INFLUENCE -...

THE INFLUENCE OF DENITROGENATIONONTHE RESPONSEOF ANESTHETIZEDDOGSTO INTRAVENOUSLY

INJECTED OXYGEN

By RAYMONDE. WESTONAND LEONARDKAREL(From the Toxicology Section, Medical Division, Edgewood Arsenal, Md.)

(Received for publication November 8, 1946)

INTRODUCTION

A marked clinical improvement in critically illhuman subjects after the intravenous administra-tion of oxygen has been reported by a number ofinvestigators (1 to 5) despite the fact that onlyabout 1.5 to 10 per cent of the calculated basal oxy-gen requirement was injected. However, in nor-mal and in anoxemic experimental animals, otherworkers (6 to 10) have observed not only rapid,shallow breathing but also decreased rather thanincreased oxygen content of the arterial blood fol-lowing the intravenous injection of oxygen atrates of 0.21 to 2.3 ml. per kgm. per minute. Theparadoxical anoxemia has been attributed to inter-ference with the pulmonic oxygenation of theblood by the formation of multiple oxygen emboliin the pulmonary capillaries (7). The accompany-ing respiratory changes, which are abolished bybilateral vagotomy, have been considered (10) assimilar to the tachypnea observed in dogs after theproduction of pulmonary capillary emboli by theintravenous injection of starch granules (11).

Recently, in seeking a simple and effectivemeans of extra-pulmonic oxygenation for sup-portive treatment in severe, acute pulmonaryedema, we became interested in the possibilities ofintravenous oxygen administration, and particu-larly in the cause and prevention of the hypothe-sized emboli resulting from this procedure. Fromtheoretical considerations, it became apparent that,since the nitrogen tension of the blood and tissuesnormally is high (573 mm.), gaseous nitrogenpresent in the blood must enter intravenously in-jected oxygen bubbles, as in a tonometer. Con-sequently, if all the oxygen injected were absorbedby the reduced venous hemoglobin before the bloodreached the right heart, residual nitrogen bubbleswould remain to obstruct the pulmonary capil-laries. In recent years, the analogous role of dis-solved nitrogen in the bubble formation of de-compression sickness and aero-embolism has been

demonstrated and the value of prophylactic de-nitrogenation by inhalation of 99.6 per cent oxy-gen has been well established (12 to 18). Toexplore the interrelationship between nitrogen ten-sion and intravascular bubble formation and theanoxemia following intravenously administeredoxygen, in the present experiments, comparisonswere made between the effects of oxygen- ad-ministered intravenously to anesthetized dogswithout prior denitrogenation and after the ni-trogen saturation of the blood and tissues was re-duced by continuous intratracheal exposure to99.6 per cent oxygen before and during the intra-venous administration of oxygen.

EXPERIMENTAL

Twenty-six healthy, normal, adult, mongrel dogsweighing from 7.7 to 34.1 kgm. were anesthetized by theintravenous injection of approximately 25 mgm. of sodiumpentobarbital per kgm. body weight. A glass, L-shapedcannula was inserted into the exposed trachea and tied inplace with heavy, silk ligatures. The femoral artery andvein were exposed bilaterally for blood sampling and forintravenous oxygen administration. The state of anes-thesia was maintained by additional pentobarbital injec-tions as required.

Denitrogenation was accomplished by continuous ad-ministration for 3 to 4 hours of dry 99.6 per cent com-mercial oxygen, or occasionally 95 per cent oxygen-5 percent carbon dioxide, supplied to the animals on demandat low pressures and without re-breathing by means ofan Army Air Force, low resistance, A-16 valve, attachedto the tracheal cannula by rubber connections as describedpreviously (19). In 3 experiments with very large dogs,the reducing valve leading to the demand valve offeredtoo much resistance at peak inspiratory flows. There-fore, oxygen was supplied from a Douglas-Haldane bag,with the oxygen removed being continuously replacedfrom a tank connected to the bag.

The intravenously administered oxygen was bubbledthrough water and, then, continuously injected into thefemoral veins through two Y-inch, 27-gauge needles.The rate of the injection was measured by a calibrated,capillary orifice flowmeter interposed between the waterbottle and the rubber tube leading to the needles. Re-spiratory rates were observed before, during, and after

837

RAYMONDE. WESTONAND LEONARDKAREL

intravenous oxygen administration. Additional detailsof experimental procedure are given below.

