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Hemodynamic and Cardiometabolic Studies in Patients with
Distributive Circulatory Dysfunctions— with Special Reference to the Effects of the
Beta-l-adrenoreceptor Agonist Prenalterol
av
Sebastian Reiz
Akademisk avhandling som med vederbörligt tillstånd av Rektorsämbetet vid Umeå Universitet för avläggande av medicine doktorsexamen kommer att offentligen försvaras i SAL C, Samhällsvetarhuset, Umeå Universitet, fredagen den 1 juni 1979, kl 09.00.
Sammanfattningen baseras på följande delarbeten.
Reiz, S., Nath. S., Pontén, E. (1979):Hemodynamic effects of prenalterol, a ßi-adrenoreceptor agonist in hypotention induced by high thoracic epidural block in man. Acta Anaesth. Scand. Vol. 23, no. 1, 93.
Reiz, S., N ath, S., Rais, O. (1979):Effects of thoracic epidural block and prenalterol on coronary vascular resistance and myocardial metabolism in patients with coronary artery disease. Acta Anaesth. Scand. Accepted for publication.
Reiz, S., N ath, S., Pontén, E., Friedman, A., Bäcklund, U., Olsson, B., Rais, O. (1979):Effects of thoracic epidural block and the ßi-adrenoreceptor agonist prenalterol on the cardiovascular response to infrarenal aortic cross clamping in man. Acta Anaesth. Scand. In press.
Reiz, S., Peter, T., Rais, O. (1979):Hemodynamic and cardiometabolic effects of infrarenal aortic and common iliac artery declamping in man — an approach to optimal volume loading. Acta Anaesth. Scand. Accepted for publication.
Reiz, S., Friedman, A. (1979):Hemodynamic and cardiometabolic effects of prenalterol in patients with gram negative septic shock. Acta Anaesth. Scand. Accepted for publication.
ABSTRACT
Sebastian, Reiz (1979). Hemodynamic and Cardiometabolic Studies in Patients with Distributive Circulatory Dysfunctions— with Special Reference to the Effects of the Beta-l-adrenoreceptor Agonist Prenalterol.
A total of 49 patients were studied, using invasive hemodynamic techniques with systemic arterial, pulmonary artery and right atrial pressure recordings together with thermodilution cardiac output determinations. Sixteen of the patients were also subjected to cardiometabolic studies, using measurement of coronary sinus blood flow by the continuous thermodilution technique and analyses of oxygen content and lactate concentration in the systemic and coronary circulation. A common denominator in the five investigations was, that a distributive cardiovascular dysequilibrium was either induced (for surgical or anaesthesiological reasons) or already present due to a pathological condition.
Thoracic epidural block from T 1 to T 12 induced marked decrease in systemic blood pressure due to vasodilation and impairment of cardiac performance. Prenalterol administration effectively abolished the low blood pressure by its marked inotropic action, having no effect on systemic vascular resistance. Myocardial oxygen consumption changed in parallel with the changes in cardiac work following both thoracic epidural block and prenalterol. Coronary vascular resistance was markedly decreased by the block and was not affected by prenalterol. It is suggested, that the critically low perfusion pressure is the main cause of the coronary vasodilation and that alpha-blockade induced by the thoracic epidural block is of less importance.
The combination of a thoracic epidural block from T 1 to T 12 and selective ßi-stimulation with prenalterol was an effective way to modify the cardiovascular response to infrarenal aortic cross clamping. This treatment transferred the patients to a more favourable cardiac function curve and possibly facilitated the redistribution of blood flow in association with clamping.
In association with declamping of the infrarenal aorta or the common iliac arteries, volume loading to a slightly elevated left ventricular filling pressure shortly before declamping was an effective way to counteract the expected blood pressure drop. A normal left ventricular filling pressure prior to declamping did not prevent the blood pressure drop following declamping. It is suggested, that mismatching between vascular volume and blood volume is the main cause of declamping hypotension.
In patients with low resistance, distributive septic shock caused by gram negative bacteremias and signs of impaired cardiac function, prenalterol effectively reversed the hypotension and improved tissue perfusion by selectively increasing cardiac output. In parallel to the increased cardiac work, an increase in myocardial metabolic demand was demonstrated.
Key words:
aortic aneurysm surgery gram negative septic shock
hemodynamics m yocard ia l metabolism therm odilu tionthoracic epidura l block volume loading prena lterol
Sebastian Reiz, M. D.Dept, of Anaesthesia & Critical Care MedicineUniversity of UmeåSWEDEN
Hemodynamic and Cardiometabolic Studies in Patients with
Distributive Circulatory Dysfunctions— with Special Reference to the Effects of the
Beta-l-adrenoreceptor Agonist Prenalterol
by
Sebastian Reiz
Umeå universitet Umeå 1979
This thesis is based on the following papers# referred to in the text by
th e i r Roman numerals:
I . Reiz# S.# Nath# S.# Pontén# E. (1979):
Hemodynamic e ffec ts of prenalterol# a 3^-adrenoreceptor agonist in
hypotention induced by high thoracic epidural block in man.
Acta Anaesth. Scand. Vol. 23# no. 1# 93.
I I . Reiz# S.# Nath# S.# Rais# 0. (1979):
Effects of thoracic epidural block and prenaltero l on coronary vascu
lar resistance and myocardial metabolism in patients with coronary
artery disease. Acta Anaesth. Scand. Accepted for publication.
I I I . Reiz# S.# Nath# S.# Pontén# E.# Friedman# A.# Bäcklund# U.# 0lsson#B.#
Rais# 0. (1979):
Effects of thoracic epidural block and the 3^-adrenoreceptor agonist
prenaltero l on the cardiovascular response to in frarena l aort ic cross
clamping in man. Acta Anaesth. Scand. In press.
IV. Reiz# S., Peter# T.# Rais# 0. (1979):
Hemodynamic and cardiometabolic e ffec ts of in frarena l aort ic and
common i l i a c a rtery declamping in man - an approach to optimal volume
loading. Acta Anaesth. Scand. Accepted for publication .
V. Reiz# S.# Friedman# A. (1979):
Hemodynamic and cardiometabolic e f fec ts of prenaltero l in patients
with gram negative septic shock. Acta Anaesth. Scand. Accepted for
publi cation.
Umeå 1979 — Norrlands-tryck i Umeå AB
Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
AIM OF THE IN V E S T IG A T IO N S . . . . . . . . . . . . ........ . . . . 7
MATERIAL . . . . . . . . . . ........ 7
METHODS AND PROCEDURES. ................... .12
RESULTS ............... .23
DISCUSSION. . ............. ................... .......... . . . . . . . . . . . . . . . . . . . . . .31
CONCLUSIONS. ............. . . . . . 4 5
ACKNOWLEDGEMENTS. .................. . ................. 47
REFERENCES 48
Introduction
5
The term "d is tr ib u t iv e defect" was defined by WEIL and SHUBIN (1972) in
th e i r revision of the c lass ica l shock d e f in i t io n s . Their re c la s s i f ic a t io n
of d i f fe re n t types of shock was based upon a simple working model of the
c ircu la to ry system consisting of the following components:
1) the transport system for the blood to the c a p i l la ry bed» i . e . the
arte r ie s and a r te r io le s .
