AldrichJames1972

San Fer nand o Val ley Sta t e C ol l eg e
AGONAL PHYSIOLOGY AND BLOOD GAS TENSIONS
''
WITH APPL ICATION TO THE SUDDEN
INFANT DEATH SYNDROME
A the s i s s ubmi tted i n par t i a l s a ti s f ac t i on
of the r e quir ement s f or the d e g r e e of
Mas t e r of Sc i enc e i n H e a l th Sc i e nc e
by
Jame s 0. Aldrich
Janua r y , 1 9 7 2
"Beauti f u l i s what can b e s e e n ,
mor e beau tiful what can b e
unde r s to od, b y f a r t h e mo s t
b eaut i f u l i s that wh i c h we
don ' t know . 11
N e i l s Ste n s e n
1 6 3 8- 1 6 8 6
ii
The the s is of Jam e s 0. Aldr i c h i s appr oved :
San Fernando Va l l e y Sta t e C o l l e ge
J anuary , 1 9 7 2
iii
'··
.-
TABLE OF CONTENTS
PAGE
L I ST OF TABLES
vi
•
L IST OF F I GURE S .
vi i
ACKNOWLEDGMENTS .
vi i i
ABSTRACT .
ix
C HAPTER
I.
II.
1
INTRODUCTION .
Statement o f the Prob l em .
3
L imitations o f the Study .
3
D e f i n i t io n of Terms
4
L ITERATURE REVIEW
•
6
•
6
SID Syndrome - Epidemio logi c .
13
SID Syndrome - Pathol o g i c
Ga s Transpor t i n Blood .
Summar y
III .
V.
25
VI .
•
41
•
43
CONCLUSION.
BIBLIOGRAPHY
APPEND I CES
A.
27
•
D I SCUSSION
18
24
PROCEDURE .
RESULTS
.
22
•
Exp er imental D e s ig n
IV.
.
44
•
48
•
D ata L i s ti n g s f o r Experiment 1.
iv
48
PAGE
B.
D ata L i s t ing s for Experi.ment 2.
C.
D ata L i s t i ng s f o r Exper iment 3
v
•
50
•
52
L I ST OF TABLES
PAGE
TABLE
I.
Exper iment 1.
Mean s , Standard D e vi at i on s
a nd P Val u e s o f O c c lud e d Airway and
C ard i ac Arr e s te d Anim a l s
.
II .
•
•
•
•
•
Experiment 2.
Means, Standard Devi ations
and P Va l u e s o f Occluded Ai rway and
Cardiac Arr e s ted Animals
•
III .
•
.
.
•
.
•
•
Expe r iment 3 .
Mean s , St andard D e vi a t i on s
and P Val u e s o f Occ luded Airway and
Cardiac A r r e s ted Anima l s
.
•
.
vi
.
•
•
•
•
.
•
•
.
•
28
32
35
LIST OF F IGURES
PAGE
F IGURE
1.
Exper iment 1 .
Sacr i f i c e by Re spiratory
o r C a r d i ac Mean s , pco 2 Va l u e s • • . .
2.
Exper iment 1 .
Sac r i f i c e by Re spiratory
or C ar d i ac Means , p0 2 Valu e s
.
•
•
•
•
29
.
.
30
3.
Expe r iment 2 .
Sa cr i f i c e by Re spir atory
or Card i ac Means , po 2 Va l u e s • . • • •
33
4.
Expe r iment 2 .
Sac r i f i c e by Re spir atory
or Cardiac Means , pC0 2 Valu e s
34
5.
Expe r iment 3 .
Sac r i f i c e by Re spir ato ry
or Card iac Mean s , p0 2 Value s • • • • •
36
6.
Exper iment 3 .
Sacr i f i c e by Re s p i ra tory
or C ar d i a c Means , pC0 2 Val u e s
37
7.
Experiment 1 .
Sac r i f ic e by Re spir atory
o r C ard i a c Mean s , pH Val u e s . . • • .
38
8.
Experiment 2 .
Sacr i f i c e by Re spiratory
o r C ar d i ac Means , pH Values •
39
9.
Exper iment 3 . Sacr i f i c e by Re s piratory
or C ard i a c Means , pH Valu e s
40
•
.
.
Vi i
�
.-
•
.
.
.
•
•
.
.
Z\CKNOWLE DGMENTS
Thi s i nv e s ·tigation was supported by PHS Training
Gr ant No . 1 A 0 4 AH 0 0 0 3 - 0 1 f r om the Department o f H e alth ,
Education and We l f ar e .
Sinc e r e app r e c i a t i on i s extended to Dr . C l aude T .
Cook and Dr . Ramon Buc k l ey f o r s erving a s members o f the
the s i s comm i t t e e .
The author w i s h e s to acknowl edg e Dr. Bernard Hane s ,
The s i s Chairman who s e co ns tant encouragement and a s s i s tance
made thi s pr e s e nt work a r e a l i ty .
The author w i s h e s to ex tend spe c i al thank s to h i s
w i f e , Hanna , f or her patience throughou t his graduate
s tudi e s .
vii i
ABSTRACT
AGONAL PHYSIOLOGY AND BLOOD GAS TENSIONS
WITH APPLIC AT ION TO THE SUDDEN
INFANT DEATH SYND ROME
by
Jame s 0 . Aldr ich
Ma s t e r of Sc i en c e i n Hea l th Sci e nc e
Jan ua ry, 1 9 7 2
The par t i a l pr e s s ur e s o f oxygen
dioxide
( p0 2 ) , c arbon
( pC0 2 ) , and pH were determined in the b lood o f
young adul t mic e s ac r i f i c e d e i ther b y c a r diac arr e s t, o r
b y a sphyx iation .
C a r diac arr e s t was pro duc e d by e l ec tr i c
shock, a n d a s phyx i at i o n by s udden o c c l us io n o f the
trache a .
A s ingl e b l o o d s amp l e, drawn f r om the l e f t
ventr i c l e thr e e m in ut e s a f ter dea th w a s anal y z e d .
Death
by a s phyxiation r e s ul ted i n a s i g n i f ic antly l ower p0 2 than
death due to c ardiac a r r e s t .
a s s o c ia t e d with pC0 2 or pH .
The type o f dea th was not
P o s s ib l e app l i ca t ion of the s e
pro c edu r e s t o t h e s tudy o f sudden i n f a n t deaths
Syndro me )
i n humans was di s c us s ed .
ix
( SID
CHAPTER I
INTRODUCT ION
A r e l i a b l e method for de termining whe ther the heart
o r lungs fail f irst during an agonal episode should be
app l i c ab l e i n determining cau s e o f dea th i n sudden infant
dea th s
(SID Syndrome )
(8) .
Lung f a i lu r e with a continued
heart beat s ho u l d r e s u l t in a sma l l er amount o f oxygen
in the blood s tr e am.
Mitho ef e r f ound that r e s p i r a tory
o b s truc tion in dog s r e s u l ted i n lower b l o o d oxygen when
c ompar e d wi th c ar di ac arr e s ted dog s
( 2 8 : 6 57 ) .
In the
c a s e of dog s , b lood c ir c ul a tion con t i nu e d for some s e ven
to n i n e minu t e s f o l lowing airway oc clu s io n
( 2 8 : 6 55 ) .
An
hypo x i c condi t io n exi s t s i n bo th mode s o f dea th becau s e
o f f a ilure o f the " re sp i r a tory cyc l e " whe re blood l o s e s
carbon diox i de
(C0 2 ) a n d take s u p oxyg en
(0 2 )
and l o s e s 0 2 and take s up co2 in the t i s sue s
i n the lungs
( 2 7 : 2 86 ) .
Mitho e f er's studi e s indic a te that o c c l u s ion of the airway
doe s not caus e c ircula ti o n to c e a s e immediate ly
(28 : 6 55) .
With t h i s conti nued c irculation and the hypoxi c c e l l
c ondi t io n i t i s po s s ib l e that more blood 02 i s r emoved by
the c e l l s in r e sp iratory obs truc tion .
Conver s e ly, in
c ardiac arr e s t oxyhemoglob i n doe s not r e aclh the hypoxic
c e l l s , r e s u l ting i n a highe r po2 •
2
Suwa ��' have shown tha t af ter thr e e m i nutes o f
c i rcu l atory a r r e s t , dog s hav e a h igher pco2 than control
anima l s
( 3 6 : 4 0 ).
I n a s phyx ia t e d m i c e it was f ou nd that
p co 2 i n c r e as e d sharply when the r e s p i r a to r was shut o f f
for thr e e minu te s
( 24 : 4 3 6).
The r emova l of b i carbonate
( HC0 3 )1 i ncluding c arbamino-bound C0 2 , and hydrated c a r
b on i c a c i d ( H 2 C0 3 ) from the b l ood o ccur s in the lung s
whe r e i t i s c o nv er ted to g a s eou s C 02
( 1 7 : 54 ) .
In both
type s o f dea th, c ar di a c a r r e s t and o c c lu s io n of the air
way, C0 2 c an no t b e e l iminated v i a the lungs, ther efore i t
s eems r ea sonab l e t h a t di f f er enc e s wou l d not exi s t except
f or s om e C0 2 liberated by the t i s s u e s .
