Methemoglobinemia Induced by a Topical Anesthetic Spray (Cetacaine)

Methemoglobinemia Anesthetic William

W.

In two

Spray

Douglas,

seriously

M.D.;

ill

a topical

anesthetic

both

cases

presence

gested

by

tension measured

he

Virgil

cyanosis spray

developed

(Cetacaine) the of

cally

development

ill patient

The

of

usually

In

used.

was

sugas

re-

in

the

a criti-

presence

of

arterial hypoxemia or a state of low cardiac output. The assessment of cyanosis in such a patient properly requires arterial blood gas analysis. Within the past

three

years,

covered the the

methemoglobinemia

in two

critically

development administration

(Cetacaine). was suggested studies, which arterial

oxygen

oxygen

pressure

In

addition,

of

(SaO2)

(Pa02)

was

when

dis-

patient followed spray

the

higher

concentration

of

In order to of oxygenated

containing were

than

normal.

read

elucidate and

indilow, and off the

these partially

different concentrations prepared and analyzed oximeter

spectrophotometric

arterial

hemoglobin

instrument was spuriously of carboxyhemoglobin

zero. samples

duced blood methemoglobin

obreof the

by

(Co-Oximeter

model

Laboratories).

Instrumentation CASE

A and

other

man

left

fentanyl,

#{176}Fromthe

Mayo

Manuscript tember 22.

underwent

hemidiaphragm on

drugs

thiopental, Minn.

different

described.

received

Reprint requests: Rochester, Minnesota

received

repair Oct the

August

Section

55901

CHEST, 71: 5, MAY, 1977

1972.

included

and

d-tubocurarine, Foundation,

11, 1975;

revision

of

Anesthetic agents

operation

Mayo

and

hernia

traumatic of a

9,

during

droperidol, Clinic

oximeter

concentrations

Physicians

of

should

to blood

con-

are

methemoglobin

administering

(Cetacaine)

opment

be aware

anesthetic

topical

this

of the

possible

devel-

of methemoglobinemia.

cinylcholine.

On Oct

left

lung

formed

with

a topical the

11, atelectasis

of the

developed. Bronchoscopic the “liberal”

anesthetic

(Cetacaine).

patientwas

was

analysis

done

lobe

severely

per-

cyanotic.

administration mechanical

tube.

before and

of the

was

of the pharynx by use of At the conclusion of

preparaton

spray

procedure, the

lower

examination

The cyanosis persisted despite cent oxygen by a pressure-preset (Bird Mark VII) via a nasotracheal

of

Arterial

100 perventilator blood gas

bronchoscopic examina-

after

1). Because of the discrepancy between the Pa02 and SaO,, arterial blood gas analysis was repeated (Table 1). Methemoglobinemia was suspected. An aliquot of the patient’s blood was exposed to air and not did become tion

(Table

red.

An

on

the

of

a

corbic

aliquot

of

blood

was

following day, 1

percentsolution)

acid

gone.

(250 Levels of

saved

for

and

60

was

given

methemoglobin mg

of

assay methylene blue

intravenously

tenWithinminutes the cyanosis

mg). arterial blood

gases

(6

with

as-

was

analyzed again

were

(Table 1). Drugs taken during the 48hours before the development of methemoglobinemia included meperidine, atropine, gentarnicin, diazepam, potassium chloride, aspirin, and a bisacodyl suppository. Each of these drugs had been administered for more than 24 hours before the onset of methemoglobinemia, with the exception of the bisacodyl suppository, which was given 131 hours before bronchoscopic examination. The patientwas dismissed on Dec 10, 1972. Neither dinical

nor

during

the

CASE

77-year-old the

of the spectrophotometric

biochemical evidence

remainder

of

of the

methemoglobinemia

patient’s

recurred

hospitalization.

