TRANSVASCULAR FLUID MOVEMENT
AND SEGMENTAL VASCULAR

RESISTANCES IN RESPONSE TO _

TRANSFUSION m ENDoroxm smcK. .

fiisssrtation for the Degree of P223 D.
MJCHiGAN 8'? TE UNEVERSITY
,W. JEFFREY WEEDNER .
~ 1973

 

LIBRARY

Michigan Steve‘-

University

»"0-m'.~ “-C

This is to certify that the

thesis entitled
TRANSVASCULAR FLUID MOVEMENT
AND SEGMENTAL VASCULAR
RESISTANCES IN RESPONSE TO
TRANSFUSION IN ENDOTOXIN SHOCK

presented by

W. Jeffrey Weidner

has been accepted towards fulfillment
of the requirements for

Ph.D. Physiology

degree in

 

 

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ABSTRACT
TRANSVASCULAR FLUID MOVEMENT AND SEGMENTAL

VASCULAR RESISTANCES IN RESPONSE TO
TRANSFUSION IN ENDOTOXIN SHOCK

BY
W. Jeffrey Weidner

The aim of this study was to determine if transfusion
leads to fluid filtration and a disproportionate rise in
extravascular fluid volume (EFV) in dogs previously injected
with endotoxin relative to that seen in saline controls.

Male mongrel dogs were anesthetized with sodium pentobarbital
and injected with either purified E. coli endotoxin (5 mg/Kg,
i.v.) or saline, and after 2 hours were transfused with 1000
m1 of cross-matched whole blood over a period of 25 min.
There was no change in forelimb weight, segmental vascular
resistances, blood flows or blood pressures in the saline
dogs prior to transfusion. Following transfusion forelimb
weight increased markedly relative to control (22 g in 2
hrs). The weight gain occurred concurrently with significant
increases in right atrial pressure (which would indicate an
increased capillary hydrostatic pressure in an intact animal),
aortic pressure, small vein pressures, and hematocrit and

‘with no change in segmental vascular resistances. Hence,

TRANSVASCULAR FLUID MOVEMENT AND SEGMENTAL
VASCULAR RESISTANCES IN RESPONSE TO

TRANSFUSION IN ENDOTOXIN SHOCK
WE -. .-

-~... «—

BY

W. Jeffrey Weidner

A DISSERTATION
Submitted to
Michigan State University

in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY

Department of Physiology
1973

DEDICATION

Thus one 416 6011. Swént Aua ofi-the-Km’fie and Duncan Idaho,
the bzeepéng dogs, and ail the £0ng necked bottled.

ii

TABLE OF CONTENTS

Chapte r Page
I. INTRODUCTION . . . . . . . . . . . . . . . . 1

II. REVIEW OF LITERATURE . . . . . . . . . . . . 4
III. STATEMENT OF THE HYPOTHESIS . . . . . . . . . 19
IV. METHODS . . . . . . . . . . . . . . . . . . . 20

V. RESULTS . . . . . . . . . . . . . . . . . . . 26

VI. DISCUSSION . . . . . . . . . . . . . . . . . 83
VII. SUMMARY . . . . . . . . . . . . . . . . ... . 92
VIII. SPECULATION AND ADVICE FOR FURTHER STUDY . . 93
BIBLIOGRAPHY . . . . . . . . . . . . . . . . . . . . 97
APPENDIX . . . . . . . . . . . . . . . . . . . . . . 103

iii

LIST OF TABLES

Table Page

1. Effect of transfusion on systemic and
forelimb parameters following endotoxin
administration (cut vein preparation) . . . . 65

2. Effect of transfusion on systemic and
forelimb parameters in control animals
(cut vein preparation) . . . . . . . . . . . . 71

3. Effect of transfusion on systemic and
forelimb parameters following endotoxin
administration (intact vein preparation) . . . 77

4. Effect of transfusion on systemic and
forelimb parameters in control animals
(intact vein preparation) . . . . . . . . . . 80

5. Hematocrits in control and experimental
animals 0 O O O O O O O O O O O I O O O O O O 82

iv

Figures

1-4

9-12

13-16

LIST OF FIGURES

Effects of transfusion on systemic pressure

(mm Hg), right atrial pressure (mm Hg),
forelimb weight (g) and total forelimb

bloodflow (ml/min/lOO g forelimb) in endo-

toxin animals (closed circles, N==7) and

saline control animals (closed triangles,

N==7) . . . . . . . . . . . . . . . . .

Effects of transfusion on blood flow
(ml/min/lOO g forelimb) and large and

small vessel pressures (mm Hg) in skin and
skeletal muscle vasculature of the canine

forelimb in endotoxin animals (closed

circles) and saline control animals (closed
squares). N values correspond to those in

Figure l O O O O O O O O O O O O O I 0

Effects of transfusion on total forelimb
and total forelimb segmental vascular

resistances (mm Hg/ml/min/lOO g forelimb)

in endotoxin animals and saline control

animals. Symbols and N values correspond

to those in Figure l . . . . . . . . .

Effects of transfusion on total and

segmental vascular resistances (mm Hg/ml/

min/100 g forelimb) in skin and skeletal

muscle vasculature of the canine forelimb
in endotoxin animals (closed circles) and

saline control animals (triangles). N
values correspond to those in Figure 1

Pages

31-37

39-45

47-53

55-61

CHAPTER 1

INTRODUCTION

A significant percentage of circulatory shock cases
resulting from endotoxin become refractory to treatment,
i.e., blood volume restoration with or without additional
pharmacological therapy (37, 47). For this reason endotoxin
shock is clinically associated with a high mortality rate.

A serious obstacle to the successful treatment of this con-
dition is the lack of complete data on its path0physiology.
This study is an attempt to provide further definitive
information on one aspect of endotoxin shock, namely, the
role of transcapillary fluid fluxes in skin and skeletal
muscle in determining irreversibility after transfusion.

Transvascular fluid efflux, especially into skeletal
muscle, has been suggested as a possible determinant of
irreversibility in endotoxin shock since it is thought to
lead to loss of plasma volume and subsequent decline in
total blood volume. The literature on this subject, however,
is inconsistent with respect to the site and magnitude of
such fluid fluxes. Several factors may account for these
conflicting observations: species variation in response to

endotoxin; error associated with plasma volume measurements

made with dilutional techniques, particularly in
vasoconstricted states since adequate mixing of the dye

may not occur; the inability of dilutional techniques to
separate measured decreases in blood volume due to fluid
efflux from decreases due to intravascular pooling. More-
over, aside from a previous study by Weidner 35 31.,
transcapillary fluid fluxes in skeletal muscle have not
been studied specifically, but alleged fluid efflux has
been inferred from changes in hematocrit and plasma volume
(61). In the previously mentioned study, which utilized a
gravimetric technique, no evidence was found for fluid
filtration during the hypotensive period in dogs subjected
to endotoxin shock; in fact, only evidence for extravascular
fluid reabsorption from skin and skeletal muscle was found
(61). Similar findings have been reported by Hinshaw and
Owen utilizing a canine forelimb preparation (30). .This
phenomenon may not occur following transfusion, however,
since the hemodynamic relationships change markedly. Blood
volume restoration increases vascular pressures, under these
conditions changes in the precapillary to poetcapillary
resistance ratio and/or microvascular membrane permeability
to plasma proteins have a quantitatively greater effect on
both the direction and rate of transvascular fluid fluxes-
than similar changes in these variables when vascular pres-

sures are low. Thus, it is important that the prolonged

effect of transfusion be critically examined to determine
if net fluid efflux into skin and skeletal muscle occurs
in animals subjected to endotoxin shock.

In an attempt to circumvent some of the problems
encountered with dilutional techniques, such as inadequate
mixing of dyes, endotoxin shock has been studied utilizing
a gravimetric technique. Transcapillary fluid fluxes in
the canine forelimb were estimated from changes in forelimb
weight and segmental vascular resistances. The forelimb has
been selected as the test organ since it is largely composed

of skin and skeletal muscle.

CHAPTER II

REVIEW OF LITERATURE

Endotoxin shock, often called bacteremic or septic
shock, is a condition resulting from the liberation of a
lipoprotein-carbohydrate complex from the cell wall of
certain gram negative bacteria, of which E. coli is an
example. Endotoxin, once it enters the vascular system of
an animal, has pronounced deleterious effects and is often
fatal. Although the response to endotoxin is not the same
in all species, hypotension is common to all.

Canine endotoxin shock following i.v. injection of
purified endotoxin is generally associated with the follow-
ing responses: systemic arterial pressure (SAP) falls
abruptly within 2-5 minutes, transiently recovers toward
control levels (min. 20-45), and then gradually falls unto
death (3); right atrial pressure (RAP) falls within 1-3
minutes and remains below control (3, 51, 56); cardiac
output (CO) falls precipitously within 2-5 minutes and
follows a pattern similar to SAP (3, 54); calculated plasma
volume (PV) has been reported to progressively decrease up

to 36% (3); after an initial brachycardia, heart rate

remains elevated above control (3); no significant change

in myocardial contractility occurs until the terminal

stages (3, 4, 51). Total peripheral resistance (TPR)
increases markedly within 2-5 minutes following endotoxin
administration, wanes (min. 20-45) and then either increases
from 60 minutes until death or further decreases (until min.
120-180) before increasing until death (3). Hematocrit,
after an initial decrease (0-10 min.), has been reported

to rise continuously (3, 4).

Decreased flow, subsequent to a decreased blood
volume resulting from vascular pooling and/or from trans-
vascular fluid loss is thought to be the major determinant
of irreversible shock from endotoxin in the dog (3, 25, 34,
56, 57). Endotoxin administration into live animals elicits
a number of responses which are known to affect transcapil-
lary water movement across capillaries and the intravascular
distribution of blood. Transcapillary water movement is
regulated by the transmural hydrostatic pressure gradient
and by the transmural colloid osmotic pressure gradient.
Capillary hydrostatic pressure (Pc) is an important deter-
minant of the former; a rise in this variable (as occurs
with transfusion) above colloid osmotic pressure (COP) pro-
motes fluid efflux, while decreased capillary hydrostatic pres-
sure (as occurs with hemorrhage) below COP facilitates fluid
influx (46). Capillary hydrostatic pressure is determined

by the compliance of the capillary wall and capillary blood

volume. Capillary blood volume is determined by the
precapillary to postcapillary resistance ratio and by aortic
pressure and right atrial pressure. Resistance in the pre-
capillary and postcapillary segments is related to vessel
caliber and blood viscosity. Vessel caliber is a function
of changes in vascular smooth muscle (active changes) and
changes in transmural pressure independent of changes in
smooth muscle activity (passive changes). A decrease in
systemic arterial pressure, right atrial pressure, or post-
capillary resistance, or increase in precapillary resistance
will tend to lower capillary hydrostatic pressure. Likewise
an increase in systemic arterial pressure, right atrial
pressure, or postcapillary resistance, or a decrease in
precapillary resistance will tend to produce the opposite
effect on capillary hydrostatic pressure. The transmural
colloid osmotic pressure gradient can be altered by a change
in microvascular permeability to plasma proteins as well as
by abnormal lymph drainage.

