[PAGE 1]
MKULTRA Subprojoct

INVOTOE CEECK LIST

[PAGE 2]
L, SoJct 124

Purposer.To develop a more sophisticaw
dioxide tenaion and pH or body fluide; to study relatiun. pH and psychophyaiological variables.

3 Initiated; September-1960 C ps a grantee of the Contractor:

Cost: \$6,500,00

Status:

[PAGE 3]
TO: mh

N/A 1. Date of Obligation:.

Research-in "The 2. Purpose of Project:. Psychophyslological Correlates of Carboa Dioxide Environment"

3. Progreao to Date: Prolect being inltlated.

4. Expiration Date:N/A

5. Project Monitor:

FROM:  TSS/cD

[PAGE 4]
SDIAUS 103 282 FORM 4.65

[PAGE 5]
CERTIFICATION

1. This is to cortify that I have received an acccunting froa MLRA, Subproject l24 vhich reflecto expensea of \$2,497.25. The accounting 1s being retained In the office of TSD vhore it may be rovieved by the certiaying ofricer upon request.

2. The belance remaining after recording the expenditures has been refunded.Thia mfund in the ancunt of \$h0.54 has been recorded on the propriotary caapeny financtal recorda.

3. I certify that eatisfactory services represented by the accounting have been received and that to the beat of my knowlelge and belior the funds expended wore for the purposes authorieed by tho project approval.

APPROVEDT

SIDREY COTTLINS NC/TsD

124.5

[PAGE 6]
W present herewith the final accounting of the Acid Base Research Project.

Receipts

Diebureemonte

Our check in the anount of \$40.54, representing the unoxponded balsnce, is enclosed.

[PAGE 7]
t have just-receiveda statement from: Mr C Controller, régarding the balance tn ou Acid Base Project. has been away on vacation and this explains the delay

The amount renaining in the fund is \$1,508.78.

Of the approximately \$1,000-expended since our last report, over 95% has gone for payroll,

At the present time we are engaged in a study in which the. background knowledge and apparatus provided in the grant will be of considerable use. We are administering carbon dioxide and air in mixtures up to 10'í carbon dioxide to hypertenștve. prisoner subjeets in an attempt to study the effect on resting blood pressure level That the acld base level is retated to the resting rate of blood pressure is-a long-shot hypothesis. If any effect is demonstrated, this could be aa important contribution, We plan to measure çhanges in the acid base bafance ant blood pressure and particularly the lengthoftime that these changes persist. There is some evidence ín the.literature that if one sets carbor dioxide tolerançe at a new level, that homeostatic mechanisms will maintain this for a considerable period of time. I will certainly keep you infozmed of our results in this experíment,

I certify thet serv!es  trials have been Since re ly, satisfactorily rece:!r cxponditures were incurred on offioi tieesise A

[PAGE 8]
Püreuant to my letter of April 25, I am reporting to you on the Acid-Base Study. During the past two monthe ve have trained a technician to\_work vith the pparetug (He yill be a atudent in Chemiatry this fall at the We expect to run experinental aubjecte on Teek-ends

We-attempted one experiment to aimplify finger blood collection by catching it under oil. This failed beceuse of oil contaminetion of the electrode Tharefore ve vill proceed vith subjects according to standaro gethode,

Funds\_remaining in the grant are sufficient for the next. year's studies. I

We-will report to you again on December 15.

[PAGE 9]
Enclosed please find the accounting for FrOA hich ahoxs a 0 balance.. This should close that

Enclosed is an accounting on which I have wade sinee I had all his records and zadgthe payments for hin. He may use the balance up in sowe small axpenditures which he has not.yet requested reimburseent for so please, don'c close this one ouc.

Enclosed also is a copy of a letter froag which you can put in his file. Ke is still apending our grant zoney and won't account imtil it is all gone

Best paraonal regards.

[PAGE 11]
This is a tre statenent of accounting from reported to the Fund

P pertify that services or materials bave been satisfactorily receivel anl the expenditures Were inourred on official buslness.

[PAGE 12]
ncheckN dated September 20. 1960 in the amount of \$1 426.22. drawn on the payable to of the

Receipt is hereby acknowledged of the following check:

[PAGE 13]
Cost Account 1125-/009-1902

Object Class

124-13.

No..533

[PAGE 14]
MEMORANTUN FORICOMPTHOLLER

AlTENTICN Pinance Diviaton

SUBJECT t ULRA, SubpraJect 224

Volar tho authority granted in the seaorantua dated 13 Apr11 1953 froa the DCI to tho DD/A, and the extenaion of this suthority in subaequont penoranda, Subprojoct 124 bas been approved and 6,500.00 of tha over-al1 10ILTRA project funde has been odligated to cover tho subproject's exponses. This obligation or funis ahould bo chargod to Allotaont 1525. 1009-1902,

APPBOVED FOR OBLIGATION CP PUNDS:

I CERTIFY THAT FUNDS ARE AVAILABLE: OBLIGATON RFERRNCE NO. 533 1950 OMRCE10 AOENT11270091902

Ori cl sianed by A

boscarch pirector

Dutoi.

Diatributiont Orig 4 2 - Adiressoe

1 - TSD/00 >1 - TSD/PASS

1244943

15 6aptomber 1960

AUTHORIZING OFFICER

[PAGE 15]
903640 00. CHEC ANCUT DF 3.500XX RET

12/10 A

[PAGE 17]
MOMORANLUN POR:- CHTEF, PIHANCS DIVISION

VIA

: Pan/Budget Officer

SUAJXCT

: HULTRA, SubproJect 124, Invoice No. 1 A110taent 1125-1009-1902

1. Invoice No. 1 in the esount of \$6,500 covering the above subproject is attached. Bovaver, due to refunde of \$5,073.78 froa other projocts (as per attachoente) paysont abould be madie as follovst

Canbier's chack.1n tha eacunt of \$1,426.22 and gade payablo E B

2. Tho chocke should be forvarded to Chief, Tso/Besearch Branch, through Tsv/Budget OfYicer, no lator than Thureiay, 22 Soptenbor 1960.