REPORTS

1

CASE

of

In each

methemoglobinemia of a topical anesthetic

saturation

cated by the the saturation

182,

ill patients.

been

The presence of methemoglobinemia on the basis of arterial blood gas showed a decrease in the apparent

the

scale below servations,

has

sponses taining spray

oxygen

hemoglobin, characteristic

cyanosis

implies

M.D.

shortly

was

arterial

between

and the oxygen saturation spectrophotometrically.

sudden

F. Fairbanks,

of methemoglobinemia

a discrepancy

by a Topical

(Cetacaine)* and

patients,

after

the

Induced

Publications,

suc-

Rochester,

accepted

Mayo

Sep-

Clinic,

An

2 80-year-old

woman

underwent

exploratory

Sept

days’

METHEMOGLOBINEMIA

26,

because 1974,

duration. Levels

of acute

of arterial

abdominal

laparotomy

of three analyzed prior to surgery (Table 1). Prior to surgery, the patient received infusions of saline solution and potassium chloride intravenously, and meperidine and atropine were given for premedication. Oral endotracheal intubation was performed after the pharynx had been sprayed with a “usual” amount of a topical anesthetic (Cetacaine). Immediately after intubation and beforeinduction of anesthesia, the patient beon

blood

gases

pain

were

INDUCED BY TOPICAL ANESTHETIC SPRAY

581

ml

Table

0/Arterial

1-Levels

Blood

Gases

and

Methemoglobulin

Sa02,

globin,

*

HemoCase,

Date,

and

Time

Case I 10/11/72,

Pa02,

percent

9:45

(Before

F1o2,

mm

PaCO2,

Hg

mm

pH

Hg

percent

gm/100

Methemoglobin,

ml

gm/100

ml

Cyanosis

Comment**

AM

bronchoscopy)

.

67

.

38

7.52

96.6

12.5

.

.

T-piece,

-

70 percent 10/11/72, (After

7:55

PM

bronchoscopy)t

10/11/72,

9:35

10/11/72,

11:50PM

(After Case

PM

methylene

blue)

96

243

43

7.44

73.6

8.7

4.45

+

MAV

(Bird)

98

227

38

7.51

80.3

9.2

.

.

+

MAV

(Bird)

170

38

7.51

99.8

13.8

.

..

-

MAV

(Bird)

84

40

7.45

94

16.1

.

.

.

-

.

+ +

MAV

(MA-i)

MAy

(MA-i)

..

.

2

9/25/74,

2:30

PM

(Before

surgery)

9/25/74,

10:15

21 PM

150

28

7.30

62

6.5

.

.

.

100

250

30

7.24

71

10.5

.

.

.

AM

100

209

33

7.34

77

11.9

2.52

+

MAV

(MA-i)

7:50

AM

100

95

29

7.45

89

14.6

..

+

MAV

(MA-i)

9/26/74,

9:50

AM

28

7.46

91

12.5

1.24

+

MAV

(MA-i)

9/26/74,

11:30

27

7.42

94

15.3

0.10

-

T-piece,

(After

surgery)

70

9/25/74,

11:30

9/26/74,

1:30

9/26/74,

(After

PM

208

98

.

AM

methylene

blue)

II

.

.

83

.

70 percent *F1o2,

Fractional

concentration

PaD2,

as measured

Sa02,

as measured

**T piece assisted

oxygen,

oximeter

spontaneous

with 50-mI

(Bird

Mark

Anesthesia

droperidol, and

in inspired gas (expressed as percent), PaCO2, arterial carbon dioxide tension,

“stack”

VII);

and

was

induced

thiopental,

and

while

intubated,

on expiratory MAV

T-piece

(MA-i)

with a

the

mixture

use

at

use

of

5:00

of pressor

during

(Table

1).

At

10:50

still severely

AM

agents. Levels of the night and on the

cyanotic.

arterial on

morning

after

Because

of the

blood

the

gases

following

surgery, persistent

were

was

discrepancy

between the PaO. and SaC)0, a diagnosis of methemoglobinemia was suggested, and the patient was given 50 mg of methylene blue (5 ml of a 1 percent solution) intravenously. Within a few minutes the cyanosis resolved. Values for arterial blood gas levels were obtained 40 minutes later (Table 1). The patient remained in irreversible shock and died at 7 PM on Sept 27, 1974.