Endotoxin shock is associated with altered net fluid
fluxes across the capillaries. Net fluid influx is believed
to occur initially. Measurements of hematocrit and plasma
protein concentration are compatible with the early influx
of fluid in that both decrease initially in the intact dog
(3, 4, 28). In splenectomized dogs similar changes are seen

in hematocrit and plasma protein concentration; also plasma

volume (PV) reportedly increases (3, 4, 58). In primates,
including man, plasma volume increases; hematocrit and
plasma protein concentration decrease (3, 21, 56). This
also suggests that the early stage of endotoxin shock is
associated with extravascular fluid reabsorption. The
initial fluid influx following endotoxin injection has been
attributed to a fall in capillary hydrostatic pressure,
especially in skeletal muscle (3, 4, 61). Capillary hydro-
static pressure is thought to fall subsequent to the fall in
systemic arterial pressure and right atrial pressure and an
increased precapillary to postcapillary resistance ratio (9,
19, 21, 26, 34). The initial fluid influx is viewed as an
important compensatory mechanism, which serves to increase
blood volume (9, 21). An increased blood volume would serve
to increase venous return and subsequently cardiac output.
The directiOn of net fluid movement has been
reported to reverse with time (45-60 minutes after endo-
toxin administration) due to increased capillary hydrostatic
pressure and/or increased microvascular permeability to pro-
teins (3, 4, 33, 37). This is viewed by some authors as
important in the deveIOpment of irreversibility since it
serves to critically reduce both the effective blood volume
and total blood volume. A decreased total blood volume
leads to decreased venous return and subsequently to de-

creased cardiac output. In dogs a continuous rise in

hematocrit and plasma protein concentration has been
observed after the initial decrease (3, 4, 53). Weight
continuously increases in forelimbs perfused at constant
flow (24). This has been interpreted as evidence for a

net fluid efflux (34, 50). However, under conditions of
constant flow, weight increases may occur subsequent to
increased capillary hydrostatic pressure due to venocon-
striction. And, although compatible with plasma volume
loss, does not necessarily mean plasma volume loss occurs

at natural flow. In this regard recent experiments by the
author are important (61). An isolated forelimb preparation
was used to investigate transvascular fluid fluxes in dogs
subjected to endotoxin shock. Forelimb weight fell through-
out a four-hour period. The weight loss was associated with
a fall in total forelimb resistance from minute 10 through-
out the remainder of the observation period. The fall in
forelimb resistance suggests that mean blood vessel caliber
and forelimb intravascular blood volume were increasing
during this period. A sustained weight loss accompanied

by an increasing intravascular blood volume must be attrib-
uted to extravascular fluid reabsorption. Like findings
have been reported recently by other investigators (30).
This data is not inconsistent with an endotoxin induced
increase in microvascular permeability to plasma proteins,

however if microvascular permeability did increase, the

increase was insufficient to promote net fluid efflux and
extravascular fluid reabsorption continued. These data
fail to provide evidence for fluid filtration into skin
and skeletal muscle during prolonged endotoxin hypotension,
but support the concept that endotoxin hypotension is
accompanied by extravascular fluid reabsorption. Dogs also
develop diarrhea, which demonstrates that some fluid is lost
into the intestinal lumen. The volume of fluid lost through
the intestine is relatively small and is not enough in it-
self to cause irreversibility (20). Intestinal necrosis and
bloody diarrhea do not occur in cats or primates (27, 36, 58).
The intravascular distribution of blood is affected
by factors that affect vascular capacity. Vascular capacity
is affected by changes in vessel compliance and by active
and passive changes in vessel caliber. Reported losses in
plasma volume in both the early and late stages of endotoxin
shock are frequently attributed by some authors to extensive
fluid efflux. These losses, however, may be due wholly or
in part to vascular pooling of blood. Peculiar to the
canine species during the early stage of endotoxin shock is
an hepatic venoconstriction occurring within 1-2 minutes
after administering endotoxin. This venoconstriction
decreases in intensity at 3 minutes and essentially disapé
pears within 20 minutes. It is responsible for the initial

rise in capillary hydrostatic pressure in the hepatosplanchnic

lO

vascular beds, and has been implicated as the cause of
impeded venous return which serves to precipitate the early
hypotensive phase of endotoxin shock in the dog (3, 24, 27,
29, 35, 38, 40, 53). This venoconstriction is reported to
be responsible for vascular pooling of blood in the hepa-
tosplanchnic beds during the early phase of endotoxin shock
(12, 20, 29, 38). Increases of up to 35 g/100 9 tissue
weight occur in the small intestine (20). Liver weight
increases from 80 to 350 9 have been reported to occur
within 3 minutes following endotoxin. This response is
short—lived, however, since weight returns to control within
30 minutes (38). In the late stage of endotoxin shock
little or no evidence exists for vascular pooling in the
hepatosplanchnic beds or other organs.

During endotoxin shock, systemic arterial and right
atrial pressures decrease appreciably while peripheral pre-
capillary resistance increases. This would tend to lower
capillary hydrostatic pressure. In order for capillary
hydrostatic pressure to increase under these conditions,
post capillary resistance would have to rise markedly to
overcome the effects of the fall in systemic arterial and
right atrial pressures and the increase in precapillary
resistance. If the rise in postcapillary resistance were»
of sufficient magnitude, a rise in capillary hydrostatic
pressure above colloid osmotic pressure would promote fluid

efflux. This is unlikely considering the hemodynamics of

11

the shock state. After endotoxin administration systemic
arterial pressure frequently falls to 30-40 mm Hg and right
atrial pressure is frequently 0 mm Hg or less. If in this
case, the precapillary to postcapillary resistance ratio
fell from a control of 4 to as low as 1, calculated capil-
lary hydrostatic pressure would be between 15 and 20 mm Hg,
well below colloid osmotic pressure (see Appendix for cal-
culation). It is thus unlikely that extravasation of fluid
takes place during extreme hypotension unless capillary
membrane permeability to plasma proteins is substantially
increased. This agrees with the author's previously pub-
lished findings for prolonged endotoxin induced hypotension
in which only evidence for extravascular fluid reabsorption
from the forelimb was found (61). However, this may not be
true following transfusion. In dogs subjected to endotoxin
shock, transfusion of either whole blood or dextran signif-
icantly increases blood pressure (2, 43). Cardiac output is
increased significantly, but may begin to fall after a vari-
able period of time, usually 3 to 6 hours after transfusion
(2). Central venous pressure increases significantly after
transfusion, but also may fall after a variable period of
time (2). Hematocrit is significantly lowered in response
to transfusion with low molecular weight dextran (59). pH.
falls significantly less in dogs subjected to transfusion

after endotoxin administration than in dogs given endotoxin

12

alone (2, 59). The marked rise in central venous pressure,
which is associated with increased cardiac output, diminished
transit time and diminished peripheral resistance suggests
an increased venous return (1, 2). Transfusion following
endotoxin shock also improves certain parameters in primates.
Infusion of either blood or dextran reportedly increases
cardiac output, central venous pressure, right atrial and
systemic arterial pressures (5). Peripheral vascular
resistance has been observed to decrease in response to
transfusion, as does heart rate (5). Conflicting evidence
exists, however, with respect to the effect of transfusion
in primates, as both cardiac output and central blood volume
have been reported to decrease in monkeys in response to
transfusion following endotoxin administration (59).
Although central venous and right atrial pressures
and cardiac output are elevated by fluid replacement, vascu-
lar behavior may not be beneficially affected in peripheral
beds, nor it does not necessarily follow that normal condi-
tions will be restored to the microvasculature. After
transfusion, then, the hemodynamic situation is altered
since transfusion increases vascular pressures. Under
conditions of increased vascular pressure, changes in the
precapillary “Us postcapillary resistance ratio and/or
microvascular permeability to plasma proteins have a far
greater effect on both the direction and rate of trans-

vascular fluid fluxes than do similar changes in these

13

variables when the vascular pressures are low. The effects
of transfusion on transvascular fluid fluxes in endotoxin
shock states have yet to be investigated.

The majority of studies in the literature pertaining
to the effect of transfusion during endotoxin shock are
concerned with survival rate. Transfusion, either of whole
blood or dextran, into both dogs and primates, including
humans, in endotoxin shock is known to markedly increase
survival time, but often does not alter ultimate hemodynamic
deterioration (49, 51).

Evidence exists which suggests that capillary
membrane permeability to plasma proteins is increased during
endotoxin shock (3, 50). A fall in the transmural colloid
osmotic pressure gradient could promote fluid efflux even if
capillary hydrostatic pressure does not increase. Since
vascular pressures are increased by transfusion, fluid
efflux in the face of increased microvascular permeability
would tend to be of greater magnitude than that caused by
increased capillary hydrostatic pressure alone. If capil-
lary hydrostatic pressure falls, however, a decreased
transmural colloid osmotic pressure gradient would not
necessarily result in extravasation of fluid. Indeed, if
the transmural hydrostatic pressure gradient fell propor-
tionately more than the transmural colloid osmotic pressure

gradient, filtration of fluid would not occur, but

l4

extravascular fluid reabsorption would result. The reported
decrease in measured blood volume is usually attributed to
intravascular fluid loss by filtration, although it could as
well be attributed to intravascular pooling of blood since,
in vasoconstricted states, the indicator may not penetrate
into the pooled blood and thus erroneously low plasma volume
measurement occurs. In splenectomized dogs dilutionally
measured plasma volume does not significantly change or may
increase slightly; hematocrit and plasma protein concentra-
tion decrease, suggesting hemodilution rather than fluid
loss (3, 4, 54). In primates, including man, there is like-
wise no evidence for a progressive plasma volume loss,
measured plasma volume does not progressively decrease, nor
do hematocrit or plasma protein concentrations progressively
increase (8, 12, 25, 34, 58). Weight has been reported to
continuously decrease for 120 minutes in response to endo-
toxin (1 mg/Kg) in autoperfused canine forelimbs (33).
These findings are consistent with the author's previously
mentioned findings. However, this may not be true following
transfusion, after which hemodynamic relationships are sig-
nificantly altered.

Following systemic administration of endotoxin in
dogs total peripheral resistance has been reported to in-
crease greatly within 5 minutes, wane from 20-45 minutes,

and either increase from 60 minutes until death or continue

15

to further decrease toward control for a variable period

and then increase until death (3, 35, 39). Systemic admin-
istration of endotoxin in dogs has been reported to produce
an early transitory phase of increased total resistances in
autoperfused splanchnic, hepatic, renal, hindlimb and fore-
limb vascular beds and then resistances partially wane with
time (23, 29, 39, 40). The cerebral and coronary vascular
beds show relatively little change in resistance in response
to systemically administered endotoxin (39, 48). Systemic
infusion of endotoxin also increases resistance in vascular
segments which are series coupled in the autoperfused fore-
limb. Segmental vascular resistances in skin and skeletal
muscle (large arterial, small vessel, large venous) increase
abruptly within 2-5 minutes and then skeletal muscle resist-
ances partially wane with time, while skin resistances
remain elevated (33).

Local i.a. administration of endotoxin to various
vascular beds has been reported to have only small transient
effects on the renal, hindlimb and forelimb vascular resist-
ances (13, 22, 34, 39). The coronary bed has been reported
to show a decreased resistance when given endotoxin locally
(11). However, the isolated canine liver and small intes-
tine when perfused with endotoxin show increased resistances

(29).

16

The observed change in total peripheral resistance
in canine endotoxemia is seemingly a phenomenon due both to
active and passive factors. Active changes in vessel
caliber are due to indirect actions of endotoxin, since
local administration apparently has little or no effect
on most vascular beds (51). Indirect active changes in
vessel caliber are due to neurogenic effects and to chemical
factors which are liberated into the bloodstream by endo-
toxin (42, 44, 45). Passive decreases in vessel caliber may
be precipitated by blood viscosity increases which increase
vascular resistance and hence lower blood flow. These may
be precipitated either directly or indirectly by endotoxin,
i.e., increased hematocrit and hypercoaguability (18).

Total peripheral resistance may also rise as the result of
passive geometrical factors, such as decreases in vessel
radius which occur as a result of a fall in transmural
pressure, especially in the late stages of endotoxin shock
(22). It has been shown that hepatosplanchnic resistance
changes and pooling are not dependent on an intact nerve
supply to the viscera or to the presence of the adrenal
glands (21). Late changes in resistance are more pronounced
in intact dogs than splenectomized dogs and can be related
to a rise in blood viscosity resulting from splenic emptying
(3, 4, 40). Monkeys, in response to endotoxin, show a
decreased total peripheral resistance throughout the

experimental period, as do eviscerated dogs (12, 25, 28).

17

The development of a progressive systemic hypotension
in the dog following endotoxin administration has been
explained by decreases in cardiac output (12, 26). Endo-
toxin has been reported to cause a lowered setting of the
baroreceptors which would result in a lowering of the reg-
ulated systemic pressure (55). Since heart rate is slightly
elevated after an initial bradycardia and cardiac strength
is reportedly unimpaired in response to endotoxin, the
decreased cardiac output is reportedly due to an impeded
venous return (4). The alleged fluid efflux would contri--
bute to the decreased venous return. Certain blood borne
substances such as serotonin, catecholamines, and histamine
have been implicated as causing venoconstriction. Increased
postcapillary resistance combined with decreases in respon-
siveness to pressor agents of peripheral precapillary
vessels and the action of vasodilator metabolites, has been
reported to facilitate fluid efflux and to participate in
decreasing venous return and in a transient waning of total
peripheral resistance (3, 4, 34, 54, 57). These effects,
especially those of the increased metabolites are said to
be the result of stagnant anoxia (3, 4) which may occur in
response to intravascular coagulation and low nutritional
blood flow (18).

