Resuscitation

83 (2012) 107–

112

Contents

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at

SciVerse

ScienceDirect

Resuscitation

j o

u

r n

a l

h o m

e p a g e

:

w w w . e l s e v i e r . c o m / l o c a t e / r e s u s c i t a t i o n

Experimental

paper

Pharmacokinetics

of

intraosseous

and

central

venous

drug

delivery

during

cardiopulmonary

resuscitation

夽,夽夽

Stephen

L.

Hoskins

a

,

Paulo

do

Nascimento

Jr.

a

,

b

,

Rodrigo

M.

Lima

a

,

b

,

Jonathan

M.

Espana-Tenorio

a

,

George

C.

Kramer

a

,

∗

a

Resuscitation

Research

Laboratory,

Department

of

Anaesthesiology,

University

of

Texas

Medical

Branch,

301

University

Blvd,

Galveston,

TX

77555-0801,

United

States

b

Sao

Paulo

Medical

school,

Department

of

Anesthesiology,

Unesp,

Botucatu,

SP,

Brazil

a

r

t

i

c

l

e

i

n

f

o

Article

history:

Received

27

January

2011

Received

in

revised

form

20

July

2011

Accepted

26

July

2011

Keywords:
Intraosseous
Cardiopulmonary

resuscitation

CPR
Pharmacokinetics
Tracers
Drug

delivery

a

b

s

t

r

a

c

t

We

compared

the

pharmacokinetics

of

intraosseous

(IO)

drug

delivery

via

tibia

or

sternum,

with

central

venous

(CV)

drug

delivery

during

cardiopulmonary

resuscitation

(CPR).

Methods:

CPR

of

anesthetized

KCl

arrest

swine

was

initiated

8

min

post

arrest.

Evans

blue

and

indocyanine

green,

each

were

simultaneously

injected

as

a

bolus

with

adrenaline

through

IO

sternal

and

tibial

needles,

respectively,

n

=

7.

In

second

group

(n

=

6)

simultaneous

IO

sternal

and

IV

central

venous

(CV)

injections

were

made.

Results:

Peak

arterial

blood

concentrations

were

achieved

faster

for

sternal

IO

vs.

tibial

IO

administration

(53

±

11

s

vs.

107

±

27

s,

p

=

0.03).

Tibial

IO

dose

delivered

was

65%

of

sternal

administration

(p

=

0.003).

Time

to

peak

blood

concentration

was

similar

for

sternal

IO

and

CV

administration

(97

±

17

s

vs.

70

±

12

s,

respectively;

p

=

0.17)

with

total

dose

delivered

of

sternal

being

86%

of

the

dose

delivered

via

CV

(p

=

0.22).

Conclusions:

IO

drug

administrations

via

either

the

sternum

or

tibia

were

effective

during

CPR

in

anes-

thetized

swine.

However,

IO

drug

administration

via

the

sternum

was

significantly

faster

and

delivered

a

larger

dose.

© 2011 Elsevier Ireland Ltd. All rights reserved.

1.

Introduction

Survival

from

out-of-hospital

cardiac

arrest

depends

on

a

sequence

of

therapeutic

interventions

termed

the

“chain

of

sur-

vival”

by

the

American

Heart

Association

(AHA).

This

sequence

includes

rapid

access

to

emergency

medical

care,

cardiopul-

monary

resuscitation

(CPR),

defibrillation,

advanced

care,

and

post

resuscitation

techniques

such

as

hypothermia,

percutaneous

coro-

nary

interventions,

and

implantable

cardioverter-defibrilators.

1,2

Unfortunately,

survival

rates

after

cardiac

arrests

are

dismal

(2.5–10.5%).

3–5

More

rapid

vascular

accesses

for

drug

delivery

dur-

ing

CPR

may

be

one

way

of

improving

survival.

Intravenous

access

during

CPR

can

be

difficult

even

for

an

experienced

caregiver.

In

one

study,

the

median

time

required

to

establish

an

intravenous

(IV)

line

by

well-trained

paramedics

夽 A

Spanish

translated

version

of

the

abstract

of

this

article

appears

as

Appendix

in

the

final

online

version

at

doi:10.1016/j.resuscitation.2011.07.041

.

夽夽 Financial

support:

American

Heart

Association

Texas

Affiliate

Grant-in-Aid

#0455157Y.

∗ Corresponding

author.

Tel.:

+1

409

772

3969;

fax:

+1

409

772

8895.

E-mail

addresses:

[e-mail]

,

[e-mail]

(G.C.

Kramer).

in

the

field

was

2

min

for

first

attempts

and

5

min

when

further

attempts

were

required.

6

The

overall

success

rate

to

establish

an

IV

line

in

the

field

for

medical

emergencies

is

less

than

75%.

6–8

There

remains

a

need

for

more

rapid

vascular

accesses

for

drug

delivery

during

CPR

may

be

one

way

of

improving

survival.

