gree

with

th

is h

ypot

hesi

s)w

eakn

ess

in c

erta

in p

atie

nt p

opul

atio

ns

Dra

wba

cks

to A

cety

lcho

lines

tera

se

Dra

wba

cks

to A

cety

lcho

lines

tera

se

Inhi

bito

rs

Inhi

bito

rs

They

are

“ind

irect

” act

ing

agon

ists

for A

ch.

You

can

not e

ffect

ivel

y re

vers

e pr

ofou

nd (T

1 <

10%

ba

selin

e) b

lock

ade

of th

e ne

urom

uscu

lar j

unct

ion

(the

time

to a

chie

ving

ext

ubat

ion

crite

ria w

ith o

r with

out

reve

rsal

usi

ng a

n A

chE

inhi

bito

r fro

m a

pro

foun

d bl

ock

is th

e sa

me)

. M

ultip

le o

r exc

essi

ve d

oses

of

Ach

E in

hibi

tors

may

incr

ease

the

degr

ee o

f res

idua

l bl

ocka

de.

The

effe

ct is

not

sel

ectiv

e, th

eref

ore,

ther

e ar

e a

few

si

de e

ffect

s w

ith th

eir u

se s

uch

as; i

ncre

ased

sa

livat

ion,

bra

dyca

rdia

, tea

ring,

mio

sis

and

bron

choc

onst

rictio

n.

They

mus

t be

give

n w

ith o

ther

dru

gs s

uch

as a

tropi

ne

and

glyc

opyr

rola

te to

ant

agon

ize

the

mus

carin

ic

effe

cts

of A

ch.

Ach

E in

hibi

tors

are

not

true

“res

cue”

reve

rsal

age

nts

for t

he “c

anno

t ven

tilat

e / c

anno

t int

ubat

e” p

atie

nt.

The

Tim

e to

Ade

quat

e R

ever

sal w

ith

The

Tim

e to

Ade

quat

e R

ever

sal w

ith

Ach

E In

hibi

tors

Dep

ends

on

the

Ach

E In

hibi

tors

Dep

ends

on

the

Spec

ific

NM

BA

.Sp

ecifi

c N

MB

A.

Inte

rmed

iate

Act

ing

Age

nts

(e. g

. roc

uron

ium

, ve

curo

nium

) -7

–12

min

utes

Long

Act

ing

Age

nts

(e. g

. pan

curo

nium

, cur

are)

–20

–40

min

utes

How

do

we

asse

ss a

dequ

acy

of

How

do

we

asse

ss a

dequ

acy

of

reve

rsal

of n

euro

mus

cula

r blo

ckad

e?

reve

rsal

of n

euro

mus

cula

r blo

ckad

e?

Twitc

h M

onito

rTw

itch

Mon

itor

Trai

n O

f Fou

r (co

mpa

re th

e 4t

htw

itch

to th

e 1s

ttw

itch)

You

wan

t the

ratio

of t

he fo

urth

/firs

t tw

itch

to b

e >

0.7

(act

ually

cur

rent

thou

ght i

s th

at a

ratio

of >

0.9

is

need

ed).

S

usta

ined

Tet

anus

D

oubl

e B

urst

Stim

ulat

ion

TOF

is u

sual

ly a

sses

sed

by v

isua

l ins

pect

ion

and

not

usin

g qu

antit

ativ

e m

easu

res

(acc

eler

omyo

grap

hy

and

mec

hano

myo

grap

hy).

Sus

tain

ed T

etan

us a

nd D

oubl

e B

urst

Stim

ulat

ion

are

also

ver

y di

fficu

lt to

qua

ntify

.

How

do

we

asse

ss a

dequ

acy

of

How

do

we

asse

ss a

dequ

acy

of

reve

rsal

of n

euro

mus

cula

r blo

ckad

e?

reve

rsal

of n

euro

mus

cula

r blo

ckad

e?

Oth

er C

linic

al In

dica

tors

Oth

er C

linic

al In

dica

tors

Hea

d Li

ft (5

or 1

0 se

cond

s)Le

g Li

ft (in

chi

ldre

n)H

and

Gra

spN

egat

ive

Insp

irato

ry F

orce

(NIF

)H

ead

Lift

> 10

sec

onds

is b

est,

but s

omet

imes

it is

har

d to

get

th

e pa

tient

to fo

llow

the

com

man

d to

lift

his/

her h

ead.

