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OFFICE OF NAVAL RESEARCH

Contract N00014-76-C-0229I ~ Project No. NR207-040

~f’1 :~~~~~~

TECHNICAL REPORT NO. 121 /

PHYSIOLOGIC CHANGES IN THE DOG ANESTHETIZED WITH .THIAMYLAL AND. ENFLURANE

G. L. White, 0. 0. Ho1mes,~and L. B. Hinshaw9C’

Prepared for Publication

3 Laboratcry Animal Science

Universit y of Oklahoma Health Scten~es. Center

Q~~~~~~~~~~~~ ~Øk4 October 19??.

Reproduction in wtiole or In psv t 1~ permitted ~fOr _________any purpose of the IMJta~ States Governmait ____________

Distri butio n of this report Is vnilm(ted _ _ _ _ _ _ _ _ _ _ _ _ _

—

OFFI CE OF NAVAL RESEARC H

Contract N000l4-76-C-0229

Project No. NR207-040

TECHNI CAL REPO RT NO. 121

PHYSIOLOGIC CHANGES IN THE DOG ANESTHETIZED WITH

TH IAMYLAL AND EN FLURANE

G. L. Wh ite, D. D. Holmes , and L. B. Hinshaw

Prepared for Publication

Laboratory Animal Science

University of Oklahoma Health Sciences CenterDQfl~ rtmPn~~~~~~~~~~~ O+~~ y-

~iit ~~ y i~ol-ogy & Ui&phj~iu—~~Div i sion of Compara~T~é Medicf~ie~~~~~

‘ Oklahoma City, Oklahoma

4 October 1977

Reproduction in whole or in part is permitted forany purpose of the United States Government

Distri bution of this report is unlimi ted/ / 3

//

L~~~.__ _ _ _ - - ~~~~~~~~~~~~ -

_ _ __ _ _ _ _ _ _ _ _ _ _ ~~~~~~~~~

SUMMARY . Enflurane anesthesia with thiamylal induction in the dog produced

only slight, statistically insignificant , changes in the heart rate and the mean

systemic blood pressure. A significant depression of the respiratory rate with

an associated significant increase in the arterial partial pressure of CO2 was

produced , accompanied by ~ decrease in the blood pH. Progressive drop of the

body temperature occurred throughout anesthesia. Significant hematologic changes

included a reduction in the packed cel l volume and the erythrocyte and leukocyte

counts. The only significant change in the blood chemistry was an increase in

alkaline phosphatase at 24 and 48 hours after induction of anesthesia.

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I ~~~~~~~~t t~

• • s”-’

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Enflurane 6 is a nonflammable fluorinated inhalation anesthetic initially

approved for use in man in 1972 and now widely used as a human anesthetic agent.

It is reported to have little effect on the pulse rate and cardiac rhythm.

Arterial pressure decreases moderately after induction and returns to near nor-

mal on surgical stimulation and then becomes stable (1). A precision vaporizer

is necessiry fo’ safe adm inistr ation (2).

ReceriLly there has been increased concern about the occupational hazards

for operatin g room personnel when certain inhalation anesthetics are used (3).

Toxic metabol i les of biotransformation of fluorinated anesthetics have been

associated with hepatic and renal toxicity (4,5). Biotransformation of toxic

metabo lites occurs to a significantly lesser extent with enflurane than wi th

either halothane or methoxy fiurane and thus would be expected to be less hazar-

dous to both patients and operating room personnel (6).

In view of enflurane ’s desirable characteristics in man , a study was con-

ducted ~o deter~iin e changes in the systemic blood pressure , heart rate, respira-

tory r~~r~ body ~.Ni perature , blood gases, b l ood pH, hematology , and blood

cheu~ s t ry in ~~~~ dog

MATER i ALS ~~~ ;~

Si ~ J a l Wv Jon ~ri?i dons , four eua les and two males weighing 10.0—18.5 kg,

were used in thi s study . Forty-eight hours prior to the first sampl i ng , an

indw e l l i i g catheter 7 was surg i cally placed in the femoral artery utilizing

thi auylal u for anesthesia so as to allow easy access at subsequent times for

arterial blood samples and blood pressure measurements .