In conclusion, this study is an attempt to provide

definitive information on the vascular response in skin and

18

skeletal muscle to tranfusion during endotoxin shock.
Transfusion is an often used procedure in the management

of endotoxemia, and although sometimes beneficial in main-
taining blood pressure, has not been found to alter the
ultimate irreversible course of endotoxin shock. It has
been reported that transfusion may lead to fluid loss from
blood to tissue by filtration from microvascular sites (51).
Skeletal muscle could provide a large reservoir for fluid
efflux since it comprises approximately 65% of total body
weight. Although a previous study by Weidner §E_gl. pro-
vides no evidence for the hypothesis that fluid efflux to
skin or skeletal muscle is a factor in determining irrevers-
ibility in endotoxin shock (61), transfusion may sufficiently
alter hemodynamic relationships in these tissues so as to
allow fluid efflux to occur. Shilight of certain inconsist-
encies in the literature surrounding the site of alleged
fluid losses during endotoxin shock, it is felt that an
examination of the responses of skin and skeletal muscle
vasculature to transfusion during endotoxin shock is war-
ranted. We have attempted to measure transcapillary fluid
fluxes in skin and skeletal muscle utilizing a gravimetric
technique. Continuous recordings of forelimb weight and
calculations of forelimb skin, skeletal muscle, and total
vascular resistances in both precapillary and postcapillary
vascular segments were made in an effort to determine the

direction and mechanism of transvascular fluid fluxes.

 

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CHAPTER III

STATEMENT OF THE HYPOTHESIS

The objective of the following study is to test
the hypothesis that transvascular fluid efflux into skin
and skeletal muscle occurs following transfusion during
prolonged endotoxin induced hypotension and to provide
meaningful and utilitarian scientific data with regard

to the mechanism causing any observed fluid movement.

19

CHAPTER IV

METHODS

Fourteen dogs of either sex having an average weight
of 18 Kg were anesthetized with sodium pentobarbital (30-35
mg/Kg) and allowed to breathe spontaneously through a cuffed
endotracheal tube. Skin of the right forelimb was circum-
ferentially sectioned 3-5 cm above the elbow. The right
brachial artery, forelimb nerves, and brachial and cephalic
veins were isolated, and the muscles and remaining connec-
tive tissue sectioned by electrocautery. The humerous was
cut and the ends of the marrow cavities packed with bone wax.
Blood entered the limb only through the brachial artery and
exited only through the brachial and cephalic veins. The
forelimb nerves (median, ulnar, radial and musculocutaneous)
were left intact and coated with an inert silicone spray to
prevent dessication. Heparin was administered in an initial
dose of 10 mg/Kg and hourly supplements of 2.5 mg/Kg. The
following cannulations were made to obtain segmental pres-
sure gradients in skin and skeletal muscle: (1) skin small
artery from the third superficial volar metacarpal artery
on the underside of the paw; (2) muscle small artery from a

vessel supplying a flexor muscle in the upper portion of the

20

21

forelimb; (3) skin small vein from the second superficial
dorsal metacarpal vein on the upper surface of the paw;

(4) muscle small vein from one of the deep vessels draining
a flexor muscle in the middle portion of the forelimb; (5)
skin large vein from the cephalic vein via a side branch at
the level of the elbow; and (6) muscle large vein from the
brachial vein via a side branch at the level of the elbow.
All cannulas were small bore polyethylene tubes (PE-10 to
PE—60) and cannulation was accompanied using the wedge
pressure technique. With this technique the cannulated
small vessel acts as an extension of the catheter, and
hence, the pressure measured is that in the first collateral
vessels joined by the cannulated vessel. The measured pres-
sure is a lateral pressure as long as the cannulated vessel
is patent and is not a terminal vessel (this is verified by
the ability to freely withdraw blood from and to flush into
the vessel). The presence of the catheter does not measur-
ably alter the pressure because, in the forelimb, the
cannulated vessel is a negligible fraction of the total
cross-sectional area of the vascular bed and there are many
artery to artery and vein to vein anastomoses (15, 16, 41).
Pressures were measured with low volume displacement Statham
transducers (P23G—B) and recorded on a Hewlett—Packard

direct-writing oscillograph.

22

Brachial and cephalic veins were partially
transsected 3-5 cm downstream from the site of the large
vein pressure measurement and the distal end of each vessel
was catheterized with a short section of PE-320 tubing.
Total venous outflow was directed into a reservoir main-
tained at constant volume by a pump which returned shed
blood to the left femoral vein. Blood flow was determined
by timed collections of the two venous outflows. In this
preparation the median cubital vein represents the major
anastomotic channel between brachial and cephalic veins.
This vessel was ligated and used for large vein pressure
measurements, one catheter directed to the cephalic vein,
the other to the brachial vein. Thus, brachial venous
outflow was predominantly from skeletal muscle while
cephalic vein flow was predominantly from skin. Although
this approach may not completely isolate the blood flow
through the skin from that through muscle, flow separation
is sufficient to compare resistance changes in the two
parallel-coupled vascular beds (6, 14, 46).

After cannulation the limb was placed on a wire mesh
platform attached to a strain-gauge balance (52). In all
experiments the balance was calibrated by the addition of
a two-gram weight, which produced a 10 to 20 mm pen deflec-
tion on the oscillograph. Calibrations were made before
each flow measurement. Right atrial pressure was contin-

uously monitored from a catheter (PE-320) in the right

23

jugular vein. Mean systemic arterial pressure was
continuously monitored from a catheter (PE-240) in the
right femoral artery which had been advanced to the region
of the abdominal aorta. Following a short control period
either 20 cc of normal saline or purified E. coli endotoxin
(5 mg/Kg) (Difco Laboratories, Detroit, Mich.) suspended in
20 cc of normal saline, was infused into a cannulated
saphenous vein by means of a Harvard constant infusion pump.
Seven dogs received endotoxin and served as experimental
animals, while the seven dogs given saline were control
animals. Infusion time was 10 minutes. Limb weight was
continuously monitored and all pressures and blood flows
were determined twice during a preinfusion control period
and thereafter for every 15th minute up to minute 120. At
minute 120, 1000 cc of whole blood was administered in a
25 minute transfusion by the means of a Sigmamotor pump.
The blood was heparinized and cross-matched. Blood pres-
sures and flows were determined at the second, fifth, tenth
and fifteenth minutes after the onset of transfusion and
every fifteen minutes thereafter for the duration of the
four hour experimental period.

Total and segmental vascular resistances (large
arterial, small vessel, large venous) in skin and muscle
were calculated by dividing cephalic or brachial blood flow

into the corresponding pressure gradient. In addition,

24

resistances in the total forelimb

combined skin and muscle segments

(14, 46):

Total forelimb resistance

where:

S-V

V

Total forelimb large
artery resistance

Total forelimb small
vessel resistance

Total forelimb large
vein resistance

resistance in mm Hg x
total

skin

skeletal muscle

large artery

small vessel

large vein

and in each of the

were calculated as

(1)

 

R R
= sa ma (2)

 

R(s-v) - R(s-V)
= s m (3)
R(s-v)S + R(s-v)m

 

___ SV mv (4)

Rsv + Rmv

 

min x ml- x 100 9-

Mean transmural pressure in each segment was obtained by:

1
pressure.

1

P + P2/2, where: P = inflow pressure; P = outflow

2

25

Hematocrit ratios were determined at minutes 0, 60,
120, 135, and 240 in triplicate by the microcapillary
technique.

Since right atrial pressure and vascular resistance
in the downstream veins between the elbow and right atrium
can affect capillary hydrostatic pressure, the brachial and
cephalic veins were left intact in some experiments. These
fourteen animals were otherwise prepared in the same manner
as described above, however, in these experiments only fore-
limb weight and segmental vascular pressures were measured.
Seven of these animals were administered endotoxin, while
seven others served as saline controls.

The mean and the standard error of the mean was
calculated for all data obtained. The paired "t" test was
used to compare data in each group. The unpaired "t" test
was used to compare data between control animals and the
experimental groups. A statistically significant difference
at the P < 0.05 level by the paired or unpaired "t" test was

considered true differences between and within the groups.

CHAPTER V

RESULTS

Forelimb weight (Tables 1, 3; Figure l) (intact or
cut vein preparations) fell rapidly and significantly in
response to endotoxin. Forelimbs continued to lose weight
until minute 120, at which time transfusion was begun.
Weight increased in reSponse to transfusion until min. 180,
after which it again fell continuously for the duration of
the experimental period.

Pressures (Tables 1, 3; Figures 2, 3, 6, 7, 8).

All vascular pressures (intact or cut vein preparations)
fell significantly in response to endotoxin. After transfu-
sion they rose for a variable period of time before again
falling until the end of the experimental period (min. 240).
Small and large vein pressures in both skin and skeletal
muscle rose to values not significantly different from
control in response to transfusion. Systemic arterial
pressure and small artery pressure in both skin and skeletal
muscle remained significantly lower than control throughout
the experimental period, as did right atrial pressure. The
latter, however, increased to levels not significantly

different from pre-endotoxin values after transfusion.

26

27

Blood flows (Tables 1, 3; Figures 4, 5). Total
forelimb blood flows fell significantly in response to
endotoxin, and, after transfusion rose transiently before
falling to low values by the end of the experimental period.
Both total blood flow and skin blood flow remained signif-
icantly lower than control throughout the experimental
period. Muscle blood flow, however, rose to values which
were not significantly different than control before return-
ing to values significantly different from controls.

Resistances (Tables 1, 3; Figures 9-16). All
vascular resistances (total forelimb vascular resistances,
total segmental vascular resistances and skin and skeletal
muscle segmental vascular resistances) increased signifi-
cantly in response to endotoxin, and, after transfusion
decreased for variable periods of time before increasing
again until minute 240. Total forelimb vascular resistance,
total forelimb large artery resistance and total forelimb
small vessel resistance fell to values which were not sig-
nificantly different than control in response to transfusion.
These parameters reached values which were significantly
different from control by the end of the experimental period.
Total forelimb large vein resistance remained significantly
above control throughout the experimental period. Total
skin vascular resistance remained significantly above con-

trol throughout the experimental period, while total muscle

28

vascular resistance transiently decreased to values which
were not significantly different than control after trans-
fusion but later increased significantly. Skin large
arterial resistance fell to a level not significantly
different from control only at min. 135, while muscle

large arterial resistance remained at values not signif-
icantly different from control for a transient period
before rising to significant levels near the end of the
experimental period. Skin small vessel resistance and
muscle small vessel resistance both fell to values not
significantly different from control after transfusion,
however, while small vessel resistance in muscle was sig-
nificantly below control for a transient period, that in
skin increased to significant values by the end of the

240 minute period. Similar results were seen in skin and
muscle venous resistances; muscle venous resistance reached
values for a transient period after transfusion which were
not significantly different from control while that in skin
remained significantly different throughout the experimental
period.

Hematocrits (Table 5). Hematocrits (intact and cut
vein preparation) increased progressively throughout the
experimental period.

Control animals (Table 2, Figures 1-16). No signif-

icant changes were seen in saline control animals from the

29

beginning of the experimental period until minute 120.
Following transfusion significant increases were observed
in forelimb weight, small vein pressure in skin and muscle
and right atrial pressure. The weight gain in control
animals was approximately 22 grams. The increases in all
pressures were transient and pressures fell toward the end
of the experimental period. No significant increases in
resistance were observed.

Intact vein preparations (Tables 3, 4). The
responses of both animals administered endotoxin and control
animals in this group to transfusion was essentially the

same as corresponding animals with the cut vein preparation.

Figure l.