2) the c a p i l la ry exchange system.
3) the capacitance vessels# in which up to 70% of the blood volume is
located (GREEN, 1950).
4) the blood volume.
5) the heart.
Hence# a dysfunction of any single or a combination of these components
w i l l induce a d is t r ib u t iv e c ircu la to ry defect# the treatment of which
must be based upon the primary s i te (s ) of the d i sturbance(s) and the phy
siology involved in the regulation of the p ar t ic u la r system(s). In the
present investigations# dysfunctions in a l l f iv e major components of the
c ircu lato ry model can be id e n t i f ie d .
Thoracic epidural block ( U l . l l l )
A thoracic epidural block w i l l induce a sympathetic block to the region
supplied by the blocked segments with vasodilation of both resistance and
capacitance vessels (BROMAGE# 1951# BONICA 1957). I f the block a ffec ts the
upper part of the thoracic region (T1 to T5) the cardiac sympathetic supp
ly is affected and cardiac function is impaired (RANDALL et al# 1957,
6
OTTON and WILSON? 1966). When extending from T4 to L2 the block w i l l
a f fe c t splanchnic ci r c u la t io n (LUND? 1966) and possi bly a lso the release
of adrenaline and norad rena l ine from the adrenal medulla (BROMAGE? 1978).
Hence? the block in the present i n v e s t ig a t io n s ? extending from 11 to T12
w i l l a f f e c t the c o n t ro l of both card iac performance and vascu la r tone in
the reg ion.
A b d o m in a l a o r t ic aneurysm surgery (111,IV)
In reconstruct!ve surgery on the abdominal aorta there are two major
causes f o r serious intraoperative compii cations besides bleedi ng# namely
aortic cross clamping hypertens ion and declamping hypotension (CAMPBELL*
1967? PERRY? 1968* THOMAS? 1971. IMPARATO et al* 1972? ATTIA et a l* 1976?
MELÖCHE et a U 1977), I n f rarenal aort ic cross clamping induces an abrupt
reduction in a r t e r i a l f low to the lower part of the body and redi s t r i bu-
t i on of blood flow occurs on ly slowly. The rapid increase in a fte r load
w i l l often induce l e f t ventri cular fa i lure (ATTIA et al# 1976) as these
patients often have a s i g n i f i c a n t degree of overt or covert cardiac d i
sease. During the clamping pe r iod about 3% of cardiac output only is d i
rected to the lower ext remeti es (RUTHERFORD, 1977), leading to tissue
dysoxia and vasodilat ion. When dec lampi ng is performed* the blood flow
directed to the lower extremit ies increases to approximately 21% of car
diac output. This increase occurs at the expense of mesenteric? hepatic
and rena I flow. In addition? cardiac output decreases by approximately 25%
(RUTHERFORD? 1977) due to p e r ip h e ra l poo l ing of blood which may be poten
t ia te d i f the in t rao p e ra t ive bleeding Is ex tens ive and the patient is not
adequately volume substituted. A o r t ic dec lamping may therefore induce
severe hypotension unless optimal blood volume is maintained.
7
Gram negative septic shock (V )
P e r i to n i t is is frequently associated with gram negative septicemia. Cha
r a c t e r is t ic a l ly there is an inflammatory vasodilation with decreased a r te
r i a l resistance and arteriovenous shunting (GUMP et al» 1970# ARCHIE#
1977). Cardiac output is often normal or may even be increased and p e r i
pheral t issue perfusion is impaired as demonstrated by lactacidemia (WEIL
et al# 1975# WEIL# 1977). In spite of normal or high measured cardiac
output# cardiac function is frequently impaired (LOEB et al# 1967# WEISEL
et al# 1977, BRUNI et al 1978# CERRA et al 1978).
Aim of the investigations
The present investigations deal with disturbances in the main compartments
of the c ircu la to ry system. The studies are focused on the treatment of
these disturbances with interventions influencing vascular volume# blood
volume and/or cardiac performance. The aim was a well defined therapeutic
strategy where interventions with target e ffec ts should be preferred to
those with more general actions on the cardiovascular system. In th is
respect# the use of the card ioselective (3,j-adrenoreceptor agonist prenal-
te ro l (CARLSSON et al# 1977# JOHNSSON et al# 1978# KNAUS et al# 1978#
RÖNN et al# 1979 a and b) fo r increasing cardiac performance has been of
p ar t ic u la r in te res t in four of the investigations (I# I I# I I I # V).
Material
Hemodynamic studies were performed in 49 patients who had given th e i r in
formed consent.Sixteen of the patients were also subjected to cardiometa-
bolic investigations. The studies were approved by the Ethics Committee
8
of the University of UmeS. In the investigations where pernaltero l was
used» beta blockers were withdrawn at least 48 hours pr io r to the study.
Study I
Eight patients scheduled for abdominal aort ic aneurysm resection and
g ra ft in g were investigated. These patients also took part in study I I I
and th e i r relevant c l in ic a l data is outlined under the headline of that
study (Table 2» group I ) .
Study II
Four patients scheduled for abdominal aort ic aneurysm resection and
g ra ft in g were included in the study. These patients a l l suffered from
coronary arte ry disease» diagnosed by a h istory of previous myocardial
in fa rc t io n (s ) and/or angina pectoris with posit ive bicycle ergometer
tes t . Thei r relevant c l in ic a l data is out lined in Table 1.
Table 1. C l in ic a l data of the four patients in study I I .
PAT. AGE SEX PREVIOUS PREVIOUS ANGINA DIURE- DIGI BETAAMI CHF PECTORIS TI CS TALIS BLOCKER
1 67 M 1 _ + _ *+
2 72 M 2 + + + + -
3 70 M 2 + + + + -
4 62 F - ~ + - -*+
AMI = acute myocardial in fa rc t io n CHF = congestive heart fa i lu r e
* = beta blocker discontinued 48 hours before the study
Study III
9
Sixteen patients scheduled for abdominal aort ic aneurysm resection and
gra ft ing were randomly assigned to two groups to study the cardiovascular
e ffec ts of in frarenal aort ic cross clamping. Group I received a thoracic
epidural block from T1 to T12 with p la in p r i lo ca in followed by the (3^-
adrenoreceptor agonist prenaltero l before general anaesthesia was induced.
Group I I was not given any treatment before general anaesthesia. The c l i
n ica l data is outlined in Table 2.
Table 2. C l in ica l data of the sixteen patients in study I I I .The patients in group I also took part in study I .