A two-channel recorder9 was used to record the mean systemic arterial blood

pressur t~. heart rate , and electrocardiogram. Heart rate was determined from the

electrocard i ogram , body temperature was recorded on a precision remote thermome-

ter10 , and respiratory rate was recorded visually. Blood for arterial

r

6Ethrane R Ohio Medical Products , Madison , W I.

7Longdwel l R Becton-DickinSon , Ru therford , NJ.

8Surital R Parke-Davis , Detroit, MI.9San born R Model 7721 . Hewlett Packard , Wal tham , MA.

10Tele Thermometer R Yellow Spri ngs Instrument Company, Yellow Spr ings, OH.

_ _ _ _ _ _ _ _ _

2

blood gases and blood pH was col l ected from the femoral artery and measured on

a blood gas anal yzer .~~Iwo levels of anesthesia were studied : 2.2% vaporization during the first

Vhour oF anesthesia and 3.3% vaporization during the second hour , with oxygen

flow ra tes of 500 mi/minute with a circle semi -closed system. The precision

vapor zer use(L was specifically designed for enflurane. It delivers a linear

concentration ol enflurane at flow rates of 0.3-10.0 liters/mi nute at room tem-

pera tures of ~0-90°F (15.6-32.2°C). The level of 2.2% was chosen because this

has b~~i~ u~ tereuii ed to be the minimum alveo lar concentration for enflurane in

the dog (7) . Tie ~inimum alveolar concentration is the anesthetic concentration

required ~o prevent gross muscular movement in response to a painful stimulus (8) .

The 3.3~ co~cer t - t ion , 1.5 times the m i n i m u m alveolar concentration , is con—

sidered to be a moderate level of surgical anesthesia.

Prior to induction of anesthesia with thiamylal , the indwelling arterial

catheter was exposed and arterial blood samples were obtai ned for blood gases,

blood i~~ . t c ~ato logy and blood chemistry . The cathether was also attached to

the reCO ’dt.~r and blood pressures a id neart rates were obtained in the awake dog .

Anes the ia w I s iuced wi th 4 .~ thiai~y1al g i v ~n intravenously at a dosage of

16 i /k~ . The doj was t hen intuba ced wi th ~~i endotracheal tube . A veterinary

anes thi~s i i ~~~~~~~~~~~~~~~~~ in coiiibination with the precisi on vaporizer was used to

admis is ier the enflurane and oxygen. The dogs were in lateral recumbancy and

ind i rect contact with the metal surface of the surgery table wi th no attempt

made to sa i n tain body temperature . The room temperature was maintained at 240C.

Hes iuto logical values were determined by an automatic blood counter)4 All

blood cheidstry deter m inations were done w ith an auto analyzer15 except for the