Kop

man

et.

al. (

1997

) –th

e to

ngue

dep

ress

or te

st –

If a

patie

nt

can

gras

p a

tong

ue d

epre

ssor

bet

wee

n hi

s/he

r tee

th a

nd it

ca

nnot

be

pulle

d ou

t, th

e TO

F is

like

ly >

0.8

5 an

d up

per a

irway

m

uscu

lar f

unct

ion

is li

kely

inta

ct.

Som

e H

isto

rySo

me

His

tory

Ali

et. a

l. (1

970

and

1971

) –W

hen

4 st

imul

i wer

e de

liver

ed a

t 0.

5-s

inte

rval

s, th

ere

was

a p

rogr

essi

ve fa

de o

f suc

cess

ive

resp

onse

s de

pend

ing

on th

e ex

tent

of c

urar

izat

ion.

TO

F w

as

defin

ed.

At v

alue

s of

> 0

.7, n

o ev

iden

ce o

f par

alys

is w

as n

oted

.E

ngba

ek e

t. al

. (19

89) –

This

stu

dy d

escr

ibed

the

tech

niqu

e of

“d

oubl

e bu

rst s

timul

atio

n” in

resp

onse

to c

ompl

aint

s of

di

fficu

lties

in th

e cl

inic

al a

sses

smen

t of T

OF

fade

.B

rull

et. a

l. (1

990)

–Th

ey n

oted

a c

lose

line

ar re

latio

nshi

p be

twee

n TO

F an

d do

uble

bur

st s

timul

atio

n.

How

do

we

asse

ss T

OF

fade

?H

ow d

o w

e as

sess

TO

F fa

de?

Mec

hano

myo

gram

(MM

G),

EM

G a

nd a

ccel

ogra

phy

can

be

used

, how

ever

the

equi

pmen

t can

be

expe

nsiv

e an

d di

fficu

lt to

us

e.M

ost o

f us

rely

on

the

subj

ectiv

e as

sess

men

t of t

he T

OF.

Vib

y-M

ogen

sen

et. A

l. (1

985)

–TO

F fa

de w

ent f

requ

ently

un

dete

cted

(eve

n va

lues

as

low

as

abou

t 0.4

).D

upui

s et

. al.

(199

0) –

Sust

aine

d te

tanu

s w

as n

oted

at T

OF

ratio

s of

< 0

.5.

Dre

nck

et. a

l. (1

989)

–Th

e ab

ility

to id

entif

y fa

de in

crea

sed

to a

le

vel o

f 0.6

with

dou

ble

burs

t stim

ulat

ion

(stil

l not

> 0

.7).

Rem

embe

r tha

t man

y be

lieve

that

a T

OF

ratio

> 7

0% is

stil

l in

adeq

uate

(> 9

0% is

nee

ded)

.

Cla

ssic

Tea

chin

g St

ates

that

a

Cla

ssic

Tea

chin

g St

ates

that

a

TOF

ratio

of 0

.7 (A

li et

. al.

1981

) TO

F ra

tio o

f 0.7

(Ali

et. a

l. 19

81)

is a

n A

ppro

pria

te L

evel

of

is a

n A

ppro

pria

te L

evel

of

Rev

ersa

l for

Ext

ubat

ion.

Rev

ersa

l for

Ext

ubat

ion.

Wha

t is

an a

ppro

pria

te T

OF

ratio

for

Wha

t is

an a

ppro

pria

te T

OF

ratio

for

adeq

uate

reve

rsal

(wha

t som

e st

udie

s ad

equa

te re

vers

al (w

hat s

ome

stud

ies

have

not

ed)?

have

not

ed)?

TOF

ratio

of 0

.63

–Yo

u m

ay s

ee p

atie

nts

com

plai

n of

diff

icul

ty

brea

thin

g an

d sw

allo

win

g as

wel

l as

a de

crea

sed

insp

irato

ry

forc

e an

d pe

ak fl

ow ra

te.

TOF

ratio

of 0

.7 to

0.7

5 –

You

may

see

dip

lopi

a, d

ecre

ased

grip

st

reng

th, i

nabi

lity

to s

it up

with

out a

ssis

tanc

e, fa

cial

wea

knes

s an

d di

fficu

lty s

wal

low

ing

and

spea

king

. A

lso,

stu

dies

hav

e sh

own

decr

ease

d co

ordi

natio

n of

eso

phag

eal m

uscu

latu

re a

nd

phar

ynge

al d

ysfu

nctio

n le

adin

g to

a 4

to 5

fold

incr

ease

in th

e ris

k of

asp

iratio

n (E

rikss

on e

t. al

. 199

7).