Intra-

venous

access

during

cardiopulmonary

resuscitation

(CPR)

can

be

difficult

even

for

an

experienced

caregiver.

Intraosseous

vascular

(IO)

access

is

an

established

rapid,

safe,

and

effective

alternative

for

peripheral

intravenous

drug

delivery.

8,9

The

American

Heart

Association

and

the

European

Resuscitation

Council

Guidelines

for

Pediatric

Life

Support

recommend

IO

access

via

the

tibia

for

pedi-

atric

patients.

12,13

In

the

last

10

years,

several

large

bore

IO

needles

for

adult

patients

have

become

available

that

use

IO

access

via

the

sternum,

tibia

and

humerus.

These

devices

have

been

evaluated

in

both

patients

and

animals.

8,10,11

Use

of

these

devices

provides

rapid

access

to

the

systemic

circulation

during

normovolemia.

7,8,10,14

However,

the

effectiveness

of

IO

drug

delivery

via

different

anatom-

ical

sites

during

CPR

has

been

under

evaluation.

We

used

a

swine

model

of

cardiac

arrest

to

determine

the

phar-

macokinetics

of

IO

delivery

of

a

double

dye

tracer

method

during

CPR

using

simultaneous

IO

injections

in

the

sternum

and

tibia.

We

also

compared

the

pharmacokinetics

of

tracer

administration

via

the

sternum

vs.

central

venous

IV

administration.

0300-9572/$

–

see

front

matter ©

2011 Elsevier Ireland Ltd. All rights reserved.

doi:

10.1016/j.resuscitation.2011.07.041

108

S.L.

Hoskins

et

al.

/

Resuscitation

83 (2012) 107–

112

2.

Methods

2.1.

Animal

preparation

The

study

protocol

was

approved

by

the

University

of

Texas

Medical

Branch’s

Institutional

Animal

Care

and

Use

Committee

(IACUC).

UTMB

animal

facilities

are

accredited

by

the

American

Association

for

the

Accreditation

of

Laboratory

Animal

Care.

The

experimental

model

was

Yorkshire

swine

(25–35

kg).

The

night

before

the

experiment

food

was

withheld

from

the

animals,

though

they

had

free

access

to

water.

Pre

sedation

was

induced

the

day

of

the

experiment

by

an

intramuscular

injection

of

telazol,

ketamine,

and

xylazine.

A

22

gauge

peripheral

intravenous

catheter

was

placed

in

the

ear

vein

to

deliver

fluids

and

alpha

chloralose.

The

animals

were

anesthetized

for

the

surgical

prep

with

2–4%

isoflu-

rane

by

facial

mask

and

then

intubated

orotracheally

using

direct

laryngoscopy.

Animals

were

placed

supine

on

a

heating

blanket

to

maintain

body

temperature

between

38

and

39

◦

C.

Surgical

areas

were

scrubbed

and

covered

with

sterile

surgical

drapes.

Mechani-

cal

ventilation

was

established

at

a

tidal

volume

of

15–20

ml/kg

and

a

ventilatory

rate

of

12–16

breaths/min

to

maintain

end

tidal

car-

bon

dioxide

between

30

and

40

mmHg.

Thereafter,

isoflurane

was

discontinued

and

anesthesia

was

maintained

with

an

IV

infusion

of

1%

alpha

chloralose

via

the

catheter

in

the

ear,

administered

as

an

initial

bolus

of

50

mg/kg

and

sustained

with

a

continuous

infusion

at

10

mg/kg/h.

The

carotid

artery

was

cannulated

for

arterial

blood

sampling

via

an

incision

of

the

right

side

of

the

neck.

A

central

venous

catheter

was

placed

via

the

external

jugular

vein

to

provide

dye

tracer

administration

into

the

central

venous

circulation.

Catheters

were

placed

into

the

aorta,

via

right

femoral

artery,

and

femoral

vein

for

acute

monitoring

and

recording

of

mean

arterial

pres-

sures

and

drug

delivery

by

sampling

arterial

blood,

respectively.

IO

needles

Jamshidi

(Baxter,

Deerfield,

IL)

or

EZ-IO

®

(VidaCare,

San

Antonio,

TX)

were

placed

in

the

manubrium

5

cm

caudal

of

the

ster-

nal

notch,

and

at

3

cm

distal

of

the

tibial

tuberosity,

respectively.

Correct

placement

was

confirmed

by

cross

section

at

necropsy.

Lac-

tated

Ringer’s

solution

was

administered

at

a

rate

of

15

ml/kg/h

during

surgery.

Standard

hemodynamics

were

monitored

(Hewlett

Packard,

Andover,

MA)

throughout

the

experiments.

Data

were

recorded

via

a

multi

channel

analog-digital

data

acquisition

pro-

gram

using

PowerLab

(AD

Instruments,

UK).

2.2.

Protocol

Two

protocols

were

employed

with

simultaneous

injections;

both

of

them

were

terminal

studies.