serum q1u~amuic pyruvic transaminase determi nati~ ich was done with a spec-

trophotometer16 utilizing test kits ,~7 and the blood glucose determi nation which

~~~~~- - —~~~~~~~-~~~‘ ~~~~-~~~~~ -—~~-~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Gas Analyzer , Model 113. Instrumentation Laboratory , m c , Lexington ,

MA.12Ethrane Vaporizer R Ohio Medical Products , Ma di son , WI.13Model 970 R Anesthesia Machine . Pi tman-Moore , Inc.,Washington Crossings , NJ.

~4Model ZF. Cou lter Electronics, Hialea h , FL.

12/60 and SMA 6/60. Technicon Industrial Systems, Tarrytown , NY.16Junior II A. Coleman Instruments , Maywood , IL.

~ Serosonic SGPT Test Kit. Mallinckrodt , Inc ., St. Louis , MO.

~ ~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ .~~~~~~~~

3

was done with a glucose analyzer)8 Systemic arterial blood pressure , heart rate,

and body temperature were monitored throughout anesthesia. The arterial blood

samples for blood gases , blood pH , hematology , and blood chemistry were taken

prior to anesthesia, after 1 hour of anes thes ia at 2.2% concen tra ti on , and after

1 additional hour of anesthesia at 3.3% concentration of enflurane. Venous blood

samples for hematology and blood chemistry were obtained at 24 and 48 hours and

at 7 days after induction of anesthesia.

RES ULTS

The mean systemic arterial blood pressure decreased slightly at both anes-

thetic levels throughout the 2 hours of anesthesia when compared to the awake

measure mim ents (Table 1). The decrease was greatest during the greatest depth of

anesthesia. There were no significant changes in the heart rate at either anes-

thetic level when compared to the awake dog. A statistically significant decrease

in body temperature of all dogs occurred at both depths of anesthesia at all

intervals of measurement (Figure 1).

The respiratory rate decreased significantly at both levels of anesthesia

(Table 1). There was a corresponding signiF icant increase in the arterial

partial pressure of CO2 and a decrease in p~ at increased l evels of anesthesia

and wi th increased time (Table 2). Significant increases in arterial partial

pressure of 02 also occurred during anesthesia.

There were statistically significant decreases in the leukocyte and eryth—

rocyte counts and in the packed cell volume during anesthesia (Figures 2,3,4),

but no significant hematologic changes at 24 and 48 hours and at 7 days after

anesthesia. The only significant change in the blood chemistry was an increase

in alkaline phosphatase at 24 and 48 hours after anesthesia. No significant

changes occurred at any time for the bi lirubin , crea tine , uric acid , inorganic

_ _ _ _ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~ . .—-- .~.- .-

18Glucose Analyzer. Beckman Instruments , Inc., Fuller ton , CA.

p

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__ -~~-~~~~~ — .. -~~~~-

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ —,

4

phosphorus , calcium , total protein, al bumin, blood urea nitrogen , glucose ,

sodium , potassium , serum glutami c oxalacetic transami nase , and serum glutamic

pyruvic tra rsan inase when compared to the pre—anesthesia values .

DISCUSSION

The slight decrease in the mean systemic arterial blood pressure was com-

parable wi th changes found in man (1).

The signif icant decreases in the respiratory rate at all level s and times

of anesthesia is important in view of the related increase in the arterial partial

pressure of CO2. The increased partial pressure possibly upset the carbonic acid

to base bicarbo nate with a resulti ng respiratory acidosis. The hypercapnia

refiects a res iratory depression from enflurane , resulting in an increased

arterial partia l pressure of CO2 level . This respiratory acidosis , although

common wi th genera l anesthetics , could possib ly effect the survival of an animal

if the acid o sis were com ipounded with a metabolic acidosis. A more frequent

flus hiw ~ ni i i ! ‘ ;as uix~u’e through the overflow valve , a higher oxygen flow

ra te , a’ sS~~ . ’u v entilat ion would probab ly decrease the partial pressure of

CO2 a~a i ii :h t ’ :~~~’ al pH 1 ito i wore r asonable range. The significant

incre.e;e n m’~~ ’~ J ) rLi a~ p ’ess mre o~ 02 that occurred is because oxygen was

used as ~ e ci’’ ie r gas. The progressive drop in body temperature wi th increased

time and dep h oF anesthesia is probably caused by either a depression of the

te 7eraLur e regulating center , peripheral vasoconstriction , or depressed basal

metabol i sm (9).

Muscle twi tching occurred only in one dog in a pi l ot study in which induc-

tion c l anesthesia with enflurane was by mask. This has been reported in a

previous study of enflurane with induction by mask. That report indicated the

muscle twitching could be prevented with either narcotic premedication or

5

thiopenta l induction (10). Since muscle twitching did not occur i n any of the

six dogs in this study , it appears that induction wi th thiamylal prevents its

appearance.

The decrease in the packed ‘cell volume and the erythrocyte count is possibly

due to sequestration of the erythrocytes in the spleen as this has been shown in

studies with other anesthetics (11 ,12). These other studies did not reveal the

fate of the leukocytes . Inhalation anesthetics have been reported to cause an

increase in plasma volume which would also account for the decrease in the packed

cell volu mii e (13). The cause of the elevated alkaline phosphatase at 24 and 48

hours after induction is unknown.

At the present time enflurane is not approved for use in the dog. Thus,

its use is limi ted to the biomedical investigator. If used , minimal changes in

the mean systemic arterial pressure and the heart rate should be expected and

controlled v eiti la t ion to provide a pH more close to the normal of 7.4+.05 may

be indic~ .ed . As w ith other anesthetics , body heat should be conserved by

covering tim e j ; a l or adding supplemental heat from water blankets .

1. Dykes , M.IL : Evaluation of a general anesthetic Enflurane (~~hrane). JAMA

225: 989-990, 1973.

2. Dob k in , A.U., Nishioka , K., Gengaje, D.B., et. al: Ethrane (Compound 347-)

anesthesia: A clinical and l aboratory review of 700 cases. Anes. & Anal g .

‘18: 4~/ 7-49 / ~ 1969.

3. Cohen , .N., [3ruce , D.L., Cascorbi , H.F., et. al : Occupationa l disease among

opera tir.g room personnel : A national survey . Anesthesiolo gy 41: 321 —340,

1974.

4. Mazzc , R.I., Trudell , J.R., Cousins , ~1.J.: Methoxyflurane metabolism and

renal dysFuaction : Clinical correlation in man. Anesthesiolo gy 35: 247-

252, 1071 .

5. Line ; b u’ , J. and Lei Fer , . : Hepatic necrosis associated with halothane

anesthesia. New Eng . J. Mcd. 268: 525-530, 1 963.

6. Chase , R.E., Holaday , D.A., E~serova-Bergerova , V., et. al: The biotrans—

for vIti o Ii oF Et hra c in ~n. Anesthesiology 35: 262~267, 1971 .

7. ~~~ F. I. , ‘.ml , C., ~;;i 1 C r , S. , et . al : Anesthetic potency of sulfu r