3. thie le a final invoice. Eovever, since it fs anticipatod that additional Nods vlll bo obligated for this project the files should not be closed.

T8D/Reseerch Branch

Attechseabs Invoice & Certifications

Diatributioar Orig & 2 - Addressco 1--TSD/FASS

1960 2 I CERTIFY THAT FUNDS ARE AVAILABLE CELIGATION REFERENCE NO. 533 CHAGE TO ALLON N 1125 1009.1902

AUTHORIZING OFFICER

CHECK#7  OUNT OF \$/ RECEY

124-16 T

16 Septeaber 1960

[PAGE 19]
KONORANEUM FOR: CHIET, PIAANCS DIVISION

VIA 1 To/Budget Ofricer

NLTRA, BubproJoct 124, Invoice o.1
A11otaent 1125-1009-1902

1. Invoice No. 1 in the amount of \$6,500 covering the atove subproject 1s attached. Hovaver, due to refunds of \$5,073.78 fron other projecte (as por attachnento) payaent should bé made as follovet

Casbier's check in the amount of \$1,426.22 and modo payable E

2. The checke ahould be forvarded to Chief, T80/Besearch Branch, throngh T80/Buigot Orficor, no later than Shuraday, 22 Septeaber 1960.

3. Tle ie a final invoice. Bovever, since it is anticipated that additional funde vill be obligated for this projoct the files should not be elosed.

Chief TSD/Bosearch Braneh

Attecheonát Invoice & Cortifications

1 - TSD/FASS

xxxx

(16 Sept (o)

16 Septeaber 1960

[PAGE 20]
\$6,500.00

(1) It 1s bereby certified that this is invoice No. 1 applying to jouLTRa. Subproject 12t. that porformanco is satiofaotorys. that the services are being acccupliahed in accordance vith autual agreements that a dotailed agenda of the peyments and recsipts is on file in TsD/RB. that tho dill is just and correct and that payuent thoreof hes not yet been mede.

Chief, TSb/Reseerch Branch

Datei\_

(2) It ie hereby certiried that this invoice applies to MUITRA, Subproject l24, which was duly approved, and that the project is being carried cut in eccordance with the memorantum dated 13 April 1953, froa the DCI to the DD/A, and the extenaion of this authority in subsequent remoranda.

[PAGE 21]
CRRTIPICATION

(3) It is hereby certified that the progiam under subprojects 39, 81 and 65 have been satisfactorily coupleted and raturned uused Dunds. However, subproject 88, vhich ia still continuing nlso refunded money. thoreforv, it ie roqueated that the encunts es chova belov cn Invoice Muzber 1 of subprojeot l2h be credited to the subprojeets as showa belov.

Ch1of, T0/Reoearch Branch

[PAGE 22]
1 - TSD/0C
1 -TSD/PASS
1 - TSD/RB

[PAGE 23]
MEMORANDUM FOR: THE RECORD SUBJECT : MKULTRA, Subproject 124

1. It is requested that Subproject-l24 be approved to support the research program of in "The Psychophysiological Correlates of Carbon Dioxide Environment"-in accordance withthe attached proposal.

2.. This study-will-add to our methodological sophistication for measuring carbon dioxide- tension and pH of body fluids as well as our knowledge of sone of the relationships between blood pH and-certain psychophysiological-variables mentioned in the attached proposal.

3. This project will be funded through th for cover purposes. The accounting for funds expended shall conforu to the established procedures of that-organization.Title to any permanent equipment P shall remain with in lieu of overheed charges.

4. The total cost of this project for six months is estimated to be \$6,500 as iniicated in the attached budget. Charges should be made against-Allotment 1525-1009-1902. Any unused funds will be returned to the at the completion of the project.

124-19

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5. has been cleared and has served as a

consultant to TSD for a number of years. He is witting of true

sponsorship of the S

Attached: Proposal

Distribution:... Original Only

Approved for Obligation of Funds:

Date: 15 Sept.60

2

124-1

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Of all the environmental factors whioh influence haman health, the most neglected may be ono of the gasequs conathients of the atmosphere - carbon dioxide. While the proportion of carbon dioxide in fresh air rans only to 3/lo0 of 1s, the blood and the body cella carry a carbon dioxide tonsion which would be in equilibriua with an atmosphere of about 5% carbon dioxide.-

Changes in the carbon dioxide tension of body fluids are rolated to many physiological and psychological processes. Over-breathing is one of the concomitants of anxiety. The corresponding reduotion of carbon dioxide tension reenlts in vasoconstriction and increased snooth and stri-. ated miscle tonus, with the creation of many aymptoms, These symptoms may to extremely unconfortable, and act to accentuate anxiety. Thisa violous cirole is very diffioult to interrupt, voluntarily, since breathing is 1 largely an autonatio function. We can interrupt it by inoreaging the carbor dioxide content of inapired air, and thie is en important method-of-treating.:sute anxioty states charactorised by hyperventilation.

An indication of the wide-spread applicability of carbon dioxide inhalation can bo seen from iwo examples. Spastics and victims of Parkinson's disoaso may obtain appreciable relief of muscle tonus, for at loast

124319

A Proposed Study of the Psychophysiological

Corrolates of the Carbon Dioxide Environment

[PAGE 26]
as mach as several hours, through breathing a mixture of 5-7% carbon dioxide. The mochanien is that by decraesing the pi or the blood, more body flaid calcium is-ionised and this is.conducive to mnsole relaxation.

