taken to find out whether "Dramamine" dominal, orthopedic

THE

USE

OF

"DRAMAMINE"

IN

THE

PREVENTION

OF

POSTOPERATIVE

NAUSEA

AND

VOMITING*

W.

BREWSTER

WOLFE,

M.D.

MASPETH,

LONG

ISLAND,

N.

Y.

FROM

THE

ANESTHESIOLOGY

DEPARTMENT,

ST.

LOUIS

UNIVERSITY

GROUP

OF

HOSPITALS,

ST.

LOUIS,

MISSOURI

SINCE

THE

INITIAL

REPORT

by

Gay

and

Carliner12

13

concerning

the

successful

use

of

B-dimethylaminoethyl

benzehydril

ether

8-chlorotheophyllinate

("Dramamine")

in

the

prevention

and

treatment

of

seasick-

ness,

other

reports

have

appeared

evaluat-

ing

this

drug

in

the

prevention

or

treatment

of

air-sickness,7'

32

nausea

vomiting

of

preg-

nancy,6

radiation

sickness,1

migraine,3'

19

Meniere's

syndrome,33

vertigo,4

35

and

ves-

tibular

disturbances.'5

In

addition,

several

authors

have

reported

its

apparent

useful-

ness

in

the

prevention

or

treatment

of

the

nausea

and

vomiting

following

cataract

extractions,26'

31

fenestration

operations,5

or

surgery23'

26

in

general.

The

last

mentioned

reports

were

in

the

form

of

correspondence,

and,

as

yet,

there has

been

no

large

con-

trolled

series

of

cases

reported

concerning

Dramamine

and

postoperative

nausea

and

vomiting.

The

following

study

was

under-

taken

to

find

out

whether

"Dramamine"

could

be

of

use

in

the

prevention

or

lessen-

ing

of

the

postoperative

nausea

and

vomit-

ing

in

an

unselected,

controlled

group

of

patients

on

an

active

surgical

service

han-

dling

all

types

of

surgery.

MATERIAL

AND

METHODS

The

material

consisted

of

250

private

patients

operated

upon

over

a

period

of

sev-

eral

months.

Pediatric

and

non-cesarean

ob-

stetric

patients

were

not

included

in

the

series,

but

the

patients

were

otherwise

unse-

lected

and

represent

a

fairly

typical

cross-

section

of

a

busy

private

hospital

surgical

service.

The

surgery

was

mainly

general,

ab-

dominal,

orthopedic,

gynecologic,

and

ENT

surgery,

with

a

lesser

number

of

thoracic,

neurosurgical,

and

cesarean

obstetric

pa-

tients

in

addition.

Of

the

250

patients,

185

were

female

and

65

male,

slightly

less

than

a

3:1

predominance

of

females.

Two

hun-

dred

and

twenty-two

patients

had

but

a

sin-

gle

type

of

anesthesia

during

the

operation,

24

patients

had

two

different

types

of

anes-

thesia,

and

four

had

three,

giving

a

total

of

282

individual

anesthesias

evaluated.

(Table

I).

No

patient

had

more

than

a

sin-

gle

operation

included

in

the

series.

Anes-

thesias

administered

consisted

mainly

of

spinal

(procaine)

or

cyclopropane,

with

a

fewer

number

of

intravenous

sodium

Pen-

tothal

alone,

Pentothal

and

nitrous

oxide,

or

ether

(Table

II).

A

considerable

number

of

the

patients

had

small

quantities

of

in-

travenous

sodium

Pentothal

for

the

purpose

of

induction,

but

these

patients

were

not

included

under

the

Pentothal

group

unless

it

was

the

only

anesthetic

agent

used.

Cau-

dal

and

local

anesthetics

were

not

included

in

the

series,

since

there

is

such

a

low

inci-

dence

of

nausea

and

vomiting

following

their

use.

Almost

all

the

patients

were

given

preoperative

medication,

usually

mor-

phine

sulphate

and

atropine

sulphate;

many

received

additional

opiates

or

analgesics

postoperatively.

Initially,

patients

were

put

alternately

into

groups,

one

receiving

Dramamine,t

f

Kindly

supplied

by

G.

D.

Searle

&

Co.,

Chi-

cago,

Ilinois.

261

*

Submitted

for

publication

November,

1951.

W.

BREWSTER

WOLFE

the

other

serving

as

control.

Later

for

con-

venience,

Dramamine

was

given

on

alter-

nate

days.