~~~~~~ no~~ ’ , c o o L ’ .~~;u ’u ~.e , do o ’oform , and Ethrane in dogs.

A ~~~~~~~~~~~~~~~~ :~~ •~~~~~ ,. . ;~~, ~~~~~~~~~~~

8. • ; . , 1;. o.~ ~~~~~~‘, . • : ~ cJ ; ..’.tL r.’e study of halothane and halopropane

II .; . !~~~ :±J 2L ~L ’Y_~~) 3’~6-3~i’/ , 1963.

9. Ln~~ , H.V. ~rd Jones , E.W. : V et e r i n a ry Anesthe !j.~~ Lea & Febiger , Philadel—

~~ id , Penn., 1973: pp. 286, 602—603.

10. ~lic le , A .~:.: Cardiopulmonary effects of Enflurane and Isoflurane in the dog .

i . 3. Vet. Res. 37: 128—131 , 1976.

11 . Usem~ k , L.A. and Cronk ite , E. P.: E ffects of barbi tuate anesthetics on leu—

kocytes in normial and spl oenectomized dogs. Anes. & Ana lg . 44: 167, 1965.

— .- ,—--—~~

--—-~~

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.-.. -.- —

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12. Grac a , J.G. and Garst, E.L.: Early blood changes in dogs following intra-

venous pentoharbital anesthesia. Anesthesiolo gy 18: 461, 1957.

13. Sawyer, D.C., Lum b, W.V. an d Stone , H.L.: Cardiovascular effects of halothane,

mcLh oxyflur~tne , pentobarbita l , and thiamylal . J. Appl. Physiol. 30: 36-43,

1971 .