AGE SEX PREVIOUS ANGINA DIURE- BETA-(RANGE) M F AMI PECTORIS TICS BLOCKER
GROUP I 67 3 5 2 6 1 6*(n=8) (62-74)
GROUP I I 66 4 4 1 3 1 5*(n=8) (59-75)
AMI = acute myocardial in fa rc t ion
* = beta blockers discontinued 48 hours before the study
Study IV
Nineteen patients undergoing abdominal aort ic aneurysm surgery were ran
domly assigned to two groups to elucidate the mechanisms of declamping
hypotension. None of the patients had taken part in any of the other
studies. The control patients in group I (9) in th is study were .kept at
an average mean pulmonary ar te ry occlusion pressure (MPAOP) of approxima-
10
te ly 11 mm Hg (1.5 kPa) before dec lamping» The patients in group I I (10)
were volume loaded to an MPAOP around 16 mm Hg (2.1 kPa) shortly before
dec lamping. The relevant c l in ic a l data of the patients is outlined in
Table 3.
Table 3. Cl i n i cal data of the 19 patients in study IV.
AGE SEX ANGINA PREVIOUS HYPER- DI ‘RE- DIGI- BETA- ( RANGE) F M PECTORIS CHF TENSION TI IS TAUS BLOCKER
GROUP I 67 3 6 8 2 4 Ó 2 6*<n=9) (61-76)
GROUP I I 67 3 7 8 4 3 i 3 5**(n=10> (62-74)
CHF = congestive heart f a i lu r e
★ = beta blockers discontinued in 2 patients 48 hours before the study.
* * = beta blocker discontinued in 1 patient 48 hours before the study.
S tudy V
Ten patients with low resistance» di s t r i b u t ive sept i c shock di agnosed by
invasive hemodynami c studies and positive blood cultures for gram negati ve
bacteremias were included in the study. Besides hypotension» a l l patients
had c l in ic a l signs of shock with o l ig u r ia and impaired tissue perfusion
with lactacidemia. The c r i t e r i a to t re a t the patients with prenaltero l
was a systo lic blood pressure of 90 mm Hg (12 kPa) or less for at least
60 min a f te r i n i t i a l volume loading with 5% albumine» human plasma and/or
crystal l o i ds to a stable mean puImonary artery occlusion pressure around
12 mm Hg (1 .6 kPa). The relevant c l in i cal pat i erit data is out I i ned in
Table 4.
Tabl
e 4.
C
lin
ical
pa
tien
t da
ta
in st
udy
V.
11
g G03 03
T3 -M TJ TJ TJ 'O +J TJ *a TJ0 03 H— CO a> 03 03 03 M— (O 03 0 0E > cg x > > > > cg X > > >G 03 rr-» co
0 O > "O t j > > > > T3 T3 > > >C 4~> G 03 g G G G cg G G G
•r- 3 3 03 K l 3 3 3 3 03 o 3 3 3H— O to 13 fM to (0 CO t/5 T3 OJ to to to
03 0) 03CO TJ a oi tO TJ 0C TJ •r- CO 0) E E o —i> E
•r- X 03 0) +J cg 03 0-}-* 0 O to CO 03 +J to +J• r- O) CD O 03 o cg 03 CD ■r- O 03 0 • i—u 3 a . C G C c™ TJ C C ö l G C C ölTJ G E O 3 O 3 —* o O — 3 O o0 TJ 0 c H- c M— 05 c C 13 H~ c c TJ
03G c: —* 4-'3 O 03 C™ G
■r- E cg 003 o O r- COC _t 03 C 03 X toO 03 03 05 K 03 03 G 03 CD G 0
■ r~ 0 +-> 4~> cg to 4~> 0 04-> 03 C C G G 03 c cg 03 C 0• r- 03 O O 03 03 OD -Û O 03 03 _Q 03 0 O 0"O 0 G t- > C D. cg G {/) C ,g c c G 0D -r- sz SZ O X *i-- O *1“ O o o o *<-03 TJ o O G sz ~a O TJ C ■ö c c O TJ
H- GO O
C 10O C ^
•<- 0 CO m un un+J +J t_03 O 3 K l un Kl (M X Kl nO Kl K l mg Cl O3 X -C
13 Ü
/-* CDto-M
E cg(Oto to (0 to t « to
C cg 03 03 cg to cg 00» 03 c c C c tu
tn +-* C> 03 c o o o o to O c O c
•r- G 03 E E E E * E 03 E 0+»• o O o O O •r- Q O03 O to TJ -Q TJ TJ —* 13 to TJ 0(0 g O .Q 3 3 3 3 O 3 O JD 3 jQ3 U u 03 0) 03 03 03 U 03 o 03 0 003 »r- to to to to ■ to 0U E 03 _X CL a a a 03 CL 03 SS a -X
G G 4-J 4-t G -MO Ü O a o —> OC C ..Q TJ 03 J3 03 C -Q 003 03 G G 0 —« GQ. a 4-* -M O cg a —*
05 cg to CO to c • 0 003 sz sz ö l en cg ö l cg +-> 0 SZ Ol 0to G i . 03 a i tg -M G G ö l03 g G G G G E to 3 G G0) O O ö l a i "M öl +-» 3 03 +-» o co ->->to E E C c CO c to cg -M a E C 0
0) 03 cg cg O cg O G C 3 0 0 O"5 SZ SZ ci ai a Cl a +j •r- G jc tn CL
X
to z : s: LL, s; z LU z s; u- s:
03ö l CM 00 co CM 00 CK K l 00 X K l03 LO K l O m O O ■vt un
•MC03
4-» * •fc ¥ ¥03 CM Kl x r in o X 00 o oCL
part
i ci
pant
in
the
card
i om
etab
oli
c st
udy
12
Methods & procedures
Hemodynamic studies
A ll patients were catheterized in the operating room ( I - IV) or at the
bedside (V). The a r t e r ia l cannulations were done percutaneously under lo
cal anaesthesia with a 60 mm long» 1.2 mm intern a l diameter te f lo n catheter
(VIGGO) in studies I - IV. The rad ia l or brachial a rte ry on the nondominant
arm was used. In study V» a 170 mm long» 1.4 mm interna l diameter te f lo n
central venous catheter (VIGGO) was introduced percutaneously under Local
anaesthesia into the right common i l i a c a rtery via the right femoral artery
to get accurate pressure readings during the hypotension. In a l l patients
(49)» a calibrated 7F balloon tipped thermodilution catheter was introduced
percutaneously under local anaesthesia into the r ight in terna l jugular vein
and placed in good occlusion position in the pulmonary arte ry under close
monitoring of the pressure curve. Occlusion of the catheter balloon in the
r ight lower segment a rtery was obtained in a l l patients where fluoroscopic
control could be performed (26). In 16 of the 49 patients» a ca librated 7F
Webster coronary sinus catheter was introduced under local anaesthesia into
the l e f t (14) or r ight (2) in te rna l jugular vein and then placed in the
coronary sinus under fluoroscopy and close monitoring of the pressure
curve. Special care was taken of the accurate positioning of the catheter
not to get interference from the blood stream through the r ight atrium at
the level of the proximal thermistor of the catheter. This was checked by
a bolus infusion of cold normal saline through the proximal o r i f ic e of the
pulmonary a rte ry catheter. Perfect sampling from the coronary sinus was
also controlled before the catheter was secured by sutures to the skin.