Pha

ryng

eal f

unct

ion

retu

rns

to n

orm

al w

ith a

TO

F ra

tio o

f 0.9

.TO

F of

0.8

5 –

You

may

see

gen

eral

dis

com

fort,

mal

aise

, pto

sis,

an

d bl

urre

d vi

sion

.TO

F of

0.9

–Yo

u m

ay s

ee s

igni

fican

t vis

ual d

istu

rban

ces

such

as

dip

lopi

a an

d di

fficu

lty tr

acki

ng o

bjec

ts.

Rec

ent s

tudi

es in

Hum

ans

Indi

cate

R

ecen

t stu

dies

in H

uman

s In

dica

te

that

the

“Bar

” fo

r an

Acc

epta

ble

that

the

“Bar

” fo

r an

Acc

epta

ble

Leve

l of R

ecov

ery

of

Leve

l of R

ecov

ery

of

Neu

rom

uscu

lar F

unct

ion

shou

ld

Neu

rom

uscu

lar F

unct

ion

shou

ld

be R

aise

d to

a T

OF

Rat

io o

f

be R

aise

d to

a T

OF

Rat

io o

f

> 0.

90.

> 0.

90.

Clin

ical

Eva

luat

ion

Clin

ical

Eva

luat

ion

Dam

and

Gul

dman

n (1

961)

–de

scrib

ed th

e “h

ead

lift”

as a

re

liabl

e si

gn o

f mus

cle

pow

er [d

idn’

t spe

cify

the

dura

tion]

Man

y ha

ve d

emon

stra

ted

that

a h

ead

lift f

or >

5 s

econ

ds is

a

relia

ble

indi

cato

r of a

dequ

ate

reve

rsal

of n

euro

mus

cula

r bl

ocka

deA

li et

. al.

(197

1) –

no p

atie

nt w

ith a

TO

F ra

tio <

0.4

cou

ld li

ft hi

s/he

r hea

d of

f of t

he b

ed

Hut

ton

et. a

l. (1

976)

–5

seco

nd h

ead

lift h

owev

er d

oes

not

guar

ante

e th

at v

olun

tary

func

tion

has

retu

rned

to n

orm

al o

r tha

tth

ey a

re c

omfo

rtabl

e.M

any

patie

nts

will

not

follo

w th

e co

mm

and

to li

ft th

eir h

ead,

or

they

will

not d

o it

seco

ndar

y to

pai

n fro

m th

e su

rgic

al s

ite.

Usi

ng “h

and

grip

” is

muc

h le

ss re

liabl

e.In

infa

nts,

a le

g lif

t cor

rela

ted

with

a “N

IF” (

nega

tive

insp

irato

ry

forc

e) o

f -58

cm

H2O

to -7

1 cm

H2O

ther

efor

e it

is a

reas

onab

le

indi

cato

r of r

etur

n of

neu

rom

uscu

lar f

unct

ion

in th

is p

opul

atio

n.

Neg

ativ

e In

spira

tory

For

ce (N

IF)

Neg

ativ

e In

spira

tory

For

ce (N

IF)

Ben

dixe

n et

. al.

–Th

ey s

ugge

sted

that

the

max

imum

neg

ativ

e pr

essu

re (n

egat

ive

insp

irato

ry fo

rce

gene

rate

d ag

ains

t a c

lose

d ai

rway

) cou

ld b

e a

mea

sure

men

t of v

entil

ator

y re

serv

e.W

esco

tt et

. al.

(196

2) –

sugg

este

d th

at a

s lit

tle a

s -2

0 cm

H2O

in

dica

ted

suffi

cien

t ven

tilat

ory

rese

rve.

-25

cm H

2O to

-30

cm H

2O b

ecam

e an

acc

epta

ble

goal

for

dete

rmin

ing

reco

very

of n

euro

mus

cula

r fun

ctio

n.H

owev

er, i

t has

bee

n sh

own

that

a h

ead

lift o

f 5 s

econ

ds

corr

elat

ed w

ith a

NIF

of -

50 c

m H

2O.

Pav

lin e

t. al

. -At

-25

cm H

2O o

r les

s N

IF, n

o pa

tient

cou

ld

swal

low

or m

aint

ain

an a

irway

.