30

Effect of transfusion on forelimb weight (9)

in endotoxin animals (closed circles, N==7)

and saline control animals (closed triangles,
N==7). Endotoxin (5 mg/Kg in 20 cc of saline)
and saline (20 cc) were given at minute 0 as a
ten-minute infusion. Transfusion of whole blood
(1000 cc/25 minutes) was begun at minute 120.
Open circles denote statistical significance at
pi<0.05. Bars denote standard error.

31

OQN

 

omp

H wusmflm

our

00

PIG—m3 ms. Sumo“.

mm.

on.

m..-

0..

mp

 

on

32

Figure 2. Effect of transfusion on systemic arterial
pressure (mm Hg) in endotoxin animals and
saline control animals. All symbols, N
values, and dosages correspond to Figure 1.

41

0‘6

00..

 

 

 

m musmflm

cup

 

 

 

{Ill 0 \\

  

 

on o o-

   

0.0. :E rib. -

\‘

 

 

 

 

 

 

 

mmammmmn— z_m> 13(2m

0..

NF

¢w

or

 

ON

42

Figure 7. Effect of transfusion on forelimb skin and
muscle small artery pressure (mm Hg) in
endotoxin and saline control animals. All
symbols, N values, and dosages correspond
to Figure 5.

43

 

 

 

GDP

 

 

n ousmflm

ON—

 

 

 
  

va Than—On—v b

on o

:33

 

 

  

AF. _O._u:.00

 

 

 

 

 

 

mmamwwmn. >¢mhm< ._._<Ew

 

on

0*-

on

00

Os.

on

GO

00p

0:

 

44

Figure 8. Effect of transfusion on forelimb skin and
muscle large vein pressure (mm Hg) in endotoxin
and saline control animals. All symbols, N
values, and dosages correspond to those in
Figure 5.

45

O?“

 

m mnsmflm

OO—

 

 

 

 

Our

 

 

 

 

 

 

.mc_o.~:oo

 

All——

 

 

 

 

mmammmma 2 _m> MGM—<4

 

Figure 9.

46

Effect of transfusion on total forelimb
resistance (mm Hg/ml/min/lOO g forelimb)
in endotoxin animals and saline control
animals. All symbols, N values, and
dosages correspond to Figure l.

37

Ova

on—

e Gunman

cup

OD

 

30..“— DOOJm ._<._.O._.

0..

ON

 

on

Figure 5.

38

Effects of transfusion on forelimb skin and
muscle blood flows (ml/min/lOO g forelimb)
in endotoxin animals (closed circles) and
saline control animals (closed squares).

N values, other symbols, and dosages corre-
spond to those in Figure l.

49

OQN

 

our

 

3 mnsmflm

our

 

 

 

 

 

on

 

 

 

moz<km.wmm ..mmmm>

....<Ew ..<...O...

or

up

¢F

0..

@—

 

ON

40

Figure 6. Effects of transfusion on forelimb skin and
muscle small vein pressures (mm Hg) in endotoxin
and saline control animals. All symbols, N
values and dosages correSpond to Figure 5.

41

m musmflm

ova cop cup

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

3

wmamwmma z.m> JA<Ew

Op

NF

er

0..

0w

 

ON

42

Figure 7. Effect of transfusion on forelimb skin and
muscle small artery pressure (mm Hg) in
endotoxin and saline control animals. All
symbols, N values, and dosages correspond
to Figure 5.

53

NH mesmem

 

 

Ova 00’ ON— 00 o a.
ll. tll ..... 4- I .OI i I b If). it”.
..O~----x.\*zi .
x. I

 

 

m02<hm.mum z.w> mama; ..<._.O...

 

44

Figure 8. Effect of transfusion on forelimb skin and
muscle large vein pressure (mm Hg) in endotoxin
and saline control animals. All symbols, N
values, and dosages correspond to those in
Figure 5.

 

 

 

 

 

new one our on o m.
o
L . 3:03:00
1 . . l. w ll) (411..---.)le11 -i rile, ......... Tu W
2 . O O . (4) J .. .tld 1 l,u 4 ii::ld-i .\\. .. O“
o . . . ._ illl. Ezozcow _ . 1%.. I.
o . . o.\\n..0..l lllll o .1.
o . o.om:E 1... cc
0 O o O O O n 0 O \\\ \W x
. 0 O \ a... \\ 00
w o , l
o . Exm 1 .
.1.
.
/ \
/ _ COP
1., 1..
._..1—.... ONP
é...
_.
é ocp
mozfimamm 4:3 8.

 

Figure 9.

46

Effect of transfusion on total forelimb
resistance (mm Hg/ml/min/lOO g forelimb)
in endotoxin animals and saline control
animals. All symbols, N values, and
dosages correspond to Figure l.

47

0.5

00'

m mesmem

oar

00

 

 

 

m02<...m.wwm. ...<...O...

0..

ON

 

0n

Figure 15.

58

Effect of transfusion on forelimb skin and
muscle large artery resistance (mm Hg/ml/
min/100 g forelimb) in endotoxin and saline
control animals. All symbols, N values, and
dosages correspond to Figure 13.

59

ma musmam

OQN 00w our 00 0 n-

 

 

 

. _ . Amy—Ohucoo .
iii.) it a _ _ x. _
6:32:00
203:. .
.,._\ 4 o
:33 .

m02<...m.mmm >mmhm< mam—<4

0..

or

ON

ON

00

 

Figure 11.

50

Effect of transfusion on total forelimb large
artery resistance (mm Hg/ml/min/loo g forelimb)
in endotoxin and saline control animals. All
symbols, N values and dosages corre8pond to
those in Figure 1.

51

0*“

00..

Ha museum

our

 

00 0

 

 

 

moz<hm.mmm >mmhm< m0m<.. ...<...O...

 

 

Figure 16.

60

Effect of transfusion on forelimb skin and
muscle large vein resistance (mm Hg/ml/min/
100 g forelimb) in endotoxin animals and
saline control animals. All symbols, N
values, and dosages correspond to those

in Figure 13.

61

 

we musmfle

 

 

   

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

0'“ 00.. our 00 0 n-
TllJTl if it til..- L: Marv—ozcmaot r Wilit. L. Lllltl/u. l. p
«.1. st - . 4 \J! . ill) .25 must—OM a 1... 4 1 4 .
fl ..... ll‘.) liq (JIJ// . — .
_ / .
///./ oxef
I/AD\ h
V,
/ \ a
I .
art/n. m02<hm .mmm z.m> u00<4

 

0p

62

Key to Tables 1, 2, 3, 4

Complete data from control and experimental groups.

All data presented as mean value 3 standard error. The

following abbreviations were used:

Accum.wt
A.P.
Pssv
Plsv
Pssa
Psmv
lev
Psma

Fs/lOOg
Fm/lOOg
Rsa
R(s-v)s
Rsv
Rms
R(s-v)m

Rmv

Rst

Rat

change in forelimb weight
systemic arterial pressure

small skin vein pressure

large skin vein pressure

skin artery pressure

small muscle vein pressure

large muscle vein pressure

muscle artery pressure

skin blood flow per 100 g forelimb
muscle blood flow per 100 g forelimb
skin arterial resistance

skin small vessel resistance

skin venous resistance

muscle arterial resistance

muscle small vessel resistance
muscle venous resistance

total muscle resistance

total skin resistance

total arterial resistance

R(s-v)t
th

Rt
Tp(A)s
Tp(s-v)s
Tp(V)s
Tp(A)m
Tp(s-v)m

Tp (Wm

63

total small vessel resistance

total venous resistance

total resistance

skin arterial transmural pressure

skin small vessel transmural pressure
skin venous transmural pressure

muscle arterial transmural pressure
muscle small vessel transmural pressure

muscle venous transmural pressure

Accum.wt is given in grams; all pressures in mm Hg;

blood flows in ml/min/lOO g forelimb; resistance in

mm Hg/ml/min/lOO g forelimb.

64

Table 1. Effect of transfusion (1000 cc whole blood/25
minutes) in animals previously administered
endotoxin (5 mg/Kg/20 cc saline) in a lO-minute
infusion. Endotoxin was administered at minute 0,
transfusion began at minute 120. Asterisk denotes
statistical significance (difference from time "0"
in pre-endotoxin period) at the p‘<0.05 level.
N==7; limb wt 474.7:tl6.01 g: brachial and
cephalic veins cut.

' time

-5

O

15

3O

45

6O

75

90

105

120

122

125

130

135

150

165

180

195

210

225

240

*p -. o,

Accum.

0.0:0.
0.2:0.

-12.0:3.

-14.o:1

-15.5:2.
-17.1:3.
-19.0:4.
—20.1:4.
-21.0:4.
-21.7:4.
-18.s:s.
-16.8:5.

-14.1:s.

-11.0:5

- 6.7:5

- 5.2:5.
- 6.2:5.
- 8.4:5.
—10.2:5.
-11.2:5.

-12.2:5.

05

wt.

00

19

80*

.94*

23*

37*

13*

29*

43*

49*

39*

40*

34*

.64*

.67

22

42

84*

64*

78*

76*

125.

125.

71.

79.

87

78.

67

59.

58.

54.

63.

68.

76.

82.

80.

78.

78.

76.

76.

75.

76.

0: 7

5:_8.
.0:10.
8:11.
.8:10.
7:10.

4: 8.

.78

.71

.51

45

96*

18*

91*

14*

26*

.68*

.15*

.75*

.42*

.79*

.28*

.17*

.02*

.80*

.19*

.O6*

.73*

Pssv

15.4:1.
15.4:0.
5.8:0.
6.7:1.
7.9:1.
8.1:1.

7.0:1.

6.5:1
6.8:1

6.9:1

9.5:1.

11.2:2.

15.2:2

18.2:2.

17.8:2

18.5:2

15.1:1.
12.7:0.
12.6:1.
11.7:0.

10.9:0.

655

Table l
Plsv

33 .7:1.75

90 .7:1.75

31* .4:0.89*
14* .0:0.99*
83* .2:1.35*
70* .6:l.44*
44* .4:i.50*
.38* .s:i.33*
.37* .s:1.40*
.44* .2:1.60*
32* .9:1.9s

3s .0:2.21
.88 .6:2.77

70 .2:2.9s
.95 .8:d.79
.17 .8:1.72

27 .0:4.54

03* .2:1.44

04* .0:1.38

64* .3:1.45

52* .0:i.40

94.

94.

48

52.

59.

47.

40.

37.

38.

37.

43.

46.

52

55.

52.

52.

54

53.

52

51.

51

Pssa

.0:8.

2:7

0:9

8:7
4:7

8:9

1:5

.4:4.

5:5
1:5
4:5

.1:5

.0:6.

7:6

.4:8.

7:3.

8:3.

8:8.

7:9.

4:6.

2:0.

17

22

06*

.37*

.35*

66*

16*

.88*

.12*

.86*

55*

.64*

74*

.23*

.78*

.62*

.81*

39*

36*

.30*

71*

Fs/lOOg-

14.2:2.24

14.

2

3:2

.5:0.
.1:0.
.3:0.
.0:1
.5:1.
.1:1.
.7:1
.4:0.
.5:1
.1:2
.8:2
.2:0.
.8:0
.1:0
.2:1
.4:1
.8:1
.6:0.

.8:1.

.24

57*

56*

89*

.36*

34*

31*

.O4*

76*

.35*

.15*

.27*

95*

.62*

.86*

.02*

.09*

.10*

90*

09*

Psmv

11.7:1.

11.

4.8:0.
5.7:0.
5.6:0.

5.8:0.

6.1:0

5.7:0.
5.8:0.
5.8:0.

8.2:1.

10.
13.
14.
14.2:2

12.

9.7:;.
8.7:0.

8.1:0.

7.8:0.

7:1.

4:1.
2:1.

8:1.

1:2.

32

32

94*
53*
69*

84*

.95*

87*

86*

98*

15*

75

80

.18

10

6O

94

83*

.85*

99*

3 time

15
3O
45
60
75
90
105
120
122
125
130
135
150
165
180
195
210
225

240

lev
6.911.
6.911.
1.710.
2.6:0.
2.910.
3.110.
3.310.
3.410.
3.6:0.
3.610.
4.811
6.1:}.
8.110.
9.7:2
8.710.
8.3:}.
6.711
5.930.
5.7:0.
5.610.