By direct femoral arterial or venous puncture, bloodsamples were collected in heparinized, air-free syringes,which were immediately sealed with mercury, and storedat 0° C. Determinations of nitrogen content and oxygencontent and capacity were performed in duplicate gener-ally by the Edwards-Roughton-Scholander techniques(20, 21). Occasionally, additional checks were made bythe usual Van Slyke manometric method (22). In someexperiments, nitrogen contents were determined by ashorter manometric method recently described by Horvathand Roughton (23).

In an effort to avoid the pulmonary passive congestionand edema which Drinker (24) has observed in anes-thetized dogs after prolonged immobilization, the animals,which were restrained in a supine position when bloodsamples were drawn or intravenous oxygen was admin-istered, were moved frequently during the experiment.

100

90

t 8049

,. 70

60at

zbi030

50

40

30

20lC

Despite this precaution, however, on autopsy many ex-hibited some congestion.

Until the day of the experiment, diets consisting of foxchow, milk, horse meat, and water ad libitum were per-mitted.

RESULTS

1. The effect of intravenous oxygen administrationon the arterial oxygen content of denitrogenateddogsAn initial series of experiments confirmed the

observations of others (6 to 10) that oxygen ad-ministered intravenously to anesthetized dogs atrates as low as 1 ml. per kgm. per minute (12 to30 per cent of the basal oxygen requirement) rap-idly produced marked increases in respiratoryrates and, often, greater than 25 per cent decreases

O-VENM ?6 COUTERT

II _ DOSDIED_- I I_-| I

0 5 10 15 20 230TIME

250 270MINUTES

290 310

FIG. 1. ARTEAL OXYGENSATURATION AND VENOUSNITROGEN CONTENTIN A 12.2 KGM.ANESTHETIZEDDoG BEFOR ANDArm INTRAVENOUSINJECTION OF OXYGENDURINGAND FOL-LOWING DENITROGENATION BY CONTINUOUSINTRATRAcHEAL ADMINISTRATION OF 99.6 PuCENTOXYGEN

Intravenous oxygen was injected at a rate corresponding to 21.9 per cent of the calculatedbasal requirement.

I NTRAVENOUS OXYGEN I.09 CCKGM1MI.

INTRATRACHEAL OXYGEN"22

I I I I III

11_x

OA0EIf WT.SaT .2KAT

O-AREIUAL Ot SATURATON

11IX taNOUS % SATURATO

C

1.0

Q5

0

z

0.0-i0->I2-

838

. .

EFFECT OF INTRAVENOUS02 ON DENITROGENATEDDOGS

1.07 CC/SMIIN.L,777777

-- E-I - I I

DOG WT. ItAKBRom.

0. ARTERIAL O SATURATIO"

XwVENOUS q SATURATION -

* I I ____ I I I

*.VEOUS CONTIUT

I I t I

0 10 20 250 270 290 310 330 350TIME MINUTES

FIG. 2. ARTERIAL OXYGENSATURATION AND VENOUSNITROGEN CONTENTIN A 21.4 KGM.ANESTHETIZEDDOGBEFOREANDAFTER INTRAVENOUSINJECTION OF OXYGENDURING AND FOL-LOWING DENITROGENATION BY CONTINUOUS INTRATRACHEAL ADMINISTRATION OF 99.6 PERCENTOXYGEN


in arterial oxygen content. A second series ofexperiments revealed that intravenously injecting1 ml. of oxygen per kgm. per minute for 20-minuteperiods in tracheotomized, anesthetized dogs which

TABLE I

Pertinent data indicating changes in arterial oxygen con-tent following the intravenous injection of oxygen for 20minutes in tracheotomized, anesthetized dogs, denitrogenatedby continuous exposure to 99.6 per cent oxygen for 3 to 4 hours

02 Injected Venous N, Arterial 02 contentExpressed as content at

no. per cent of time of Before Afterbslrequire- injection injection injectionment of 0 ofOs of 02

per cent voluue per cost1 12.5 0.19 19.6 15.02 16.9 19.9 20.8

17.3 17.5 18.43 22.0 0.18 19.6 18.04 33.1 0.27 21.0 16.0

had been denitrogenated for from 3 to 4 hours, as

described above, by exposure to 99.6 per cent oxy-

gen usually produced falls in arterial oxygen con-

tent, frequently of the magnitude of 5 volumes per

cent, although occasionally there occurred slightincreases. Table I gives the pertinent data for 4representative experiments in which venous ni-trogen content was reduced to 0.18 to 0.27 volumesper cent before oxygen (12.5 to 33.1 per cent ofthe basal requirement) was administered intra-venously.