Protocol

I

(sternum

vs.

tibia)

compared

the

pharmacokinetics

of

two

different

dye

tracers

administered

intraosseously

and

simultaneously

via

the

sternum

and

the

tibia,

respectively.

Protocol

II

(sternum

vs.

central

venous

IV)

compared

the

pharmacokinetics

of

IO

administration

of

dye

tracers

via

the

sternum

with

a

simultaneous

administration

via

central

venous

IV.

A

60-min

baseline

time

period

was

established

after

completion

of

instrumentation.

Lactate

and

blood

gas

vari-

ables

were

monitored

to

ensure

that

the

animals

had

sufficiently

recovered

from

the

surgical

procedure

and

reached

a

physio-

logic

baseline

before

experimental

data

was

collected.

Heparin,

10,000

units

was

administered

IV

prior

to

the

induction

of

cardiac

arrest.

During

low

flow

states

such

as

cardiac

arrest,

blood

sampling

can

be

difficult

if

the

lines

become

clotted.

Prior

to

the

induction

of

cardiac

arrest,

the

animals

were

administered

a

ketamine

bolus

(30

mg/kg)

to

achieve

a

deeper

anesthesia

plane

and

avoid

any

dis-

tress

during

the

cardiac

arrest

and

resuscitation.

Cardiac

arrest

was

induced

by

rapid

IV

administration

of

10

ml

of

saturated

potassium

chloride

(KCl)

(Hospira

Inc.,

Lake

Forest,

IL)

solution

via

central

venous

catheter

followed

by

a

10

ml

saline

flush.

Immediately

following

the

injection

of

KCl

the

electrocardiogram

(EKG)

displayed

a

typical

ventricular

fibrillation

(VF)

waveform.

Ventilator

support

was

terminated

at

this

time.

Cardiac

arrest

was

followed

by

an

8-min

period

of

untreated

ventricular

fibrillation.

CPR

was

then

initiated

and

delivered

by

a

mechanical

chest

com-

pression

device

(Thumper

®

Michigan

Instruments,

Grand

Rapids,

MI)

at

100

compressions

per

min

(without

supplemental

O

2

)

and

at

duty

cycle

rate

of

50%.

A

compression

depth

was

set

at

2-in.

and

chest

compressions

were

delivered

in

an

anterior/posterior

posi-

tion

centered

on

the

sternal

body.

After

1-min

of

CPR

pre-tracer

arterial

blood

samples

were

taken.

The

volume

of

solution

utilized

was

1.5

ml

followed

by

a

1.0

ml

of

saline

flush.

2.3.

Tracers

Evans

blue

(EB)

(Sigma–Aldrich,

St.

Louis,

MO)

5.0

mg/ml,

and

indocyanine

green

(ICG)

(Alkorn,

Buffalo

Grove,

IL)

2.5

mg/ml

were

used

randomly

in

each

site

for

the

consecutive

experiments

as

trac-

ers

to

determine

the

relative

arterial

appearance

times

and

dose

delivered

from

the

IO

and

central

venous

routes.

Both

ICG

and

EB

dyes

are

inert

and

have

no

known

biological

activity.

Each

bolus

of

tracer

contained

0.014

mg/kg

of

adrenaline

(epinephrine).

At

2-min

post

CPR

(0

time

point)

the

tracers

EB

and

ICG

were

co-administered

simultaneously

to

the

designated

two

paired

sites

in

Protocol

I

(sternal

IO

and

tibial

IO)

and

in

Protocol

II

(central

venous

IV

and

sternal

IO).

Rapid

injection

of

the

2–3

ml

of

tracer

solution

was

immediately

followed

by

a

1

ml

flush

to

clear

the

needle.

Arterial

blood

samples

were

taken

every

10-s

for

5

1/2

min

and

then

at

every

30-s

for

the

remainder

of

the

8-min

time

period.

After

completion

of

the

study

CPR

was

stopped

and

the

animal

was

euthanized

with

a

high

dose

of

ketamine

and

KCl.

Plasma

tracer

concentrations

in

arterial

blood

were

determined

spectrophotometrically

(Beckman

Coulter

DU

800

spectropho-

tometer,

Brea,

CA)

using

absorbance

wavelengths

of

805

nm

for

ICG

and

620

nm

for

EB.

Calibration

standards

of

EB

and

ICG

were

pre-

pared

in

plasma

and

used

to

calculate

the

concentrations

of

EB

and

ICG

from

arterial

blood

samples.

The

area

under

the

curve

(AUC)

of

arterial

tracer

concentration

divided

by

the

tracer

dose

was

used

as

a

measure

of

the

drug

delivered

to

the

systemic

circulation

during

the

first

8

min

after

drug

injection

(0–480

s).

The

ratio

of

the

AUC

for

both

tracers

was

used

as

a

measure

of

the

relative

drug

delivery.

2.4.