588

DOUGLAS, FAIRBANKS

from

oxygen analyzer; electrode; and

by Severinghaus

mechanically

assisted Methylene Methylene

PM.

humidifier MAV

(Puritan-Bennett)

(Bird

)indicates

ventilation

at 10:00 at 10:50

set to

mechanically

(Puritan-Bennett

blue given blue given

of

morning

the patient

gas

flow set at 10 L/min;

PM.

nitrous

oxygen. During dexamethasone, digoxin, plasma lactate solution,

analyzed

polarigraphic

by

as measured

with inspired

and

indicates at 7

the operation, the patient also mephentermine, pancuronium protein intravenously, dextrose in and an infusion of isoproterenol. At surgery, the patient was found to have chronically distended small and large intestines, which were markedly pale and ischemic but not infarcted. It was elected not to attempt resection of the bowel or a procedure for revascularization, ‘and the abdomen was closed. After the operation the patient remained cyanotic. For several hours after the operation, the patient received sodium bicarbonate, calcium gluconate, and methylprednisolone sodium succinate intravenously. Later during the night, she was given gentamicin, an aqueous solution of penicillin, and an infusion of dopainine. The patient was hypotensive despite adequate volume replacement and the received bromide, Ringer’s

as measured

(CO-Oximeter).

ventilation

with topical anesthetic spray (Cetacaine) after topical anesthetic spray (Cetacaine)

cyanotic.

oxide

electrode;

indicates

ventilation

tBronchoscopy §Intubation

fentanyl,

of oxygen

Clark

by spectrophotometric

70 percent,

deliver 70 percent

came

by

MA-i).

PM. AM.

METHODS Concentrations of methemoglobin were measured spectrophotometrically.1 2 Unfortunately, in our present cases, the measurements were made several hours after the specimens of blood were drawn, and the actual concentrations of methemoglobin may have been higher than those reported. The topical anesthetic spray (Cetacaine) was added to blood from our first patient on the day after administration of methylene blue, as well as to the blood from an otherwise normal patient. Neither sample developed the color characteristic of methemoglobinemia, and spectrophotometric analysis of the first of these samples showed no methemoglobin. Hemoglobin electrophoresis of the blood of each of our two patients showed no abnormality; no hemoglobin M was detected. Assays for reductase linked to reduced nicotinamideadenine dinucleotide (NADH) were performed in case 1 by the method of Hegesh et al3 and revealed 4.2 units/gm of hemoglobin (normal, 3.4 ± 0.5 units/gm of hemoglobin, [mean ± SD)). Three bottles of the topical anesthetic spray (Cetacaine) were available in our supply, one of which had been used for topical anesthesia in case 1. The three bottles were analyzed by gas-liquid chromatographic studies for the relative concentrations of the active ingredients and for the presence of a possible degradation compound. All three samples had identical patterns. (Determinations were performed in the Metals and Toxicology Laboratory of Mayo

Clinic,

under

the

supervision

of

John

T.

McCall,

Ph.D.).

CHEST, 71: 5, MAY, 1977

The rate of delivery of benzocaine for a bottie of this topical anesthetic spray (Cetacaine) was estimated by spraying into containers, dissolving the residue in chloroform, and comparing the result against a standard for benzocaine by gas-liquid chromatographic studies. Benzocaine was delivered into a volumetric flask at a rate of 50 mg/sec and into an open beaker at a rate of 57 mg/sec (determinations performed

in

Metals

and

Toxicology

vision of Dr. McCall). The characteristics were evaluated using

ent

concentrations

prepared

by

to convert

of

under

of blood

methemoglobin. These an aliquot of blood with

of

hemoglobin

repeated nitrite

ion.