2. Effect of intravenous oxygen on the arterial oxy-

gen saturation in dogs before and after denitro-genation by exposure to 99.6 per cent oxygen

Binger, Brow, and Branch (11) found that in-halation of 90 per cent oxygen abolished the anox-

emia observed in dogs after the production of

INTRAVENOUS OXYGENI ,&Aa o

nv ia

I1100

90zo 804£ 70I-,

0 60of 50

,x, 40

I1

X0i

30

20

10A

z

839

I

AL-

840 RAYMONDE. WESTON

multiple pulmonary capillary emboli by intra-venous injection of starch suspensions. Therefore,the less marked fall in arterial oxygen content ofthe denitrogenated dogs following the injection ofintravenous oxygen may have resulted not-fromthe prophylactic denitrogenation but from thera-peutic effects of the 99.6 per cent oxygen by meansof which denitrogenation was achieved and main-tained. Consequently, the following experimentswere performed to determine whether the simul-taneous administration of 99.6 per cent oxygen in-tratracheally without "complete" denitrogenationwould also prevent the development of the anox-emia.

i AND LEONARDKAREL

Figures 1 to 4 graphically illustrate 4 representa-tive experiments in which intravenous oxygen wasadministered at rates of 1.03 to 1.09 ml. per kgm.per minute to anesthetized dogs for three 15-min-ute periods as follows: (1) two.minutes after thestart of the intratracheal exposure to 99.6 per centoxygen and, therefore, presumably before deni-trogenation was complete; (2) after 4 hours ofintratracheal oxygenation to achieve marked deni-trogenation; and (3) if the animal survived the 2earlier injections, approximately 30 to 60 minutesafter discontinuing the intratracheal oxygen topermit the animals to become renitrogenated bybreathing air.

INTRAVENOUS OXYGEN 1.O3CC/KGM/MiN.rII!ITRTRC -

HEAL 2OY22JIINTRATRACHEAL, OXYGEN

100

902o 8C

Z 70

h 60

I ., -I I------: I

0A- d I

X

O I

D06 J, WT.-ofl.4 KOM.

O-ARTERIAL Ot SATURATION

A%-4-

z 40w40) 30

20

10lC

1.0w a0'0-I.

OO.5c

n>

X.VENOUS 0s SATURATION

*.VENOUS N" CONTENT

I III0 5 10 15 20 250 270 290 310

TI ME MINUTESFIG. 3. ARTERIAL OXYGENSATURATION AND VENOUSNITROGEN CONTENTIN A 21.4 KGM.

ANESTHETIZED DOGBEFOREANDAFTER INTRAVENOUSINJECTION OF OXYGENDURING AND FOL-LOWING DENITROGENATION BY CONTINUOUS INTRATRACHEAL ADMINISTRATION OF 99.6 PERCENTOXYGEN

Intravenous oxygenn was injected at a rate coresponding to 23.4 per cent of the calculatedbasal requirement.

I I I II

9

I I I


INTRATRACHEAL OXYGENI1I C _ __I I,. -...-

x I1I

40I

I1

110 5 10 15 20

so-.-I I I I I I

270 280 290TI ME MINUTES

I,

DOG s WT7.?7 KOM.

OsARTERIAL Og SATURATION

X.EOS0STRTO

X-VENOUS Ol SATURATION

WVENOUSN, CONTENT

110* DIE

I it

365 375

FIG. 4. ARTERIAL OXYGENSATURATION AND VENOUSNITROGEN CONTENTIN A 7.7 KGM.ANESTHETIZEDDOGBEFOREANDAFTER INTRAVENOUSINJECTION OF OXYGENDURINGAND FOL-LOWING DENITROGENATION BY CONTINUOUS INTRATRACHEAL ADMINISTRATION OF 99.6 PERCENTOXYGEN


In 2 of the animals (Figures 1, 3) administra-tion of intravenous oxygen 2 minutes after thestart of intratracheal oxygen resulted in increasesin oxygen saturation of the arterial blood. How-ever, in both of these animals, the venous nitrogencontent by the end of the 15-minute injection pe-

riod had fallen to values of 0.36 volume per centand 0.26 volume per cent respectively. During thefirst period of intravenous oxygenation in theother 2 animals, there was a fall in the arterial oxy-

gen saturation, and the decrease in venous ni-trogen content was not so marked; i.e., it fell from0.89 and 0.87 volume per cent to 0.43 and 0.50volume per cent, respectively (cf. Figures 2 and4). Similarly, when the intravenous oxygen in-

jections were repeated after more complete deni-trogenation, in 2 of the 4 animals, there was a rise(Figures 1, 2), whereas in the other 2 there was

a fall (Figures 3, 4) in arterial oxygen saturationalthough the nitrogen contents of the venous bloodat the start of the injection periods were 0.21, 0.23,0.09, and 0.15 volume per cent, respectively. Thus,in these experiments, there was no direct rela-tionship between the nitrogen content of the venous

blood and the response to intravenous oxygenation.However, the final intravenous injections of oxy-gen at the same rate, when the dogs were more

completely nitrogenated and were breathing notoxygen but air, produced rapid, marked drops inarterial oxygen saturation in 3 of the animals and