Statistics

Summary

data

are

expressed

as

means

±

standard

error

of

the

mean

(SEM).

To

test

for

differences

of

appearance

times

a

paired

Student’s

t-test

was

conducted.

Correlation

coefficients

for

the

rela-

tionship

of

mean

arterial

pressure

(MAP)

to

appearance

time

were

calculated

utilizing

Sigma

plot

software

(Systat

Software

Inc.,

Ver-

sion

11,

San

Jose,

CA).

A

two-sided

alpha

level

of

significance

of

<0.05

was

used

for

assessing

statistical

significance.

3.

Results

Data

on

appearance

time

and

dose

delivered

for

all

individual

animals

and

groups

are

presented

in

figures

and

tables.

3.1.

Appearance

times

Fig.

1

(A

and

C)

and

Table

1

display

data

for

each

experiment

of

appearance

times

calculated

in

seconds,

between

injection

and

time

to

peak

tracer

concentration,

in

Protocol

I—sternal

IO

and

tibial

IO

injections

(n

=

7).

Mean

time

to

maximum

concentration

was

53

±

11

s

for

the

sternal

injection

compared

to

107

±

27

s

the

tibial

injection.

The

range

was

from

20

to

90

s

and

40

to

240

s

for

the

sternal

and

tibial

routes,

respectively

(p

=

0.03).

Time

to

half

(50%)

S.L.

Hoskins

et

al.

/

Resuscitation

83 (2012) 107–

112

109

Fig.

1.

The

two

upper

graphs

show

appearance

times

of

tracers

vs.

time:

Protocol-I

(tibial

IO

vs.

the

sternal

IO):

appearance

times

of

tracers

tibia

(Graph-A)

vs.

sternum

(Graph-C).

Concentrations

were

normalized

in

this

figure

to

the

maximal

concentration

in

order

to

better

visualize

time

differences

to

peak

concentration.

The

two

lower

graphs

show

dose

delivered

to

the

arterial

blood

calculated

as

dose

injected

(mg)

by

aortic

blood

concentration

(

␮g/ml)

for

the

same

protocol

tibia

(Graph-B)

and

sternum

(Graph-D).

maximum

concentration

was

22

±

3

s

using

the

sternal

route

and

50

±

8

s

for

the

tibial

route

(p

=

0.006).

Fig.

2

(A

and

C)

and

Table

2

show

the

appearance

times

of

trac-

ers

for

Protocol

II,

sternal

IO

and

central

venous

IV

injections

(n

=

6).

Mean

peak

time

to

the

maximum

tracer

concentrations

after

simul-

taneous

injections,

via

IO

and

central

vein

were

not

significantly

different

97

±

17

s

and

70

±

12

s,

respectively

(p

=

0.17).

Times

for

tracers

to

reach

their

50%

maximal

concentrations

were

36

±

4

s

for

sternal

IO

and

30

±

4

s

for

the

central

vein

routes

(p

=

0.06).

3.2.

Dose

delivered

Dose

delivered

was

determined

by

using

an

area

under

the

curve

analysis

(AUC)

for

aortic

concentration

divided

by

injected

dose.

Fig.

1

(B

and

D)

and

Table

3

show

the

doses

of

tracer

delivery

to

the

aortic

blood,

for

each

animal

of

Protocol

I,

calculated

as

AUC.

The

ratio

of

the

AUC

between

Protocol

I

(tibial

IO

vs.

sternal

IO)

is

a

measure

of

the

relative

effectiveness

of

dose

delivery

via

the

two

routes.

The

tibial

IO

route

delivered

less

dose

to

the

arterial

blood

or

Fig.

2.

The

two

upper

graphs

show

appearance

times

of

tracers

vs.

time:

Protocol-II

(sternal

IO

vs.

central

venous

IV):

appearance

times

of

tracers

central

venous

(Graph-A)

vs.

sternum

(Graph-C).

Concentrations

were

normalized

in

this

figure

to

the

maximal

concentration

in

order

to

better

visualize

time

differences

to

peak

concentration.

The

two

lower

graphs

show

dose

delivered

to

the

arterial

blood

calculated

as

dose

injected

(mg)

by

aortic

blood

concentration

(

␮g/ml)

for

the

same

protocol

central

venous

(Graph-B)

and

sternum

(Graph-D).

110

S.L.

Hoskins

et

al.

/

Resuscitation

83 (2012) 107–

112

Table

1

Appearance

times

in

seconds

from

injection

to

maximum

tracer

concentrations

and

half

(50%)

maximal

concentration.

Tibial

IO

vs.

sternal

IO

injection

Animal

(n

=

7)

Peak

concentration

*

50%Peak

concentration

§

Sternum

Tibia

Sternum

Tibia

86

80

110

36

57

21

90

150

22

68

18

80

240

25

85

34

20

40

15

25

35

30

100

18

50

39

20

50

22

33

36

50

60

13

35

Mean

53

107

22

50

SEM

11

27

3

8

CI

30–75

55–158

16–27

34–65

CI,

confidence

interval

(confidence

level

=

95%);

SEM,

standard

error

of

the

mean.