Ano ther impor tant con s i de ration i n studi e s attempt
ing to di agno s e cau s e o f dea th through the u s e of blood
.
gas a na l y s i s is the e f f e c t o f t ime o n the p0 2 and pco2
o f the b lood s ampl e .
Earl i er work indicated tha t the
d i s ti nction b e tween mode s of dea th cou ld be ma de up
to s ix hour s f ol l owing the agonal e p i s o de
(2 8 : 6 5 7 ) .
This
d i s t i nction w a s i n par t a r e su l t o f t h e r e1a tionship
b e twee n time a n d blood temperatur e .
The iJiilt ernal
organs have a temper a ture drop o f approxim�tely 0 . 5 °C for
s ix h our s f o l lowing the agonal epi s o de
( 2 8�6 5 7 ) .
Thi s
rel a t iv e ly small t emperature dec r ea s e doe s not g r e a t ly
e f f ect the p0 2 .
A s t rup, e t al , have s hown that a b lood
s amp l e of known 0 2 s a turation
po2 o f 1 1 .0 mmHg
(41) .
( 1 0 %) a t 3 8°C y i e l ds a
A s amp l e at 3 0 °C imdi cates a
3
po2 o f 6 . 0 mmHg
(4 ) .
Thi s sma l l di f f er en c e o f 4 mmHg for
a soc temper atur e d i f f e re nce indi c a t e s that a s ix hour
period foJ lowing de a t h
(temperat.ure de c re a s e of approx i-·
mately 3 °C ) woul d no t appre c i ably a f f e c t the p0 2 rea di ngs .
Eve n a t h igher p0 2 va lues o f 3 0 mmHg the diff erence for
an S°C c hange was 7 . 3 mmHg .
There f o r e the variation o f
s amp l i ng time i n thi s p re s en t work o f 0 t o 3 mi nute s woul d
no t af f e c t the p0 2 va l ue s with regards to temperature
dec r e as e .
.
Fo l l owing dea th, whe th e r by c a rdiac or r e spir a tory
o b s t r uction, the r e is a lower ing of pH
(2 4 : 4 4 5 )
(2 5 : 1 7 9 ) .
Ther e f o re , pH i s not a val i d indi ca to r a s to type of death .
Stat ement o f the Problem
The purpo s e o f thi s s t udy i s to extend Mitheo f er ' s
work by mea s uring p0 2 val ue s po s t mortem .
It i s hypothe
s i z e d tha t mice s ac r i f i c e d vi a cardia c arre s t or r e spira�
tory obs truc tion wi l l h ave s t a t i st i c a l l y s igni f i c an t
dif f erences i n b lo o d p0 2 •
Ext:ent. of This Study
D i f f e rent methods o f determin ing po2, pC0 2 and pH
of a blood s ampl e w i l l be r epor ted i n the r e vi ew o f the
l it er a ture s e c t i o n of thi s paper .
.
Thi s s tudy uti l i z ed the
gla s s e l e c tr o de technique for pH me a s ur ement .
The
determ inations of the p0 2 and pC0 2 va l ue s in b l o od (in
Swi s s s t r a i n mic e ) were b a s e d on the princ iple of
4
s e l ec t i ve absorption o f g a s e s .
Def in ition o f Terms
Ac id:
Hydrogen i o n donor .
Exampl e:
carbonic a c i d
may g i ve o f f a hydrogen ion f orming a b i
c arbonate ion .
Base:
Hydrogen ion accepto r .
Example:
b icarbonate
i o n s may ac cept a hydrogen ion form i ng
c arbonic a c i d .
·
Actu·a l pH :
Re f er s to the pH o f anaerobic a l ly drawn
b l o o d.
Actual pC0 2 mmHg:
The par tial pre s s ur e o f c arbon
dioxi de i n anaerob i c all y drawn blood.
The
s um o f the c arbo nic a c i d concentration and
the conc e n tr ation of di s s o l ved carbon
dioxide i s der i ved as 0 . 0 3 x pC0 2 .
·Ac tua l · Bicar bonate Conce ntration:
(HC0 3 )
Bic arbo nate
concentration i n p l a sma a t the pC0 2
a c t ua l l y p r e s e n t .
To·t a·l · co2· o f Pl a �ma:
Expre s s e d i n mMo l /L .
The .C0 2 der i ve d f rom c arbonic
a c id and b i c arbonate in p l a sma f rom
anaerob i c a l ly drawn bl ood .
co 2 · ·- · Combin i ng P o wer o f P l a s ma :
p l a sma,
The total C02 o f
s ep arated a t the a c tua l pC0 2 f rom the
c e l l and e qui l ibr a t e d with co2 at pC0 2 o f
4 0 mmHg .
5
Standar d Bi carbonate :
The b i c arbonate concentration
in the p l a sma o f b lood e qu i l ibrated at a
pco2 o f 4 0 mmHg and with oxygen for f u l l
s a tu r ation o f the hemo g l obi n.
Buf f e r Ba s e
(BB) :
The sum o f bu f f er anion s , i . e . ,
mainly b ic arbonate and prote inate ions.
Who l e b lood BB r e f e r s to f u l ly oxyg enated
blood a n d g i ve s the val u e i n meq/L b lood .
P l a sma BB g i ve s the value in meq/L plasma .
BB w i thout s p e c i f ic a tion r e f e r s to who l e
blood.
Base E xc e s s
(BE ) :
It i s def in e d a s z ero for b lood
with pH of 7 .4 0 at pco2 of 4 0 mmHg.
val u e s indi c ate an exc e s s of b a s e
Po s i ti ve
(or
def ic it of f ix e d acid) i negative va lue s
indi c a t e a def ic i t o f b a s e (or exc e s s of
f ix e d acid) .
Who l e b l o o d BE g i ve s the
va lue in meq/L blood r e f e r r ing to fu l ly
oxygena ted bloo d.
iri meq/i p l a sma�
P l a sma BE g i ve s �he va lue
Without spec if i ca tion
BE r e f e r s to who l e blood .
Meq/L : A s ys tem o f e qu i va l e n t s or m i l l ie qu i valents
(meq) , whi ch expre s s e s concentrations in
terms o f the number o f
per u ni t volume .
(+)
and (- )
charge r s
C HAPTER II
REVIEW OF THE L ITERATURE
SID Syndrome - Ep idemio lo g i c
The abi l i ty t o determine cause o f death i s often a
ma tter o f o b s er va t io n .
Howeve � i n the c a s e o f sudden and
u nexpl a i ned i nf a nt deaths
( SID Syndrome ) , cau s e o f de ath
h a s s o f a r e luded i nve s t i g a tor s .
Sinc e the r e su l t s o f the
exper ime nt de s c r ibed in thi s the s i s a r e direc t l y appl i c able
to SID Syndrome vic t ims a r eview o f thi s l iteratur e wi l l
b e g i ve n ( 8 ) .
Ba s ic al ly there a r e two c a tegor i e s o f
s tudi e s tha t are exam i ned :
1)
Tho s e dea l i ng with
contr i butions o f epidemio logy i n s tudy i ng the SID Syndrome
and 2 )
phy s i o l o g i c o r p a tho l o g ic f i nding s i n the s tudy o f
the SID.Syndrome .
�A r e vi ew o f the l i terature o n the SID Syndrome
i nva r iably r e ve a l s the exce l le nt ar tic l e by Va l de s -Dapena
( 3 8 : 1 2 3 ).
Thi s particular paper surveys the l i teratur e
f r om 1 9 5 4 to 1 966.
It was wr itten to edu c a t e prarititioner s
i n p e di a tr i c s .a nd pa tho logy , a s we l l a s r e s e ar chers i n
thi s a r ea, a s to wha t r e s earch ha s take n p l a c e throughou t
t h e wor l d from 1 9 5 4 t o 1 9 6 6 .
In dea l i ng with the
e p i demio logic f a c t o r s it is po i nted out that the r e is a
s e r i ou s prob l em i n g e tt i ng accurate dea th r a te s s i nce
7
p a tho l o g i s t s do no t enter " cau s e unknown " o n a death
c er t i f i c a te .
It i s s ta te d that Landing h a s s e t the f igur e
t o b e 2 5 ,0 0 0 to 3 0 , 0 0 0 p e r year i n t h e United State s
(44 : 1) .
Age i s a l so a n impo r tant epidemiologic f a c to r with a peak
i n c i dence o f b e tween two and f our months
(45: 291)
22 : 134 ) .
(39 : 630)
( 20 : 291)
The cons e ns u s o f r e v i ewed artic l e s
indi c a tffia prepobderance o f ma l e deaths i n the SID
Syndrome
(12 : 31 ) .
Rac e wa s found to b e an addi tiona l
f a c to r w i t h a di s propo r t ionate numbe r o f v i c tims b e ing
Negro
(19 : 53 ) .