100

90

z 800

49 70

<, 60, 0

ae 50

z

x0

30

20

10I0

z 1.0

tr 0.5t >z

or -,-,I

841

I I I

I


a moderate drop in the fourth, with deathoccurring within a few minutes after the cesof the injection (Figures 1 to 4). In all instthe injection of oxygen resulted in a sharp arespiratory rate, the increases being, respecfrom 24 to 120, 40 to 70, 19 to 116, and 26It will be noted that the least renitrogenaticgreatest fall in arterial oxygen saturation ocoin the dog represented by Figure 4. This aat autopsy, showed appreciable congestionlungs.

0.73INTRATRACHEAL OXYGEI

'110

100

9020F 804

= 7014' 60

50zw 40

x 30

20

10

2

0'C.;

z

01

0.5

0l0 5 10 15 20 240

TIME

X

3. Effect of intravenously injected air on oxygensaturation in dogsThere was no significant difference in the re-

sponse to intravenous oxygen of dogs when eithermore completely denitrogenated or only partiallydenitrogenated by exposure to intratracheal oxy-gen for 2 minutes before and during the 15-minuteperiod of injection. As a result, it was not clearwhether the lesser drop or slight rise in arterialoxygen saturation following intravenous oxygeninjection in both the partially and more completely

OARTERIAL (, SATURATION

\X.VENOUS q SATURATION

270250 260MINUTES

FIG. 5. ARmmrnL OXYGENSATURATION AND VENOUSNITROGEN CONTENTIN A 19.1 KGM.ANESTHTZEDDOGB5FORE ANDAFTR THE INTRAVENOUSINJECTION OF AIR DURINGAND FOL-LOWING DENITROGENATION BY CONTINUOUS INTRATRACHEAL ADMINISTRATION OF 99.6 PERCENTOXYGEN

I I I I-

0

DOG t WT.- 19.1 KOM.

lII

l l

*sVENOUS % CONTENT

DII DOIG 4DIED I

- I I_ t

bBJ"wwl

I I - .

842

I

rl

X


100

z0; 704

m 604

50

40z

0 30x0 20

10

0zW0 1.00 j

0 0.52

INTRAVENOUS AIR 0.92 CC/KGM/MIN.

INTRATRACHEAL OXYGENI~ ~ ~ _- _ _ _ , -

0 5 10 15 20 250 260 270TIME MINUTES

FIG. 6. ARTERIAL OXYGENSATURATION AND VENOUSNITROGEN CONTENTIN A 33.9 KGM.ANESTHETIZEDDOGBEFOREANDAFTERTHE INTRAVENOUSINJECTION OF AIR DURING AND FOL-LOWING DENITROGENATION BY CONTINUOUS INTRATRACHEAL ADMINISTRATION OF 99.6 PECENTOXYGEN

denitrogenated dogs was a consequence of the

beneficial effects of the prophylactic denitrogena-tion or of hyperventilation in the presence of thehigh intratracheal oxygen concentration. If the

less severe reactions to intravenous oxygen re-

sulted merely from hyperventilation due to bubbleformation in the pulmonary capillaries of animalswhich were breathing high concentrations of oxy-

gen, similar results should be obtained if the hy-perventilation were produced by injection of an

inert gas-even nitrogen itself-at comparablerates. Therefore, the previous experiment was re-

peated in a series of dogs in which air rather thanoxygen was injected intravenously.

Figures 5 to 7 illustrate typical experiments inwhich air was injected intravenously at rates of0.73, 0.92, and 1.16 ml. per kgm. per minute, re-spectively. In contrast to the injection of oxygen,the .intravenous injection of air during simultane-ous administration of intratracheal oxygen pro-duced a rapid and extensive fall in arterial oxygensaturation both before and after considerable low-ering of venous nitrogen content had been achieved,despite the marked hyperventilation which oc-

843


INTRAVENOUS AIR L1S CCIKSMIMIN.