*

p

=

0.03

–

peak

concentration

–

tibia

vs.

sternum.

§

p

=

0.006

–

50%

peak

concentration

–

tibia

vs.

sternum.

65

±

5%

as

compared

with

the

sternal

route,

mean

AUC’s

difference

was

statically

significant

(p

=

0.003).

Fig.

2

(B

and

D)

and

Table

4

show

the

actual

values

and

ratio

of

the

AUC

between

Protocol

II

(sternal

IO

vs.

central

venous

IV).

The

ster-

nal

IO

route

was

86

±

10%

as

effective

as

the

central

venous

route

in

tracer

delivery,

although

the

mean

AUCs

were

not

significantly

different

(p

=

0.22).

4.

Discussion

To

the

best

of

our

knowledge

the

present

study

is

the

first

to

use

a

double

tracer

technique

to

assess

effectiveness

of

simultaneous

drug

delivery,

during

CPR

into

two

IO

sites.

Overall

the

study

demonstrated

that

the

intraosseous

(IO)

route

is

an

effective

means

of

delivering

drugs

during

CPR

for

tibia

and

sternum

IO

sites.

Peripheral

IV

lines

are

the

most

commonly

used

routes

for

drug

delivery

by

EMS

personnel.

An

absence

of

venous

blood

flow

and

low

pressure

during

cardiac

arrest

can

lengthen

the

time

to

obtain

peripheral

IV

access

and

delay

critically

needed

drug

ther-

apy.

Experienced

medics

can

achieve

IV

access

rapidly

under

ideal

conditions.

However,

prehospital

conditions

in

the

field

transport

to

hospital,

and

the

skill

levels

of

medics

can

vary

widely.

Clini-

cal

studies

have

shown

that

peripheral

IV

access

times

can

range

from

2

to

49

min.

6–8,15

The

success

rate

for

establishing

periph-

eral

IV

access

after

cardiac

arrest

and

difficult

IV

is

variable

and

ranges

broadly

between

30

and

75%

in

adult

6–8

patients,

with

lower

Table

2

Appearance

times

in

seconds

from

injection

to

maximum

tracer

concentrations

and

half

(50%)

maximal

concentration.

Sternal

IO

vs.

central

venous

IV

injection

Animal

(n

=

6)

Peak

concentration

50%Peak

concentration

Sternum

IV

Sternum

IV

87

100

50

36.4

24

89

70

50

34

23

105

60

50

29

28

95

110

110

52

48

110

70

90

28

27

92

170

110

38

36

Mean

97

70

36

30

SEM

17

12

4

4

CI

64–129

45–94

28–42

22–37

p

=

0.17

–

peak

concentration

–

sternum

vs.

central

venous

infusion.

p

=

0.06

– 50%

peak

concentration

–

sternum

vs.

central

venous

infusion.

CI,

confidence

interval

(confidence

level

=

95%);

SEM,

standard

error

of

the

mean.

Table

3

Dose

delivered

for

tibial

vs.

sternal

IO

injections

calculated

as

area

under

the

curve

for

aortic

concentration

␮g/ml

divided

by

dose

injected

(mg)

over

480

s

after

injec-

tion.

The

relative

effectiveness

of

the

two

routes

is

shown

as

a

ratio

of

the

area

under

the

curve

(AUC),

tibial

IO

divided

by

sternal

IO.

Relative

dose

delivered

of

tracers

(Tibial

IO

vs.

sternal

IO

injection—AUC

0–480

s

)

Animal

AUC

*

(

␮g

s/ml)

Ratio

Sternum

Tibia

Tibia/sternum

21

912

450

0.49

18

776

382

0.49

34

601

400

0.67

35

645

368

0.57

39

509

423

0.83

36

511

418

0.82

86

783

545

0.70

Mean

677

427

0.65

SEM

57

22

0.05

CI

564–789

383–470

0.6–0.7

CI,

confidence

interval

(confidence

level

=

95%);

SEM,

standard

error

of

the

mean.

*

p

=

0.003

– comparison

between

AUC

0–480

– tibia

vs.

sternum.

success

rates

for

the

pediatric

patient

population

18–65%.

16,17

A

prospective

study

of

successful

prehospital

IV

placement

in

583

patients

showed

that

the

success

rate

at

first

attempt

was

74%

(368

patients).

6

Physicians

have

long

sought

alternate

routes

for

the

rapid

administration

of

drugs

during

cardiac

emergencies,

circulatory

shock,

and

low

flow

states.

The

endotracheal

route

is

often

used

as

a

convenient

and

rapid

alternative

for

IV

delivery

of

selected

drugs.

However,

efficacy

of

endotracheal

delivery

of

drugs

is

controversial.