O ther f ac to r s r epor t e d i n th i s review
a r ti c l e dea l w i th s ea s o n
( h igher i nc i dence dur ing co l d
month s ) , geo gr aphi c loc ation
( genera l l y acc epted tha t i t
i s mo s t pr eva l e n t i n urban a r e a s ) , time f a c tor
( gr eat
ma j or i ty di e b e tween m i dn ight a n d 6 A.M. ( 2 1 : 5 9 2 ) .
Recur r enc e s w i th i n the family was a l so f o und to b e
mentioned i n s ix r epor t s , b u t the number o f r ecurr enc e s
were v ery sma l l
( 32 : 914 ) .
( 1 : 633 )
Cooke po ints o u t that c au s e o f dea th i n mo s t
c a s e s r ema i n s obscure a l though many rea s on s are o f ten
put f or th
In this study 1 2 2 c a s e s o f sudden
(1 5 : 1 5 5 0 ) .
i n f an t death were s tudi e d for epidemiologic and pathologic
patt e rn s in the syndr ome .
T ho s e f ac to r s having to do
with the e p i demi o logy o f the s yndr om e w i l l b e di s cu s s e d
here .
The i nc i denc e r a t e r epor ted i n th i s s tudy wa s nine
sudden and unexp e c t e d dea ths per 1 0 0 , 0 0 0 popu latio n .
A
def in i te s e a s on a l var i a t io n was a l s o s hown i n this s tudy
�.
- ....
8
with a h igher p r e va l ence i n co l der month s .
Other f acto r s
such a s s o c i a l g r a de o f parents , bir th weight of the
i n f a n t and s i z e of f am i ly were l ooke d at and found to
compare w i th other studi e s
( 3 8 : 1 2 5 -2 7) (1 8 : 4 5 8 ) .
conclus io n s t h e autho r s s tate that,
In the i r
" no o n e theory f its
a l l the f a ct s , and the pro b l em r emai n s ope n . "
The only
r e a l di f f e r ence in o b s e r vations i n thi s s tudy was the
s tr iking f ea tur e of the humbe r of ch i l dren who wer e
memb e r s o f a twi n pair , the r e wer e s ixteen such chi l dren.
No r e a l exp l anation or theory for th i s was pr e s ented .
It s hou l d b e no t e d that e ven though the author s con s i de r
t h e probl em o p e n , they be l i e ve t h e mo s t tenab l e theory
i s tha t the infants di e f r om anoxia du e to l aryngo
s pa sm medi ated through the autonom i c nervou s s y s t em .
F roggatt al so ment ions many f actor s i denti f i e d
b y Val de z -Dapena
(1 8 : 4 5 7 - 6 8 ) .
T h i s s tu dy took place i n
B el f a s t, Northern Ir e l and ( popu l ation 1 . 4 m i l l io n ) whe r e
1 6 2 ca s e s wer e o b s erve d from Augus t 1 ,
1967.
1 9 6 5 t o Ju ly 3 1 ,
The def inition o f sudden infant death u s e d by the s e
i n ve s t igators i s as f o l l ows :
" Th e de ath o f a chi l d who
was thought to b e i n good h e a l th or who s e t ermin a l i l lne s s
appeared t o b e s o m i l d that the pos s ib i l ity o f a fat al out
come was not anticipated . "
They ex tende d thi s to include
the contingency that the autopsy l e s ions wer e no t s u ch
a s are g en e r a l ly conceded to s how a " cau s e " for dea th .
9
T h i s s t udy e xami ne d the c l in i c a l pro f i l e o f the i n f an t
It was found that
and cons idered i t a n impor tant f a c tor .
the i n f ants were either s ympt.om f r e e whe n l a s t a l ive or
e l s e h ad minor s ymptoms , us ua l ly in the upper respir atory
trac t .
Death was f ound to b e us ua l ly quie t i n the s e n s e
that the mo the r w a s no t d i s turbed-- even when i n the s ame
room w i th the c h i l d .
Froggatt po inted o ut that i n Ire l and
the SID Syndr om e i s not a c e r t i fi a b l e caus e of death ,
there f o r e l im i t ing the i nc idence rates ava i l abl e
In
Froggatt's s t udy an i n c id en c e o f 2 . 3 d eaths per 1 , 0 0 0
J..i v e b i r ths was found whi ch compar ed favorab l e with
Amer i can rates
(1 : 664 )
(31 : 478)
( 1 0 : 5) .
It was pointed
o ut that there is a r ea l i rnrnu�i ty e n j oyed i n the f i r s t
months o f l i f e and a sharp dec l ine o f i n c idence a f ter
f o ur months .
The usual s ea sonal pattern was ver i f ie d .
C a s e s o f SID Syndrome were found to occur i n colder
months with the highe s t pr eval enc e of deaths o c c ur r i ng
b e tween midnight and b r eakfa s t .
The author warns
however that t h i s mus t be· i nt e rpr eted with c a r e b e c aus e
the n at ur al r e g imen o f hous eho ld s bia s the e s t imated
time of d e a th .
Soc io - economi c level ind i cates that
f am i li e s of i nf an t s who d i e d were at a d i sadvantage
comp a r e d to f a mi l i e s whe r e no death s occurred .
Maternal f a c tor s d e a l i ng with pregnancy
( o b s t e tric
h i s to r y no d i f ferent for mo th e r s o f dead i n f ants and
mo th e r s of c on tro l )
and i l l eg i t imacy
( s udden death found to
10
b e more c ommon i n i l l eg i t imate than l e g i t imate c h i l dr en )
were addi t ional f actors examined by Froggatt.
Inf an t
f ac to r s indi cated that t h e infants dy ing w e r e on the
aver age l e s s matur e than the cho sen contro l s .
Her i t able
mechani sms wer e looked f o r and on the ba s i s o f co l l e c ted
data it wa s c o n c l ude d tha t they p l ay a t mo s t a sma l l
par t i n s udden unexpec ted dea th i n infants .
The author s
f ur ther s t a te that 11 epidemiology a l one canno t expl ain
how or why infants die .
i s r equired"
Knowledg e f rom o ther di s c ip l i ne s
(18 : 468) .
V a l de s - Dapena a l s o s t udi e d the r e l a tionship between
the i n c idenc e of s udden unexpec ted death in i n f ancy and
pover ty
( 4 0 : 3 87-9 4 ) .
O f the 3 3 7 deaths o c c ur r ing dur ing
a thre e year period it was shown th at s uc h deaths
o c c ur r e d more frequently among Negro i n f an t s
( 2 1 5 ) than
among Cauc a s i a n o ne s , r e l ative e i ther to the to tal number
of l ive b i r th s or to the to tal number of dea th s o f
i n f ants s even day s t o one year o f age.
T h i s di f f erence
was i n large part dependent upo n the very h igh i n c i dence
of s udden dea th dur ing infancy i n Negro infants o f
low s o c io-e conomic leve l .
P e t e r s o n s t udi e d the SID Syndrome in King County,
Washing ton
(31 : 478 ) .
P e t e r s on r eports that one s udden
i n f a n t death could be expe cted for every thr e e hundred
b ab i e s born a l i ve .
The ag e di s tr ibution is typ i c a l , a s were
11
the d a t a o n s e x, r a c e and s ea s o n o f d e a th .
He a l s o
o b s erved tha t ther e i s a r egular prog re s s io n o f s u s c epti
It
b i l ity whi c h is i nver s e ly re lated to b ir th weight .
was a l s o pointed out that the h igher r i sk a s s o c ia te d with
i l l eg i t imacy mu s t b e i nterprete d with caution b e c au s e
o ther fac to r s may contr ibu te t o the i ncr e a s ed d eath rate
among i l le g i timate ch i ldren .
The authors d i d not r eport
hour o f death b e c au s e they f e l t that the s e data were fre
quently a "ma tter o f conj e c tur e . "
P e t e r s o n conclude s that
"de aths occur in c e r t a i n h ig h r i s k inf ants under d iurnal
inf luences and a r e triggered by mi ld, unrecog n i z e d i n f e c
tion w i th m i crob iologic ag ents no t fou nd i n previou s
s tud i e s , o r perhaps by s ome s e a sonally inf luenc ed f actor . "
The important and d i f f erent d a t a pre s en te d in thi s paper
d e a l wi th the i nver s e r e lationship of b i r th we ight and the
regu lar progr e s s io n of su s ceptib i l i ty al though it wa s not
d i sc u s s ed in d e t a i l .
J. J . O ' Re i l l y d id a s tudy o £ "co t death" o r "cr ib
d e a th " f o r the Sta t e H e a l th Department i n Que e n s l and,
Aus tr a l i a
( 3 0 :1 0 8 4 -8 7 ) .
1962 to 1966,
I n the f ive y ear period f rom
autop s i e s wer e performed on e ighty
inf ants
who d ie d suddenly and unexpectedly i n the Br i s b ane metro
pol it an are a
( popu l ation 7 0 0 , 0 0 0 ) .
It was· s ta ted that thi s
numbe r repre s e nts a lmo s t thir ty percent o f all i n f ant
deaths b e tween the ages o f f our weeks and twelve month s in
tha t a r e a .