Patients

in

the

Dramamine

series

received

100

mg.

orally

at

the

time

of

their

preoperative

medication,

and

an-

other

100

mg.

postoperatively

as

soon

as

swallowing

was

possible.

Control

patients

were

given

nothing

except

their

regular

pre-

and

postoperative

medication.

The

Drama-

mine

patients

were

not

told

the

type

of

medication,

nor

the

reason

for

administra-

tion.

All

patients

were

seen

four

to

ten

hours

after

operation

and

they,

nurses,

and

relatives

were

questioned

objectively

as

to

the

occurrence

of

nausea

and

vomiting

either

during

(spinal)

or

after

operation.

(An

incidental

finding

of

interest

was

the

fact

that

a

considerable

number

of

patients

did

not

become

sick

postoperatively

until

they

received

a

meal

or

oral

intake

of

some

sort,

thus

necessitating

questioning

of

the

patient

as

late

as

possible

after

operation.)

The

relevant

data

were

recorded

at

once,

and

results

evaluated

later.

The

evaluation

was

done

without

knowledge

of

whether

the

patient

was

in

the

Dramamine

or

con-

trol

series.

The

few

patients

who

died

soon

after

operation

or

who

remained

uncon-

scious

for

a

long

time

after

operation,

those

who

required

postoperative

gastric

suction,

and

those

who

did

not

receive

the

full

amounts

of

Dramamine

mentioned

above

were

deleted

from

the

series-a

total

of

34

patients.

RESULTS

Table

III

tabulates

the

results

according

to

total

anesthetics

used;

i.e.,

when

two

or

more

anesthetics

were

used

on

the

same

pa-

tient,

the

results

are

included

under

each

anesthetic.

Results

were

also

tabulated,

but

not

shown,

of

the

same

breakdown

accord-

ing

to

total

patients,

patients

receiving

but

one

anesthetic,

and

patients

receiving

more

than

one

anesthetic;

results

of

the

former

two

groups

were

almost

identical

to

those

in

Table

III,

while

the

latter

group

was

too

small

for

comparison.

Results

were

evaluated

as

follows:

Excellent-no

nausea,

no

vomiting

Good-slight

nausea,

no

vomiting

Fair-moderate

nausea

or

slight

vomiting

Poor-more

than

moderate

nausea

or

more

than

slight

vomiting

The

criteria

for

the

"excellent"

(denoting

no

distress

at

all)

and

for

the

"poor"

(denoting

severe

distress)

are

probably

considerably

more

sharply

defined

than

those

for

"good"

and

"fair"

(denoting

degrees

of

moderate

distress)

and

as

such

are

probably

more

significant.

The

total

group

of

patients

receiving

Dramamine

had

more

"excellent"

results

(56

per

cent

as

compared

to

38

per

cent)

and

fewer

"poor"-

results

(18

per

cent

as

compared

to

40

per

cent)

than

the

total

group

of

control

patients.

Or,

combining

the

"excellent"

and

the

"good"

results,

74

per

cent

of

the

Dramamine

group

had

favor-

able

results

as

against

55

per

cent

of

the

control

group.

Upon

breaking

down

the

figures

according

to

the

anesthetic

agent

used,

it

can

be

seen

that

the

patients

re-

ceiving

spinal

anesthesia

fared

no

better

during

the

operation

if

they

had

had

Dram-

amine,

and

after

operation

fared

better

only

in

that

they

had

fewer

"poor"

results.

Cyclopropane

patients,

on

the

other

hand,

seem

to

have

been

helped

by

Dramamine,

there

being

a

reversal

of

the

"excellent"

and

"poor"

results

in

the

control

and

Drama-

mine

groups.

The

Pentothal

and

"other"

groups

are

too

small

for

definite

evaluation,

but

in

these,

again,

the

only

significant

fact

appears

to

be

that

there

were

fewer

"poor"

results

in

the

Dramamine

group.

Finally,

it

should

be

noted

that

in

the

control

group

there

were

three

cases

of

severely

pro-

tracted

"pernicious"

postoperative

vomit-

ing,

while

there

were

none

in

the

Drama-

mine

group.

Dramamine

produced

no

defi-

nite

toxic

effects,

but

their

presence

would

have

been

difficult

to

ascertain

because

of

262

Annals

of

Surgery

A

u

g

u

s

t,

1952

Volume

136

"DRAMAMINE"

IN

PREVENTION

OF

POSTOPERATIVE

NAUSEA

Number

2

the

underlying

pathologic

conditions,

oper-

ation,

and

anesthesia

coincident

with

the

Dramamine

administration.