18,19

The

IO

route

provides

access

to

systemic

circu-

lation

via

the

bone

marrow

cavity

which

provides

a

noncollapsible

delivery

point

into

the

central

circulation

for

emergency

infu-

sions

and

for

drug

delivery

in

the

operation

room

setting.

20

Current

American

Heart

Association

guidelines

and

the

Interna-

tional

Resuscitation

Council

Guidelines

recommend

the

IO

route

as

first

vascular

access

in

pediatric

emergencies

such

a

cardiac

arrest.

13–21

For

adult

cardiac

arrest

IO

is

the

first

alternative

when

intravenous

access

is

delayed

or

impossible.

13,22

The

success

rate

when

IO

access

is

used

is

81–100%

8,10,11

and

the

time

to

establish

a

IO

line

varies

between

20

s

and

1.5

min.

8,10,23

The

most

common

adverse

effect

associated

with

IO

infusion

is

extravasation

and

this

complication

has

been

reported

in

12%

of

patients.

24

Compartment

syndrome,

osteomyelitis,

and

tibial

fracture

are

rare,

but

have

been

reported.

9,24,25

Table

4

Dose

delivered

for

sternal

IO

versus

central

venous

IV

injections

calculated

as

area

under

the

curve

for

aortic

concentration

␮g/ml

divided

by

dose

injected

(mg)

over

480

seconds

after

injection.

The

relative

effectiveness

of

the

two

routes

is

shown

as

a

ratio

of

the

area

under

the

curve

(AUC),

sternal

IO

divided

by

central

venous

IV.

Relative

dose

delivered

of

tracers

(sternal

IO

vs.

central

venous

IV

injection—AUC

0–480

s

)

Animal

AUC

␮g

s/ml

Ratio

IV

Sternum

Sternum/IV

89

694

589

0.85

105

855

939

1.10

95

879

805

0.92

110

854

783

0.92

92

956

923

0.97

87

934

385

0.41

Mean

862

737

0.86

SEM

38

87

0.10

CI

788–935

566–907

0.7–1.0

p

=

0.22

– comparison

between

AUC

0–480

–

sternum

vs.

central

venous

infusion.

CI,

confidence

interval

(confidence

level

=

95%);

SEM,

standard

error

of

the

mean.

S.L.

Hoskins

et

al.

/

Resuscitation

83 (2012) 107–

112

111

Voelckel

et

al.

showed

that

bone

marrow

blood

flow

was

reduced

by

70–80%

after

hemorrhage.

26

During

CPR

the

bone

mar-

row

flow

is

expected

to

be

lower

than

in

hemorrhagic

shock.

Sato

et

al.

and

Del

Guercio

et

al.

showed

in

dogs

and

humans,

respec-

tively

that

during

CPR

the

cardiac

output

is

only

approximately

20–30%

of

normal.

27,28

In

our

study

mean

aortic

appearance

times

to

the

peak

concentration

of

the

tracer

was

97

±

17

s

for

the

sternal

IO

route

which

was

not

statistically

significant

(p

=

0.17)

compared

to

70

±

12

s

for

central

venous

route.

Barsan

et

al.

showed

similar

result

in

dogs

with

mean

time

to

peak

times

for

central

venous

infusion

of

84

s

with

range

between

53

and

100

s.

29

Kuhn

et

al.

showed

that

the

peak

concentration

of

dye

obtained

with

central

venous

injection

of

indocyanine

green

during

CPR

in

humans

was

at

30

s.

However,

only

three

patients

were

included

on

the

study.

30

Emerman

et

al.

demonstrated

in

dogs

that

the

interval

of

central

venous

injection

to

first

appearance

of

the

indocyanine

green

dur-

ing

CPR

was

37

±

17

s.

31

Zuercher

et

al.

showed

mean

time

from

adrenaline

injection

to

peak

coronary

perfusion

of

60

±

6

s

when

the

drug

was

delivered

via

IO

vs.

43

±

4

after

IV

injection

during

CPR.

32

These

results

are

similar

to

our

finding

of

time

to

the

50%

peak

concentration,

i.e.

central

venous

(30

s),

sternal

(22

s—Protocol

I;

36

s—Protocol

II),

and

tibia

(50

s).

Some

factors

can

affect

the

appearance

times

and

the

dose

delivery

in

this

study.

One

is

that

sternum

is

located

closer

to

the

central

circulation

when

compared

with

the

tibia

location,

which

may

facilitate

the

faster

appearance

of

the

drug

on

the

systemic

circulation

when

the

drug

is

delivered

into

the

ster-

num.

Second,

there

is

a

difference

of

blood

perfusion

between

the

two

bones.

It

is

likely

that

the

sternum

perfusion

is

better

than

the

tibia

perfusion

and

this

may

facilitate

the

absorption

of

the

drug

to

the

systemic

circulation.