The age of infants i n thi s s tudy was r epo rted
to be thr e e to f ive month s and apparently no t i l l . However,
12
they were foun d dea d f o l lowing a period o f s l e ep .
o b s e r vations agree with other s tudi e s
(1 : 6 3 3 )
The se
(1 8 : 4 5 8 ) .
Af ter reviewing the s e preceding ar t i c l e s i t woul d
s e em important that a thre e - ti e r e d approa c h b e us e d i n
a s s e s s ing the wor th o f the ep i demiological approach to
the prob l em of the SID Syndr ome.
(1)
Ar e there dif f er ences i n the i nc i denc e o f
t h e condi t ion between di f f er ent countr i e s
o r commun i t ie s a n d can t h e e t iology of the
s yndrome be a ttribute d to some f a c to r ?
I n g e ne r a l the data r epor ted i n thi s repor t s e em to
i ndic at e tha t the i n c i dence of the SID Syndrome i s f a ir ly
un i form whi c h agr e e s with i nves t i g ato r s who have r eviewed
o ther l iteratur e .
The s e data s eem to i n di c ate a higher
i nc i dence in urban a r e a s which i s l e f t unexp lained.
Th i s
could b e a n a r t i f a c t r e s ul t i ng f r om b e tter reporting of
c a s e s i n urban ar e a s .
At present the e t i o l ogy cannot
b e attributed to a s ing l e o r number o f f a c tor s .
(2 )
Havi ng i dent i f i e d a f a c to r or f acto r s , we can
e s tab l i sh the r e a l i ty of c aus e and e f f ect, and
no t j us t c o r r e l ation, by s e e ing whether the
di s ea s e c a n be preven t e d by chang i ng the pre
va l en c e o f the s uspec t e d agent.
T hi s po int i n the c l a s s i c a l ep i demio logic a l approach has
not been reached i n th i s prob l em and, therefor e , the technic a l and pro f e s s i o na l pro b l em s canno t b e con s i der e d at
t h i s time .
(3)
Can we convi nc i ng l y t e s t f ormul a t e d hypo
the s is whi c h r el a t e the occurr en c e o f the
condi t i o n to a per sonal charact e r i s tic of
the vic tim in r e l ation to the deg r e e of ex
po s ur e to an environmenta l agent?
13
However a ny r e l a tionship e s tab l i s hed may b e
a
s econdary one and the r e a l cause or cau s e s may b e s ome
unknown commo n f ac tor.
Quot i ng
Dr.
J.
Berkson
(11 : 9 9 ) :
If an e s s e n t i a l b io lo g i c a s sociation i s to b e
e s tab l i s hed a s a d e f i n i t i ve s c i e n t i f i c conc lus ion,
that is to s ay , i f it i s to be cons idered "proved, "
the popula ti o n mu s t not b e anything e l s e than an
expe r imental popu l a tion.
An a s s o c i ation found
i s pur e l y s t at i s ti c a l inve s tigation made on an
exi s tent popu l ation, by wh ich I mean an inve s t i
gation wh i c h i s r e trospec tive a s r egards e i ther
of the var i ab l e s concerne d , howeve r s trongly i t
m a y sugg e s t a s s o c i ation a s a pr esumptive conclu
s ion, is tentative unt i l i t is corroborated fully
by means o f exper iment.
If however, we s tudy the SID Syndrome in the human
popu l a t ion, wh e r e expe r imentation and produ c tion of
contr o l l e d popu l ations are impo s s ib l e , then Berkson ' s
d i c tum mus t b e r e l ax ed .
The data r e s u l t i ng f r om the epidemiolog i c a l s tud i e s
sugg e s t that i t wou ld b e very d i f f i cult t o p i npo i n t
c asua l f ac tor s .
It would s e em tha t ep idemio logy h a s made
i t s contr ibu tion, and further s tud i e s in thi s ar e a are
not indic ated .
SID Syndrome
�
Patholog�c
D r . Beckw i th s ta t e s tha t i t i s e s s entia l that we
make a d i s t i nc ti o n b e tween sudd en unexplain ed d e a th and
s udden unexpec ted death
(9 : 4 4 ) .
D e ath s whi c h ar e
d e f i n i te l y unexp l a i ned and show no a p r i o r i l e s i o n upon
patho l o g i c i nve s t igation can b e c l a s s i f ie d as the SID
Syndrom e .
He b e l i eve s that petechial h emo rrhag e s ar e
14
the mo s t d i s t i nc ti ve f ea tur e o f the s yndr ome.
Othe r
f a ir l y constant p a tho logic charac teris t i c s a r e, pulmonary
edema,
f l uid b lood in the heart and empty ur ina r y b l add e r .
Beckwith s t a t e s that "the mechanism o f s udden death-may
b e pr e c ipitated by a numbe r o f inter r e l a ted f a c tor s . "
It i s their be l i e f tha t the s e f ac to r s t e rm i na t e in
l a ryngo s pa s m via a f ina l conunon pa thway .
This type o f
hypoth e s i s wo uld argue f o r d e a th d u e to r e sp iratory
obs tr uc ti on ( l ung fa i l ur e ) .
Some o f the factors b e l ieved
to c a u s e the spasm inc l ud e s l eep, c ons t i t utiona l autonomi c
r ea c t ivity and upper r e s p iratory inf e c t ion .
The author s
s tr e s s t h e pauc i ty o f r e s e arch in agona l phy s io logy and
a s k why the p a thogene s i s o f the SID Syndrome has not been
e xp l o red.
In conc l us ion it is s t a t ed that, "a prime goal
of s uc h r e s ear ch would be to d evelop an appropr iate
anim a l mo d el . "
Immunoglobul i n l eve l s in infants dying o f SID Syndrome
have b e e n e xamined by Bald uz z i
(5 : 6 � 9 -9 2 ) .
Balduz z i
b e l ie ve s that a ho s t f a c to r r athe r than s p e c if ic externa l
c a us e may b e r es pons ib l e f o r d e a th.
The b a s is of this
hypo t he s i s e vo lve s from the stud i e s showing the peak
inc id e nc e at a g e s two to f o ur months .
In c ertain chi ldren
in thi s age group cond iti ons c ould e xi s t which might
r e s ul t i n inc r ea s ed s us c eptibil ity to fac to rs ul t imately
res pons ib l e for d ea th.
At two and thr e e months o f age
the immune d e f ense s ar e at a minimum a s a cons e quenc e o f
15
d e cr e a s ed amount o f certain gamma globu l ins .
Baldu z z i
therefo re inve s t i gated the l e ve l s o f the immunoglobu l i ns
in a g roup o f infants who d ie d suddenly and unexpec tedl y
a nd in a contr o l g roup o f i nfant s .
The r e su l ts from thi rty
f i ve inf ants i nd i c a t ed that ther e was no o b s er vab l e
d i f f e rence b e tween the SID Syndrome vi c t i ms and t h e control
infa nt s .
Jam e s explai ns the r o l e of the h e a r t i n sudden infant
d e a th
( 23 :4 7 9 -5 0 4 ) .
One hundred and f i f ty hearts f r om
i nf ants of whi ch s ixty p erc ent of thei r d e a th s were
unexpl a ine d wer e s tud i ed .
It was h i s conte nti on that in
a ny sudd e n death the mechani c s o f a l ethal c ardiac
arrhy thmi a s or conduc tion d i s turbanc e is o f u tmo s t
importanc e .
In h i s s tudy the condu ction s y s t ems o f SID
Syndr ome vict im s were exami ned .
It was f ound that there
was a pre s enc e of focal r e sorptive d e genera tion in a l l
t h e p o s t nata l hearts , both o f " contro l s " a nd o f sudden
unexpl ained d e a th s , which sugge s t s tha t it wa s an ubi
quitous po s t na tal pro c e s s.
Jam e s a l s o f e lt that
conduc t i on d i s turbanc e s were cons equenc e s of deve lopmental
hi s t o l o g i c c hang e s in the c r i t i c a l r e g ions whi ch ma y b e
---the f inal c ommon p a thway in sudden inf a nt dea ths .
Morgan s tud ied heart rat e s o f i nf a nts
(29 :6 5 8 ) .
She i nd i ca t ed that i t h a s b e e n theor i z ed tha t s ince the
e t i o l ogy o f arrhythm i a s ha s not been documented it
wou l d b e r e a so na bl e to suspect immatur ity of ·the sympathetic
16
and parasympathetic c ar diac r e g ul a tion a s c aus a l factors
( 2 : 17 9 )
i n the i n i ti atio n o f s uc h r hythms
( 13 : 54 5 ) .
It
wa s pointed out by Morgan that Stowens had sugge s ted that
a gener a l i z e d neur a l spa sm , mediated thr o ugh the auto nomi c
n e r vo us s y s tem, may b e r e spons i bl e for the SID Syndrome
(35 : 674 ) .
Morgan found marked s inus arrhythmia and
s inus brady c ardia i n i nfants .
Thi s e vi den c e woul d s ugge s t
tha t s in c e the s e c ardiac rhythms ar e p r e s ent i n norma l
i nf a nts the n perhaps the r o l e they have
Syndrome s ho ul d b e inve s tig ated.