5.2:0.

*p < 0.05

04

O4

62*
49*
70*
87*
88*
90*
90*

90*

.08

25

65

.04

72

80

.46

81
73
77

77

Psma

107.
107.
60.
64.
71.
64.
52.
47.
46.
44.

51.

55

60.

63.

58

59

62.
59.
59.
59.

60.

1: 3.92 11.4:1.

1: 3.92
7: 7.13
5: 9.77*
4:11.09*
5:10.42*
3:10.37*
7: 9.12*
9: 8.14*
7: 6.89*

4: 6.60*

.0: 6.09*

2: 4.65*

0: 5.16*

.5: 4.78*

.4: 5.76*

1: 6.41*
7: 6.60*
0: 6.75*
7: 6.87*

4: 7.22*

66

Table l--Continued

Fm/lOOg

11.4:1.
1.
1.7:0.
1.
2.
1.

1.

1:0.

9:0.
1:0 .
8:0.
8:0.
. 9:0 .

.O+O.

. 9:1 .
. 1:1 .
.3:2
. 8:3.
.5:4.
. 6:4
. 7:3.
. 2:2
. 4:1.
.4:1.

.0:0.

27

27

53*
35*
63*
70*
57*
58*
70*
83*
26*

61*

.48

21

O7

.05

3O

.68*

89*

21*

60*

Ft/lOOg

25.7:l.60

25.7:1.
3.6:1.
4.8:0.

u: C: u: u: c~ U\ U1
u: c» 0* m) c~ P‘ u:
|+ |+ l+ |+ l+ l+ l+
hi hi #4 h‘ h‘ hi hi

CD
N
|+
N

11.2

H-
u:

12.

H
1+
(.0

12.4

'1.

12.7

'it

11.0:3

8.6:2

6.0:1.

5.8:1.

6O

00*

72*

.32*
.86*
.78*
.59*
.37*
.23*
.96*
.73*
.36*
.37*
.36*
.4o*
.65*
.99*

.Ol*

29*

19*

2

2

Rap

.1:0.
.1:0.
.4:0
.2:0.
.2:0
.2:0.
.6:0
.6:0.
.4:0.
.4:0.

.1:0.
.4:0.

.3:0.

.6:0.

.4:1.
.2:1.
.4:0.
.2:1.
.0:0.

.1:0.

38

38

.58*

61*

.61*

66*

.61*

75*

78*

74*

81*
67*
55

66

.82

24

02

99

01

95

93

11

10.

11.

22

24.

21.

23.

21.

15

11.

11.

10.

15

14.

15.

Rsa

.2:0.
. 2:0.
.2:2
1:3.
9:7 .

.6:7.

9:5

7:5

8:5 .
0:4 .

.2:3.

7:3

0:1.
. 0:3
. 9:2 .
.1:2

.5:2

1:2

.4:4.

4:4

3:5

24

26

.02*

60*

14*

13*

.82*

.61*

81*

23*

69*

.73*

74

.41*

41*

.17*

.15*

.98*

38*

.11*

.12*

Ris-v)s

6.7: 1.35

6.6: 1.35

18.

16.

21.

32

33.

32

39.

37.

29

25.
23.
13.

9.
10.
13.
19.
27.
26.

24.

1: 5
.0:10

8:11

.6: 9.

.0:9

5:4
5:1
3:2

1:3

5: 3.

6: 4.

3:12.

6:10.

2:10.

3: 8.

0: 5.
5: 9.
3: 8.

7: 7.

09*

16*

.95*
.42*

.63*

62*

31*

61*

.81*

53*

03*

.O7

33

.28

.82*

93*
78*
19*

40*

time Rev
-5 0.910.
0 0.910.
15 2.510.
30 2.210.
45 3.011
60 6.412.
75 6.612.
90 7.212.
105 9.413.
120 9.113.
122 7.512.
125 6.312.
130 6.512.
135 4.011.
150 3.610.
165 4.411.
180 3.811.
195 4.211
210 6.912.
225 5.612.
240 4.811.

*p«

0.05

25

25

69*

64*

.09*

21*

31*

17*

02*

08*

21*

13*

32*

03*

80*

56*

57*

.60*

75*

15*

59*

29.

36.

61.

65.

61.

72.

67.

51.

43.

40.

23.

23.

25.

33.

49.

46.

44.

9:16.
4:13.

9:12.

.66

.67

.16*

.63*

.74*

.57*

.36*

.02*

.09*

.12*

.99*

.17*

.03*

24*

69*

76*

Table

Rma

1.

21

10.

12.

14.

10.

10.

7:0.
.7:0.
.0:6.
1:1.
3:3.
.9:2

2:4.

212

5:2

.9:1.
.9:1
.3:1.
.3:1.
.5:0.
.1:0.
.5:0.
.9:0
.8:1
.9:1.
.9:1

.0:1.

26

38*

91*

20*

.60

37*

.25*

.99*

93*

.88*

39*

39*

67

87

67

.87

.19*

02*

.28*

08*

6'7

1--Continued

 

R(s—v)m

114.
39.
48.
43.
39.
38.
41.
43.
33.
26.
18.
12.

10.

12.
17.
17.
19.

19.

.0: 1

.0: 1.

8:26

9: 8.
0:10.
7:10.

7: 9.

.05

05

.08*

71*

77*

50*

97*

.72*

.32*

.09*

.09*

.38

.06*

.67

.16

.56

.11

.72*

.31*

.16*

.64*

Rmv

0.4:0.

0.4:0.

7.3:2

2.1:0.
2.3:0.

2.5:0.

2.9:1

2.5:0.
2.4:0.
2.5:0.

2.9:0.

2.9:1

2.1:0.
1.4:0.
1.1:0.
0.810.
0.7:0.

1.0:0.

0.8:0

1.0:0.

52

52

26* 52

91*

91*

.05*

94*

93*

96*

98

.34

89

57

33

33

15

3O

.20

21

.20

Rmt

11.2: 1.33

11.2:_1.3o

.82*143

62

56.

56

51

54

54

43.

35.

17.

15.

13.

17.

24.

24.

26.

26.

.2:33.25*

.2: 8.39*

.7:12.31*

2:11.91*

.9:13.27*
.5:11.97*
.2:13.05*

.8113.61*

6113.22*

1:13.93*

.5: 9.02*

9: 5.40
5: 3.60

4+ 2.09

0.

O.

2

2

Rat

9:0.
9:0.
.4:1
.4:0.
.610.
.6:1.
.8:1.
.8:1
.9:1.
.2:0.
.0:0.
.9:0.
.6:0.
.3:0.
.7:0.
.3:0.
.4:0.
.3:0.
.5:0.
.4:0.

.610.

07

07

.68*

67*

67*

30*

99*

.09*

36*
88*
94*
77*
84*
47*
70*
48*
57*
67*
60*
62*

58*

A time
-5
O
15
30
45
60
75
90
105
120
122
125
130
135
150
165
180
195
210
225

240

R(s-v):
3.310.24
3.310.24

14.510.S4*
10.21}.47*
12.512.29*
15.714.68*
16.715.38*
16.414.74*
18.115.19*
17.614.50*
14.215.30*
11.7:§.60*
8.513.53*
5.912.02
4.310.85
4.310.68
5.711.13
8.010.00*
8.712.21*
9.212.02*

9.311.81*

*p < 0.05

th

0.210.03

0.210.03

1.210.34*
0.910.11*
1.010.29*
1.510.56*
1.610.61*
1.410.56*
1.410.58*
1.210.58*
1.610.64*
1.610.81*
1.210.51*
0.810.31*
0.610.12*
0.410.11*
O.410.09*
0.610.14*
0.610.14*
0.710.13*

o.7:0.12*

{P503113

Rt
4.7:0.28
4.710.28

23.8:3.41*

16.611.77*

19.3:3.15*

25.2:5.99*
27.3:6.67*
24.8:6.02*
26.6:6.47*
25.2:§.71*
20.7:6.77*
16.8:7.09*

12.714.63*
9.4:2.55*
8.1:1.25*
7.6:1.15
9.2:1.59*

12.4:2.43*

13.412.68*

13.8:2.30*

14.1:2.02*

£58

1--Continued

 

Tp(A)s
110.0: 3.56
110.1: 3.56

59.5:_7.57*

65.91_7.83*

73.0110.08*

63.3: 9,774

54.3: 9.82*

48.7: 8.86*

48.41_7.52*

46.1: 7.05*

53.S1_6.55*

57.21_5.83*
64.41.4.58*
69.01_5.12*
66.21_5.23*
65.41'6.32*
66.31'6.35*
64.91_6.50*
64.21_6.61*
63.5:,6.52*

64.11l6.93*

Tp(A)m

116.3:_4.3o

116.2: 4.27

65.8:,7.28*
72.0: 9.08*
79.2:91.07*
71.7:1o.71*
60.1:1o.59*
53.7:_9.59*
52.6: 8.13*
49.7: 7.23*
57.5: 6.75*
61.3: 6.29*
68.3: 4.87*
72.7: 5.22*
69.3: 4.78*
68.91_6.37*
70.3: 6.63*
68.11_6.64*
67.8:_6.9o*
67.51.6.88*

68.61_7.40*

Tp(a-v)s
55.012.15
55.112.18
26.914.32*
29.510.83*
33.510.16*
28.015.09*
23.815.21*
22.214.42*
22.613.99*
22.113.90*
26.513.86*
28.710.17*
33.812.57*
36.910.02*
35.0:3.55*
35.514.00*
34.6:3.83*
33.013.50*
32.313.50*
31.713.39*

31.1:3.53*

Tp(a-v)m
59.412.43
59.412.43
32.710.61*
35.114.95*
38.510.78*
35.21§.S3*
29.215.63*
26.714.92*
26.314.408
25.213.87‘k
29.813.80k
32 . 713. 69!
36.712.83':
38.913.02k
36.3:2 .919:
35.713.63*
35.913.80*
34.210.63*
33.613.69*
33.813.70*

34.113.81*

69

Table 1--Continued

 

A time Tp(V)I TPCVMn

 

IT

-5 10.0:1.01 9.3:1.18
o 10.0:1.01 9.3:1.18
15 3.1:0.63* 3.2:0.73*
3o 3.810.56* 4.1:0.5o*
45 4.5:0.93* 4.2:0.67*
60 4.3:1.3o* 4.510.84*
75 3.7:1.27* 4.7:0.89*
9o 3.5:1.11* 4.610.87*
105 3.6:1.06* 4.710.86*
120 4.0:1.17* 4.7:0.92*
122 5.711.46* 6.5:1.1o*
125 7.1:1.67* 8.2:1.31
130 9.9:2.41* 10.7:1.64
135 12.2:2.73* 12.3:1.93
150 11.3:1.75* 11.5:1.91
165 11.7:1.73* 10.2:1.89
180 9.5:1.25* 8.2:1.51
195 7.9:0.73* 7.310.86
21o 7.810.77* 6.9:0.77*
225 7.5:0.79* 6.8:0.79*
24o 7.010.83* 6.5:0.87*

*p < 0.05

Table 2.

70

Effect of transfusion (1000 cc whole blood/25
minutes) on saline control animals. Saline was
administered 20 cc/lO minutes at minute 0.
Transfusion was begun at minute 120. Asterisk
denotes statistical significance (difference
from time "0" in pre-infusion period) at the
p<0.05 level. N=7; limb wt 477.1:13.67 9.
Abbreviations correspond to Table l. Brachial
and cephalic veins cut.

A time Accun. wt.

-5
0
15
30
45
60
75
90
105
120
122
125
130
135

150

165
180
195
210
225
240

o.0:0.oo
o.0:0.22
-o.6:0.30
o.o:0.49
0.1:0.55
0.3:p.68
0.2:0,87

' 0.6:1.11

1.3:1.28
1.7:1.32
2.7:1.25*
4.1:g.16*
5.910.87*
7.6:1.04*
10.0:1.36*
12.4:1.21*
14.311.78*
15.4:1.73*
18.1:1.79*
18.911.70*

19.3:1.61*

*p < 0.05

1.9.