A ll intravascular catheters were flushed with normal saline using the
I n t r a f lo CFS® at 3 ml/h.
13
A r te r ia l i pulmonary artery and right a t r i a l pressures were recorded con
tinuously throughout the investigations using Siemens-Elema's pressure
transducers 746/51 positioned at midchest ( 0 - le v e l ) . Ca libration with
e le c t r ic and normal saline standards were done regularly before and a f te r
scheduled pressure reg is tra tions . A Mingograf 62 or 82 recorder was used
for the pressure recordings. In studies I and I I I no pressure gradient
between the pulmonary a rte ry d ia s to l ic pressure (PAp) and the mean pulmo
nary a rtery occlusion pressure was noted in any of the patients . Subse
quently# PAp was regarded as a representative re f le c t io n of the Left a t r i
al pressure varia t ions (FORRESTER et a l , 1971). In the other invest igat ions,
mean pulmonary a rte ry occlusion pressure was registered a f te r balloon in
f la t io n during periods scheduled for hemodynamic calculations (see flow
charts for the d i f fe re n t investigations, Figures 1 - 4 ) . Cardiac output
was determined by the thermodilution method (GANZ et a l , 1971, 1972,
FORRESTER et a l , 1972). The means of two measurements not d i f fe r in g more
than 10% were used in studies I - IV and of three measurements not d i f f e
ring more than 10% in study V. To standardize the ind icator in jec t ion
technique, a pneumatic infusion pump (U-LAB, ATI - 1 ) , synchronized to
the cardiac output computer (CARDIOVASCULAR INSTRUMENTS, CV 600 or 3750)
and de liver ing 10 ml of 5.5% glucose at room temperature in 1.2 s was used.
A ll catheters were thoroughly calibrated at 37 and 40°C before insert ion .
The thermodilution curves were recorded on the Mingograf and judged before
the results were accepted or re jected.
Coronary sinus blood flow (CSF) was determined by the continuous thermo
d i lu t io n technique described by GANZ et al (1971). The method requires a
stable position of the catheter within the coronary sinus and even i f the
placement and securing is p er fec t , softening of the te f lo n catheter may
a f fe c t the thermistor positions (WEISSE and REGAN, 1974). Furthermore, the
14
position of the proximal thermistor in re la t ion to the posterior descending
a r t e r ia l drainage wi11 determine to what extent coronary sinus blood flow
is re f lec t in g to ta l myocardial blood flow. With knowledge of the problems
of the catheter positioning and other l im ita t ions mainly due to anatomi ca I
varia t ions the method w i l l s t i l l give reproducible values (GANZ» 1977). In
the present investigations ( I I » IV» V)» double measurements within 5 min in
the 16 pati ents were analyzed. The standard devi at ion of a single measure
ment was 5 ml/mi n and the coeffi ci ent of vari ation was 3%. A deta i led re
view of the method has been published by KLOCKE (1976).
The thermistors of the CSF catheter were thoroughly ca librated before usage
and the resi stance/temperature re Ia t ion was found to be l inear within 0 . 1°C
from 20 to 40°C. Glucose (5.5%) at room temperature was used as the indica
tor and infused by a ca librated constant rate infusion pump (SAGE 355) at
a rate of 40 ml/min d ur ing approximately 20 s for each measurement. A Wheat
stone bridge (WEBSTER INSTRUMENTS) was used for balanci ng the thermi stor
resi stances and recordi ngs of the resistance changes were done on the
Mingograf 82.
ECG ( lead V^) was reg istered cont inuous(y throughout the investigations on
the Mingograf. A paper speed of 10 mm/s was used except duri ng the sche
duled hemodynamic measurement periods when 25 mm/s was used. Heart rate
was calculated from the ECG recordi ngs.
Measured & derived hemodynamic variables
SAP systo lic a r t e r ia l pressure (mm Hg» kPa)
DAP di as to li c a r te r i a I pressure (mm Hg» kPa)
MAP mean a r te r i al pressure (mm Hg» kPa)
15
PAß p u lm o n a ry a r t e r y d i a s t o l i c p re s s u re (mm Hg» kPa)
MPAOP mean p u lm o n a ry a r t e r y o c c lu s io n p re s s u re (mm Hg» kP a)
a ls o c a l l e d mean p u lm o n a ry a r t e r y wedge p re s s u re (PAW) in
s tu d ie s I and I I I .
MRAP mean r i ght a t r ia I pressure (mm Hg» kPa)
a Iso shown as RAP in studi es I and I I I
CO card iac output ( l .min )
HR heart rate (bpm)
BSA body s u r fa c e area - “ — —— + 1 (m^) » where L = length100
in cm and W ~ weight in kg
T, blood temperature» measured in the coronary sinus (°K)b
T . coronary sinus blood flow in d icator temperature» measured
i n the coronary si nus (°K)
T te m p e ra tu re o f th e m ix e d i n d icator-coronary sinus b lo o d (°K)m- 1.
V. . coronary si nus blood flow indi cator infusion rate (ml.min )inj
SV stroke volume - CO/HR (ml)
SVI stroke volume i ndex - SV/BSA (ml.m ^)
LVSWI l e f t v e n t r icular stroke work index - SVI x (MAP - MPAOP)
X 0.0144* (g-m.m 2)
~1 -2CI cardi ac i ndex - CO/BSA ( l . min .m ')-'I
SVR systemi c vascular resi stance - (MAP - MRAP)/C I (mm Hg.l .min.
2 .-1 . 2, m » kPa. I .min.m )
Tb ~ TiCSF coronary s in u s blood flow - V. . x 1.08 x ( — —— - 1)m j t — t
, . . - 1 , b m(ml .min )
CVR coronary vascular resi stance - (DAP - MPAOP)/(CSF x 10 "S
-1 -1 (mm Hg»l .min» kPa. I .min)
* for deri vation of the constant see Bowie» E.J.W» Thomson Jr.» J.H. Mayo Laboratory ManuaI of Hemostasis. Ph i lade lph ia» Saunders 1971» p. 31.