How

do

we

asse

ss a

dequ

acy

of

How

do

we

asse

ss a

dequ

acy

of

reve

rsal

of n

euro

mus

cula

r blo

ckad

e?

reve

rsal

of n

euro

mus

cula

r blo

ckad

e?

(Joe

’s R

ules

)(J

oe’s

Rul

es)

(1) T

witc

h M

onito

r –(2

) Clin

ical

Indi

cato

rs –

(3) O

ur

unde

rsta

ndin

g of

the

usua

l dur

atio

n of

act

ion

of a

pa

rticu

lar N

MB

AR

ule

1 -I

f any

one

of t

he th

ree

indi

cato

rs is

not

ad

equa

te, r

ever

sal i

s in

dica

ted.

Rul

e 2

–If

ther

e ar

e m

ore

than

one

ane

sthe

sia

prov

ider

invo

lved

in th

e ca

se, e

very

one

mus

t agr

ee

on th

e ad

equa

cy o

f rev

ersa

l of n

euro

mus

cula

r bl

ocka

de.

If no

t, re

vers

al is

indi

cate

d.R

ule

3 –

The

side

effe

cts

of re

vers

al a

gent

s ar

e an

noyi

ng, t

he c

ompl

icat

ions

of p

rem

atur

e ex

tuba

tion

coul

d be

dea

dly.

Shou

ld y

ou re

vers

e or

not

?Sh

ould

you

reve

rse

or n

ot?

Rec

over

y is

qui

cker

and

mor

e re

liabl

e w

ith in

term

edia

te a

ctin

g ag

ents

.Lu

nn e

t. A

l. –

11of

32

deat

hs d

ue to

ane

sthe

sia

wer

e se

cond

ary

to

post

-ope

rativ

e re

spira

tory

failu

re.

Neu

rom

uscu

lar b

lock

ade

was

a

defin

ite c

ontri

buto

r in

six

of th

e ca

ses.

Tire

t et.

Al.

–50

% o

f 65

deat

hs d

ue to

ane

sthe

sia

wer

e re

late

d to

pos

t-op

erat

ive

resp

irato

ry fa

ilure

.C

oope

r et.

Al.

–24

of 5

3 ad

mis

sion

s to

the

ICU

sec

onda

ry to

an

esth

esia

rela

ted

prob

lem

s w

ere

seco

ndar

y to

pos

t-ope

rativ

e re

spira

tory

failu

re a

nd re

sidu

al n

euro

mus

cula

r blo

ckad

e.B

ailla

rd e

t. A

l. –

With

an

incr

ease

d us

e of

qua

ntita

tive

mea

sure

men

ts o

f ne

urom

uscu

lar b

lock

ade

(TO

F) a

nd th

e us

e of

reve

rsal

age

nts,

resi

dual

bl

ocka

de (T

OF

< 90

%) d

ecre

ased

from

62%

to 3

% [b

etw

een

1995

and

20

04].

Deb

aene

et.

al. –

In p

atie

nts

not r

ecei

ving

reve

rsal

age

nts,

a T

OF

ratio

of

< 0

.7 o

ccur

red

37%

of t

he ti

me

two

hour

s af

ter a

sin

gle

dose

of

NM

BA

. C

aldw

ell e

t. al

. –Th

ey fo

und

a TO

F <

0.7

up to

4 h

ours

afte

r a s

ingl

e

intu

batin

g do

se o

f vec

uron

ium

.M

any

toda

y us

e a

TOF

> 90

% (i

nste

ad o

f > 7

0%) a

s an

indi

cato

r of

appr

opria

tere

turn

ofne

urom

uscu

larf

unct

ion.

Shou

ld y

ou re

vers

e or

not

? Sh

ould

you

reve

rse

or n

ot?

(con

tinue

d)

(con

tinue

d)

The

surg

ical

pat

ient

pop

ulat

ion

is b

ecom

ing

olde

r and

will

like

ly

have

the

pres

ence

of c

onco

mita

nt d

isea

se b

oth

lead

ing

to a

de

crea

sed

clea

ranc

e of

the

NM

BA

s.Fu

rther

mor

e, th

e po

pula

tion

is b

ecom

ing

incr

easi

ngly

mor

e de

bilit

ated

whe

n co

mpa

red

to a

few

yea

rs a

go.

Ane

sthe

tics

are

beco

min

g sh

orte

r act

ing

(e. g

. rem

ifent

anil,

de

sflu

rane

, sev

oflu

rane

and

pro

pofo

l), th

eref

ore,

pat

ient

s ar

e fu

lly a

wak

e m

ore

quic

kly.