INTRATRACHEALL OXYSE! ___~ --.I I I I

11 DOG ." WT.-17.7 KGM -

omARTERIAL Og DURATION

IIlx

X u VENOUS q SATURATION

IIl*- VENOUS N. CONTENT

p-

0 5 10 15 20 260TIME

270 280MINUTES

290

FIG. 7. ARTERIAL OXYGENSATURATION AND VENOUSNITROGEN CONTENTIN A 17.7 KGM.ANESTHETIZEDDOGBEFOREANDAFTFER THE INTRAVENOUSINJECTION OF AIR DURINGAND FOL-LOWING DENITROGENATION BY CONTINUOUS INTRATRACHEAL ADMINISTRATION OF 99.6 PERCENTOXYGEN

curred. In no experiment could the third injec-tion without intratracheal oxygen be made, sincethe animals all died after the second injection,although in some (cf. Figures 5, 6) the intra-venous air was injected at a much slower rate thanwas the intravenous oxygen.

4. The effect of injecting intravenous oxygen atvery slow rates in normal anesthetized dogswithout previous denitrogenationInasmuch as there have been reports of marked

clinical improvement in anoxemic human subjectswho received prolonged intravenous injections of

very small amounts of oxygen (1 to 5), arterialand venous oxygen saturations were followed inpentobarbitalized dogs during the intravenous ad-ministration of oxygen at comparable rates forperiods up to 3 hours. Because of the brieferduration of these experiments, reinforcing dosesof pentobarbital were not required to maintain theanesthesia. In Figure 8, 3 such experiments aregraphically presented.

In all 3 animals, although the venous oxygensaturation was only 44 per cent to 73 per centat the start of the experiment, as would be expectedin deeply barbitalized animals breathing air, the

100

90

80

o 70

a: 60

40

= 30

I20

10

(1

1.0

05.zIabe0.W-II->re

844

)L-

I


intravenous injection of oxygen at rates of 0.082(A) to 0.345 ml. per kgm. per minute (B) re-sulted in continued fall of both arterial and venousoxygen saturation. In one experiment (Figure 8,B), the animal died after 150 minutes although theoxygen administered intravenously was only 7.4per cent of the basal requirement.

The decline in oxygen saturation in all 3 animalsand the death of the 1 animal must have been re-lated to the intravenously administered oxygenfor the following reasons: (1) generally, in pento-barbitalized animals, the blood oxygen saturationdoes not decrease but increases after several hoursas the anesthesia tends to lighten, (2) the onlyother experimental procedure to which these largedogs were subjected was the withdrawal of a totalof 30 to 50 ml. of blood over a period of about 180minutes, and (3) at autopsy, no other significantcontributory pulmonary pathology was found.

The results of these studies are graphically il-lustrated in Table II.

TABLE II

Tabular summary of the representative general effects ofintravenously administered oxygen and air on the respirationand arterial oxygen saturation of denitrogenated and noit-denitrogenated, anoxemic dogs

Denitrogenated dogs Non-denitrogenatedanoxemic dogs

Sub-stanceadmin- Per cent Resfr Arte- Per cent Re'rArte-istered of basal atory rial O2 of basal atory rial O9

require- rate satura- require- ato sment ~tion ment rte iura

L-. 02 15.2 to 33.1 + .9 to 7.4 ++ -7*ix.vAir - +- +

+ = increase.= decrease.

DISCUSSION

The better response of dogs to the intravenousinjection of oxygen at rates of approximately 1ml. per kgm. per minute when intratracheal oxy-gen is administered simultaneously probably isnot due solely to the beneficial effects of the in-haled oxygen. It should be recalled that when airwas injected intravenously at equivalent or slowerrates in dogs which were breathing 99.6 per centoxygen after more or less denitrogenation, thefall in arterial oxygen saturation was as markedand rapid as that observed in animals given intra-venous oxygen while breathing air (Figures 5 to 7,8) This indicates that the therapeutic effect of

z2 90

!a:a0!i 70

b 60

so,

60

oZ 50

4cc 40

30

202

dr to

.06 ccio"su. A

WC6 1 243 KOM

0 60 120 IO0TIME MINUTES

D0345 CC/26o"*n B

0O00 1777KGM

T oM IMIN SOTIME MINUTES

. INTRAVENOUS OXY6th

o . ARTERIAL 0 SATURATION

X ' YERUS 06 SATURATION

o 03 CCWKswims C

90 000 1 21X KG",z0 80

r 70

40

30 _U 0 s MINUT0E

- TIME MINUTES

FIG. 8. ARTERIAL AND VENOUSOXYGENSATURATIONOF ANESTHETIZED, TRACHEOTOMIZEDDOGSBREATHINGAIRDURING THE CONTINUOUS INTRAVENOUS INJECTION OFOXYGENAT RATESWHICHCORRESPONDEDTO THE FOLLOW-ING PERCENTAGESOF THE CALCULATEDBASAL REQUIRE-MENT: 1.9 PER CENT IN A, 7.4 PER CENT IN B, AND 3.2PER CENT IN C

99.6 per cent intratracheal oxygen alone is in-sufficient to effect the anoxemia produced by thehypothesized pulmonary emboli. Consequently,some other factor must be involved.