120.0:6.89
120.0:6.89
118.1:7.48
114.6:5.56
115.6:4.88
114.9:4.74
110.6:§.87
108.9:6.29
112.0:5.68
117.1:5.76
120.0:4.9o
127.3:6.3o
129.7:6.81
132.6:6.44
135.6:6.4o
130.0:9.45
127.6:7.7o
126.7:7.38
128.3:5.o3
127.0:4.47

126.4:4.81

Pssv
12.412.48
12.512.41
12.l12.31
12.110.23
12.512.23
12.210.23
11.912.15
12.511.79
12.611.62
12.111.89
13.410.37
15.710.71
18.110.31
19.310.53
19.013.44
17.312.84
17.110.89
17.012.77
17.610.44
17.412.22

16.9:2.51

7].

{Dadalxa 2

Plhv
7.311.42
7.311.42
6.611.42
6.911.41
7.111.43
7.01;.42
6.511.25
6.611.04
6.910.92
6.610.20
7.311.55

8.9:1.92

10.3:2.27
11.5:2.49

10.612.56

9.8:2.38
9.5:2.09
9.2:1.68
9.5:1.43
9.6:1.47

9.3:1.50

Pssa
88.01'9.65
88.01 9.65
86.7:11.oo
84.01 8.85
84.31_8.58
81.11 9.02
77.9110.48
77.61 8.34
79.01 8.84
80.91 6.38
82.61.6.19
85.01 7.23
88.01 7.26
88.91.7.28
89.91 8.89
89.9:.8.24
88.3: 6.15
96.71 7.66
90.91 4.33
91.01_3.4l

92.0: 3.06

FollOOg
13.4:1.87
13.4:1.87
12.2:1.7o
12.3:1.69
12.3:1.64

11.8:1.29

11.4:1.17.

12.5:1.45
13.3:1.48

13.1:1.71 '

13.7:1.81
15.3:2.49

16.418.01

'16.3:2.86

14.5:g.41
13.7:1.26
13.0:1.14
12.7:1.23
13.5:1.01
12.910.98

12.3:1.10

Psmv
8.610.81
8.610.81
8.610.84
8.710.94
8.910.78
9.010.78
8.410.75
8.310.84
8.410.72
8.410.79
9.110.68

10.510.50*
ll.710.75*
13.2:1.03*
14.611.09*
12.910.84*
11.910.88*
11.110.81*
10.910.56*
10.710.68*

10.410.48*

A time lev
-5 5.010.58
0 5.010.58
15 5.210.82
30 5.210.76
45 5.010.49
60 5.210.60
75 5.110.71
90 5.110.77
105 5.110.71
120 5.010.66
122 5.610.68
125 6.910.77*
130 8.111.04*
135 8.811.04*
150 8.710.70*
165 8.210.57*
180 7.911.63*
195 7.610.58*
210 7.910.75*
225 7.710.76*
240 7.510.6l*

*p < 0.05

Psma

90.9:6.
90.9:6.
87.9:4.
87.0:3.
87.410.
85.6:2.

77.1:4.

83.6:5

82.1:3.
85.6:4.

86.7:4.

94.9:6

95.6:7.
97.3:7.
94.7:9.
96.4:9.
94.3:8.
97.6:7.

98.1:6.

99.3:6

98.1:7.

00
00
73
35
14
77

33

.20

09
01

84

.44

64
90
32
15
96
37

84

.63

04

Table

Fm/lOOg
7.910.86
7.910.86
7.5:1.11
7.5:1.o4
7.5:1.1o
7.0:1.09
6.5:0.9o
6.3:0.8o
6.410.74
6.3:0.82
7.9:1.47
6.2:1.56
7.6:1.39
8.5:1.32
8.7:1.45
8.2:1.28
7.4:1.1o
6.7:1.29
6.6:1.16
6.1:1.42

6.0:1.44

72

 

2-—Continued

Pt/lOOg Rap
21.3:2.o7 .0:0.38
21.3:2.o7 .0:0.38
19.3:1.76 .010.38
19.9:1.83 .0:0.38
19.7:1.82 .1:0.35
18.8:1.37 .1:0.35
17.9:1.19 .9:0.44
18.3:1.25 .8:0.39
19.7:1.35 .8:0.39
19.0:1.89 .9:0.44
21.6:2.40 .1:0.46
21.6:3.63 .5:0.82
24.0:3.95 .9:1.oo*
25.010.69 .511.46*
23.3:g.42 .9:1.44*
21.9:2.32 .6:1.01*
20.4:g.11 .610.85*
19.5:2.29 .5:0.97
20.1:2.9o .8:0.75*
19.012.32 .110.66*
18.3:2.44 .210.68*

Rsa
2.310.47
2.310.47
2.610.56
2.510.57
2.610.54
2.710.48
2.810.45
2.610.51
2.610.50
2.810.34
2.710.34
2.810.42
2.110.38
2.710.41
3.110.42
2.910.59
2.910.43
2.310.42
2.810.41
2.810.41

2.8:0.42

R(s-v)s

6.610.38
6.611.37
6.911.41
6.611.27
6.611.30
6.511.19
6.411.45
5.610.95
5.510.93
5.911.06
5.811.20
5.511.23
5.311.27
5.211.27
5.110.97
5.510.85
5.810.91
6.811.14
5.610.66
5.910.65

6.510.83

A time
—5
0
15
30
45
60
75
90
105
120
122
125
130
135
150
165
180
195
210
225

240

Rev
0.410.09
0.410.08
0.510.09
0.510.09
0.510.08
0.410.07
0.510.08
0.510.03
0.510.07
0.410.05
0.510.05
0.510.05
0.510.07
0.510.06
0.610.07:
0.510.06
0.610.108
0.610.09K
0.610.098
0.010.08‘
0.610.10*

*p < 0.05

Rst
9.311.10
9.310.10

10.011.24
9.511.05
9.711.05
9.710.93
9.711.09
8.810.91
8.510.79
9.210.97
9.011.04
8.711.10
8.511.19
8.411.11
8.810.67
8.910.57
9.310.63
9.710.99
9.010.51
9.310.51

9.8:0.60

73

Table 2—-Continued

Rma
4.010.58
4.010.58
5.1:1.33
4.5:1.o3
4.7:1.14
5.1:1.10
6.1:1.16
4.5:1.26
5.4:1.11
5.7:1.16
5.6:1.39
4.9:1.3o
5.6:1.25
5.2:1.35
6.0:1.44
4.610.75
5.0:0.78
5.0:0.90
5.310.83
4.2:1.o7

4.5:1.2o

 

R(s-v)m

11.912.34
11.912.34
12.712.68
12.2:g.24
12.312.10
12.112.16
12.112.06
13.412.25
12.611.72
13.211.79
12.012.05
11.412.42
12.511.61
11.410.96
10.1:1.25
10.811.05
11.811.22
14.912.17
15.210.18
12.012.56

12.2:2.57

Rmv
o.s:0.10
o.5:0.1o
0.5:0.13
0.610.15
0.610.14

0.610.14

0.610.12'

0.610.13
0.610.12
0.6:0.14
0.610.18
0.5:0.16
0.6:0.15
0.610.15
0.810.14
0.610.24
0.6:0.13
0.610.16
o.5:0.14
o.4:0.14

o.4:0.12

Rmt
16.4:2.84
16.4:2.84
18.3:4.04
17.2:3.37
17.0:3.34
18.510.29
18.8:3.25
18.5:3.08
18.6:2.89
19.5:3.o1
18.3:3.75
16.8:3.76
18.712.88
17.2:8.37
16.912.70
16.1:1.64
17.4:1.59
20.5:2.70
21.0:2.73
16.610.59

17.1:8.73

Rat
1.310.19
1.310.19
1.410.13
1.210.17
1.310.17
1.510.19
1.610.20
1.510.23
1.510.19
1.710.14
1.610.17
1.410.28
1.610.17
1.510.12
1.810.21
1.610.24
1.710.21
1.410.25
1.610.23
1.310.33

1.3:0.33

A time R(s—v)t
—5 4.010.84
0 4.010.84
15 4.310.83
30 4.110.89
45 4.110.77
60 4.110.78
75 4.010.85
9O 3.810.59
105 3.610.53
120 3.910.61
122 3.710.74
125 3.210.93
130 3.710.76
135 3.510.79
150 3.410.56
165 3.610.48
180 3.810.54
195 4.510.69
210 4.010.49
225 3.510.72
240 3.710.81
*p 0.05

th

2flx
2:0
.39
2:0
2:0
2:0
251

2gx

03

03

.03

03

O3

O3

O3

04

.03

.03

.03

.05

.04

.03

.03

.05

.05

.03

.05

.05

74

Table 2--Continued

Rt

SJflL
009.
56flx
5251
00y.
00w.
Sfifll
SJflL
00m.
009.
5210
5632
03g.
000.
00w.
00w.
04w.
62y1

5¢g0

56:1

.71

71

71

90

71

76

72

80

57

45

64

81

12

83

82

54

36

42

66

97

.05

 

Tp(A)s

104

104.

102

99

100.

98.

94.

93.

95.

99.

101.

106.

108.

110.

112.

109.

107.

111.

109

109.

109.

.0@.
@fi-
2:0
630

0+6.

~q ~o Pl 0: i? a: n: n:
l+ 1+ l+ 11. I l+ 1+ I+
U1 u: u: u: 0\ ox s1

\J
1+
\J

09.
fifi.
Hi
6:3
32.

3g.

36
36
80
48

11

.32

.81

.81

.46

.28

.46

.25

.99

.73

.85

88

13

19

75

75

54

Tp(A)m

105.

105

103.

100.

101

100.

93.

96.

97

101

103.

112

115.

115.

113.

110.

01.

2:0

@0

0g.
51L

2:3

914

Q?-
AyL

.414.

414

2:0
61%

1:1

H8

a9.
9:0
2:0
250
2:0

.30

26

26

.99

38

86

60

.98

31

30

70

.66

08

O6

.59

11

86

6O

34

24

63

Tp(s-v)s

50.

50

49

48.

48.

47.

44.

45

45.

46

48

50.

53.

54.

54.

53.

52

56.

54.

54.

54.

3g.
210

651

£5

Q0

09.
14.

233

a:

:10

.Q9

4g
0g

1g

0g.
0g.
.32
9g”

2fl2

25

411.

31

33

16

.04

.76

99

83

92

.22

77

.54

.97

.89

.40

90

77

.53

33

56

.17

15

775

Table 2--Continued

9 time Tp(s—v)m
—5 49.713.19
O 49.713.19
15 48.212.72
3O 47.912.06
45 48.111.84
60 47.311.66
75 42.812.50
90 45.912.89
105 45.311.86
120 47.0:2.17
122 47.912.55
125 52.713.18
130 53.613.70
135 55.513.88
150 54.613.88
165 54.614.60
180 53.114.35
195 54.413.51
210 54.513.26
225 55.013.21
240 54.313.44
*p ~ 0.05

Tp(v)s

 

9.8:1.95

9.

9.

10.

12

14

15.

14.

13.

13.

13.

13.

13.

13.

9:1.
4:1.
.5:1
.8:1.
.6:1.
.2:1
.611.
.8:1.
.4:1
4:1.
.3:2.
.2:2.

4:2.

8:2

1:2.

5:1

5:1.

1:1

91

85

.81

82

81

.69

39

25

.53

75

98

.93

.56

.40

11

.83

76

.90

Tp(v)m

6.810.60

6.

6.

11.

10.

8:0.
9:0.
.o+o.
.0:0.
.1:0.
.7:0.
.7+0.

.8:0.

.9:0.
.0:0.
6:0.
5:0.
.9:0.
.4:0.

.4:0.

60

56

62

65

77

66

.68

.53*

81*

92*

603':

42*

40*

47*

76

Table 3. Effect of transfusion (1000 cc whole blood/25
minutes) on animals previously administered
endotoxin (5 mg/Kg/ZO cc saline) in a ten-
minute infusion. Endotoxin was administered
at minute 0. Transfusion began at minute 120.
Asterisk denotes statistical significance
(difference from time "0" in pre-endotoxin
period) at the p1<0.05 level. N==7; limb wt.
495.12119.09 g. Brachial and cephalic veins
intact. Abbreviations correspond to Table l.