( i f any )
i n SID
Onc e again, a method
of determin ing i f heart di s f un c tion wa s c a us e o f death
wo ul d prove va l uab l e in the i niti ation o f s uch a s tudy .
An a ttempt to i s o late vira l agents r e spon s ib l e for
s udden unexpe cted death in appar ently w e l l inf ants was
conduc ted by V a l de s - Dapena
( 4 1 : 398 ) .
I n thi s early s tudy
i t was found that a s f ar a s pr e s e nt technique s co uld
demon s tr a te vir a l inf e c ti o n s did not p l ay a r o l e i n the
c aus e of s udden dea th s in i n f an ts .
Studi e s b y Ray s ome y e a r s late r again f a i l e d to
y i e ld any s ig n i fi c an t da ta pe rtaining to viruses among the
SID Syndrome c a s e s
(10 : 14 5 ) .
However,
in addi tional stud
ie s us ing a di f f erent proto c o l , i n whi ch the SID Syndrome
c a s e s and contro l s wer e studi e d as s oon as pos s ib l e a f te r
dea th, non-po l i vi r us i s o l ate s were reporte d.
I n the
S I D g r o up 3 7 . 5 % s howe d the vir us e s and i n the contr o l group
17
only 1 6 .2 % had the i s o l a t e
( 1 0 : 1 55 ) .
It was Ray ' s con
c lu s i o n tha t v i ru s e s may have a s ig n i f icant ro l e in the
patho g e n e s is of the SID Syndrome, and that s o me s tereo types
may have r el a t iv e l y greater impor tanc e than other s .
Ray
went on to s ay " un t i l the pathogene s i s of thi s syndrome i s
mor e c l early d e f i ned, the r e l a t iv e s i g n i f ic an c e o f any
s ing l e f a c tor mu s t r ema i n specu l a t ive."
A r ec ent theory is that death is cau s ed by s evere
imbalance o f e l e c tr o ly t e s
( 26 : 1 4 4 0) .
McGa f f ey b e l ieves
tha t thi s imb a l a n c e may r e su l t i n a c ido s i s l eading to
r apid d e a th f r om card i a c a rr e s t or anox ia.
Ac ido s i s may
r e su l t f rom a metab o l i c d e f i c i ency and it wa s theor i z ed
tha t perhaps the adrenal g land s may b e hypoac tive s i n c e
they wer e found t o b e l ighter than t h e " c ontro l '' g l and s .
I t wa s a l so r eported tha t c a s e s showed evid ence o f pulmon
a r y cong e s tion a nd petechial hewnorrha g e .
Sinc e t h e r e i s
a normal a c ido s i s o f s l eep, t h e n subacute o r chronic
a c ido s i s c au s ed by chronic hypoad r e na l i sm might c au s e
sudden d e a th.
McGa f f ey s ta t e s " a borde r l ine c a s e o f
ac ido s i s aggrava ted by mild additio na l anoxia and carbon
dioxide retention, such a s with an a cu t e r e spiratory
i n f ec tion or a sp ir a t i 6n, plus the a c ido s i s of s l eep, might
be suf f ic i e n t t o c au s e d ea th . "
P r e s en t d at a, both exper i mental a nd epidemio l o g i c a l,
ind i c a t e that we are s t il l i gnorant with r espect to the
e t i o logy o f the SID Syndrome.
�
--
Ba s ic r e s earch i s needed to
18
promo te theor i e s abou t wha t happens to the infant s v i ta l
funct i on s dur i ng the agonal epi so de .
T h e r ema inde r of
thi s r eport is concerned w i th b a s ic r e s e arch per formed to
e s tab l i s h whe th e r the heart or lungs f a il e d f ir s t i n the
SID Syndrome a n ima l mode l .
G a s Transport i n Bl ood
This s tudy is l imited to the analy s i s o f thr e e
parameters o f t h e blood, pH, pC0 2 , a n d p0 2 .
pco2 ,
Blood pH,
and p0 2 , indi c a t e the ac i d- ba s e s tatus of the bloo d .
A r e v i ew of how 0 2 a n d co 2 a r e transported i n the blood
i s now prov i de d .
When o 2 di f f u s e s into the blood i n external r e spira
t ion, mo s t o f i t enters the r e d b lood c e l l s o r erythrocytes and u n i t e s with the hemoglobin i n the s e c e l l s forming
a c ompound c a l l e d oxyhemoglob i n .
The c omp l ex pro t e i n
h emo g lobin conta i n s i r o n a n d h a s a g r e a t a f f inity for 0 2 .
As the b l o o d pas s e s through the alveolar c ap i l lar i e s , the
h emo g lobin b ecomes s a tur a ted w i th 0 2 .
The di s solved
ox yg e n and h emog lob i n react to form the oxyhemoglobin
. g iv e n by e qu ation 1
(1)
( 16 : 9 ) .
0 2 + Hb
:;:,...
Hb0 2
Oxyhemoglobin i s a very uns ta b l e compound and whe n the
blood reaches the cap i l l ar i es in the t i s su e s throughou t
the body whe r e p0 2 i s low,
the c ompoun d breaks down into
h emo g lo b i n and the o2 di f f u s e s i nto the cel l s .
The
19
r ea c t i o n that occur s i n the ti s s ue c ap i l l a r i e s i s prov ided
i n e quation 2 .
( 2)
Hb + o 2
Whe n co 2 enter s the b l o o d from the t i s s ue s , i t
f ir s t comb i n e s with water f orming c arboni c a c i d , H 2 co3
a c co r di ng to equation 3
( 3)
co 2
( 1 7 :53 ).
H 20
+
H 2 co 3
Sodium and Potas s i um ions then r ea c t wi th H 2 co3 to form
b i carbonate s .
Mo s t of the co 2 is transported in the
p l a s ma in the f orm of s odium b i c arbonate
( NaHco 3 ).
Sin c e the concentration of g a s e s in the blood i s
propo r tional t o the partia l pre s s ur e o f the g a s , the
ac tua l amount of co 2 and o 2 can be c a l cula ted by measur ing
the s e pr e s s ur e s .
T h i s par ti a l pr e s s ur e i s a us e f ul index
in the deve lo pment of a pos t mor tem m e thod of diagno s ing
c aus e of dea th ( 2 8 : 6 57 ) .
Bloo d Gas Analy s i s
One method o f meas ur ing the par t i a l pre s s ur e of
a g a s i n blood i s to ex tr ac t tha t gas f rom the blood s amp le
with a microm anometric apparatus
( 4 2 : S 2 3).
'l'he g a s
pr e s en t p e r uni t vo lum e o f the s amp l e i s then cal c ula ted
usi ng f ormul a 4 .
(4)
Gas
Wher e :
P
=
X
ft
X
Rv
G a s i s i n mi l l imol e s p er l i te r of blood
P = pr e s s ur e i n mmHg
f t = temperatur e f ac tor ( 4 3 : 2 9 )
Rv = i n s tr ument vo lume r a t i o a/b
'··
_.,.,_
20
a
=
b
=
whe r e :
vo lume o f g a s i n the chamber whe n
P i s measured
volume o f s ampl e blood
This me thod of measur ing the partial pr e s sur e s of
b lo o d g a s e s i s e f fe c t i ve and was u s ed i n thi s s tudy with
cer t a i n
modi f i c atio n s .
Thi s n ew method w a s o f s uf f i c i ent
s e n s i ti vi ty for the p r e s e nt s tu dy .
A b r i e f de s c r iption
of the m e tho ds f ollows .
p02 Measurement
In 1 9 5 6 , C l ark deve loped the f ir s t practic al dire c tr eading po2 e l e c tr o de
(1 4 : 4 2 ) .
In the Cla r k e l e c trode ,
a p l at inum c a tho de and a s i l ve r r e f erence e l ec tr ode
a r e s epar a t e d f r om the s amp l e by a thin membrane .
(anode )
A
thi n l ay e r o f e l e c trolyte compr i s ing a pho sphate bu f f er
and pota s s ium chlor i de i s tr apped b e tween the membr ane
and the tip of the e le c tr o de .
o 2 mo l e cul e s pas s f r om the
s ampl e through the membrane and into the e l e c trolyte until
· an equ i l ibr ium is e s tab l i s h e d and the po2 i n the ele ctro
l yt e is the s am e a s that o f the s ampl e .
o 2 r eaching the
cathode i s r e du c e d t o water and as a r e s u l t of e l e c tr o n
lo s s f rom the cathode, a curr e n t wi l l f low b e tween the
catho de and the anode .
Thi s current i s proportional to the
p0 2 o f the s amp l e o n the o ther s ide of the membrane .
'·
_ ....
21
pC0 2 Me asur ement
An el e ctrode which wo uld dir e c t l y me a s ur e pC0 2 was
o r i g i n a l l y dev i s e d by Stow and Randal l
( 3 4 : 646 ) .
This
e l ec tr o de wa s modi f i e d a n d put into a mor e us able form
by Seve r i nghaus and Br adl ey
( 3 3 : 5 15 ) .