STATISTICAL

EVALUATION*

Lack

of

controls

in

past

studies

of

this

type

have

resulted

in

the

enthusiastic

sup-

port

of

agents

proved

later

by

well-con-

trolled

studies

to

be

of

no

use.14

The

prin-

cipal

reason

for

the

necessity

of

controls

is

the

degree

to

which

the

incidence

and

severity

of

postoperative

nausea

and

vom-

iting

is

influenced

by

a

considerable

num-

ber

of

'variables,

some

of

which

are

as

fol-

lows:

(1)

age,

sex,

and

emotional

stability

of

the

patient,

(2)

pathology

present;

(3)

type

and

duration

of

operation;

(4)

sur-

geon;

(5)

pre-

and

postoperative

medica-

tion

and

oral

intake;

and

(6)

anesthesia

and

anesthetist.

For

example,

statistical

analy-

sis

in

this

study

revealed

that

(a)

female

patients

tended

to

have

more

postoperative

nausea

and

vomiting

than

males;f

and

(b)

patients

receiving

cyclopropane

anesthesia

tended

to

have

more

postoperative

nausea

and

vomiting

than

those

receiving

spinal

anesthesia;

while

the

latter

had

more

than

those

receiving

sodium

Pentothal.

Thus,

while

the

results

in

this

study

on

the

whole

show

a

difference

between

the

Dram-

amine

and

control

groups,

they

do

not

nec-

essarily

indicate

that

Dramamine

was

re-

sponsible.

A

perfectly

controlled

series

in

which

the

various

factors

in

the

Dramamine

and

the

control

groups

were

exactly

the

same was

impossible.

However,

one

way

of

reducing

the

variable

factors

to

some

extent

was

by

selecting

comparable

small

sets

of

patients

(e.g.,

same

sex,

operation,

and

anesthesia)

and

judging

in

these

sets

whether

the

*

My

gratitude

is

expressed

to

Dr.

D.

Main-

land,

Professor

of

Bio-Statistics,

New

York

Univer-

sity,

for

the

interest

and

time

which

he

gave

to

this

analysis.

t

Sex

distribution

in

control

and

Dramamine

groups

was

as

follows:

Control-88

female,

38

male;

Dramamine-87

female,

27

male.

Dramamine

or

control

groups

had

the

larger

number

of

favorable

("excellent"

or

"good"

in

Table

III)

results,

as,

for

exam-

ple,

female

patients

having

had

hernior-

raphy

with

spinal

anesthesia:

Results

good

poor

Control

1

1

Dramamine

3

2

The

dramamine

patients

had

a

higher

percentage

(60

per

cent)

of

favorable

re-

sults

than

the

control

(50

per

cent)

group.

TABLE

I.

Dramamine

Control

Total

Number

of

patients

.............

120

130

250

Number

of

patients

receiving

but

one

type

of

anesthesia

.........

101

121

222

Nuimber

of

patients

receiving

more

than

one

type

of

anesthesia*.

..

19

9

28

*

Twenty-four

patients

received

two

types

of

anesthesia,

four

received

three

types-222

plus

24x2

plus

4x3

=282

anesthetics.

The

results

of

26

such

small

samples

utiliz-

ing

172

of

the

patients

were

as

follows:

Number

of

Proportion

of

good

results

samples

Higher

in

the

Dramamine

group

19

Higher

in

the

control

group

2

No

difference

5

Such

a

difference

from

a

50:50

ratio

would

occur

by

chance

alone

only

once

in

5000

times.

Another

method

of

evaluation

of

the

groups

is

to

subtract

the

differences

in

percentage;

e.g.,

in

the

above

sample

60

per

cent

(Dramamine)

minus

50

per

cent

(control)

equals

plus

(in

favor

of

Drama-

mine)

10

per

cent.

Such

percentage

differ-

ences

varied

from

plus

100

per

cent

to

minus

100

per

cent,

but

the

mean

was

plus

22

per

cent.

Thus,

this

method

likewise

gives

sup-

port

to

the

fact

that

the

observed

differences

were

due

to

Dramamine,

but

is

not

abso-

lutely

conclusive

because

factors

such

as

age

of

the

patient,

duration

of

operation,

and

medication

were

not

included

in

the

sampling.