Another uee of carbon dioxide inhalation lies in the treatment of classical migraine. In this disease, the aura phase is characterized by marked vasoconstriction of cerebral vessels which constitute part of the tree of one or the other carotid arteries. Aural phenomena, such as visual ecotomata, are a reflection of temporary cerebral anoxemia. After minutes to hours of vasospasm, the affected vessols bocone totally exhausted and epring into vasodilation. The painful phase of migraine\_is thought \_to be an action on pain fibers in the stretched walls of the vessela. Preliminary observations indicate that inhalation of carbon dloxide in the aura phase of classical migraine can atort the syodrone by ceusing vasodilation before the amooth musoles of the cerebral vessels aro totally exhanstod.

Research in the effeots of tho cellular carbon dioxide onvironment has teen negligible.-This neglect may bo attributablo to several reasone: In the firat placo, accurate studios of the acid-baso balance of tho blood havo uaually required a slzeable amount of:arterial blood. This is not easy to come by, since artorial pancture is a diffioult and painful procedure. In the second place, there has been no simple portable device for providing carbon dioxide for inhalation." Finally, there has been no

1.24-1

[PAGE 27]
concertod effort by pharmaceutical compenies to atady the problem, since no patentable durg is involved. Carbon dioxide ia cheap - omnipresent ia the environnent.

Long ago, one of the applicants vorked on the acid-base balanco with mioro methoda and capillary finger blood. The methods were fairly accurate but very complicated.-Wo knew that simple methods vould be perfected, bat were unable to.do this ourselves. In May of l960 a simple mioro system vas e aralable in

We have developed and used a simpla portable-sourcezof carbogen. and are prosently using it in explorations of the treatzent of migraine.

The situation is now ripo for a coaprehensive study of the biocheaical physiological, psyohological and treatment aspects of alteration of the carbon dioxide level of body fluids.

It is proposed that tho acid-base equilibriua of psychiatric =Qalu= S'gar patients bo surveyed, using tho nev mothod of Lis. Variations related to diagnosis and cource of illness may be readily peroieved.Then, with the same kind of patients, the feasibility of altering tho acid-base equllibrium be carbogen inhalation, and the duration of alteration after euch inhalation, would be studied on patients on normal vctnteers, The effect of carbogen inhalation of selected patients, ospeoially spastico, viotims of aigriine and patients with anxiety would bo studied, with repeat-Aetiup, f. lndon, 0.s. gegn, k. Enge, K. "Dhn acie Be metatdn a new Apr." h2neet y ray 1i60 1035.1039.

-3-

124-1

[PAGE 28]
ed phyaical determinations of acid-base variables. Elrect of acid-base changes on FEo. Ero and blood pressure woald be detornined with a polygraph which is already available.

In sumary, tho primary objective of the proposed study is to
explcre the parasotors of acid-base psychophysiologiçal correlates, using
a method which hes just been-mado availablo. Whlle there are spooific treat
ront objectivos, sich as in cases of excess motor tonus, migraine and anxi
eity, these are secondary. . .1

2. Yothods are esgentially the mioroanalytio system of Andersen C standard inhalation nethods and a versatile polygraph.khero appropriate, psychological-tests as well as psyohiatric intervlevs would te used.

Tho basic facility is a very active psychiutrio service speoialising in aoute illnesses, togother with the ataff and faoillties of a general hospital.

3. Bagic exploration shonld hot require over 6 moths.

L. Budget.We do not -yet have a breakdown on the Siegaard Andersan apparatis, but this should bo-available in a few weeks and will be sent in as a sopplement. Total cost of apparatus is here estimated as \$2,500.-

Personnel: Psychiatrist \$ 2,000−(1/3 timo) Technician 1,500 Apparatus 2,500 Miscollaneons and Overhead 500 \$ 6,500

124-1

[PAGE 29]
5. Qualifications.

general hospital with an active\_2k-bed paychiatric service. Extensive laboratory and consultativg faoilities are avallable. The Hospital is incorporated as a non-profit organization and is tax-exeapt. Gualifications of the Project Direotor and psychiatrist are indicated below.

6. With the exception of preliminary clinical observations on the treatont of nigraine, there have been no stidies bearing directly on the aubject of this proposal.

124-1

[PAGE 30]
and overlap with tho clinical study is minimal.

9. A rather interesting application of this study might bo in the field of personality evaluation. Since thure are certain psychological variables, such as-anxicty, which relate-to the acid-baso equilibriun, it is just possible that the new and simple nothod of acid-bass study would apply here. Poesibly, the ability of an individaal to withstand marked aoidbase changos withoat developrent of disabling syaptoas or-other physical chenges would be an index of paychological stability! The induction of acidbase changes, through hyporventilation, coald be a kind of atress test. With the apparatus which.is proposed, tho extent of acid-base change coald be-deterained readtly.

124-1

[PAGE 31]
The Lancet : Saturday-14 May–1960

THE ACID-BÀSE METABOLISM A NEW ARPROACH

POUL ATRUP
M.D. Copeahagea
O. SIOCAAD ANDERSEN
M.D. Copeabagca

K. JercenSEN M.D Capenbars K. ENGEL ase. Cpentagea

Fre ds Deprru of Clrmical Chamstry, Repitale, Copoages

Ie this peper we evaluate facton which churscterize disturbeocet of the rid-base metabotiam.- Pbeimportance o using chesnical values, which are relevant fyun à clinical s wo as  chemicl point of view, is sreised and exaaplified; and m analyticel method is descibed foi mearunng the relesant chemical coocentrations wng capillary biood, and avaitable us a bedside procedure

Claaifcadoa of Dleturbanccs

The termn acidosus sbould denote a patbologncal condition due to eccumulation of scid or to loss of bee. These two poesíbilities may lead to the sare clinica! picture, as both tend to lower pH in the organism. Sicitariy, alkalosis, or better dasecsis, should mean a pathological conditina-due to sccumulation of base or ku of scid.