16
Methods for blood gas & lac ta te ana lyzes
For the metabolic studies (16 patients) a r t e r i a l i pulmonary a r te ry and
coronary sinus blood was sampled simultaneously and anaerobically in he-
parinized glass syringes and immediately analyzed on a Radiometer ABL - 2
(KOKHOLM and van SCHAICK# 1976) blood gas analyzer for pQ , pCQ and pH
and on a Radiometer OSM - 2 (SIGGARD-ANDERSEN# 1976) for hemoglobin con
centration and oxygen saturation. pQ - and pCQ - values were corrected
for body temperature according to SEVERINGHAUS (1958) and pH was correc
ted according to ROSENTHAL (1948). Lactate was analyzed in simultaneously
sampled a r t e r ia l and coronary sinus blood according to the enzymatic
method described by MARBACH and WEIL (1967). The oxygen content was ca l
culated from the formula:
where S is the saturation of oxygen (%) and the hemoglobin concentrate ->
CQ = 10 X ((Hb X 1.39 X S0 X 10 2) + 0.0031 x pQ ) (ml 02 - l 1)
“1tion (Hb) is expressed in g.dOO ml) -1
The following variables were derived:
(a - v)D,
(a - cs)D,
(a - cs)D.
0.
0.
’2
L
'2
-1arterio-mixed venous oxygen difference (ml 0^.1 )
arterio -coronary sinus oxygen d ifference (ml C^.l )-1
arterio-coronary sinus lactate d ifference (mmole.I )
- -1 to ta l body oxygen consumption - CO x (a - v)Dn (ml 07 .min )2 _3
myocardial oxygen consumption - CSF x (a - cs)D x 10
-1 2 (ml O^.min )
myocardial lactate extraction - CSF x (a - cs)DL -1
(micromole.I )
17
Thoracic epidural block
No premedication had been given p r io r to the investigations. A thoracic
epidural block was induced and kept stable in 12 patients by a continuous
infusion (IVAC 530) of prilocain» (10 mg/ml)» without vasoconstrictor
through a Portex epidural catheter. This was inserted by the paramedian
and loss of resistance techniques through the thoracic 8 - 9 interspace.
The t ip of the catheter was at the T6 to T7 leve l. The spread of the
block was followed by the pin prick method and within 15 min a block from
T1 to T12 was obtained in a l l but one patient» in whom the extension of
the block was from T1 to T11.
General anaesthesia
No premedication had been given p r io r to the investigations. A balanced
format of anaesthesia was used. I t consisted of 0.5 mg of atropine f o l
lowed by thiopentone sodium 4 - 6 mg/kg. Intubation was performed under
suxamethonium 1 - 1 . 5 mg/kg followed by pancuronium bromide 0.1 mg/kg. In
study I I I an average of 0.3 ± 0.1 mg of fentanyl and 7.5 ± 2.5 mg of dro-
peridol had been given in the two groups p r io r to aort ic cross clamping.
In study IV» an average of 0 .7 ± 0.3 mg of fentanyl and 7.5 ± 2.5 mg of
droperidol had been given in group I (co n tro l) . The corresponding f igures
for the volume loaded group ( I I ) were 0 .8 ± 0.2 mg of fentanyl and 7.5 ±
2.5 mg of droperidol. The patients were a l l vent i la ted with N2 Q/O2
(75/25) by an Engström 2000 v e n t i la to r and paCQ maintained around 4.2
kPa.
Surgical procedures
18
In study I I I » in frarena l aort ic cross clamping was performed on an average
35 min (range 23 - 47 min) a f te r induction of general anaesthesia in group
I (thoracic epidural block + prenaltero l p re-treatm ent) . For group I I
(control) ao r t ic cross clamping occurred on an average 33 min (range 29 -
39 min) a f t e r induction of general anaesthesia. A ll the patients in study
I I I were operated on fo r fusiform a o r to i l ia c aneurysms with insertion of
a b ifu rca tion g ra f t .
In study IV» 16 of the 19 patients had resection of a fusiform a o r to i l ia c
aneurysm and three had a saccular aort ic aneurysm. The patients with fu
siform aneurysms had a b ifu rcation g ra f t inserted» while the patients
with saccular aneurysms had a tube g ra f t . Seven patients with fusiform
and 2 with saccular aneurysms were assigned to group I (control) and 9
patients with fusiform and 1 with a saccular aneurysm were assigned to
group I I . In the patients operated on for an a o r to i l ia c aneurysm» the
r ight common i l i a c arte ry was always declamped f i r s t» an average of 23
min (range 15 - 46 min) p r io r to the declamping of the l e f t common i l i a c
arte ry . The average clamping time for group I was 62 min (range 55 to 81
min) and for group I I 67 min (range 48 - 80 min).
Fluid administrat ion
In study I and I I no f lu id besides the 5.5% glucose for measuring cardiac
output and coronary sinus blood flow was administered. In study I I I no
f lu id besides the 5.5% glucose for measuring cardiac output was given
p r io r to the operation. A fter induction of general anaesthesia» isotonic
sodium chloride acetate and/or sodium chloride glucose was administered
19
at a rate of 20 ml/kg/h to a l l pat ients . In study_IV the patients in group
I (control) were given an isotonic sodium chloride glucose infusion besides
the necessary transfusions to maintain a stable MPAOP around 10 mm Hg
(1 .3 kPa) p r io r to declamping. The patients in group I I were volume loaded
with 5% albumine or human plasma from approximately 10 min p r io r to declam
ping to reach an MPAOP around 16 mm Hg (2.1 kPa) when declamping was per
formed. In addition» these patients had the same treatment as the patients
in the control group» including 5.5% glucose for measuring cardiac output
and coronary sinus blood flow. In study V volume loading with 5% albumine»
human plasma and/or isotonic c rys ta l lo ids to an MPAOP around 12 mm Hg (1.6
kPa) was used as the primary treatment of the hypotension. As none of the
patients increased cardiac output at higher levels of l e f t ventr icu la r f i l
ling pressure or improved c l in ic a l ly » no fu r ther f lu id challenge was t r ie d
during the 160 min investigation period. Besides the 5.5% glucose for
measuring cardiac output and coronary sinus blood flow» isotonic sodium
chloride glucose was administered at 100 ml/h to a l l patients .
Prenaltero l
1 )Prenalterol (and the racemic form H 80/62) is a se lect ive ß^-adrenore-
ceptor agonist. Compared to isoprenaline i t has a more pronounced inotro
pic than chronotropic e ffe c t (CARLSSON et al» 1977). I t was also noted
that the drug had no e ffec t on the vascular resistance. JOHNSSON et al
(1978) and KNAUS et a l (1978) confirmed the findings in animals in human
pharmacological studies. ARINIEGO et al (1979) could show that H 80/62
was a highly specif ic antidote to card iose lec t ive ß-blockers and in th is
1) H 80/62 = C.50.005/ABa - racemic form Prenalterol - levo isomer of H 80/62
20
respect superior to i soprenal ine. RÖNN et al (1979) have shown that pre-
n a lte ro l also counteracts the e ffec ts of ß-blockers. The e l imination half
l i f e of prenaltero l in man is approximately 120 min (RÖNN et al» 1979).
Prenalterol was administered intravenously over a period of 15 min in a
to ta l dose of 10 mg in study I and I I I . In study I I and V the drug was
given intravenously over a 10 min period in a to ta l dose of 150 microgram
/k g .