As noted above, Binger, Brow, and Branch (11)found that the administration of 90 per cent oxygencould abolish the anoxemia following productionof multiple pulmonary capillary emboli by the in-travenous injection of starch granules in dogs.Consequently, because the anoxemia following airinjections was not compensated by the simultane-ous administration of 99.6 per cent oxygen it couldbe argued that the air injections do not constitutean adequate control and that the 2 types of experi-ments reported in the present study differ only inthat perhaps more absorption occurred from theoxygen bubbles than from the air bubbles, leavingsmaller bubbles in the former case; producing aless severe anoxemia which could be better com-pensated by the inhaled 99.6 per cent oxygen.

However, because of the demonstrated role ofdissolved gaseous nitrogen in the genesis and per-petuation of bubbles in the blood and tissues indecompression sickness and aero-embolism, it isprobable that in fully nitrogenated animals, dis-

845


solved nitrogen similarly enters the injected oxy-gen bubbles in accordance with Henry's law andthat the less severe reaction to this procedure whenintratracheal oxygen is simultaneously adminis-tered is a consequence of the denitrogenationachieved by the oxygen inhalations. In the deni-trogenated dogs, on the other hand, as a result ofthe lower nitrogen tension, particularly of theblood, probably less nitrogen enters the injectedoxygen bubbles which, therefore, may becomesmaller in size if oxygen is taken up by the re-duced hemoglobin in the venous blood. In thisregard, it is interesting to note that the initial andfinal increase in respiratory rate during intra-venous oxygen injections in dogs simultaneouslyinhaling 99.6 per cent oxygen was markedly lessthan that observed during either intravenous oxy-gen injections in dogs breathing air or during airinjections in dogs breathing 99.6 per cent oxygen,indicating that the oxygen bubbles in the deni-trogenated animals possibly were of smaller sizeor less persistent than in the other animals.

The prolonged injections of intravenous oxygenat very slow rates in anesthetized dogs withoutdenitrogenation reported in the present communi-cation establish further the physiological hazard ofthis procedure. Despite the slow rate of injectionand the initial post-barbiturate anoxemia, arterialand venous oxygen saturation continued to fall orto remain low throughout the injection period,with death occurring in 1 animal before the 180-minute injection period was completed.

Moreover, several incidental experimental ob-servations demonstrate that even with denitrogena-tion and simultaneous intratracheal oxygen, intra-venous oxygen constitutes an added hazard ratherthan a therapeutic aid in the anoxemic state. Inexperiments with 3 very large dogs and a smallerreducing valve leading from the oxygen tank tothe demand valve, the resistance to respirationwas markedly increased at peak inspiratory flows.Consequently, these animals while being denitro-genated by oxygen inhalation became progressivelymore anoxemic because of the inspiratory resist-ance which produced an inadequate respiratoryflow and, ultimately, pulmonary congestion andpulmonary edema. In one animal, for example,arterial oxygen saturation was 63.5 per cent, ve-nous oxygen saturation was 30.9 per cent, and ve-

nous nitrogen content was 0.23 per cent, when theinjection of intravenous oxygen at a rate of 1 ml.per kgm. per minute (23.2 per cent of basal oxygenrequirement) was begun. Within 14 minutes, res-piration had stopped, and at 15 minutes no cardiacsounds were audible. Similar observations madeon the 2 other animals indicate, in addition, thatthe failure of intravenous oxygen administrationin the remaining denitrogenated dogs was notnecessarily a consequence of any elevation inoxygen saturation of the venous blood, whichmight result from simultaneous inhalation of 99.6per cent oxygen.

These experiments establish the practical thera-peutic inadequacy of intravenous oxygen adminis-tration, even when the effect of gaseous nitrogenin the blood and tissues is minimized by prophy-lactic denitrogenation. Other considerations alsomake it evident that until some means of prevent-ing bubble formation is developed, introduction ofsignificant amounts of oxygen by injection into thevenous blood will not be successful. For example,if oxygen is injected into peripheral vessels, theamount which can be absorbed rapidly before-coa-lescence of bubbles occurs is limited immediately tothat which will saturate fully the venous returnfrom the areas drained. Because the peripheralblood flow is small in comparison with the totalcardiac output, Goodwin et al. (25) attempted toinject oxygen into the inferior vena cava througha special catheter which produces small bubbles,but had no particular success in preventing the de-velopment of the usual signs and symptoms of pul-monary capillary embolization.