The term "soid " od "bese " ere in thit peper ued for. hydrogen-ion dooor and scceptor, respectively, scoording to Brorwted (1923).

The use of these widely accepted defnitiocs increavee darity (Devoe 1953, Praetorius 1954, Retran 1954), especial!y becwuse the acid-tase mreuabolisn can be dealt with iodependenty o the catioa avecabolisc. Caricns are neither acidh nor beres end shoukd cocsequently not be designated bases (e.g, "wouay buses "), but ctiona.

Of all acids and baset, carboric acid it physiologically unique tecause of its bigh endogenous production, afd beomuse its coocentratioa ia reguiated byrespirstiga. Distuartances primarily due to curbonic acid shopld. therefare te cinicatly grouped separtely.- Accordingly. h of the two cooditions-acdosis and batoie fan be further classified as either rupiratory or non-respirafory. The bast group, often pamet "mctabolic ", compriofs all dipcurbences primarily due to faxed (ocn-volstile) acida d b.

Priatry ditartance of the wcid-bae metsboligm in wmully cxnpcasated to vune extent. A repfatory distartee is coenpeasated by  renal mechanismfand noa-repiratory disoubeoce by a respirstory mectalsm. If, fe inrasce, pH teoda to fall because of an sccpaulttioo of socse pon-volatile acid, hyperventilarion lovfer the aterial pCO, (eg, Kusaul'e respiretion). Ttf actual erte of a patbological coedition can therefore bethartetrised slro by ita degree of compeosation: u for compwwated (compeomtcry mechaaism nos working). porrially cowpmusted (pH noe brought to peomel valug), fully cpeuated (pH normal, or cvrcompmuazed.

The tenms acdia aod alkododa ee uied in sone covotrses for cooditiona in which the pH of arterialblood is deressed or iocrtued. These teros do not interfere with the diaion piva bore.

ErGmatrest for DHegeosle

To indicate the severity of an acid-bure disceder the felowiet estimations have paoved vahuatle in oue epcricoct.

Artemal biod pl fepends on the relarion between the respirutory and-thefaon-respiratory- coanpopents of dhe scid-bese metatolikn. It Ous reñects the aumbined inßuence of respigftory and noa-respirarory disturhances.

Any deiatisnffromn the norm cobon-dionde teston (arterisl pCO) gefecs a respirator scid bare disturbance, either primsryfor compensatory. This acoords with the generat view./

Any. devinfon from the normal comtent of base ln blood redlecs. a gorrespiracay sad-tase distubane, eithet primary og compensatory.The bae cuotear should be expresedfas itanlird bcarbvate or a buse ecess or dare defgr. Standard bicarbeeate is the concentration of bicarbogate in plasaa, when whoke bloed hs been equibbgatęd with carbea dioxide at a pCO, of 4) mum. Hg a 38, and whea the hzmoglobta is fully oxygeuated Uergghsen and Astrup 1957). Base ex es or base deficyt) direaly expreises the amount (in mEq.) of strong Abase or acid) added per liue bicod, when the normal mcan h ybitruity fixed at zero. Zeobus certespoods te the nograal tean for suanderd bicarbonate (229 mFs. pe liyar-When the term tase excess (s e.) is used exclusively Uie peance values will cxpreu the excess of base while the negative valuee will cpress the defcit-of bare ece ef-sed) ud thn makes for simpleity ia fprctice.

The nongal 95 ranges of these veiies are: zcteria pH 7.35-74, arterial pCO 3445 mm. Hgi Mandard bicarbonate 21 3-248 mEq. per liure; base excess -23 to + 2.3 mEq peritre (Siggaard Anderseo et al. 1960).

When actual éyues found are conatdered the pustible dugnote ure limitel, aod. tegether with clinical informaton, they uruatly leaj readily to the exact Jiagnceis.

-Standard Blekgboaaté and Bat Ercen

The word "saadard y in standard bicntbonte sbould signify that the bicarbonage is measured under standart conditions in order to expçesh only the non-reipirstory side of the acid-base metabohgen. The atandard conditions are a hzed pCO, and a fxed ygenatioar of hemoglobin. so that the inducoce of respirtion on the tus content of the blood is climinated. Wéuve chwen to meaure with the hxrioglobin completeh oxygenated and at a pCO of 40 mum. Hg and at 38 C. I with thete conditions fuinled, the pH of blosd is meataged, the Henderson-Haaseibelch equation

- pH= 610+gpCO030

wal give the stendard bicartonste directly wben the value of pH found and the value of pCO, (40 mm ) choren tre inserted. Pull orygcoation of huetnoglobin s choten fot convenience, and also because it eliminate the unall effect of acidental variations in oxygen ururaion when venous samples are drawn.: The determihation of mandard bicarbonere is very easy (Jergensen and Astrup 1957).