These

mixed

with

untreated

washes

with

samples

nitrite

to remove

solution

nitrited,

washed

red

blood

saline-washed

red

blood

followed

by

traces

of were

cells

The

total

determined ment with

of hemoglobin

concentration in gm/100

ml)

(hemoglobin

Each

oximeter. containing

of the dioxide

then

2-Readings

of

Spectrophotometric

Oximeter

Containing

Methemoglobin, Samples Fully

Partially

reducedt

*oxygen

tOxygen

pressure,

530

to 648

off of scale, below

pressure,

cause methemoglobinemia. The spray (Cetacaine)

has

examinations cyanosis

and

Methemoglobin, gm/iOO

nor

bottle states

to deliver reported

of cause

ill.

why

of

Each

,-

would

benzocaine

cyanosis

in

a spray

occurred thousand patients

had and

Ac-

excess

of

sufficient in our two pasimilarly aneswere febrile and

cyanosis

Partially

be pre-

adults. in

methemoglobinemia

patient

Oxygenated

of

of

the manufacturer, is contraindicated. clear

seconds

a quantity to

anesthetic spraying

50 to 55 mg/sec.

three

within

Reduced

minutes

Blood

Methemoglobin Readings Spectrophotometric

of

.

Oxygen

gm/100

Saturation, ml

percent

4.8

15.5

7.6

87.5

1.5 (13)

11.3

10.9

93.0

1.0 (9)

11.7

11.2

96.5

0.5 (4)

11.8

11.3

96.5

0.03

11.8

11.7

98.0

8.7 (87)

11.0

4.8

2.9

11.2

8.0

55.5

1.5 (13)

11.3

10.7

54.5

1.0

11.7

10.9

54.5

11.8 11.8

11.3 11.7

56.0 56.5

mm

1968. been

at average room temthat benzocaine is de-

11.2

(9)

bronchosince has

of this topical that a one-second

11.0

(26)

as a topical

7,000

of approximately

Hemoglobin, ml

none is known

used

at our institution methemoglobinemia

a spraying

It is not

Values

been

approximately

to cause obvious cyanosis tients and not in several thetized patients. Both

Samples

and with

knowledge,

benzocaine

for

the

at a rate

cording to two seconds

for

butyl hydro-

chloride bromide,

our

340 mg of “residue” Our data suggest

viously

Concentratioas

percent

tetracaine

previously.

label on (Cetacaine)

required

very

(Cetacaine)

Oximeter

Carboxyhemoglobin, gm/100

ml

**

-0.4 0.8

9.0

**

-0.7

0.8 1.9

Hg.

zero.

42 to 47 mm

CHEST, 71: 5, MAY, 1977

than

agent

2

To

other

supmouth.8

administered

benzalkonium ammonium

2.9 (26)

(0.3)

the

spray

percent

8.7 (87)

0.5 (4) 0.03 (0.3) **Reading

propellant.

livered

Hemoglobin

ml

(percent)

oxygenated*

the

ingredients

- .-.-----------------‘

Measured

gm/iOO

Different

as

of the

Therefore,

mixtures and

2

Freon

delivers perature.

low oxygen

Table

into

benzocaine,

and well as ethyl

The spray

exposed to gas carbon a pressure (producing in the mixtures an oxygen pressure of 42 to 47 mm Hg and a carbon dioxide tension of 43 to 46 mm Hg) and was again analyzed in duplicate for oxygen saturation and levels of hemoglobin and carboxyhemoglobin on the spectrophometric analyzer. The pH of these mixtures was less than 8.8. The results are shown in Table 2. was

a rectal

anesthetic

percent

recognized

was

after

spectrophotometric

when

ointment, vaporized

topical

as

scopic Neither

conversion to cya.nmethemoglobin by treatDrabkin’s solution. The remainder of each of these mixtures was studied in the blood gas laboratory. After tonometric studies with 100 percent oxygen (producing in the mixtures values for oxygen pressure ranging from 570 to 637 mm Hg and values for carbon dioxide tension slightly less than 10 mm Hg), each of these mixtures was analyzed in duplicate for oxygen saturation (percent); hemoglobin level (gm/100 ml), and carboxyhemoglobin level (gm/100 ml)

on the

14

anesthetic

plus

of the mixtures

of each

particular

chloride, cetyldimethyl

to

cells in the

method.2,3

methemoglobin,

an

a powder

aminobenzoate,

proportions required to yield the desired concentrations of methemoglobin. The concentrations of methemoglobin in these mixtures were then verified independently by a spectrophometric

methemoglobinemia

as

In adults, 0.15 to 0.3 gm of benzocaine orally has caused cyanosis.9 contains

sodium

to methemoglobin, saline

and

This

differwere

cause

infants

pository,7

oximeter

that contained

can

to

super-

spectrophotometric

samples

mixing the

the

Laboratory

DISCUSSION

Benzocaine

Hg.