Flowcharts of a l l measurements» samples and interventions in the f iv e in
vestigations are presented in Figures 1 to 4.
ÇH O i OCH2CHCH2NHCH A * CH
OH
Prenalterol
Statist ics
The paired and unpaired t - t e s ts were used for s ta t i s t i c a l analysis of the
results»which are presented as means ± S.D. A p-value less than 0.05 was
considered s ta t i s t i c a l l y s ig n i f ic a n t .
21
ECG & PRESSURES CARDIAC OUTPUT CORONARY SINUS FLOW ARTERIAL, MIXED VENOUS AND CORONARY SINUS BLOOD GASSESARTERIAL AND CORONARY SINUS LACTATEPRILOCAIN INFUSION THORACIC ED BLOCK STABLE PRENALTEROL INFUSION
• • • • • • • •
• • •
• • •
TIME (MIN) (3 I0 20 30 40 50 60 70
Figure 1. Flowchart of measurements# blood samples and interventions in study I I .
I G
ROUP
1
||
ECG & Press. Ree ,
Cardiac Output (
Prilocain Infusion
Epidural Stable
Prenait. Infusion
Gen. Anaesthesia
Clamping
• i • • i * i • • • • • • • • • i > • ••< I •
f G
ROUP
II
I
ECG & Press. Ree. ,
Cardiac Output Meas.<
Gen. Anaesthesia
Clamping
() 113 213 30 4O 5O 6iO 7O 8O 9O 1C>0 11IO V.20
Figure 2. Flowchart of measurements and interventions in study I I I . The patients in study I are presented in group I from 0 to 70 min.
22
RIGHT LIMB LEFT LIMB
CARDIAC OUTPUT . • • . • . • , • . .
CORONARY SINUS FLOW • • . . . . . • • . . • •
VOLUME LOADINGZDOca ART AND C S BLOOD GAS • • • • •u
ART LACTATE AND pH
CORONARY SIN. LACTATE • • • • •
PRESSURES AND ECG
CARDIAC OUTPUT 9 • . . • • • • • •
CORONARY SINUS FLOW • • • . . • . .= VOLUME LOADINGZDOoa ART. AND C S. BLOOD GAS • • • • •L3 ART LACTATE AND pH
CORONARY SIN. LACTATE • • • . •
TIME (MIN) 0 5 10 15 20 0 5 10 15 20
DECLAMPING I t
Figure 3. Flowchart of measurements# blood samples and interventions in study IV.
ECG & PRESSURES
CARDIAC OUTPUT
CORONARY SINUS FLOW
ARTERIAL,MIXED VENOUS ANDCORONAR SINUS BLOOD GASSES
ARTERIAL AND CORONARYSINUS LACTATE
VOLUME LOADING ------- -PRENALTEROL INFUSION ---URINARY OUTPUT ---------------- -TIME (MIN) 0 10 20 30 A0 50 60 70 80 90 100 110 120 130 140 150 160 170
Figure 4. Flowchart of measurements# samples and interventions in study V.
Results
23
Hemodynamic effects of thoracic epidural block & p re n a lte ro l ( I )
Thoracic epidural block from T1 to T12 induced a marked reduction in mean
a r t e r ia l pressure due to a decrease of both systemic vascular resistance
and cardiac output. There was no s ig n if ican t change in heart rate» mean
r ight a t r i a l pressure or pulmonary artery d ia s to l ic pressure» nor were any
arrythmias recorded. On ind iv idual analysis i t was found that 3 patients
had a moderate decrease in heart rate» 3 remained unchanged and 2 had a
moderate increase following the' block.
A fter administration of p renaltero l mean a r t e r ia l pressure increased a l
most to pre-epidural control level due to marked increase in cardiac out
put. No s ig n if ican t changes in heart rate» systemic vascular resistance
or pulmonary arte ry d ia s to l ic pressure were seen» nor were any arrythmias
recorded. The hemodynamic e ffec ts are summarized in Table 5.
Table 5. Hemodynamic e ffec ts of thoracic epidural block from T1 to T12(ED) followed by intravenous administration of 10 mg prenaltero l (P). C-control value before epidural block. Results are means ± S.D.» n= 8.
MAP MPAOP HR CI SVR-1 -2 -1 -2 (mm Hg) (mm Hg) (bpm) ( l . min .m ) (mm Hg.l .min.m )
C 98 ± 14 8 ± 2 68 ± 6 3.1 ± 0.5 31 ± 8
ED 58 ± 9** 7 ± 3 77 ± 13 2 .6 ± 0 .6 * * 22 ± 8*
P 88 ± 13** 8 ± 2 75 ± 10 3 .7 ± 0 .5 * * * 23 ± 5
* = p<0.05 * * = p<0.01 * * * = p<;0.001
24
Cardiom etabolic effects of thoracic epidural block & prenalterol ( l l)
The hemodynamic e ffec ts in the four patients in th is study were about the
same as for the patients in study I# both a f te r thoracic epidural block
and prena lte ro l . However# there was a more uniform response in heart rate
as a l l the patients had a 5 - 10 bpm decrease following the block and then
increased th e i r heart rate to s l ig h t ly above pre-epidural control value
a f te r administration of p rena lte ro l .
Following the epidural block there was only a moderate decrease in coro
nary sinus blood flow in spite of the marked reduction in coronary artery
perfusion pressure. Subsequently# calculated coronary vascular resistance
decreased subs tan tia l ly . Myocardial oxygen consumption decreased by
approximately 30% and myocardial lacta te extraction by approximately 55%.
An increased coronary sinus lactate concentration was measured. Total body
oxygen consumption decreased by about 20% in a l l pat ients .
Following prenaltero l coronary sinus blood flow increased to above pre
epidural control value but coronary vascular resistance was not a ffected .
Myocardial oxygen consumption and lactate extraction returned to control
values and to ta l body oxygen consumption increased to above pre-epidural
control value. The cardiometabolic e ffec ts are shown in Table 6.
Table 6. Cardiometabolic e ffe c ts of thoracic epidural block from T1 to T12 in 3 p a tien ts and from T1 to T11 in one (no 4) (ED) followed by p re n a lte ro l (P) as compared to pre -ep idu ra l control s itu a tio n (C ). The re su lts are given fo r the ind iv idua l p a tien ts .