Two eher bicarbonate quautitict, commoaly uled to indcate ton-reapiratory distutdances, are brießy menbooed for caapsrisoa. Fetal CO, of papna is the nlue deternined by dhe mazoncuic, volumeuic, or titemacnc tedhniqua uung pluama sgerzed anserobically frvm the cell. The rahoe varies,

O

O

424-19

7133

0

[PAGE 32]
TAMS PLASMA TALCS A TOTAL CO CO-COMDONG POWIR A STAND BCNAT DO    TA D  ? A   AD  . , W AMOOLON CMPLTT GAT AND CCMRCOD

Hangtha FCO, O, CO
Tol CO, (mM: 11-8 x00 190 H1
Ccoohinar p 19 0 21 in 314 212 212 11-2 212 thsrd btnpn,  e
thsorta

pow, with the stuel pCO, s well  wtte o srurrion of the biood, and con chertfore aoe bae iteal evepgre of non-respiratory dirturtapce. Thi ts iltegod in uNe I.

COconbiy  of plaa  the toul CO,  ph which js apered frocn the cels at the wtual pCO, and tea equlibrsd a a pCo, of 4 ma. Hg beve moartg T vale so vanes with the tal pO, ad the oyr teurstjor, though les than totl CO, (tadle 1).

Thus it teens cvident thes stegdard bicarbonete is the best dcarbns ve to mreure whcn it it daired to dimicnte the infhuene of the reepirutinn mod to determire the pon-ttsprrarory componeot anly. The effect of equilibrating whole bood seerra to be appcusimuately the seme in viuo s in vivo (Shok aod Hastings t9)5)-i.e., s if the tepirtxy fareóoa wu tandadised.

The gandrd bicatoare ralue has, like ccher bicarboorse viues, te drwbakt that it docs not shaw directly the arsount, in mEq. per lite blood, of fire d or bese cavring  change in the beve conrent of afblood sople. (Thie is bocsuse the carbon-dlonde, ticagbonate ayrtem in responsibie for coty ebout 75% of the buffer stion of the biod sgaiart fzed eikés and beses,,ihen the pCO, it kept coosupt (e udle n)). Therefore, to fnd the tou defcit or excess for. bese. per litre pblood, the deviation of standand bicarhooace froen the normel mocen munt be correced: this can be mppesimetehiachieved by anltiplring by 1 20. An exaat cretion rquiras kpwkedae of the bufter capeigy of the bhood-ie, the hermodobin coocentrtioo. The vaatae o uing quentitics which directly give the turptus anount of fred süds or tases contained per lite dlood is thus evident. Here the we of churage in bufer bere or of bese czens is helpful.

Ad Les (Singrr and Haarg 1942), hikch in all aes shaid be uod in the for agrecing with thé acid bas ornorp esd (1), inctude butr anigs vther dn bctate, exceially hancgkbioste jora Jbcrtby itt vahuc becrs badeoansect ol Co, aod a cori ln tufer boe, in tnBq per litre, drocty cgreosed the aoount of acid oe bece cosing the chepe (oable r). Oa that cbbr dand, it repeeseats ran of fasocs of éiez br egirioa.Purtrmore, the hagr bur vehe of a bed upls deosb rs iu haykin end protein awranicn (totle r). A patcat wit a low buffer-due ratee duc to  low bannogfotin cocccotrton do seede bemgkbia and n bicetonot

Coocerning thé quantity baué axoaw (for dehniton we above), this give directly, in aEq. per litre blood, the surphus aszat of fzod ecid or bee (tste n). It is e quantity caly undermtood by those urfaniliar. wth dintical acid-base pirotlensa. Paher it alkom the trestaot of acld-bate peoblomne in  qoenriuztire wey. So, froc boch i theocedral and • precticd poist of view, beee excese ia prefereble to buffer bere. Ooe srgurseat againe the use of bese czcéa ie thuat it doca pot gire ae ica-vahue Ae the tene-coocetrstion in bhood. If dhin is pranted the saotend bicarbonate ouud te used, than giviog the bicarbonate conceattation of plaama uader Manderd conditiona,

Fuat A indi  daad H rha 112 da lhtie a O- 6 w  sialy p 8 e p 1 pOO, =  ra. He. If, for toeuec, te acaal pH of the murabie ady dree bod had ba meked t 7  asenl p, paoid

Toal CO COrovabtadng pywer, aated Mcerboxate, buffer hase, aad bese exctés caa be dotergined by the aew aiaciscaniçue outlined beke.

Qenosudre Tregte Resiratery Ditustence Chanar ia the shveoiar wetibarico, lratog ta raqpiretry dintances, are detandoad qaaodreiy by Uhe pCO of arterial blood, te vake of whach ia pecni ore be pnunel t bé ienricl wita the rare of  of uveotar mr.

A te egeted ao df cuton daaide r unit is coostant foe tn indiridunl ia a scaty otte, t

0A V AL, AD SANRO  D   L W B CCNTSATION OP HOLCN (1) AND 7.5G.  100 ) D W WU O  D (10 μ. L 0)

Jeves

1036 MAY 14, 160

QRIGINAL ARTICIES

DHO LANGT

[PAGE 33]
prodact of the diveolar vennlanon (A) and the pCO, of the arterial blcod hás a consunt value $\because A _ { 2 } + A = \frac { 1 } { 2 } ( 1 - i ) _ { 2 }$ K. Accotdingly, tf the alveolar veatilatitn decreaes de pCO, must iacrtis, and vice vera. For instaace decresse of A to half must double the $\gamma ^ { \prime \prime } \wp _ { \prime \prime }$

In sccne cuscs additional babortory mearureneots helà in dhudidtting the ceuse of a respiriory disturbance. Anroog these the meaorement of the uxygen saruration or the oaygen tension $\{ \infty , \}$ of arteriad blood is imporctant. Tbus, a lew cxyzen saturation with a low $\ell ^ { \mathrm { { r } } } \hat { \mathbf { ! } } _ { \ell } ^ { }$ is e1xciated with coxopletcly different discaes to a low oxygen eanration with a bigh $\infty .$

Nom-rupratory Duturboncas

When dealing with the non-repratory Jetrdarwes, hoowedge of the total amount of rzces, acid or tase in dhe ceganinn can be of clinical umportance. The prollens iavotred e roher compler, mnd for pouper uostmett knowledge of che bstritutica of scid and tase in the differcat body-speces aad the rwe of euchuange betueen thera is required. 'Nhe folowing approzimetices are bんw.