A

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FIGURE LEGEND S

Fig 1. Effect of thiamylal-enflurane anesthesia on body temperature of dog

(in °C ). Enflurane concentration was 2.2% duri ng the first 60 mi nutes

and 3.3% during the next 60 minutes

Fig 2. Effect of thiamylal-enflurane anesthesia on periphera l leukocyte count

of dog (in cells per m3). From the 2nd hour through the 7th day, no

other anesthesia or agents were used .

Fig 3. Effect of thiamylal -enflurane anesthesia LO peripheral erythrocyte count

of dog (in cells X l06/m3).

Fig 4. Effect of thiamy lal-enflurane anesthesia on packed cel l volume of dog

(in percent).

--~~~~~~ _ ---- ~~~~~~~ - -

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18.000 -

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FIGURE 2

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

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FIGURE 3

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50 .

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FIGURE 4

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UNCLASS I F lEDS.’y r i r i t y C Ia%s * ( Icat I on

DOCUMENT CONTROL DATA - R & D‘ uri C. .las s,f,t at,on at (j ( 1c l ,ods sit ebstreet ,r.d inde sri 4’ an nulAti -n - C - u - C 2 , 1 en tered s. lien the Os -.- rol l report i. cia. rnIlseJ)

I ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~.. RF r ON~ % L C u f l T ( c L a S S l r I c a - r , o .

UNCLASSIFIEDUNIVERSITY OF OKLAH OMA HEALTH SCIENCES CENTER 2b. GR O U P

OKLAHOMA CITY , OKLAHOMA UNCLASSIFIED3 ~~ O W t T I T L E

t — -—- - — - -

~~~~

—-.—.-.-—-.- .----- — — - .

- .~PHYSIQLOGIC CHANGES IN THE DOG ANESTHETIZED WITH ~HIA MYLA L AN D E NFLURAN E .~

( 0 ( report and.,ncl.,slve dates)

J~~l~cPinical/e •ta!, last name)

G. L./White . D. D.jHoimes L. B.’Hinshaw

6- EP OR I OAJ~~ la. T O T A L NO. OF P A G ES ,. ..._Itb. ~.O OF B E E S�) Oct i ~~) 18 (T2-~ ~~j 1~ 13I ~~~r n . -8-a ~~~..NlNO. sa. O R I O I NA T O VfLP, ,.. .

(~ . T

NR 207-040 ___________________________________________c. 611. O T H E R R E P O R T NOIS I (Any oth~ ? nwnber. that may ae a.s.gn.d

(hi. report)

d.

1 0 D I ST R I B U T I O N S T A T C U E N T

Distri bution of this report is unlimi ted

I SOPPL~~S . ( E N T A R Y N O T E S SPONSORING MILl T A R S A C T I V I T y

-

Office of Nava l Research

I ) AV ~~I R A C 1 ’‘4{Enflurance anesthesia with thiamylal induction in the dog produced only slight

statistically insignificant changes in the heart rate and the mean systemicblood pressure. A significant depression of the respiratory rate wi th anassociated significant increase in the arterial ~artia1 pressure of CO-~ wasproduced , accompanied by a decrease in the blood pH. Progressive drop of thebody temperature occurred throughout anesthesia. Significant hematologic changesincluded a reduction In the packed cel l volume and the erythrocyte and leukocytecounts. The only significant change in the blood chemistry was an increase inalkaline phosphatase at 24 and 48 hours after induction of anesthesia. ,,

D D FORM 14’ (PAGE 1 Unclassified1 NOV 66 ~

S/N 0 10 1 - 50 7 - 66 1 1 Security CI.s~~flc.Uon A-3140$

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OFFICE OF NAVAL RES EARCHBI OLOGICAL SCIENCES DIVISIONBIOPHYSICS PROGRAM , Cod e 44’~DISTRIBUTION LIST FOR TECHNICAL , ANNUAL AN. ‘NAL REPORTS

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