PAT. CSF CVR V02myoc MYOC. LACT.EXTR. V
02to t(m l.min (mmHg. 1 .min) (m l.min ) (mi cromo le.m in ^) (m l.min ^)
C ED P C ED P C ED P C ED P C ED P1 156/131/195 600/290/290 1 4 .8 / 9 .5 /1 3 .3 3 2 .0 /1 4 .2 /4 4 .0 218/171/267
2 133/112/168 530/330/370 1 2 .9 / 8 .6 /1 5 .0 2 9 .9 /1 1 .8 /3 2 .3 229/198/295
3 148/123/189 460/290/290 1 2 .4 /1 0 .9 /1 2 .7 3 1 .8 /1 5 .1 /3 0 .9 241/212/304
4 151/119/209 490/270/310 1 3 .2 /1 0 .1 /1 4 .3 3 8 .6 /1 7 .0 /3 6 .9 241/203/304
25
Hemodynamic effects o f aort ic c la m p in g ( I I I )
Before any intervention» the only hemodynamic d ifference between the two
groups was a s l ig h t ly lower (8 versus 11 mm Hg) pulmonary artery d ia s to l ic
pressure in group I (thoracic epidural block + prenaItero I ) . The epidural
block and prenaltero l induced the hemodynamic changes shown in study I
(Table 5 ) . Subsequently» group I had a s ig n i f ic a n t ly lower pulmonary a r
tery d ia s to l ic pressure and systemic vascular resistance but higher car
diac and stroke volume indices than group I I (control) before general
anaesthesia. These d ifferences were maintained during general anaesthesia
and persisted t i l l immediately before cross clamping as shown in Figure 5.
In group I aor t ic cross clamping induced an immediate r ise (w ith in 30 s)
in mean a r t e r ia l pressure» pulmonary a r te ry d ia s to l ic pressure and cardiac
and stroke volume indices. Systemic vascular resistance did not r ise s ig
n i f ic a n t ly u n t i l 2 min a f te r clamping. Mean r ight a t r i a l pressure and
heart rate did not change and no arrythmias were recorded in any p a t ien t .
In group I I aor t ic cross clamping induced a r ise within 30 s in mean ar
t e r i a l pressure» pulmonary a rte ry d ia s to l ic pressure and systemic vascu
la r resistance. In contrast to group I» cardiac and stroke volume indices
decreased. Mean r ight a t r i a l pressure decreased from 3.2 ± 0.4 to 0 .8 ±
0.3 mm Hg» (0.43 ± 0.05 to 0.11 ± 0.04 kPa)» (p < 0 .0 1 ) . There was no
change in heart rate a f te r clamping but frequent supraventricular and
ven tr icu lar ectopic beats were recorded in 7 of the 8 patients in group I I
from 1 min a f te r cross clamping throughout the 5 min post clamping obser
vation period. The hemodynamic e ffec ts of aort ic cross clamping in the
two groups are shown in Figure 5.
26
WEAN ARTERIAL PRESSURE (MM HG)
200
180
160
K0120
100
80
--------------------- thorepid ♦ prenait
l P rr t i
clamping
-5 -4 -3 -2 -1 0 *1 * 2 * 3 »4 *5TIME (MIN)
100
9080
HEART RATE (BPM)
- contro l. thor «pid ♦ prena it.
- 5 - 4 -3 -2 -1 0 *1 *2 *3 *4 *5TIME(MIN)
CARDIAC INDEX ( L.MIN.M )
4 0 -
3.0 - L_____ L''i r
M - J
STROKE VOLUME INDEX (ML M )
controlthor «pid »p ren a it.
con tro lthor epid ♦ prenait
" Y -clamping
- 5 -4 -3 -2 -1 0 * ] * 2 * 3 +4 *5TIME (MIN)
SYST. VASC. RES. (MM HG L MN.M ) control t th o r ad. »pr«n. I
- 5 - 4 -3 -2 -1 0 *1 »2 +3 ♦ 4 »5TIME ( MIN )
HG)
> prenait15
10
5
5 -4 -3 -2 -1 0 ♦! *2 *3 *4 *5
Figure 5. Cardiovascular e f fec ts of in frarena l aort ic clamping in group I (thoracic epidural block + p rena lte ro l) and group I I (co n tro l) . S ign if ican t dif ferences in systemic vascular resistance» pulmonary artery d ia s to l ic pressure» cardiac and stroke volume indices are seen before cross-clamping.
In the control group» cross-clamping is followed by a sharp increase in systemic vascular resistance» mean a r t e r ia l pressure and pulmonary arte ry d ia s to l ic pressure in p a r a l le l to a drop in cardiac and stroke volume indices.
Group I shows the same increases in mean a r t e r ia l and pulmonary arte ry d ia s to l ic pressures» but in contrast to the control group» a very slow increase in systemic vascular resistance in p a ra l le l to an increase in stroke volume and cardiac indices» suggesting an increase in venous return and myocardial performance. Results shown are means ± S.D.(n = 8 ) .
27
Declamping hypotension ( I V )
In the patients who were operated on with insertion of a b ifu rca tio n
g ra ft there was no d ifference between the hemodynamic or cardiometabolic
responses to declamping of the r ight or le f t common i l i a c a r te ry . There
fore» only the results from the r ight common i l i a c a rte ry declamping
which always occurred f i r s t are presented.
The only hemodynamic and cardiometabolic d ifference between the two
groups before declamping was the higher mean pulmonary arte ry occlusion
pressure in group I I induced by the volume loading. In group I (control)»
declamping induced decreases in mean a r t e r ia l pressure» mean pulmonary
artery occlusion pressure» cardiac and stroke volume indices and l e f t
ven tr icu lar stroke work index. Heart rate and systemic vascular resistance
did not change» nor were any arrythmias recorded. In group I I» there was
an equal drop in mean pulmonary artery occlusion pressure following de
clamping while the decreases in mean a r t e r ia l pressure and le f t ventr icu
la r stroke work index were s ig n i f ic a n t ly less than in group I . In contrast
to group I» systemic vascular resistance decreased while cardiac and
stroke volume indices did not change. Like in group I there was no change
in heart rate» nor were any arrythmias recorded in any p a t ien t . The hemo
dynamic e ffec ts of declamping in the two groups are shown in Figure 6.
Declamping in group I induced decreases in coronary sinus blood flow and
myocardial oxygen consumption and lactate ex trac tion . Total body oxygen
consumption also decreased s ig n i f ic a n t ly . In group I I» none of these va
r iab les changed s ig n i f ic a n t ly a f te r declamping. There was an equal r ise
in a r t e r i a l lactate concentration 2 min a f te r declamping in both groups.
Five min a f te r declamping» a r t e r ia l lactate had returned to about the
28
MEAN ART PR. (mmHg) MEAN PULM ART OC Cl PR (mm Hg )
160
120
100
80
60
AO
20
20 AO 60 80 100 120 1A0 160
18
16
1A
12
10
8
6
A
A 6 8 10 12 1A 16 18 20 22before declamping
after declamping CARDIAC INDEX (Lmin^m2)
before declamping
after declamping STROKE VOLUME INDEX (m ini2)
3.0
2 0
10
1.0 2.0 3 0
70
60
50
A0
30
20
10
10 20 30 A0 50 60 70before declamping before declamping
after declamping SYST. VASC. RESIST (mm Hgfminm2) after declamping LEFT VENTR STROKE WORK INDEX (g-m.m2)
80
70
60
50
A0
30
20
10
10 20 30 A0 50 60 70 80
80
70
60
50
30
20
0
10 20 30 A0 50 60 70 d0before declamping
Figure 6. Maximal hemodynamic changes 2 min a f te r declamping in the ind iv idual control patients (x) and the volume loaded patients (o ) . Note the s ig n i f ic a n t d ifference in the reduction of MAP, (p < 0 .0 1 ) , SVI, (p < 0.01) and LVSWI, (p < 0.001) between the two groups of patients .
same level as before declamping. A s l igh t but in s ig n i f ica n t decrease in
a r t e r ia l pH p a r a l le l l in g the increase in lactate concentration was seen.