The debcit or exces of base in te extraccldar bodympwe can be estimated in mEq. ty multiplyiog the negative

a oecrioa snd dr cas o.

A, B, nd C teprat saple of poreal blood with a hemogibin cooceorraka of $a$ 10, nd 20  pt 100 and. répeitiv -A A d $t _ { 3 }$ show dh dapiacernt aut edlaen of faed wid s me. axt ecd per litre blood); t $\mathbb { A } _ { 1 1 } \mathbb { B } _ { 1 2 }$ und $\pmb { \hat { \mathrm { \Lambda } } } _ { \pmb { \mathrm { \Lambda } } }$ aher addition of base (15 mq. diaa cartoeats per litre boed Tbe peunt of inter snriee of theee hne foom a cuave the base eaces curvei ahich idoa de acont of bant crra pouve vauet and baie deñct (sgettre reluesy ia sny blood sample.

or positive value found for base exces, in mqí per liure bhood, by 0.3 x the bxty-weight in $\pmb { \mathrm { x } } .$ where the factor 0-3 is found experimentally (Mellemngaard and Artrup 1960). This umount cur;esponds Jirtatly to the amount of sodium bicarbonste o of amnonnm chlonde required to peutralise  soa-reipiratory Juturçance in the extrocelhdar space.

In doling wah peticnts, bowever, the amoun( of ercess or dehcit of buse in the wbote dody does not always secrt to be dirccty propordonal to the excest or defict of bese tn the

Pa. 3 piog pCo: t lor a blood semple, deermhed  di co4la  1

The poupt ot igiersectéa D) with the bee escan cute indicte the amount ví bas caccinto be s 0 mEg pet hue bood, whe pint E todeptes the bufet base (= 40 aE. per litre The: saodard baubocate (1a é mEa. pt lare) cn be Serived fom the pH ruue cocespondag to rO   aun. Hg (F. Te theiue dhows pH viiurs and saaiar bicechoaare The toal $\mathbb { C } \mathbb { O } _ { \ast }$ of the pleama froch the aerobally drawa od and the CO mbiing poeer cag be found from thdbgire. (For thit celoulation ra Sunard,Anderxn tnd Cngel 1e)

blond When, therefore, patient wre to be treated with intre vewza infusions of acit or bae,  in adrisabie to estioute the dosg-aceuuay. to aormeise the puse content of ube entr celjula: spee oaly, and then folloethe effest of the treatpent by frequent blood aalyes and aise dy clisical obuervation, béfore dew ufusioan are given. Thatovertrtatneat it avoided. (Mellengrard und Autrup 1960)..

In treating the noa-respuutorya diturbancer, it is importeat to estimate ao abocrmal ss of acid or base. Thíiis epeoally so when the lo is pxtrreoal- eg, in

MAY 141900

VR:INAL AKIICLET

THE LANCET 1.37

Pe. Cy  e or te

[PAGE 34]
pyloric stenosis end peactreatic fistule. Io such caf the kort amount of scid or base ahould be Jeterminéd by titrwtion together with the tweaty-four-bour erareaod of id or base in urine (Jargecsen 1957).

Mierotethad for Deteralaiag pH, pCO, Staadard Bicarbonate, aad Base Facese

When uing macromethods for decermining the above relevant vatues for chanarriting the acid-besc status, antcriad puncturet are neccssary. Thin is a dawteck when frequent analyse are: needed for inetante at intervsls of minutes in casce with rpid changa in ths rapiration (in antrthesicko, tretnct in a ripirtor,&c.). A micromethod, using about 100 pl. blood, was therefore devckoçed (Sigpard Andersen et al 1960).

When fred aid it assed to the blood, thyline it dit placed to the left. Wbon base in assed, ye line is deplaced to the right. Now  praph (fe. 2) cyh be conatructed expressing the displacensent cmused by phy anount ofacid or basc, independent of the bemogltin concentreton (Siggurd Anderiea and Eogel 196g).

ing a bood wmçle at owo koown O. tensu nd mearariag the pH vahues, the line forthe sample is determined (g. 1). If the actual pH offthe bxd sample is knowo, then the wrual pCO, canasily be found.

The point of intervection bergeen thit curre and found pHlog pCO, line for  bood mple thua indicaten, in mFq., the base exces per ditre blood.

Thn eract meagdremeot of blood pH et the actual pCO, and at two knowu vahuee for pCO, will allow the caicalation of alarclevaot blood data cocceraing the acidbere tatus. Ths io iDurtnsted in bg. 3.

The thearetical bedgroand for the cakulariog of pCO randard bicarbonste, and base ezce in that graphs thowing the relarioos betsern $1 0 0 0$ ad pH ae approzimady uuraight fnee (abowa eaperimentsily by Brewin t al. 19 and Astrup 1956). The slope of the liaa deppóds on the buffer crpacity of the blood. By egilibrat-

Io che asme digna  curcen be coanructed (Siggsard Andersen and Eogel 1960)fpresing the cootene of buer bue scording to the defniroo of Singer and Hadngs (19s). T he curre ia shown ia thupper het coroér in g. 3. By wkg this cirve the amount of buffer beoe in blood caa be fbusd

Principle

The colpneot is dercribed in detail chewbere (SiggngAnderen, et al. 1960). It cnsist of  pH-

Pig.7-Ces 3i va for, pCO, tad b evoc o Wod frm a aecmel T dinH. n.etinint

meter, a cinularing theraoets, a pactioa ponp, a miorodetrade (6g. 4) tpording to Sear (1957) ad A micro equilibretioa chambor (g. 5). Al theee paoe cao be mounted on a patuble wbk togotéer with nwo noal cylipdo cuntining hswt of oygen and corbon dicride.