263

W.

BREWSTER

WOLFE

DISCUSSION

The

causes

for

postoperative

nausea

and

vomiting

are

numerous.

Gastro-intestinal

irritation

or

trauma,

sudden

hypotension,2'

anoxia,2'

and

emotional

disturbances

are

some

of

the

known

factors

that

either

di-

rectly

or

indirectly,

through

the

"vomiting

center,"

cause

surgical

patients

to

have

common

gastro-intestinal

symptoms

which

at

best

are

inconvenient

and

at

the

worst

lead

to

serious

complications.24

The

type

of

anesthesia

and

the

particular

agent

itself,

either

through

the

above

or

through

un-

known

factors,

also

seems

to

influence

the

incidence

of

postoperative

nausea

and

vom-

iting

considerably;

for

example,

most

will

agree

with

Kaye's

findings'8

that

nausea

and

vomiting

are

more

prone

to

occur

after

ether

than

after

nitrous

oxide

anesthesia.

However,

as

Dripps'0

has

pointed

out

in

a

recent

article

concerning

research

in

anes-

thesiology,

the

actual

incidence

with

each

particular

anesthetic

agent

is

not

known.

Likewise,

different

types

of

surgery'8

and

different

operations29

have

considerable

in-

fluence

upon

postoperative

sickness.

Finally,

the

factor

probably

most

often

overlooked

in

any

evaluation

of

postoper-

ative

nausea

and

vomiting

is

the

type22

and

amount29

of

pre-

and

postoperative

medica-

tion.

Morphine

appears

to

be

particularly

important

in

this

respect,8

9

27

30

a

fact

brought

out

clearly

by

Nardick

and

Steele.22

These

authors

found,

in

a

study

of

472

operations,

a

27

per

cent

incidence

of

post-

operative

sickness

when

morphine

medica-

tion

was

used

as

compared

to

4

per

cent

when

Demerol

was

used.

The

presence

of

so

many

different

causa-

tive

factors

makes

it

likely

that

no

one

agent

will

be

able

to

eliminate

postoperative

nausea

and

vomiting

completely.

Also,

if

a

drug

does

appear

to

cause

a

significant

de-

crease

in

the

postoperative

nausea

and

vomiting,

these

same

factors

make

it

diffi-

cult

to

ascertain

exactly

how

the

drug

af-

fects

the

decrease.

Such

is

the

case

with

Dramamine,

which

is

a

theophylline

ester

of

the

antihistamine

"Benadryl."

There

ap-

pears

to

be

good

evidence

that

the

whole

Dramamine

molecule

(dimenhydrinate)

is

not

necessary

for

its

action,

the

Benadryl

portion

(diphenhydramine)

being

the

ac-

tive

component.

White

and

his

co-workers34

have

shown

that

while

dimenhydrinate

is

able

to

prevent

apomorphine-induced

eme-

sis

in

dogs,

the

theophyllinate

portion

has

no

effect

and

the

diphenhydramine

alone

is

able

to

reproduce

the

results

of

the

dimen-

hydrinate.

Furthermore,

others

have

re-

ported

the

probable

efficacy

of

Benadryl

in

the

nausea

and

vomiting

of

pregnancy,2

TABLE

II.

Type

Anesthesia

Dramamine

Control

Total

Spinal

(procaine)

...............

44

45

89

Cyclopropane

..................

49

58

107

Pentothal

(alone)

...............

35

24

59

Others*

.......................

15

12

27

Total

.......................

143

139

282

*

Nitrous

oxide

and

Pentothal,

17;

ether

10.

motion

sickness,7

streptomycin

therapy,1"

uremia,20

and

inhalation

anesthesia.20

The

diphenhydramine

probably

works

by

its

de-

pressant

action

on

the

central

nervous

sys-

tem,

a

not

uncommonly

observed

side-reac-

tion

of

this

anti-histaminic

agent.

This

de-

pression

may

be

carried

out

by

a

selective

anti-cholinergic

action,

according

to

Him-

wich

and

his

co-workers.'7'

28

Also

of

im-

portance

in

its

action

is

the

fact

that

Dram-

amine

has

been

shown

to

depress

markedly

labyrinthine

function.'6

Rubin

and

Win-

ston25

found

that

the

"vestibular

stimulation

following

the

administration

of

morphine

sulphate

resulted

in

marked

increase

of

nausea

and

vomiting,"

and

that

symptoms

were

prevented

or

relieved

by

Dramamine.