T h i s e l ec trode i s
b a s i c a l ly a p H e l e c tr o de-mea s ur ing the p H o f a very small
v o l ume o f sodium b i c arbonate trappe d b e tween the s e n s i tive
g l a s s s ur f a c e o f the e l e c trode , and a thi n membran e of
t e f lon .
The tef lon is permeab l e to C 02 but not to the
b i c ar bonate ion of the blood s ampl e on the o ther s i de
o f the tef lon b a r r i e r .
The C0 2 from the s amp l e e n t e r s
t h e b i carbonate s o l ution and c hang e s i t s pH
( C0 2 c ombines
with water to f o rm c arbonic a c id, H 2 C 0 3 , thus lowering the
·pH , and thi s chang e i s det e c t e d by the g l a s s e l e c trode .
The pH mea s ur e d b y the g la s s e lec trode depends upo n the
r at i o between C0 2 and b i c a rbonate i n the l ayer between
the e l ec trode and the membrane; the r e f or e, the pH
mea s ur e d is a f unc t i o n o f the pC0 2 of the s ampl e o ut s i de
the membrane .
pH Mea surement
E l e ct rometr i c and c o l o rmetric technique s a r e us e d
to mea s ur e pH.
Many peopl e are f ami l i a r with the t e s t
whe r e l i tmus paper t ur n s p ink when imm e r s e d in an a c i d and
b l ue when imme r s ed i n a b a s e .
Thi s i s a c o lorme t r i c pH
mea s ur ement in its s impl i s t f o rm.
The uti l i ty of the
22
c o lormetr i c t e s t i s very l imited and g enera l l y th i s method
i s not v e r y accurate .
El ectrometric pH measurements are ba s ed o n the fac t
that whe n immer s e d i n a l iqui d , c er t a i n e l e c trode s
(such
a s hydro g e n , qu i nhydrome , e tc.) dev e lop voltag e s that
depend o n the hydrogen-ion c o nc entr a t i o n o f the l i qu i d .
O r ig i na l ly only this type o f e l e c trod e was ava i lable for
e l ec tr omet r i c pH mea surement s and th i s was not highly
a c curate .
Bates d e s c r ibed the theory and p rac t i c e o f
e l ec trom e tr i c me thod s o f p H determina tions wh i ch u ti l i z e
h i g h l y ac curate g l a s s e l e c trodes
(6 : 19 )
( 7 : 126 ) .
The
a c tive e l ement o f a g l a s s e l e c tr ode i s a membrane of a
special glas s .
I f the membrane forms a partition between
two l iqu ids o f d i f f e r i ng hydrogen-ion concentra t i on s , a
po tent i a l i s produced b e tween the two s ides of the membrane .
Thi s potential i s propor tional to the d i f f erence i n pH
between the l i qu id s .
I n t h i s exper iment a rad iomet e r ,
thermo s ta tted e l ec trode o r i g i n a l l y d e s cr ibed b y Siggaard
Ande r s o n et al wa s u s ed for e l e ctromet ri c pH determina
t i ons
( 3 : 4 9)
•
summary
A r ev i ew of the l it e rature r ev e a l s a pau c i ty of re
s earc h i n b lood g a s ana lys i s fo l lowing death .
Be ckwith sug�
. g e s ted that one impor tant s tep i n s o lv ing the p ro b l em o f
the SID Syndrome wou l d b e to d ev e l op a method o f determin
ing whether the h e art o r lungs f a i led f i rs t
(8) .
Such
23
knowledge wou ld h e lp cons iderably in eventu a l l y gett i ng
a t a c au s e o f d eath .
Initial work by Mi thoe f er i nd i ca ted that a po s t
mor t em d iagno s i s to dif f er entiate between d eath c au s ed by
c ardiac or r e s p i r a tory f a i lur e could b e made via b lood
g a s d e te rminations
(2 8 : 6 5 4 ) .
I t was found tha t the most
app l i cab l e method of blood determinations was through
the u s e of g l a s s and d i f fu s io n type e l e c trode s .
�
--
CHAP TER III
P RO C EDURE
Thr e e exper iments wer e performed .
the Swi s s s tr a i n we ighing 14 to 24 g r am s ,
to f iv e weeks wer e u s ed .
Male mice of
and aged four
Anima l s wer e anes theti z ed with
a s odium pentobarbi tal i n j e c tion
with the anticoagu l ant hepa r i n
(6 5 mg/kg)
and tr eated
(0 . 0 5m l /mou s e ,
I.P.) .
Once anes the t i z ed , a v entral s ag i ttal inc i s ion was
made from the mentum to approx imate l y 1 mm above the
gen i ta l i a , and the s k i n was pu l led back .
I n thos e mice
r e c e iving the r e sp i r a tory ob s truc tion , the tr achea was
expos ed and oc c luded with a hemostatic c l amp.
Af ter
thre e minutes e l ap s ed , and wi thou t r emov ing the c l amp , the
s ternum was spl i t and the l e f t rib c ag e r emoved expos i ng
the hear t .
In a l l cases ,
the hear t h ad c e a s ed to beat
b y the time the thor ax was opened .
Bl ood was then
r emoved f r om the l e f t ventr i c l e v i a 1 5 0 microliter g l a s s
cap i l l ar y tube .
Care was taken to insure that the s amp le
was ob tained under s tr ic tl y anaerob i c cond i tion s .
In
mos t anima l s , c ap i l l ar y a ction w a s suf f i c i en t t o acqu i r e
t h e 1 3 0 mic rol iter s ample , bu t in some c a s e s a g e n t l e
kne ed ing o f the animal wa s r e qu i r ed .
Blood s ampl e s wer e
immed i ately ana l yz ed u s i ng a Radiometer BMS-3 whi c h
·. .. .
.
25
u til i z e s a g l a s s e l e c trode for pH, Sever i nghau s e l e c trode
for pC0 2 and a C lark e le c tr od e for p0 2 .
In expe r iments whe r e c ardiac arr e s t was the mode of
d e a th , anima l s wer e a ne s theti z e d and tr e ated with hepar in
a s wer e the o c c luded a irway s ub j e c t s .
Cardi a c arr e s t
wa s induced b y pa s s i ng a 1 2 0 vo l t a lter na ting curr e n t
acr o s s t h e che s t f o r four t o f ive s e cond s v i a e l e c trod e s
c l ipped to e a c h s id e o f the tho r ax.
Surg i c a l techniqu e s
were t h e s ame , exc ept tha t the trachea w a s no t c l ampe d .
F o l lowing e l e c tr i c shock the animal ' s s ternum was spl i t,
and b lo od r emov ed f r om the le f t ventr i c l e .
B lood samp l e s
were analyzed a s i n occ luded a irway anima l s .
Expe rimental D e s ign
Exper iment 1 .
The agonal ep i s od e was induc ed
in
n i n e anim a l s i n each o f the two g roup s - -cardiac arr e s t
and o c c luded trachea .
Blood s amp l e s wer e taken immed iately
from animal s s ac r if i c ed b y c ardiac ar re s t .
Samp l e s wer e
obtai n ed f rom s ub j e c t s s a cr i f ic ed b y a irway o c c lu s ion af ter
a three minute interval .
This time i nterval was necessary
for the c e s s ation of a l l r e s p i r a tion movements .
Al l
s amp l e s wer e ana l y z ed immediately t o d etermine the pC0 2 ,
p0 2 a nd pH val ue s .
Experiment 2 .
contai ning s ix m i c e .
Thr e e groups were s a c r i f i ced , each
Group A w a s s a c r i f i c ed b y o c c l u s ion
o f the a i rwa y w i th a n e l ap s e o f thr e e minu tes b e f o r e blood
26
wa s r e moved.
Group B was s ac r i f i c ed by card i a c arre s t
wi th a thr ee minute e laps e b e f o r e b lood was r e moved.
Group � was also sacrif i c e d by c ardiac ar r e st bu t the
b l ood was r e moved i mmed i a te l y .
A thr e e minute t i me·
per iod i n Group B was e mp l o yed i n order to detect any
e f f e c t o f the s ampl ing t i me Gi f f erential on po 2 , pC02 or
pH value s .
Exper iment 3 .
Ten anima l s wer e s a c r i f i ced v i a
car d i a c a r r e s t , and t e n anima l s b y oc c lus ion o f the a irway .
Sub j e c ts in the o c cluded airway group wer e treated as in
previous exper i ments .
I n the c ard iac arre s ted sub j e c t s ,
thr e e minu t e s e lapsed be f o r e t h e s ternum was s p l i t and
the l e f t ventr i c l e punc tured as in g roup two of Experiment
3.
Bloods wer e ana l yz ed a s in the o th e r s tud i e s .
CHAPTER IV
RESULTS
The blood gas c h anges af ter death wer e such that
the di s c:cimin a t i on between each mode of death could be
made o n the po 2 va lu e s but not on pC02 or pH va lu e s .
In
a l l thr e e exper imen t s , e ar l ier work was c onf irmed (2 8 : 6 54 )
(3 7 : 5 2 0 ) .
Ex peri me n t 1.
As indi c a t e d in Tab l e I ,
stati s tica l
di f f er enc e s wer e obta ined o n pC02 between occluded a irway
and c ar di ac a r r e s t e d sub j e c t s
f o r thi s ar e no t c l ea r ,
(s e e Figure 1 ) .