METHEMOGLOBINEMIA

INDUCED BY TOPICAL ANESTHETIC SPRAY

589

of

the

administration

(Cetacaine).

of the

Although

topical

each

anesthetic

patient

drugs, none globinemia,

of these is known to cause and almost all of the drugs

been

given

at

onset

of cyanosis

There either

was no patient

NADH was

a considerable

in the

The

one

prompt

methemoglobin dinucleotide

intact.

was

There

suggests

no

possibilities

to its

to phosphate an

for

one

of

markedly abnormal

I

for

70

at the

Of anesthe

probably (case 1).

is not

the

be

points, of two length

when

In

methemoglobin lower than was

of

light

An

at

performed elapsed, reported in vivo

the

of

our conafter that

so

herevalues

observed.

three

of absorbance

of blood each

in use in our model 182, Inthe principle

given are

wavelengths.

made

at isobestic

that is, at wavelengths where the absorbance or more of the species is identical. A wavethat is virtually isobestic for oxyhemoglobin,

portional

it

the the

of the

was had

time

cyanosis

deoxyhemoglobin,

(that globin,

from

methylene

in samples

measurement

methemoglobin of

levels for spuriously

and

nm. Therefore, of a mixture

of the with

Hg),

intravenously

promptly.

inte rval

time

given

stable

quantitative of

with

weight)

measured

Measurements

me-

mm blood

diagnosis.

be

of absorption

ab-

568

143

The spectrophotometric oximeter blood gas laboratory (CO-Oximeter strumentation Laboratories) utilizes

pa-

was agitated exposing

548

should

measured in may

of purple;

treatment

of body

the

centration a significant

accumulation metabolic

patients (thereby

findings,

(1 mg/kg

patients,

a marked decrease higher-than-normal

a

blood from these cup for 20 minutes

and

pressure brownish

Methemoglobin

erythrocytic

and

these

confirmed

this

enhanced

abnormally enhanced methemoglobin-producing

oxygen

without methemoglobinemia developed characteristic of oxyhemoglobin. On

of

blue in

abnormal

amount of the spray to one of our patients

of oxygen, Sa02, despite

basis

reduced were

derivative of one of the ingredients. The diagnosis was suggested on the basis occurrence of cyanosis, which did not improve

PaOs. When in a plastic

the

pathways

for

used

unrecognized

patients red hue

onset.

or the accumulation in the topical

include

tabolism, and of an active

the linked

evidence

(Cetacaine)

tients. An excessive was administered

administration in apparent

remained

to administration

that

concentration of ingredients a toxic degradation compound

sorption,

air;

color

in whom

response

blue

Other

after

patient

reduction of nicotinamide-adenine

spray

prior

given

of methylene

thetic

ambient

the

evidence of abnormal hemoglobin or of a deficiency of methemoglobin

reductase tested.

only

to

other

methemoeither had

interval

or were

spray

received

carboxyhemoglobin

at this wavelength of these three pigments

to the

total

concentration

is, the sum of the carboxyhemoglobin, isobestic

578

point

for

is

548

the absorbance is directly proof hemoglobin

concentrations of oxyhemoand deoxyhemoglobin). oxyhemoglobin

and

deoxy-

Oxyhemoglobin Carboxyhemoglobin Deoxyhemoglobin Methemoglobin

“#{149}#{149}#{149}‘#{149}“

60 -

50 40 30

20 10

550

530

I

570

590

610

Wave length in nm for oxyhemoglobin, carboxyhemoglobin, deoxyhemoglobin, and methemoglobin, at pH 7.3 (0.1 M potassium phosphate buffer; this pH corresponds to that employed in CO-Oximeter). Vertical bars at 548, 568, and 578 nm represent wavelengths at which measurements of absorbance are made by instrument used in this study to monitor concentrations of blood gases. Fxcunx

590

1.