That

much

vestibular

stimulation

appears

in

patients

after

operation

is

difficult

to

imagine,

but

it

is

a

common

finding

that

patients

often

do

get

sick

when

they

are

moved

or

if

they

sit

up

after

operation.

The

fact

that

a

great

majority

of

the

patients

in

264

Annals

of

Surgery

August,

1952

Volume

136

"DRAMAMINE"

IN

PREVENTION

OF

POSTOPERATIVE

NAUSEA

Number

2

this

series

received

morphine

sulphate

may

explain

the

unexpectedly

high

incidence

of

nausea

and

vomiting

in

the

patients

receiv-

ing

only

sodium

Pentothal

as

anesthesia.

The

correlation

of

the

morphine

medication

and

incidence

of

the

postoperative

sickness

is

not

reported

in

this

paper.

Thus,

summarizing,

it

can

be

postulated

that

much,

but

not

all,

postoperative

nausea

and

vomiting

is

predisposed

or

caused

by

excitation

of

either

or

both

the

"vomiting

center"

and

the

labyrinth,

the

latter

possibly

Dramamine

patients

had

severe

nausea

or

vomiting,

as

compared

to

40

per

cent

of

the

control

cases.

Statistical

analysis

revealed

that

the

results

could

not

be

considered

conclusive,

but

were

strongly

suggestive

that

Dramamine

was

of

value.

3.

It

is

concluded

that

Dramamine

re-

duces

postoperative

nausea

and

vomiting,

particularly

nausea

and

vomiting

of

severe

degree.

However,

the

reduction

is

not

great

enough

to

warrant

its

routine

use

on

a

general

surgical

service.

TABLE

III.

Results

Dramamine

(D)

Excellent

Good

Fair

Poor

or

Total

Type

Anesthesia

Control

(C)

No.'

%

No.'

%

No.'

%

No.0

%

Patients

Spinal

(During

operation)

D

26

(60%)

10

(23%)

1 (

4%)

6

(13%)

43

C

29

(65%)

10

(22%)

0

6

(13%)

45

Spinal

(After

operation)

D

24

(54%)

10

(23%)

4

(10%)

6

(13%)

44

C

25

(55%)

7

(15%)

0

13

(30%)

45

Cyclopropane

D

27

(55%)

6

(12%)

5

(10%)

11

(23%)

49

C

13

(22%)

9

(15%)

5

(

9%)

31

(54%)

58

Pentothal

D

19

(54%)

8

(23%)

2

(16%)

6

(17%)

35

C

11

(46%)

6

(25%)

1

(

4%)

6

(25%)

24

Others

D

10

(67%)

2

(13%)

0

3

(20%)

15

C

4

(33%)

2

(17%)

1

(

8%)

5

(42%)

12

Total

D

80

(56%)

26

(18%)

11

(

8%)

26

(18%)

143

C

53

(35%)

24

(17%)

7

(

5%)

55

(40%)

139

sensitized

by

morphine

sulphate

medica-

tion.

The

diphenhydramine

portion

of

Dramamine

may

depress

this

excitation

and

thus

cause

a

decrease

in

the

amount

and

severity

of

postoperative

nausea

and

vomiting.

SUMMARY

AND

CONCLUSIONS

1.

An

unselected

group

of

250

patients

from

an

active

surgical

service

was

divided

into

two

approximately

equal

groups:

one

received

Dramamine

before

and

after

oper-

ation,

the

other

served

as

a

control.

The

two

groups

were

then

compared

as

to

the

incidence

and

severity

of

postoperative

nausea

and

vomiting.

2.

Fifty-six

per

cent

of

the

Dramamine

cases

had

no

nausea

or

vomiting

whatso-

ever,

as

compared

to

38

per

cent

of

the

control

cases.

Eighteen

per

cent

of

the

My

appreciation

is

expressed

to

Dr.

Joseph

McNearney,

Assistant

Professor

Anesthesiology,

St.

Louis

University

School

of

Medicine

for

his

advice

and

encouragement;

to

Dr.

L.

M.

Lawton,

Dr.

B.

Duval,

and

Dr.

Fitzgerald

for

their

assist-

ance

in

compiling

data;

and

to

the

nursing

staff

of

the

surgical

wards

of

St.

Mary's

Hospital.

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266