Gross

et

al.

showed

a

wide

heterogeneity

of

bone

blood

flow

comparing

hematopoietic

can-

cellous

bones

(red

marrow)

such

as

sternum,

rib,

ilium,

and

femur

epiphysis

(24

ml

min

−1

100

g

−1

)

vs.

nonhematopoietic

bones

(yel-

low

marrow)

such

as

tibia

and

mandible

(2

ml

min

−1

100

g

−1

).

The

authors

also

described

a

significant

decrease

in

blood

flow

and

an

increase

in

vascular

resistance

in

bone

during

hemorrhagic

hypotension.

33

A

key

point

during

the

CPR

maneuvers

is

the

quality

of

the

chest

compressions.

To

give

effective

chest

compression

is

impor-

tant

that

the

rescuers

or

the

devices

used

to

perform

the

CPR

push

hard

(

≥5

cm)

and

fast

(

≥100/min).

22

The

chest

should

be

allowed

to

recoil

freely

after

each

compression.

Besides,

approximately

equal

compressions

and

relaxation

times

should

be

used

and

interrup-

tions

in

chest

compressions

should

be

minimized.

If

these

chest

compressions

are

not

effective

all

the

circulatory

blood

flow

can

be

affected

including

the

bone

marrow

flow.

22,34

Any

anatomic

dif-

ference

between

the

animals

or

any

other

factor

that

impair

the

dynamic

of

the

chest

compressions

might

result

in

differences

in

cardiac

output

during

this

period,

which

might

consequently

delay

the

appearance

time

of

tracers

on

the

systemic

circulation.

The

dose

delivered

of

tracer

via

the

IO

route

was

similar

to

that

delivered

by

central

venous

route.

The

sternal

IO

route

delivered

86%

of

the

tracer

to

the

aorta

compared

with

central

vein

drug

deliv-

ery.

However,

in

one

animal,

the

ratio

between

sternum/central

venous

infusions

was

0.41

(

Table

4

).

When

we

exclude

this

outlier

data

point

from

the

analysis,

the

resultant

sternum

dose

delivered

via

the

route

was

95%

that

of

the

central

venous.

The

effectiveness

of

the

IO

sternal

route

for

drug

delivery

during

CPR

may

be

due

to

one

or

more

factors.

The

red

bone

marrow

of

the

sternum

could

pro-

vide

sufficient

blood

flow

for

rapid

delivery

of

drugs

to

the

great

veins.

Further,

chest

compressions

may

facilitate

the

drug

egress

out

of

the

marrow

and

into

the

vasculature.

35

Alternatively,

the

IO

delivery

of

tracer

may

be

independent

of

marrow

blood

flow.

It

may

be

that

a

1.5

ml

bolus

of

tracer

followed

by

the

1

ml

flush

used

in

our

study

is

sufficient

volume

to

advance

most

of

the

tracer

through

the

marrow,

out

of

the

injection

site

and

into

the

venous

circulation.

The

mean

dose

delivered

via

the

tibial

route

was

65%

and

53%

of

the

drug

delivery

via

the

sternum

and

central

venous

route,

respectively.

However,

even

for

the

tibial

route

the

half

maxi-

mal

concentrations

were

achieved

in

less

than

1

min.

Andropoulos

et

al.

used

HPLC

analysis

for

the

determination

of

tibial

adrenaline

delivery

during

CPR

in

lambs.

The

authors

determined

that

the

maximum

arterial

plasma

adrenaline

concentrations

were

similar

between

central

venous

and

tibial

IO

delivery.

However,

they

noted

reduced

appearance

time,

after

central

venous

administration

com-

pared

to

tibial

IO

injection

after

adrenaline

injection.

36

Our

measurements

of

appearance

times

and

doses

delivered,

coupled

with

an

additional

one

or

more

minutes

for

establishing

a

peripheral

IV,

suggest

that

even

when

using

the

slower

tibial

IO

route,

one

would

effectively

deliver

drugs

into

the

arterial

cir-

culation

during

CPR

in

a

shorter

time

than

the

time

needed

to

successfully

start

a

peripheral

IV.

As

such,

the

tibial

IO

route

is

both

an

efficacious

and

rapid

means

of

delivering

drug

therapy

dur-

ing

CPR.

The

size

of

the

saline

bolus

after

the

drug

infusion

may

also

have

an

important

role

on

the

time

for

maximum

concentra-

tion

of

the

dye.

If

we

had

used

a

larger

flush

the

effectiveness

of

the

IO

tibial

delivery

may

have

increased.

Wenzel

et

al.

demon-

strated

comparable

vasopressin

plasma

level

and

hemodynamic

variables

when

the

drug

was

delivered

both

by

the

intravenous

and

the

tibial

IO

routes

during

CPR.

However,

the

authors

infused

20

ml

of

saline

bolus

compared

with

1.0

ml

used

in

the

present

study.