Capiñey blood ie drewa froen ear or friger. Rog the atual pi obout 20-25 pl it rucked directy inzo the caçdDery edeccrode (the płjociple of Seaz 1997) snd the réeding ia bade bamotarcy, or it k pucked fromplood drwa soacrobicetly into e bepericiled apiDery gaei rube wita sodium fuoride About Do 90 μl. of bood from rwo capinity gaps dubes is divided betwem two of the chamnbers in the equilibrarion apperatud, Thle is then thakrn mechanically (2600( pm) tand aAter thres minutes the pH vahe in the two saopics ue meaured socesirely. By using thec two vatues and the oocrepooding pO0 vatuer (fror the cylinderi), the pH/log pCO, line in driwa-and the pCO odard biarbocate, and ben ac can te cakulated (fg. 3). Tbe mhod ia

O

1038H4Y 14, 1960

ORIGINAL ARTICLES

nyLANCH

[PAGE 35]
highly accurate, as the ihrce values can be found with an ér of la thn: 2

Iunirative Casca

The alvantage of frequent registration of pH, pCOp and base ercess by tbe method Jescribed here is illustrated in the following two 、ases Figs. 6 and 7 show a convenicat graphic sysicm tor thcse thrce quantiäes.

Cas 1.—Fig o shous bicel values fron a pant female, 13 yean old, operated on for a defect in the atrial ptun. At the berincung of the operation the values for the nog-respiratory comçonent sadicate e alight baę deâct, possibly e to the postsbeoeptive phase. A nuanfest noa-respiratory Tudsis develops u son as the blood of the peticat is nixed wh the rsther acid dooor bked from the heart-lung machine apptoximately 4 titres wah a bese excess of - 12 mEq. pet btre, tnhly due  latc acdIhe d ercesa quicly decrea, partdy digibyuioa between th different dody compartmenn, anã partly by oxidsuon of the laçuc aidt. The secood day. after the operstion a norinat vaiue is rcached.

The curve for the respuratory sompxnent (pCO) shows firt the efest of overventlabon durug the anentheia.A slight nte in pCO, is sen when (he heurt-lung machne-ia responuble for the CO, excretoa. When sponunéoustopiri. tica wa established wfter the operrtion the pCO, wa between 0 and 60 oun. Hg, teaching a porul vuue within  few houts.

The pH curve shows the tesuiting actica of the respiratory and aoo-repirtory conpocent oo the hydregen-ion con-Ctottion.

C4ee 2-The pronounced Jevitions froma nermst acid-bete vues sea in a noral unvidul (mle-26 year old dy pazinal hypervcntilatn, reriod of apote, and intentive mvacvlu czercs of short durtion are illustrated in ág. 7.

The rise in pCO, and tbe fel io pH duting the two apnae peroda are moderaic and obviously the fal in ozygen saturation (to about 802., not mcasured accurutely) is the limiting factor ke the length of voluptay tuvpension of breath. During tiypets veotlauon  fnll un pC0, to about 20 om. Hg wii obierved The murculur axeroise w followed by erornous hypervghtlezion, but the pCo, wu now pratically withun pochut limin. The expiacatico munt be that the greatly iocréssed. CO, production is conpenuated by an equslly increaseg CO excrcton dy ueaot of tbe bypervertilatioa.

Only umail vanatioct, within the pocmal lipit, e seen duriag the pure repiratory changes. A pomible crus of these eall varaticoa is diplcement of bae detween the diffeteat body-opaces; thu poiat deserver further inveicigatigóDuring the musoular exercise a beavy non-respiratory acidgña devtlops, whth a bae rran of 12 enq per litre, indicage accumula don of large amcunts of lactic eod.

Grrt fucruan ia the pH from 7 38 and7.21, obtered orer e period of ten to aern minutes, wu qpued ezcluatreiy by à A in pCO, ad in bue excesy.

Samaary

Disturbences In the scid-bure megboliim heve been cuified according to the relation bofwcen blood valucs for pH, pCOp and an indea of aaespiratory. dinturbsoces. This index should te either bikarbonate copcentratoo meneured under sandard cgditiocs n"aundard bicarbcoate"or ehe dhe surphh amount, u "base eceu ", of faed scid or bae inmEq. per litre blood. Knowledge of the vahue of besekaceu enabler the toual defcit or exces of bese in theBlood-volume and in the extricellular spece to te culoulaped

An accvrate bedaide methcà, uing capillary blood, foe determiring all relevwat blodd vahves for the identifeston of dirturbancet in 'he tkid-bese uet.xolium, qualitativchy tad quanttatpcly, has been devised.

MEDICAL ASPECTS OF ROAD SAFEIY

L. G. NoRmaN MD, B.Sc Lond. M.R.C.P, P.H. CHUEP MRDICA CPICA, LGNPON TRANAT CUTIVE

To drive safely requites the use operain phyiical and mentat qualiues in reasonzble degye. But these qualties can aeldom\_te. precusely defngd and they aannot be quantified. Perhaps the nature'ghd amount of the eyenight required for driving have beegnore fully established than thoe of other qualities, tgh even hete the bordertine between boness and unhtnei to drive is somewhat ubitrary.