Moreover, as Adriani has noted recently (26),intravenously injected oxygen, like air, producesbubbles which are surrounded by a thin proteinfilm through which neither nitrogen nor oxygen canpenetrate too readily. Adriani explains the per-sistence of the emboli by quoting Langmuir (27)who suggested that the films are persistent andresistant, because the protein is denatured. Thus,any oxygen bubble introduced in the circulationwill be only slowly absorbed even in markedly un-*saturated blood. Therefore, successful extrapul-monic oxygenation probably will require not intra-venous injection but some other technique for in-troducing oxygen into the blood -without bubbleformation.

846


Cessation of the intravenous injection of oxygenwas followed within 1 minute in a number of in-stances by a sudden and variable, but non-per-sistent, rise in the arterial oxygen saturation. Asimilar phenomenon was observed and is morefully commented upon by Goodwin et al. (25).

Because of the observations made by a numberof workers regarding oxygen depression, followingthe inhalation of pure oxygen during anoxemiaresulting from deep barbiturate anesthesia, andcentral nervous system depression (28), the ob-jection may be raised that the intravenous adminis-tration of oxygen to anoxemic dogs under pento-barbital anesthesia can depress or completely checkrespiration. It should be pointed out that althoughoxygen depression is readily obtained in the in-tact pentobarbitalized dog, it is accompanied by analmost immediate precipitous fall in respiratoryrate and depth, which may happen even after only1 breath of pure oxygen. In the series of experi-ments currently being reported, however, theintravenous injection of oxygen to the anoxemicdogs produced not a decrease, but an increase inrespiratory rate, suggesting that the stimulus ofanoxemia to the carotid and aortic bodies had notbeen removed.

SUMMARY

1. The observations of others that oxygen ad-ministered intravenously to dogs at rates as lowas 1 ml. per kgm. per minute rapidly producedmarked increases in respiratory rates and oftengreater than 25 per cent decreases in arterial oxy-gen content were confirmed.

2. Prior to the administration of intravenousoxygen, animals were denitrogenated in orderto reduce the incidence of intravascular bubbleformation.

3. In tracheotomized, anesthetized dogs deni-trogenated by exposure to 99.6 per cent oxygen for3 to 4 hours, the intravenous injection of oxygenat a rate of 1 ml. per kgm. per minute for 20-minute periods usually produced falls in arterialoxygen content, frequently of the magnitude of 5volumes per cent, although occasionally there oc-curred slight increases.

4. In dogs which were first denitrogenated andthen renitrogenated by breathing air, the intra-venous administration of oxygen at rates thesame as those previously used produced a rapid,

significant drop in arterial oxygen saturation inmost instances, and, in some cases, death.

5. In contrast to the results obtained on injectionof oxygen during the simultaneous administrationof intratracheal 99.6 per cent oxygen, the intra-venous injection of air under similar conditionsproduced a rapid, extensive fall in arterial oxygensaturation both before and after considerablelowering of venous nitrogen content had beenachieved, despite the marked hyperventilationwhich occurred.

6. The intravenous injection of oxygen for 180minutes at very slow rates (0.082 to 0.345 ml. perkgm. per minute) in deeply anesthetized and an-oxemic dogs breathing air also resulted in a con-tinued fall of the arterial and venous oxygen satu-ration, although the amount of oxygen adminis-tered represented merely 1.9 to 7.4 per cent of thebasal requirement.

7. It is suggested that because of the physio-logical and physical factors involved in bubbleformation, successful extra-pulmonic oxygenationwill require some technique by which oxygen canbe introduced into the blood without the forma-tion of bubbles.

8. Even with denitrogenation and simultaneousintratracheal oxygen, intravenous oxygen con-stitutes an added hazard rather than a therapeuticaid in the anoxemic state.

ACKNOWLEDGMENTS

The authors wish to acknowledge gratefully the tech-nical assistance of Misses America Moreno, JosephineSchaffer, and T/4 Patricia A. Gogins, WAC.

BIBLIOGRAPHY1. Neudorfer, A., Zur intraven6sen Sauerstoffinfusion.

Wien Klin. Wchnschr., 1905, 18, 89.2. Tunnicliffe, F. W., and Stebbing, G. F., The intra-

venous injection of oxygen gas as a therapeuticmeasure. Lancet, 1916, 2, 321.