A time

15

3O

45

60

75

90

105

125

130

135

150

165

180

195

210

225

240

*p.

A wt.

o.o:0.oo

o.3:0.33

—12.4:0.73*

-12.

—12.

~15

—17.

—18.

—18.

-18.

—17

-15.

—13.

-10.

.05

4:1.
9:1.
.9:2.
5:3.
6:4.

9:4.

7:5

.6:5.
3:4.
1:4.
6:4.
.9:4.
.6:5.
.4:6
.1:7.
.9:7.
.7:7

.817.’

14*

71*

75*

24*

45*

91*

.25*

08*

79*

15:1:

09*

53*

35*

.67

89

35

.45

149.

149.

107.

122.

112.

87.

75.

72.

72.

75.

83.

98.

103.

107.

107.

103.

102.

96.

92.

86

.9: 9.

.45

.45

.23*
.11*
.10*
.07*
.70*
.80*
.59*
.67*
.57*
.12*

.78*

.21*
.32*
.98*
.50*
.68*

.70*

13.
13.

7.3:0.

10.

12

15.

16.

17.

18.

16.

15.

14.

12

11.

10.

Pssv
411.

4:1.

.2:0.
.3:0.
.6:g
.6:1.
.3:1.
.9:1.
3:1.
.9:2
4:2.
3:3.
3:3.

4:2.

7:2
7:2

111

.5:1.

9:1

4:0.

777

Table 3

Plsv
14 7.3:0.
14 7.3:0.
86* 3.5:0.
62* 4.510.
72* 4.4:0
.42* 3.9:0.
50* 3.9:0.
44* 4.1:0.
58 5 3:0.
58 5.5:1.
.59 7.8:2
83 9.4:3.
04 9.7:3.
08 10 0:3.
61* 9.3:2.
.66 8.8:1
.31 8.3:1.
.67 8.0:1.
25 7.3:0.
.19 6.8:0.
95 5.8:0.

90

90

72

62

.63

6O

68

62

97

20

.51

19

18

55

.60

34

15

85

89

65

Pssa

111.2:6

111.2:6

93.4:9.

96

88.

68.

57.

48.

48.

51.

57.

62.

63.

65

63.

64.

66.

65.

63.

57.

.2:6

0:4

7:7

4:8.

9:8.

7:6

916

.816.

3:8.

0:7

3:7.
.016.

0:6.

.02

.02

69

.27
.98*

.02*

28*

06*

.75*
.91*
.87*
.21*

.64*

43*

563‘:

.50*

.35*

.68*

14*

85*

73*

Psmv

13.7:2

13.7:2

5.8:0.
7.

7.

11.

12.

12

14.

14.

13.

11

10.

810.
5:1.
.1:0
.5:0.
.8:0.
.5:0.
.0:1
0:1.
3:1.

.4:1.

3:1

6:1

1:1.
.9:1.
4:0.
.9:0.
.3:0.

.4:0.

.51

.51

91
96*

16*

.93*

73*
77*

88*

.18*

36

47

76

.89

.92

70

05

65

64

60*

lev

6.910.76

6.910.76

4.3:0.90*

5.

5.

5:0.
3:1.
.2:1
.8:1.
.811
.3:1.
.8:1
.8:1.
.7:1.
.8:1.
.1:1.
.9:1.
.810.
.8:0.
.1:0.
.8:0.
.2:0.

.5:0.

86

02

.10

12

.09

09

.55

3o
36
28
59*
10*
91
78
53
42
69

66

778

Table 3--Continued

"1 t 11119

15

3O

45

6O

75

90

105

120

122

125

130

150

165

180

195

210

Psma
115.614
115.614

93.919
100.214.
92.214.
71.618
61.517.
53.217.
56.417
58.310.
66.018.
72.416
75.117.

76.1:7.

76.3:11.oo*

74.2:10.48*

74.6:9.
72.0:7.
69.2:6.
68.5:6.

65.0:6.

.62

.62

.48*

84

71*

.85*

96*

77*

.54*

91*

50*

.64*

23*

02*

24*

72*

82*

72*

69*

3.

l

1.

Rap

.8:0.
.8:0.
.9:0.
.9:0.
.2:0.
.0:0.
.5:0.
.8:0.
.0:0.
.0:0.
.4:0.
.2:0.
.1:0.

.8:0.

0:1

.8:0.
9:0.
.0:0.
.5:0.
.5:0.

.3:0.

46

46

32*

47*

58*

63*

64*

76*

75*

61*

47

42

61

.06

6O

67

86

69

73

Table 4.

79

Effect of transfusion (1000 cc whole blood/25
minutes) on saline control animals. Saline was
administered 20 cc/lO minutes at minute 0.
Transfusion was begun at minute 120. Asterisk
denotes statistical significance (difference
from time "0" in pre-infusion period) at the
p<0.05 level. N=7; limb wt 492.9 :32 9.
Abbreviations correspond to Table 1. Brachial
and cephalic veins intact.

- time
-5 C
0 0
15 0
30 C
45 1
6O 2
75 2
90 2
105 2
120 2
122 4
125 6
130 9
135 12
150 15
165 19.
180 21
195 22.
210 22
225 23.
240 23.
*p 0.05

7 wt.

.010
.410.
.510.
.910.
.310.
.M1
.611.
.611.
.611.
.611.
.311.
.110.
.QL
.011

.32

3g

flfl

0g

6g
4g.

10.

.00

30

61

70

84

0?

07*

85*

31*

.70*

29*

.62*

.63*

.50*

.42*

M*

11*

144.

145.

145

144.

143.

144

141.

138.

139.

149.

152.

158.

161.

149.

145

145.

144.

A.P.

32
.00

%1

fifl.

.&L

411

2g.

flfl.

912

.w3

6:1

6g.

fiL

HL

EL

3+1.

3+1 .

713.

Q0

9%.

%3

.50

.52

.96

39

77

58

77

94

.46

70

86*

65

.27

02

42

91

12.

12

12.

12

11

11

11.

11

11

11.

12.

13.

15

17.

18

15.

14.

14.

14.

13.

Pssv

.10

250
.10

.10

.10

6@.

6g

2g.

.3?

6y

0g.

10.

Q0

10
Q0.

00.

5g.

10
g0
1m.

00.

80

Table 4

57 6.

57 6.

70 6.

38 5.

50 5.

56 5.

55- 6.

61 5.

72 5.

59 5.

69 6.

86 6

.24* 8.

39* 9.

95*10.

.12* 8.

.44* 7

98 7.

93 7

69 7.

65 7

Plsv

10

go

m0.
$0.
%0
00
m0.
10.
Q0
30.
30.
9m.
30

Q0

El

30

.30
Q0
.10
30

-H9

26

.26

22

18

18

35

26

24

38

29

37

41

70*

60*

.18*

.97*

55

52

34

32

32

Pssa
118.61
119.
120.
120.
119.
119.
118.
116.
116.
118.
121.
125.
125.
122.
122.
110.
109.
109.
113.
112.

110.

.79
.33
.71
.59
.96
.79
.68
.17

.09

.94
.39
.29
.88
.50
.86
.51
.43
.43
.22

.08

10.

11

12.

13.

14.

11.

10.

10.

Psmv lev
.711.15 5.410
.711.15 5.410.
.911.16 5.410
.111.06 5.4+0
.411.13 5.610.
.611.23 5.810.
.611.23 5.710.
.21 1.22 5.710.
.411.23 5.810.
.411.25 5.910.
611.11 6.710.
.011.15 7.110.
311.25 8.611
411.11* 9.610.
110.77* 10.110.
410.76 7.710
510.97 7.310.
410.99 7.010.
.910.94 6.910.
.810.84 6.710.
.510.76 6.610.

.48

52

.48

.48

72

70

75

72

63

7O

70

76

.02*

90*

89*

.89

89

89

76

64

61

At

-5

15

30

45

60

75

90

105

120

122

125

130

135

150

165

180

195

210

225

240

*p c

81.

Table 4--ggptinued

ime

0.05

Psma
113.916.54
114.416.51
116.715.68
118.314.92
118.914.79
116.614.83
114.915.01
113.415.65
114.716.02
115.616.51
119.715.63
123.415.79
126.417.04
130.319.97
125.718.59
116.418.17
114.716.44
114.716.88
115.117.32
116.017.25

115.216.56

Rap

0.310.
0.210.
0.219.
0.119.
-o.2:p.
-o.2:o.
-o.1ip.

-o.1:p.

0.219

0.310.
1.010.
2.010.
3.810.

5.210.

7.011

3.711.
1.110.
1.210.
1.610.
1.510.

1.610.

61

57

59

61

61

61

59

56

.55

53

56

54*

55*

86*

.04*

63*

82

88

81

75

73

82

 

 

 

 

 

 

 

TABLE 5. Effect of transfusion (1000 cc whole blood in 25
minutes) on hematocrits of animals administered
endotoxin (5 mg/Kg) at time "0” and saline control
animals. (N = 7) Transfusion was begun at minute
120

égntrol Groups
Time ._ --
(minutes) Veins Intact Veins Cut
0 43.611.57 42.911.42
120 45.711.17 45.612.1‘7
135 46.111.72 49.112.32"
240 49.712.40“r 53.7:2.66*
Experimental Groups
Time
(minutes) Veins Intact Veins Cut
0 43.711.36 38.1:2.54
60 48.611.62“r 41.312.93
120 53.4il.OO* 49.614.01"
135 53.611.04 51.0:3.46*
240 55.7io.68* 56.913.54*

CHAPTER VI

DISCUSSION

Forelimb weight fell rapidly initially (0-15 min.)
in response to endotoxin (5 mg/Kg) and then more slowly up
to minute 120. Forelimb weight did not change significantly
during this time period in saline infused control animals.

A continuous fall in forelimb weight following endotoxin
administration has been reported in a previous study by the
author (61) and by Hinshaw and his co-workers (30). Both
utilized the isolated autoperfused canine foreleg prepara-
tion. The weight loss is theoretically attributable to a
decreased vascular volume, interstitial fluid volume, intra-
cellular fluid volume or some combination of these three
factors. The weight loss, during the first 15 minutes, was
associated with increases in all segmental vascular resist-
ances. This suggests that mean vascular caliber was
decreased, with a consequent decrease of vascular blood
volume. From minutes 15 to 120 resistance in all vascular
segments, particularly in the capacitance vessels, i.e.,
small vessels and large veins, increased in skin but'
declined toward control in skeletal muscle; the net effect

being a slight rise (small vessel segment) and a virtual

83

84

plateauing (large vein segment) of resistance in the
capacitance vessels. These responses suggest that mean
vessel caliber was unchanged or somewhat reduced during this
period and that forelimb blood volume was also constant or
decreasing slightly. It is unlikely then that the large
weight loss observed during this period was caused comr
pletely by a reduction in vascular volume and probably
represented extravascular fluid reabsorption. This is
essentially as has been previously reported by the author
(61). The response of isolated forelimbs with intact
brachial and cephalic veins was essentially the same as
that of the limbs in which these vessels were cut, and sug-
gests that the responses observed with the cut vein prepa-
ration were not altered by the cannulation of the brachial
and cephalic veins or the ligation of the uncannulated ends
of these vessels.

Although forelimb weight continuously decreased from
minutes 0—120, it is nonetheless still possible that micro-
vascular permeability to plasma proteins increased. Fluid
influx could still occur if the transmural hydrostatic
pressure gradient fell to a lower level than the transmural
colloid osmotic pressure gradient or, if the extracellular-
intracellular osmolarity gradient changed in a direction
which promoted fluid movement from tissue to blood. However,

if microvascular permeability did increase, the increase was

'85

insufficient to casue net fluid efflux, and, in view of
the response of the limb to transfusion (minutes 120-240)
it is unlikely that microvascular permeability was increased.

It is possible that the observed loss of weight
could have been in part influenced by leakage of fluid from
the cut ends of lymphatic vessels at the severed end of the
limb or by losses of water due to evaporation. As to the
latter possibility, all exposed tissues were treated with
inert silicon spray to prevent evaporation, hence it is
doubtful that evaporation added substantially to the ob-
served weight loss. The weight response in the control
animals supports this conclusion. Loss of fluid through
lymphatic channels is also unlikely since lymph flow is
known to decrease drastically as a result of circulatory
shock states and resultant hypotension (62).