Sur

gerie

s ar

e be

ing

done

on

an a

mbu

lato

ry b

asis

at i

ncre

asin

g ra

tes,

ther

efor

e, p

atie

nts

are

expe

cted

to b

e aw

ake,

wal

k ou

t of

the

cent

er a

nd b

e fu

nctio

nal a

t hom

e ea

rlier

.

Shou

ld y

ou re

vers

e or

not

?Sh

ould

you

reve

rse

or n

ot?

The

bene

fits

outw

eigh

the

risks

of g

ivin

g re

vers

al a

gent

s in

mos

t situ

atio

ns.

Wha

t do

I fre

quen

tly te

ll m

y te

enag

ers?

Wha

t do

I fre

quen

tly te

ll m

y te

enag

ers?

“You

can

mes

s up

any

thin

g if

you

try

hard

eno

ugh!

!!”

Org

259

69 (S

ugam

mad

ex)

Org

259

69 (S

ugam

mad

ex)

The

1stse

lect

ive

rela

xant

bin

ding

age

nt (S

RB

A)

It is

a s

ynth

etic

cyc

lode

xtrin

esp

ecia

lly d

esig

ned

to

bind

the

ster

oida

l NM

BA

rocu

roni

umO

rg 2

5969

cau

ses

a do

se d

epen

dant

fast

reco

very

of

neur

omus

cula

r blo

ckad

e of

rocu

roni

umIt

is ra

pidl

y ex

cret

ed b

y th

e ki

dney

sTh

e re

vers

al o

f the

neu

rom

uscu

lar b

lock

ade

is

depe

nden

t on

the

bind

ing

of th

e N

MB

A n

ot th

e ex

cret

ion

of th

e dr

ug b

y th

e ki

dney

s

Ther

e do

es n

ot a

ppea

r to

be s

igni

fican

t sid

e ef

fect

s w

ith th

is d

rug.

Org

259

69O

rg 2

5969

Org

259

69 (g

reen

) and

Org

259

69 (g

reen

) and

Roc

uron

ium

(blu

e)R

ocur

oniu

m (b

lue)

Org

259

69 a

dmin

iste

red

5 m

inut

es

Org

259

69 a

dmin

iste

red

5 m

inut

es

afte

r 1.2

mg/

kg o

f Roc

uron

ium

unt

il af

ter 1

.2 m

g/kg

of R

ocur

oniu

m u

ntil

TOF

> 90

%

TOF

> 90

%

plac

ebo

(n=4

)122

:05

2.0

mg.

kg-1

(n=

5)56

:30

min

utes

4.0

mg.

kg-1

(n=

5)15

:47

min

utes

8.0

mg.

kg-1

(n=

12)2

:45

min

utes

12.0

mg.

kg-1

(n=7

)1:2

3 m

inut

es16

.0 m

g.kg

-1 (n

=7)1

:55

min

utes

Sid

e E

ffect

s: T

hree

pat

ient

s ha

d Q

T pr

olon

gatio

n, b

ut n

one

wer

efe

lt to

be

seco

ndar

y to

OR

G 2

5969

. Tw

o re

actio

ns m

ay h

ave

been

sec

onda

ry to

OR

G

2596

9; d

iarr

hea

and

mov

emen

t und

er li

ght a

nest

hesi

a.

[200

5] [A

1117

] Rev

ersa

l of R

ocur

oniu

m-In

duce

d (1

.2 m

g.kg

-1) N

euro

mus

cula

r B

lock

by

Org

259

69: A

Mul

ti C

ente

r Dos

e Fi

ndin

g an

d Sa

fety

Stu

dy

“Firs

t Hum

an E

xpos

ure

of O

rg 2

5969

, a

“Firs

t Hum

an E

xpos

ure

of O

rg 2

5969

, a

Nov

el A

gent

to R

ever

se th

e A

ctio

n of

N

ovel

Age

nt to

Rev

erse

the

Act

ion

of

Roc

uron

ium

Bro

mid

e”.

Gijs

enbe

rgh

et. a

l.

Roc

uron

ium

Bro

mid

e”.

Gijs

enbe

rgh

et. a

l.

Ane

sthe

siol

ogy

2005

; 103

: 695

Ane

sthe

siol

ogy

2005

; 103

: 695

-- 703703

29 h

ealth

y m

ales

, Org

259

69 v

s. p

lace

bo, g

iven

3

min

utes

afte

r Roc

uron

ium

Bro

mid

e (0

.6 m

g/kg

)S

ix d

iffer

ent d

oses

of O

rg 2

5969

wer

e us

ed (0

.1

mg/

kg to

0.8

mg/

kg).