The reasons
s i nc e a s im i l ar r e spon s e was not
o b s e r ve d in othe r exper ime n t s .
I t was found tha t p02
di f fe r e n c e s wer e highly s igni f i c a n t in e a ch exp er iment
and ther efor e cons i s te n t wi th the hypo the s i s that p02
shou l d b e l ower i n the o c c lude d a i r way group (s e e
F igur e 2 ) .
Exper iment 2 .
C a r di a c arr e s t was s tudied in two
ways ; Group B had a thr e e minute wai t i ng period b e f o r e
b lood s amp l e s wer e take n , whi l e i n Group C b lood s ampl e s
were ·taken i mmedi ate ly .
Re s u l t s indi c ated tha t a thr e e
m i nu t e interva l d i d not cau s e sig n i f i cant di f f erences
in po 2 , pC02 or pH va lu e s ; howeve r , s ig n i f icant
di f f er en c e s i n p02 w e r e obta ined when b lood s ampl e s f rom
28
TABLE I
MEANS , STANDARD D EVIAT I ON, AND P VALUES
F OR ANIVillL S SUBJECTED T O CARD IAC
ARREST AND RESP I RATORY
OBSTRUC T I ON
1
-
O c c luded
Airway
pco2 mmHg
·Numbe r Subj ec ts
Standard D e vi at i o n
p02 mmHg
9
9
Mean
P<
•
Cardiac
Arr e s t
66 . 20
58 . 34
.9 . 6 6
.6. 4 6
05 *
Mean
5 . 84
16 . 58
Standard Deviation
3 . 80
7 . 28
Mean
7 . 048
7 . 083
. 0 54
. 099
Sta ndar d D e viation
P> .05
*Con s i de r ed s t a t i s t ic a lly s ig n i ficant� evaluated at 16
degr e e s o f f r eedom . ( Stude nt ' s t Te s t was u s ed a s the
p r i nc ip l e s ta t i s t i c al proc edure to obtain p va lu e s )
FIGURE
1
EXP ERIMENT I
SACRIFICE BY RESPIRATORY OR CARDIAC MEANS
pC0 2 VALUES
10 0
90
1'-il
c.;J
�
E--i
:z;
J:ij
u
p::;
1'-il
P-i
�
:>
H
8
�
H
::::J
::8
::::J
u
80
70
60
50
40
30
20
10
0.
6- V"""45
50
55
60
65
70
75
80
85
mmHg
(1)
(2 )
Cardiac
Re spi ra tory
!:V
\.0
t
FIGURE
2
EXPERIMENT 1
SACRIF�ICE BY RESPIRATORY OR CARDIAC MEANS
p0 2 VALUES
100
90
r:::l
(.')
,::rz
E-i
:z;
li4
u
�
r:::l
ill
r:::l
:>
H
E-i
,::rz
....:I
::::>
�
::::>
u
80
70
60
50
40
J
30
20
10
0
0
5
10
15
20
25
30
mmHg
( 1)
( 2)
Respir atory
Car diac
w
0
31
the o c c lu ded a irway gr oup wer e compa r e d to e i ther car diac
arr e s t group .
Onc e aga i n , pco 2 values were not s ig ni f i
cantl y diff e rent (s e e Tabl e I I · and F i gu r e s 3 and 4 ) .
Experime nt 3 .
As i l lu s tr ate d in Tabl e I I I , F igure 5
and F igure 6 , r e su l ts support and conf i rm the pr ev iou s
exper iment .
Stati s ti c ally s ig ni f i c ant di f f erenc e s f or
po 2 wer e obta i ne d .
Appar e ntl y p H i s not a s s o c i a te d with mode o f de ath
( s e e Tabl e I , Tabl e II , Tab l e I I I , F igure 7 , Figure 8 and
Figure 9 ) .
TABLE I I
MEANS , STANDARD DEVIATIONS , AND P VALUES OF
OCCLUDED AIRWAY AND CARD IAC
ARREST ANIMALS - 2
pco2 mm:Hg
Number Subjects
Mea n
Standard Dev i a tio n
Group A
Oc cluded Airway
6
8 9.9 6
15.1 0
Gro up C
Cardiac Arres t Onl y
Group B
Card i ac Arres t + 3 m i n.
6
8 8 .76
1 5.3 7
Group A v s . B : p > 0 5
Group A v s . C : p > . 0 5
Group B v s . C : p > .0 5
6
78 . 34
11 .1 0
2 5.3 0
8 .9 9
B : p <: • 0 5*
Group A vs
Group A v s . C : P< . 0 5*
Group B v s . C : p > . 0 5
2 8 .1 8
10 .38
•
po 2 mmHg
Mea n
Sta ndard Dev i ati o n
13 .58
7.3 3
•
pH
Mea n
Sta ndard Dev i a tio n
6 .9 6
.0 58
Group
Group
Group
*Co ns idered Stati stically Sig ni f icant;
,
6 .9 2 0
.0 6 0
A v s . B : p .> 0 5
A v s . C : p.c:::.0 5*
B v s . C : P<·0 5*
Evaluated a t 1 0 Degrees of Freedom
.
_
7.0 3 4
.0 4 9
•
w
[',)
FIGURE
3
EXPERIMENT 2
SACRIFICE BY RESP IRATORY OR CARDIAC MEANS
p0 2 Vl\LUES
100
90
r..:l
0
o::c:
E-1
:z;
r,il
u
p:;
r,il
P;
r,il
:>
H
E-1
o::c:
.....:1
::J
:a:
::J
u
80
70
60
50
40
30
20
10
0
-
0
5
10
15
20
25
30
35
40
rnrnHg
(1)
(2)
(3)
Re spiratory
Cardi a c
Cardiac + 3 minute s
w
w
. FIGURE
4
EXPERIMENT 2
SACRIFICE BY RESPIRATORY OR CARDIAC MEANS
pC0 2 VALUES
100
90
Pi:!
l?
80
E-i
70
,::4·
z
r.r:;
u
60
r:::::
Pi:!
P-i
50
Pi:!
:>
40
H
E-1
,::4
H
D
�
D
u
30
20
10
0
o-"65
70
75
80
85
90
95
100
1 10
105
rnmHg
( 1)
( 2)
(3)
Cardiac
Car diac + 3 minute s
Re spiratory
w
�
t
35
T ABLE I I I
MEANS , STANDARD DEVIAT ION , AND P VALUES
FOR CARD I AC ARRESTED AND OCCLUDED
3
AIRWAY ANIMALS
-
pco2 mmHg
_
Occ l uded
Airway
Card i a c
Arr e s t
Numbe r Subjects
10
10
Mean
8 1 . 67
72 . 70
Standard Deviation
1 6 . 4 (;
13 . 76
------�--��----------�P>· 0�5�---p02 mmHg
Mean
3 . 43
13 . 93
Standard D ev i atio n
3 . 89
8 . 39
p <. 0 5 *
Mean
6. 9 9
. 0 61
Stand a rd Deviation
7 .00
. 083
p .> . 0 5
* C o ns i de r ed s ta ti s ti c a l l y s ignif icant ; evaluated at 1 8
degre e s of f re edom
FIGURE
5
EXP ERIMENT 3
SACRIFICE BY RESPIRATORY OR CARDIAC MEANS
p0 2 VALUES
100
90
�
(.')
�
80
70
E-t
:z;
�
u
p::
�
Pol
50
�
:>
40
H
E-t
�
....::!
::J
�
::J
u
60
30
20
1 0 ..
0
0
5
10
20
15
25
30
35
mmHg
( 1)
(2 )
Re spirato ry
Card i a c
w
0"1
FIGURE
6
EXPERI MENT
3
SACRIFICE BY RESPIRATORY OR CARD IAC MEANS
pco 2 VAL UES
100
90
t:£1
(j
�
E-1
:z;
Pi<
· u
p::;
t:£1
P-1
t:£1
>
H
E-1
�
H
::J
:8
::J
u
80
70
60
50
40
30
20
10
0
...., .,_...
45
55
65
75
85
95
10 5
115
rnmHg
(1)
( 2)
Car diac
Respiratory
w
"
FIG URE
100
7
EXPERIMENT 1
SACRIFICE BY RESPIRATORY OR CARDIAC MEANS
pH VALUES
1
I
90
rLI
c.;:>
F::G
8
z
fil
u
r::r:;
�
0;
rLI
:>
H
8
F::G
r-::1
0
:a:
:::>
u
� 1
80
70
60
50
40
30
20
10
0
I
-
6.8 8 4
6.9 2 8
6.9 7 2
7.0 1 6
7.0 60
7.1 0 4
.
·
7.1 4 8
.
J
7.1 9 2
mmHg
(1 )
( 2)
Respiratory
Cardi ac
w
00
FIGURE
8
EXPERIMENT 2
SAC RIFICE BY RESPIRATORY OR CARDIAC MEANS
pH VALUES
100
�----�------�
__________________________________
90
1£1
0
�·
E-i
z
1£1
u
p::;
1£1
Pol
1£1
>
H
E-i
�
....:!