After transfusion was begun (min. 120), forelimb
weight increased approximately 10 g (min. 120-180) but did
not return to pre-endotoxin levels. In control animals a
weight gain of approximately 22 g was observed from min. 120
until the end of the experimental period. The weight gain
in control animals was associated with significant increases
in right atrial pressures, aortic pressure, small vein pres-
sures, and hematocrit, hematocrit may have increased in part
due to spontaneous splenic discharge, since increased hema-

tocrits were observed in control animals; however, no change

86

in segmental vascular resistances occurred. Therefore, this
weight gain may be attributed largely to a rise in extra-
vascular fluid volume subsequent to a rise in capillary
hydrostatic pressure.

The rise in hematocrit with no change in vascular
resistances suggests that mean vessel caliber possibly
increased somewhat and that vascular volume may have in-
creased slightly also. The weight gain observed in endo-
toxin animals (min. 120-180) is theoretically attributable
to an increase in vascular volume, to an increase in extra-
vascular fluid volume, or to a combination of these two
factors. The weight gain was associated with increases in
right atrial pressure, which rose to levels which were not
significantly different from pre-endotoxin levels; aortic
pressure, which remained below pre-endotoxin levels; small
vein pressures, which rose to levels slightly above pre-
endotoxin levels; and hematocrit, which was above pre-
endotoxin levels. In this case, all segmental vascular
resistances decreased. These responses indicate that mean
vessel caliber and inferentially vascular volume were in-
creasing during this time. Indeed, total blood flow was
observed to increase during this time period. The weight
gain which occurred during this period is then largely due
to an increased vascular volume subsequent to an increased

vascular radius and a fall in segmental vascular resistances.

87

Although an increase in extravascular fluid volume may have
occurred, such an increase was of little significance when
compared with that which occurred in saline control animals
after transfusion. It is unlikely that microvascular per-
meability was increased in the limb, since during this
period, both small vein pressure in skin and skeletal muscle
rose to values above pre-endotoxin levels and although these
pressures had risen to relatively high values, inferring
that capillary hydrostatic pressure was above pre-endotoxin
levels, the weight gain which occurred during this period
was significantly less than that which occurred in the con-
trol animals.

While forelimb weight climbed continuously from
min. 120 to min. 240 in control animals, weight in endotoxin
animals, after the transient rise (min. 120-180), declined
until the end of the experimental period. The weight loss
during this period was associated with a continuous fall in
all vascular pressures, blood flows, and a rise in both
total skin and total muscle vascular resistances and hema-
tocrit. It is likely then that the weight loss (approx-
imately 5 g) which occurred during this period was largely
due to decreased vascular volume, although capillary hydro-
static pressure, as indicated by falling small vein pres-
sures in skin and skeletal muscle, may have been falling

at this time. Thus, fluid influx from interstitial and/or

88

intercellular sites may have contributed to the weight loss,
subsequent to a decrease in the transmural hydrostatic
pressure gradient below that of the transmural colloid
osmotic pressure gradient.

Constriction of all vascular segments contributed
to the increases in total skin and muscle segmental vascular
resistances. This was especially so in the skin vasculature
and is reflected in total vascular resistance, which remained
well above corresponding skeletal muscle total resistance
from min. 60 throughout the experimental period although
marked muscle vascular constriction was observed from min-
utes 0-45 (Figures 3, 4). These results agree with those
previously reported by Weidner §£_31. in autoperfused canine
forelimbs during endotoxin shock (61).

The resistance increases during the first 15 minutes
of endotoxin shock can be ascribed both to active changes,
i.e., vascular smooth muscle contraction; passive changes,
i.e., decreased transmural pressure (Tables 1, 3); and
possibly an increased blood viscosity, due to increased
hematocrit. The continued increases in skin resistance up
to min. 120 can be ascribed to active decreases in vessel
caliber, since average transmural pressures and hematocrit
were relatively constant. However, muscle total and seg-
mental vascular resistances waned during this period. This

decrease of muscle resistance was concurrent with relatively

89

constant or falling transmural pressures, thus an active
dilation must be involved. Since systemic pressure fell
from min. 15-20, the vasodilation was probably not due to
decreased baroreceptor stimulus. This decline in muscle
resistance could have represented a failure of vasocon-
strictor nerve activity due to cerebral ischemia, a gradual
failure of the local vasoconstrictor mechanisms, or a
greater accumulation of vasodilator metabolites, or some
combination of the three. Various blood borne substances
(7, 8, 44, 45) have been suggested as contributing to this
phenomenon and undoubtedly play a role in maintaining muscle
vascular resistances at levels which were at or below corre-
sponding skin vascular resistances from minute 60 until
minute 240. Among these substances has been suggested
serotonin (5 HT) which reportedly increases skin resistances
while having little effect on muscle resistances (6), and
catecholamines, which when infused systemically at high dose
levels, increase skin resistance proportionately more than
skeletal muscle resistance (14). Previously reported
increases in plasma [K+], [H+], and osmolarity support the
concept that metabolic vasodilation contributed at least
partially to the waning of muscle vascular resistances (17).
All total and segmental vascular resistances were
decreased after transfusion from pretransfusion levels and

remained below pretransfusion levels until approximately

90

minute 180, at which time a significant rise was observed
in these parameters from approximately minute 180 until
minute 240. The transient decreases in vascular resistances
following transfusion are associated with greatly increased
transmural pressures, and thus can be largely ascribed to
passive increases in vessel caliber subsequent to increased
vascular volume. The increases in vascular resistances
observed from minutes 180-240 are concurrent with falling
transmural pressures in skin and muscle small vessel and
large vein segments and probably reflect passive decreases
in vessel caliber. Transmural pressure in skin and muscle
large artery segments were nearly constant during this
period and thus the increased resistance in these segments
may reflect an active change resulting from contraction of
vascular smooth muscle, and subsequent constriction of ves-
sel caliber. Increased blood viscosity as is reflected by
increased hematocrit may also play a part in the late
increases in resistance (Table 5).

In conclusion, this study supports the author's
previous findings that endotoxin shock is associated with
marked skin vascular constriction, but lesser muscle vas-
cular constriction (61). The data herein presented provide
no evidence for a greater rise in extravascular fluid volume
following transfusion in dogs subjected to endotoxin shock

than in saline control animals. This study also fails to

91

support the hypothesis that transvascular fluid efflux into
skin and skeletal muscle occurs following transfusion during
endotoxin shock. And, infers that if a progressive plasma
volume loss occurs subsequent to fluid filtration following
transfusion during endotoxin shock states such a loss does

not occur in skin or skeletal muscle.

CHAPTER VI I

SUMMARY

A study was undertaken to determine if transfusion
leads to excessive filtration of vascular fluid and a dis-
proportionate rise in extravascular fluid volume, especially
in skin and skeletal muscle, in dogs previously injected
with endotoxin relative to that observed in saline control
animals. Male mongrel dogs were anesthetized with sodium
pentobarbital, and then administered either endotoxin or
saline as an i.v. infusion. After two hours these animals
were transfused with 1000 ml of cross-matched whole blood.
In endotoxin dogs forelimb weight,pressures and blood flows
and segmental vascular resistances in the skin and muscle
of the collateral-free, innervated, autoperfused forelimb
decreased up to min. 120 as previously reported. Following
transfusion forelimb weight increased, but failed to return
to pre-endotoxin levels. This initial transient weight gain
was due largely to increased vascular volume subsequent to a
fall in all segmental vascular resistances in the limb.

The study provides no evidence for an excesSive
fluid loss from.the vascular system to the skin and skeletal
muscle of the canine forelimb following transfusion during

endotoxin shock.

92

CHAPTER VIII

SPECULATION AND ADVICE FOR FURTHER STUDY

It seems likely to me on the strength of this study,
and an earlier work by Weidner 31.31., that the primary
lesion which occurs in endotoxin shock is not related to
transvascular fluid efflux into skin or skeletal muscle
(61). However, insofar as the canine model of endotoxemia
is concerned much work remains to be done with regard to
fluid fluxes, specifically extravasation of fluid from
blood to tissue in the visceral circulation. Although many
studies have been undertaken with respect to the visceral
circulation (12, 20, 26, 27, 29, 31, 38, 40), the actual
contribution of the splanchnic vascular beds to the alleged
fluid loss is not known with certainty. Application of a
gravimetric technique employing the use of segmental vas-
cular resistances to a systematic study of the response of
the isolated liver, spleen, and large and small intestines
to lethal endotoxemia would certainly help to determine if
fluid losses into these beds could account for irreversible
canine endotoxemia.

Unfortunately the dog is quite atypical of most

other species in that the canine model manifests gross

93

94

visceral complications, and, thus makes it a less than ideal
model for comparison to human bacteremia, since in the human
no visceral complications are seen and, indeed, there is no
evidence for plasma volume loss (12, 49). Primates, includ-
ing humans do exhibit hypotension in response to endotoxin
though and approximately 70,000 persons die from gram nega-
tive bacteremia every year (58). Thus, the need for quanti-
tative data on the subject is warranted.

I suggest two possible areas for study which might
provide much potentially valuable hard data with regard to
the locus of the central problem at issue in the study,
that is the genesis of irreversibility caused by lethal
endotoxemia. The first I suggest, since in all forms of
irreversible shock, anoxia is thought to be primary in the
"vicious cycle" of events that lead to irreversibility and
death (3, 4, 49). However, the effect of endotoxin shock
on nutritional blood flow has not been definitively examined.
The intestine of the primate is the only vascular bed
studied to date (25). Endotoxin shock is said to cause
a deleterious redistribution of blood flow in the intestine

as measured by D O extraction (R. R. Rayner g; 31., Circ.

2
Res., 8:1212, 1960). A greater percentage of blood flow
passes through non nutritional channels which do not permit
effective exchange of nutrients between blood and tissue.

This redistribution of flow is considered to be important

95

in determining irreversibility (J. T. Gourzis ggflg1., in
Shock and Hypotension, ed. L. C. Mills and J. H. Meyer,
Grune and Stratton, p. 289, 1965). The consequences of such
a deleterious redistribution of blood flow are easily
imagined, however evidence in support of this concept is
far from conclusive in my opinion since no other vascular
beds have been studied. Therefore, a critical and systemr
atic examination of vascular beds other than the small
intestine is warranted.

Secondly, there is much evidence to support the
concept that all types of circulatory shock render the
reticuloendothelial system of the body incapable of clearing
circulating endotoxin from the blood, and that this progres-
sive failure of the reticuloendothelial system allows the
perpetuation of the "vicious cycle" by allowing an already
compromised systemic circulation to be subjected to pro-
gressively higher titers of endotoxin (58).

It is possible, through the use of various kinds
of pharmacological means, such as the introduction of cer-
tain colloid substances into the portal circulation of the
splanchnic vascular bed, to render the liver and spleen
either hyperactive or hypoactive in terms of their ability
to clear colloidal materials from the blood (T. M. Saba,

Arch. Int. Med., 126:1031, 1970). In order to assess the

 

relative contribution of the reticuloendothelial system in

96

preventing irreversibility in lethal endotoxemia. I suggest
that the reticuloendothelial system could be rendered either
functionally hypoactive or hyperactive, blood levels of
endotoxin could be measured over an arbitrary period of time
by the limulus lysate method (121d,), and nutritional blood
flow or segmental vascular resistances or other hemodynamic
parameters studied to assess the effect that the functional
ability of the reticuloendothelial system to rid the blood
of endotoxin has upon the severity of lethal endotoxemia
insofar as its ability to produce deleterious derangements

of the cardiovascular system is concerned.

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APPENDIX

THE PAPPENHEIMER EQUATION FOR DETERMINATION

OF CAPILLARY HYDROSTATIC PRESSURE

PC

RV)
=(-R—aPa+Pv

RV
1 + fiE

In the example cited in the text

where

RV

Ra

Pa

PV

 

RV _ . _ . =
(fig—LPa—BmPv 0
-(1)30+o
PC“ -1+(1)
Pc = 15 mm Hg
postcapillary resistance

precapillary resistance

arterial pressure

right atrial pressure.

103

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