37

Based

on

the

present

data,

we

recommend

that

sternal

IO

route

be

considered

as

the

first

choice

of

drug

delivery

during

CPR

when

IV

access

has

not

been

established,

and

that

the

tibial

IO

route

is

also

justified

as

second

choice.

The

practical

choices

of

which

route

to

use

in

adults

also

depend

on

which

IO

devices

are

avail-

able.

There

are

currently

6

adult

IO

devices

allowed

for

marketing

by

the

Food

and

Drug

Administration

(FDA).

This

includes

two

IO

devices

for

adult

sternal

access

(FAST1

(Pyng

Medical

Corp.,

Rich-

mond,

BC,

Canada)

and

Sternal

EZ-IO

(Vidacare

Corp.,

San

Antonio,

TX))

and

four

IO

devices

for

tibial

access

(SurFast

(Cook

Criti-

cal

Care,

Bloomington,

IN),

Jamishidi

(Baxter

Allegiance,

McGraw

Park),

Bone

Injection

Gun

(B.I.G.,

Waismed,

Houston,

TX),

EZ-IO

(Vidacare

Corp.,

San

Antonio,

TX)).

9,38,39

In

pediatric

patients,

stan-

dard

butterfly

needle,

spinal

needle,

and

pediatric

versions

of

adult

IO

needles

can

be

used.

Most

recently

the

humerus

has

been

sug-

gested

as

a

route

for

IO

delivery.

Further

work

will

be

required

to

assess

the

relative

success

of

this

route

vs.

the

sternal

and

the

tibial

route.

There

are

limitations

to

our

study.

First,

swine

are

not

humans

and

conclusive

extrapolation

to

human

patient

responses

cannot

be

made.

The

shape

of

the

pig

thorax

is

different

from

the

human

thorax.

In

pigs,

the

ventricles

are

positioned

in

the

center

of

the

tho-

racic

cavity,

surrounded

by

lung

tissues

on

all

sides.

In

humans,

the

right

ventricle

is

positioned

just

under

the

sternum.

This

anatomic

difference

makes

it

more

difficult

to

get

a

compression

effect

on

the

heart

of

pigs.

Chest

compressions

in

pigs

increase

intratho-

racic

pressure

(thoracic

pump

mechanism),

which

in

turns

affects

the

heart.

In

humans

we

have

not

only

the

thoracic

pump

effect

but

also

the

direct

heart

pump

mechanism

affecting

the

heart

by

chest

compression.

34

Moreover,

we

did

not

measure

the

plasma

concentrations

of

adrenaline.

We

used

dye

tracers

as

a

surrogate

of

drug

delivery

in

place

of

the

biologically

active

drug.

However,

measurement

of

adrenaline

would

preclude

comparison

of

simulta-

neous

injections.

The

significant

variability

of

cardiac

output

during

CPR

results

in

an

animal

to

animal

variability

of

time

to

peak

con-

centration

and

dose

delivered;

while

simultaneous

2

tracer

paired

studies

provides

for

great

precision

for

comparing

differences.

Fur-

ther,

high

background

levels

of

endogenous

adrenaline

during

CPR

112

S.L.

Hoskins

et

al.

/

Resuscitation

83 (2012) 107–

112

make

precise

assessment

exogenous

drug

epinephrine

impossible.

Our

study

suggests

that

either

bone

marrow

blood

flow

or

the

vol-

ume

of

injectate,

or

both,

are

sufficient

for

tracer

delivery

through

the

emissary

veins

to

the

superior

vena

cava.

We

studied

young

pigs

with

healthy

hearts

and

peripheral

vessels,

while

clinical

ventric-

ular

fibrillation

occurs

largely

in

older

patients

with

some

amount

of

peripheral

artery

disease.

The

pig

is

the

most

often

used

animal

model

of

cardiac

arrest

and

CPR.

26,37

Finally,

data

on

tibial

IO

injec-

tions

in

swine

with

their

short

legs

may

not

be

comparable

to

that

of

adult

humans

with

longer

legs

farther

from

the

heart.

Blood

flow

in

the

leg

and

bone

marrow

cavities

below

the

diaphragm

could

be

less

in

humans

than

in

pigs

during

CPR.

5.

Conclusions

Both

tibial

and

sternal

IO

routes

are

an

effective

means

of

deliv-

ering

life

saving

drugs

during

CPR.

Dye

tracers

delivered

via

tibial

IO

or

sternal

IO

routes

of

anesthetized

swine

reached

maximal

con-

centrations

in

the

arterial

blood

during

CPR

in

less

than

2

min

with

both,

a

faster

and

a

greater

dose

delivered

using

the

sternum

route

than

with

the

tibial

route.

Sternal

IO

and

central

venous

routes

are

not

different

considering

pharmacokinetics

of

tracers

during

CPR

in

swine.

Conflict

of

interest

Dr.

Kramer

is

an

inventor

on

patents

for

intraosseous

technolo-

gies

and

a

compensated

consultant

to

Vidacare

2007–2010.

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