Absorption

DOUGLAS, FAIRBANKS

spectra

CHEST, 71: 5, MAY, 1977

hemoglobin sorbance

of

is 568 nm. At this carboxyhemoglobin

wavelength the is considerably

higher; therefore, a change in urn, compared with the absorbance cates

a change

absorbance at 548

in a concentration

at

An

isobestic

point

for

of carboxyhemo-

tive

to

a change

of

at

nm

that

concentration

548

The

The

absorbance

at

at

indicates

values

if

rela-

eters

when

the

to the

sum

relative

concentration

surements the

can

of absorbance

sum

of their

a small

comand

quires,

as

be present Thus, the

tions). tration

an

of

tions

and

and

578

for the

calculations

(Fig

coeffideand reother

minute

pig-

concentra-

of a significant

concen-

renders

assump-

light that

1).

these

by methemoglobin of oxyhemoglobin,

Therefore,

significant

is de-

at 548, when

quantities

as calculated spuriously

CHEST, 71: 5, MAY, 1977

reduced

568,

a sample

of

of methemo-

by this apparatus, three are observed. First, the

saturation is

and

ascertained

no

that

in

mea-

invalid. of than

is analyzed responses

oximeter

be

or carboxyhemoglobin

nm

oxygen

can

methemoglobin

containing

globin acteristic

by

wavelengths,

condition,

(except presence

The absorbance considerably less

blood

ascertained

The computer contains only for oxyhemoglobin, carboxyhemoglobin

essential

oxyhemoglobin,

data is that, present, their

concentrations

at an isobestic point. cients for calculation oxyhemoglobin, and ments

be

and

reported and

in for

the total

for of the

confronted significant

patient. Secconcentration

Thirdly, the saturation

reporting

blood

response

with

calcureads

oxim-

of

blood

samples

concentrations

gas

of their of

methemo-

globin.

carboxy-

these are

at three

containing

cyanosis value

is spuriously low. carboxyhemoglobin

for

responsible

of absorbance

principle of analysis of and only three pigments

of hemoglobin lated value

be aware

10

The three

and the presence of ondly, the calculated

should

displays the concentration of hemoglobin, the percentage of oxygen saturation of hemoglobin, and the percentage of carboxyhemoglobin on a digital display.

oxygen tension as measured by the reported value for oxygen with the color of the blood

levels

in

and

contains

these

nm

to the however, correlates

nm;

578

578

correspond electrode; saturation

below zero. Personnel

of

a change relative

instrument

analyzes

and

absorbance

of deoxyhemoglobin

hemoglobin. that

of oxy-

greater

of oxyhemoglobin

of concentrations puter

nm.

is considerably

therefore,

indi-

deoxyhemoglobin

is 578

oxyhemoglobin

568

nm,

globin relative to the sum of concentrations hemoglobin and deoxyhemoglobin. carboxyhemoglobin

ab-

does

charvalue by not

ACKNOWLEDCMENTS: Yvonne M. Seipel

oximetric

studies.

performed

Mr. Lester J. the tonometric,

Clapp and Miss blood gas, and

REFERENCES

1

Evelyn KA, hemoglobin,

Malloy

HT:

Microdetermination

methemoglobin,

and

of

sulfhemoglobin

oxy-

in a 1938

single sample of blood. J Biol Chem 126:655-662, 2 Fairbanks VF: Hemoglobin, hemoglobin derivatives, and myoglobin. in Tietz NW (ed): Fundamentals of Clinical Chemistry (2nd ed). Philadelphia, WB Saunders Co, 1976 3 Hegesh E, Calmanovici N, Avron M: New method for determining ferrihemoglobin reductase (NADH-methemoglobin reductase) in erythrocytes. J Lab Clin Med 72:339-344, 1968 4 Wolff JA: Methemoglobinemia due to benzocaine. Pediatrics 20:915-916, 1957 5 Coluboff N, MacFadyen Di: Methemoglobinemia in an infant: Associated with application of a tar-benzocaine ointment. J Pediatr 47:222-226, 1955 6 Goluboff N: Methemoglobinemia due to benzocaine (letter to the editor). Pediatrics 21:340-341, 1958 7 Peterson HdeC: Acquired methemoglobinemia in an infant

due

to

benzocaine

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