Sid

e ef

fect

s in

clud

ed; d

ry m

outh

, fas

cicu

latio

ns a

nd

pare

sthe

sias

. N

one

requ

ired

treat

men

t.W

ithin

2 m

inut

es, t

he p

atie

nts

rece

ivin

g 8

mg/

kg o

f O

rg 2

5969

reac

hed

a TO

F ra

tio o

f > 0

.9 w

ithin

two

min

utes

.C

oncl

usio

ns:

Org

259

69 w

as w

ell t

oler

ated

and

ve

ry e

ffect

ive

in re

vers

ing

Roc

uron

ium

Bro

mid

e in

29

hum

an v

olun

teer

s.

[Abs

trac

t A11

19] A

noth

er s

tudy

[A

bstr

act A

1119

] Ano

ther

stu

dy

look

ing

at R

ocur

oniu

m (0

.6 m

g/kg

) and

lo

okin

g at

Roc

uron

ium

(0.6

mg/

kg) a

nd

Vecu

roni

um (0

.1 m

g/kg

)Ve

curo

nium

(0.1

mg/

kg)

Roc

uron

ium

Vec

uron

ium

Pla

cebo

3

1:48

+/-2

1:00

(min

:sec

) 48

:45+

/-27:

530.

5 m

g/kg

3:

40+/

-1:0

2

7:43

+/-2

:34

1.0

mg/

kg

2:19

+/-0

:35

2:

30+/

-0:4

92.

0 m

g/kg

1:

43+/

-0:3

6

2:15

+/-0

:48

3.0

mg/

kg

1:53

+/-1

:10

1:

31+/

-0:3

24.

0 m

g/kg

1:

07+/

-0:1

8

1:24

+/-0

:28

Sid

e E

ffect

s: (r

ocur

oniu

m) t

achy

card

ia (v

ecur

oniu

m) a

bdom

inal

pai

n,

mild

ery

them

a, a

nd d

elay

ed re

cove

ry fr

om a

nest

hesi

a

Wha

t if y

ou h

ave

to re

intu

bate

(re

Wha

t if y

ou h

ave

to re

intu

bate

(re --

para

lyze

) afte

r the

use

of O

rg 2

5969

? pa

raly

ze) a

fter t

he u

se o

f Org

259

69?

Ant

on e

t. al

. (A

SA

abs

tract

s / A

-114

4 / 2

004)

“Afte

r ind

uctio

n of

neu

rom

uscu

lar b

lock

ade

with

rocu

roni

um a

nd ra

pid

reve

rsal

with

Org

25

969,

the

non-

ster

oida

l NM

BA

s (a

tracu

rium

, cis

-atra

curiu

m, m

ivac

uriu

m a

nd

succ

inyl

chol

ine)

wer

e st

ill p

oten

t and

ef

ficac

ious

.”“…

show

ing

that

Org

259

69 h

as a

ver

y lo

w

affin

ity fo

r non

-ste

roid

al N

MB

As.

”

(Sug

amm

adex

) Que

stio

ns y

et to

be

(Sug

amm

adex

) Que

stio

ns y

et to

be

answ

ered

:an

swer

ed:

Wou

ld S

ugam

mad

exbe

equ

ally

as

effe

ctiv

e af

ter a

pr

olon

ged

infu

sion

of v

ecur

oniu

m o

r roc

uron

ium

in

the

ICU

, or e

ven

repe

ated

dos

es in

the

OR

?

Wha

t dos

e of

Sug

amm

adex

is re

quire

d in

an

elde

rly

seve

rely

ill p

atie

nt, a

pat

ient

with

ele

ctro

lyte

ab

norm

aliti

es, o

r a p

atie

nt o

n m

ultip

le m

edic

atio

ns

know

n to

pot

entia

te N

MB

As?

“Rev

ersa

l of N

euro

mus

cula

r “R

ever

sal o

f Neu

rom

uscu

lar

Blo

ckad

e”; A

nest

hesi

olog

y, 7

7: 7

85B

lock

ade”

; Ane

sthe

siol

ogy,

77:

785

--80

5, 1

992

(Bev

an e

t. al

.)

805,

199

2 (B

evan

et.

al.)

Q

uest

ions

any

one?

??

??

?

?

?

??

?