3. Singh, I., and Shah, M. J., Intravenous injection ofoxygen under normal atmospheric pressure. Lancet,1940, 1, 922.

4. Ziegler, E. E., The intravenous administration of oxy-gen. J. Lab. & Clin. Med., 1941, 27, 222.

5. Jacobi, M., Klein, B., Rascoff, H., Kogut, B., Auer-bach, R. W., and Jennings, J. E., The effect of in-travenous administration of oxygen on shock inin dogs and in human beings. Arch. of Surg., 1946,S2, 42.

6. Stuertz, E., Ueber intravenose Sauerstoffinfusion.Ztschr. f. diatet. phys. ther., 1904, 7, 67.

847


7. Bourne, G., and Smith, R. G., The value of intravenousand intraperitoneal administration of oxygen. Am.J. Physiol., 1927, 82, 328.

8. Singh, I., Intravenous injection of oxygen with theanimal under ordinary and increased atmosphericpressure. J. Physiol, 1935, 84, 315.

9. Dick, M., Respiratory and circulatory responses tointravenous oxygen and their relation to anoxemia.Am. J. Physiol., 1939, 127, 228.

10. Grodins, F. S., Ivy, A. C., and Adler, H. F., Intra-venous administration of oxygen. J. Lab. & Clin.Med., 1943, 28, 1009.

11. Binger, C. A. L., Brow, G. R., and Branch, A., Ex-perimental studies on rapid breathing. I. Tachyp-nea, independent of anoxemia, resulting from multi-ple emboli in the pulmonary arterioles and capil-laries. J. Clin. Invest., 1924, 1, 127.

12. Behnke, A. R., Thomson, R. M., and Shaw, L. A.,The rate of elimination of dissolved nitrogen in man

in relation to the fat and water content of the body.Am. J. Physiol., 1935, 114, 137.

13. Behnke, A. R., Application of measurements of nitro-gen elimination to the problem of decompressingdivers. U. S. Nav. Med. Bull., 1937, 35, 219.

14. Behnke, A. R., The absorption and elimination ofgases of the body in relation to its fat and watercontent. Medicine, 1945, 24, 359.

15. Whiteley, A. H., McElroy, W. D., Warren, G. H.,and Harvey, E. N., Bubble formation in animals.V. Denitrogenation. J. Cell. and Comp. Physiol.,1944, 24, 257.

16. Whitaker, D. M., Blinks, L. R., Berg, W. R., Twitty,V. C., and Harris, M., Muscular activity and bubbleformation in animals decompressed to simulatedaltitudes. J. Gen. Physiol., 1945, 28, 213.

17. Eggleton, P., Elsden, S. R., Fegler, J., and Hebb, C.E., A study of the effects of rapid decompression incertain animals. J. Physiol., 1945, 104, 129.

18. Whiteley, A. H., and McElroy, W. D., Denitrogena-tion of muscle and fat tissues of the anesthetizedcat. Am. J. Physiol., 1946, 146, 229.

19. Karel, L., and Weston, R. E., The nitrogen contentof femoral arterial and venous blood in anesthetizeddogs during denitrogenation by continuous inhala-tion of 99.6 per cent oxygen-In press.

20. Edwards, G. A., Scholander, P. F., and Roughton,F. J. W., Micro gasometric estimation of the bloodgases. III. Nitrogen. J. Biol. Chem., 1943, 148,565.

21. Roughton, F. J. W., and Scholander, P. F., Microgasometric estimation of the blood gases I. Oxygen.J. Biol. Chem., 1943, 148, 541.

22. Van Slyke, D. D., and Neill, J. M., The determinationof gases in blood and other solutions by vacuumextraction and manometric measurement. J. Biol.Chem., 1924, 61, 523.

23. Horvath, S. M., and Roughton, F. J. W., Improve-ments in the gasometric estimation of carbon mon-oxide in blood. J. Biol. Chem., 1942, 144, 747.

24. Drinker, C. K., Pulmonary Edema and Inflammation.Harvard Univ. Press, Cambridge, 1945.

25. Goodwin, W. E., Harmel, M., and Lamont, A., Ex-periments with intravascular gases: oxygen andhelium-to be published.

26. Adriani, J., The Chemistry of Anesthesia. Charles C.Thomas, Springfield, Ill., 1946.

27. Langmuir, I., Cold Spring Harbor Symp. Quant. Biol.1938, 6, 136.

28. Marshall, E. K., Jr., and Rosenfeld, M., Depression ofrespiration by oxygen. J. Pharmacol. Exper.Therap., 1936, 57, 437.

848

INFLUENCE -...

Documents

Transcript of INFLUENCE -...