::J
�
::J
u
80
70
60
50
40
30
20
10
0
6,8 5
6. 8 8
6.9 1
6 .9 7
6. 9 4
7. 00
7. 03
7.0 6
pH
( 1)
( 2)
(3)
Car diac + 3 minutes
Respiratory
Car diac
w
1..0
FIGURE
\
9
EXPERH1ENT 3
SA.CRI;F'ICE BY RESPIRATORY OR CARDIAC r-1EANS
pH VALUES
100
r----=--
90
80
�
!:-'
�
E-!
:z;
�
u
r::r;
r.Li
1=4
50
�
�
40
H
E-!
�
H
::J
:a:
::J
u
70
60
30
20
10
0
6. 8 8 6
6.9 2 0
6.9 54
7 . 022
6. 9 8 8
7 .0 56
7 . 090
7 .1 2 4
pH
( 1)
( 2)
Respiratory
Cardiac
�
0
C HAPTER V
D I SC USSION
The purpo s e o f the s e exper iments was to s tudy blood
. g a s tens ions f o l l owing death .
b y mea s u r i ng po 2 i n mi c e ,
I t wa s hypoth e s i z ed tha t
it wou ld be po s s ib l e to pr ed i c t
whe ther the h e a r t o r the lung s f a i led f i r s t during the
agonal event .
I n addition the r e shou ld b e no s igni f i cant
d i f f er e nc e i n pco 2 o f pH .
P r ev ious wo rke r s have reported
that when dog s wer e s a c r i f i c ed by car d i a c arr e s t or r e s
piratory o b s truc tio n ,
and po 2 measur ed fo l l owi ng d e a th ,
� th e · mo d e o f death could be d e termined
(28 : 657 ) .
I t was
f ou nd tha t the po 2 r ema i ned h igher f o l low ing cardiac
ar r e s t then when d e ath r e s u l ted from r e spiratory obstruc
tion .
The pr e s ent exper iments with mi c e i nd i c a te tha t
mode o f d eath c an a l s o b e determined i n thi s s pec i e s by
s imi lar method s .
Mitho e f er c o nc lude d tha t a p0 2 v alue of
more than 2 5 mmHg s hould i nd i c ate cardiac a r r e s t · ( 2 8 : 6 5 6 ) .
Valu e s of Swi s s strain mice a r e extremely c l o s e , 2 0 mmHg ,
(mean p0 2 o f al l cardiac a rr e s ted anima l s ) .
The low p0 2 i n
both exper iments i s probably due to r emova l o f 0 2 from
the b l o od by ti s su e s a s c ir cu lation continu e s f o l l owing
a irway o c c l u s i o n .
I n the pre s e nt study , the heart wa s
obs e rved to continu e bea ting u p to two and one hal f
'·
--
42
m i nu t e s f o l lowing the c l amping of the trachea .
Ear l i e r
s tu di e s h a v e s hown t h a t thi s t i s su e hypoxia doe s r e su l t
i n m i c e a f t er thr ee m i nu t e s o f a s phyx i a
(24 : 435) .
No di f f er en c e s wer e not e d i n pC0 2 value s i n two of
the thr e e exper iments .
( s e e Tab l e I I )
The obta ined p value for pC0 2
i n Expe r iment l wa s s ig n i f i c ant
(p< . 05) .
Two a n im a l s i n the o c c luded a i rway group of th i s exper iment
hypov en t i l a t e d exc e s s ively on r eceiving the ane s thet i c .
The s e two s ub j e c t s had muc h h igher pco 2 values than the
group average whi c h cou l d account for th i s i ncon s i s tency .
A s s hown i n Tab l e s I I and I I I , s igni f i cant di f f er e n c e s
wer e not o b t a i n e d o n pco 2 i n Exper iments 2 and 3 .
Th i s
i s con s i stent with the hypoth e s i s .
D i f f er e nc e s i n pH wer e observed in Expe r iment 2
b e twee n bo th the o c c lu de d a i rway sub j e c t s and a l s o the
c ar di a c arr e s t s ub j e ct s
c o u l d n o t b e r epl i c a te d .
( s e e Tab l e I I ) .
The r e su l t s
I t i s , ther e f or e , u n l i k e ly
that hydrogen ion conc entr ations a r e a s s o c i a t e d with the s e
mode s o f dea th .
C HAPTER V I
CONCLU S IONS
Re sults s trongly s ugge s t that by mea suring p0 2
f o l l ow i ng d e ath it i s po s s ible to pr ed i c t whe ther the
lung s or heart f a i l e d f i r s t .
Ti s su e hypox i a ex i s ts in
both mode s of d e a th , but i n the occ lud ed a irway anima l s
the c i rculation o f b l o o d continue s , a l l owi ng oxyhemoglobin
to r each the ti s su e s .
With cardiac ar r e s t , b l ood is no t
f o r c ed through the ti s su e s , and d eoxyg ena tion i s
r e tarded .
44
B IB L IOGRAPHY
1.
and E . R . K inney .
" Sudden and U n e xpe c t e d
I n f an c y an c C h i l dren , "
P ed i atric s , 1 9 5 6 ,
Ad e l s on , L . ,
D e a th i n
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48
APPEND IX A
D a ta L i s t i ng s for Exper iment 1
49
Group A
Occ l ude d Airway
Anima l s
pH
1
2
3
4
5
6
7
8
9
10
7 . 0 22
7 . 0 54
7 . 120
6 . 992
7 . 01 8
7 . 126
7 . 012
7 . 091
7 . 013
7 . 033
G roup B
. pco2 mmHg
76 . 0
66 . 4
60 . 9
64 . 3
66 . 6
57 . 6
66 . 7
53 . 5
62 . 3
87 . 7
P02 mmHg
2.1
2.1
6.7
2.8
2.9
8.3
10 . 8
11 . 2
9.2
2.3
Cardiac Arr e s t
· Anima l s
. pH
1
2
3
4
5
6
7
8
9
10
7 . 187
7 . 141
6 . 8 84
7 . 105
6 . 989
7 . 00 8
7 . 137
7 . 069
7 . 208
7 . 097
.
pC0 2 mmHg
58 . 0
51 . 4
59 . 4
48.3
61 . 2
65. 4
55 . 2
52 . 3
65 . 7
66 . 5
· po 2 mmHg
17 . 8
21 . 1
10 . 5
24 . 8
20 . 2
11 . 6
28 . 3
4.2
12 . 2
15 . 1
50
APPEND IX B
Data L i s t i ng s f o r Exp e r imen t 2
51
Group A
O c c luded Airway
pH
Anima l s
M1 c e
1
2
3
4
5
6
Group B
6 . 97 2
6 . 904
7 . 041
7 . 012
6 . 906
6 . 926
Cardiac Arr e s t
· An imal s
Mi c e
1
2
3
4
5
6
Group c
· Animal s
1
2
3
4
5
6
6
6
6
6
6
7
+
pC02 tnmHg
;eo 2 romHg
84. 9
106 . 6
76. 8
70 . 3
105 . 7
95. 5
3.2
15. 4
11 . 7
24 . 5
17 . 5
9.2
3 M i nu t e s
pH
pC0 2 tnmHg
p0 2 tnmHg
. 875
. 917
. 9 23
. 850
. 958
. 01 7
108. 3
88 . 9
71 . 8
102 . 9
89 . 6
71 . 1
7 .4
29 . 6
28 . 3
25. 3
30. 0
31 . 2
pC02 tnmHg
p 0 2 mmHg
Cardiac Arr e s t
pH
7 . 009
7 . 063
7 . 07 6
7 . 025
6 . 954
7 . 082
85. 9
75. 1
67 . 0
73 . 3
97 .1
71 . 8
13 . 5
27 . 9
26 . 5
37 . 5
21 . 7
42 .0
52
APPEND I X C
Da ta L i s t ing s f or Exper iment 3
53
Group A
Animal s
1
2
3
4
5
6
7
8
9
10
Group B
Oc c l uded Ai rway
pH
6 . 913
7 . 0 53
6 . 993
6 . 8 97
7 . 0 29
6 . 951
6 . 93 8
7 . 0 28
6 . 97 5
7 . 077
Card iac Arr e s t
Anim a l s
pH
l
2
3
6 . 993
6 . 896
6 . 999
6 . 97 2
6 . 956
6 . 886
7 . 13 8
6 . 999
7 . 10 5
7 . 069
4
5
6
7
8
9
10
+
+
3 M i nute s
pC 02 mmHg
po 2 mmHg
11 8 . 8
78.7
86 . 1
96 . 4
75. 9
77 . 6
82. 7
59 . 4
73 . 8
67 . 3
2. 1
6
.8
1.8
9.8
1.1
3.7
11 . 4
1.2
1.8
•
3 Minu t e s
pcoz mmn9_
79. 5
96. 2
67 . 8
63 . 5
77 . 3
85. 7
49. 3
7 2. 5
57 . 4
77 . 8
pO i mmHg
10 . 6
9.8
15 . 5
3 2. 1
5.9
5.6
22 . 6
15 . 9
15 . 1
6.2

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