In Great Britan in 1y58 the police reported 992 road pecudenty in which a Jgfver wu ll or in which his physicai defect was regardéd as a contributory cause Road Acctdcot iv58. Tis is a smal proportion of the total nuinber of accidenrt, but their prevention is of particular imedical interest.

A The clinical gstessnent of ftnesu to drive des not Huotve the deytkopmeot of yet another branch\_eCMedi: emeIt is upmply the application of clinical knowledge to he partigular tequirement of driving vehicles mafely; and,  uigost all doctors drive themseives, they are in the foaugtte -and unusual—porition of having prsctical expericae of both sider of this question.  Many adult peucap se drivers who muy sek advice oa sheic fiueu to dgãe dérng convalercence or in relation to chronic duce. 1hés is especially imporuant fot profeisional driver who ey be reponsisle for the wfety of many pöiengets

A genaad gurde for physiciano-oo the suteument of Sáunes to drive u been published by the American Medical Associationt(1959) whch bas also produced brght lintle booktet fo petienu, entited " Are You Fit to Drive ?". The Břuh Medical Anociation (1954) and the World Heanh gniution(195o) have aso publithed helpful guides ohphyucians. Tbese ue not a well known a they thoune

In uteuing the btnen of Jers it ia usun to contider
three typct of vehicle: (1) thepublic-service vehicle in
which teventy or more paisengcfmay te carricd, (2) the
heavy commercial vehicle, and Thghe privete car. The
drver of public-tervice and, cornáigrcial vehides is
profeniocal who nerally driver for Tyerl hour a day;
the private-car drivet is ujually aaamateur wboze
driving may be for uüule as hal an hois a weck or an
much-u eight-houri-Nayfr exampl some wes
-repretenutiver. The risk of wecident due tg• medicat
aunditioa in driver increaks with the timéhe speoda
drivng. Hence, ià uésig the fune of pienn to
• Tpe noad Mitroy lecture for li6o, delivered before E Roye Colert of Physicuat of Londea ea Feb. 4. The árueture appeared teit wek

DA ATRUP OTHLAS: RFEAENC

Anve. P ' ad.J. ka. L. 1avn. D, 33 Rp. 144, 177
B F N.(1923:  J. h Pa-B, 42, 7.
Dever. Ari9s Abtc f pçen, Amencn (beeicalSocier, h t. 7C
gan-K-1937 S.and 9. chn. Lo. 1s \$, 217. 二 Avur.1.7, . p. 121
Mr, K Au, , )  in  p)
a, an S,P.D97. C. , .
7, P1954: g.11, 151.
Pria, A 5 10 . Md. 17, 4.
\$aa, MC1057} Cl4. Ch1, 604
S ,H,A B193... . 2
Srd Ander, O Eg, K. 19 Scond . cha L (mr a t J, K., Aup, P. 9o) din th pr).
3an. 8 à, Hoe, A.  [194, Mafhir, Bes, 27, 21).

MAY 14. 124

0

O

ORCNA,I

Refermce a fon of next colume

[PAGE 36]
MMORANDUM FOR: THE RECORD

SUEJECT

: Approval of Study of the"Psychopnysiologicat Correlates of the Carbon Dioxide Environment."

ATTENDANCE

C

SUMMARY: 1. Request for-\$6,500 to carry out
study was approved. It was recognized that this is primarily a technique.study as proposed but that, once becare familiar vith-the apraratus, a tighter design could bé developed. hgreed to work with when the time was proortious.

B 2.Funding will-be effected through the mechanism Hient equiptent wiil remain With

TsD/Resetrch Brench

Distribution: Orig & 3 - TSD/KB

rvd. Rec'd. A /19 808t 2 JO 27 g0dyp60 pan 20 d pl6d

for file

124-20

26 August 1960

[PAGE 37]
9 8/w
3/23 23
22. Mg 23Ang

[PAGE 38]
Ra: "A Proposed Shody of tha Paychophyiiologicol Coralotes of the Corbon-Dioxide Enviconmant by C

Do

I hove ravlewed this request corefully. It is really very intsresting for me to se how methods for the onalysis of blood CO2r pH alc. are becoming increcsingly ovoilotle for use at the bedside, ond l am also hoppy to sea that people such o de nterasted in using these methods to study mon's raocnas is mhoir lile sifuations. Howevar, I an not at all happy about the hypothesls that they ors putting forword for thair proposed research. This hypothasis-seams to came -in that category of, "Let's study a group of potlants and see if they aron't otnormal with regard to this or that. Theré ore so many things that con cause the ocld -base equilibrium of peopls Who change ropldly over short periods of time that, no matter whot wes found in a survey of psychiatric petients os compared to normals, il would be unlikely thot one could draw ony concluslons from the find ngs which would help one undershand the role\_of the Introcellulor CO in vorious Forms of psychiatric disaare. My suggestion then Is that these investigotors have good methods but that thair hypothesis ond exparimentol design leave something to be desired.

I would supgest thot we davote the sums available for work in this area to so pro cts that are different, but malntain on open mind obout tl.ese Inverigcton.

Sinceroly.

B

July 18,-1960

[PAGE 39]
Jane 24, 1960

Harewith ia  propoeal for inveatigation of the puychophysiological correlates of tho cnrboa dioxide environzent. \_I hope that you will fini it iateresting.

an poglocing à single reprint of the stady which I did vithee 935, which is roferrad to in the application, together vith phctocopy of the recant report froa Copeniagen on siaplified mothods for atadying the aoid-baes equilibriua.

Sincaroly,

Approvad for Honpital Adainiotratce

[PAGE 40]
KULTRA Subprojecs

10 124-25

IIVONCE OEECK LIST