The cardiometaboli c e f fec ts of declamping in the two groups are shown in
Figure 7.
29
MYOCARDIAL OXYDEN CONS (
MYOCARDIAL LACTATE E)
Figure 7. Myocardial substrate u t i l i zation# to ta l body oxygen consumption and a r t e r ia l lactate concentration inthe control group (x x) and thevolume loaded group o— ~o) before (C) and 2 and 5 minutes a f te r declamping. S ign if icant decreases in myocard ial oxygen and lactate extraction rates (p < 0.001# p < 0.01) as well as to ta l body oxygen consumption#(p < 0.01)# are seen in the control group. There is no s ign if ican t change in these variables in the volume loaded patients . A transient increase in a r t e r i a l lactate concentration is seen 2 minutes a f te r declamping in both groups. Results shown are means ± S.D.# n = 4.
G ram negative septic shock ( V )
A ll patients responded rap idly to prenaltero l administration with increa
ses in mean a r t e r ia l pressure and cardiac output within 2 min a f te r
termination of prenaltero l infusion. F ifteen min a f te r completion of the
drug infusion# a l l patients were hemodynamically improved and stable and
remained so for the remaining 60 min of the observation period. The hemo
dynamic e ffec ts of prenaltero l are shown during steady state before ad
m in is tra tion of the drug and 15 min a f te r the termination of prenaltero l
infusion in Table 7.
30
Table 7. Hemodynamic e ffec ts of prenaltero l (P)# 150 microgram/kg i . v .in 10 patients with low resistance# d is t r ib u t iv e septic shock. C-control value before p ren a lte ro l . Results are given as means ± S.D.
MAP MPAOP CI SVR HR-1 ~p -1 ?
(mm Hg) (mm Hg) ( l . min .m ) (mm Hg.l .min.m ) (bpm)
C 57 ± 11 12.8 ± 4 .3 2.65 ± 0.40 18 ± 5 125 ± 16
P 75 ± 20** 12.0 ± 3 .0 3.80 ± 0 .4 7 * * * 19 ± 5 119 ± 14
**p < 0.01 * * *p < 0.001
Coronary sinus blood flow# myocardial oxygen consumption and lactate
extraction increased s ig n i f ic a n t ly following p re na lte ro l . A r te r ia l lac
ta te concentration decreased and to ta l body oxygen consumption increased
a f te r the drug. The metabolic e ffec ts of prenaltero l are summarized in
Table 8.
Table 8. Cardiometabolic e ffec ts of prenaltero l (P) in four patients with gram negative septic shock. Results are means ± S.D.
CSF C lact Vn . Vn Myoc.lactatea 0-,tot Onmyoc2 2 extraction(ml.ml ) (mmole.I ) (m l.min ) (m l.min ) (micromole.min )
C 185 ± 14 5.51 ± 0.55 287 ± 13 19.8 ± 2.1 33.2 ± 2.3
P 246 ± 14 ***3 .94 ± 0 .16** 348 ± 23** 26.6 ± 2 .1 * * * 44.7 ± 2 .1 * * *
p < 0.01 p < 0.001
31
Discussion
The major function of the cardiovascular system is to d e l iv e r s u f f i
c ient oxygenated blood to meet the metabolic requirements of the
t issues. As these are variab le within and between d i f fe re n t organs
there is a close in terp lay between cardiac output and vascular tone.
The determinants of cardiac output are heart rate and stroke volume.
Heart rate is regulated by in t r in s ic rythm icity and neurohumoral
a c t iv i ty» whereas stroke volume is depending mainly on preload» con
t r a c t i l i t y and a fte r load (BRAUNWALD 1974). Vascular tone is regulated
by in t r in s ic myogenic and metabolic mechanisms (BAYLISS 1902» GUYTON
1973) as well as by neurohumoral factors (FOLKOW & NEIL» 1971» WHITE
et al 1971). The following discussion w i l l be focused on how d i f fe re n t
interventions such as high thoracic epidural block and aort ic clamping
and declamping or base pathophysiology during gram negative septic
shock may a f fe c t these regulatory mechanisms. Possible treatments of
the c ircu la to ry dysequilibriums w i l l also be discussed.
Hemodynamic & card iom etabo l ic effects of
thorac ic epidural block & prenalterol (I,II)
In the present investigations ( I and I I ) » a substantial drop in blood
pressure was recorded a f te r thoracic epidural block from T1 to T12 with
pla in p r i lo c a in . The f a l l in blood pressure was due to a vasodilation
and a decreased cardiac output. These results are in agreement with
e a r l i e r reports on the hemodynamic e ffec ts of an epidural block in the
thoracic region (BROMAGE 1951, BONICA 1957, OTTON & WILSON 1966,
McLEAN et a l 1967, OTTESEN et al 1978). A fter a widespread epidural
32
block there is a pronounced vasodilation inducing a marked decrease
in blood pressure. The e ffe c t on the blood pressure is to a certa in
extent counteracted by a compensatory vasoconstr iction within non
blocked areas (BONICA et al 1970, SJÖGREN & WRIGHT 1972). A c o n tr i -
butary fac tor to the decrease of the a r t e r ia l blood pressure a f te r
high thoracic epidural block is the presynaptic block of the cardiac
sympathetic nerve supply (T1 to T5) (RANDALL et al 1957) with a
concomitant decrease of cardiac output (OTTON & WILSON 1966, McLEAN et al
1967). The findings of a decreased cardiac output and vascular re s is t
ance together with unchanged pulmonary arte ry d ia s to l ic pressure in
the present investigations indicate a depressed cardiac function
following the epidural block. Normally, a f a l l in g blood pressure is
accompanied by a reflexogenic increase in heart ra te . In the present
investigations there was however a varying heart rate response. Six
of the patients decreased, three increased and three had unchanged
heart rate following the block. The reason for th is varying e ffec t
on the heart rate might be an incomplete sympathetic block due to the
use of an anaesthetic solution of low concentration without vaso
constr ic tor agent (BROMAGE 1978). Furthermore, the vagal influence
on the heart was in tac t and there was s t i l l a minor and unaffected
supply of cardiac sympathetic nerve f ib res from the C5 to C8 segments
(WIESMAN et al 1966), which might modify the cardiovascular e ffec ts
of the thoracic epidural block.
D if fe ren t treatments to avoid a r t e r ia l hypotension a f te r thoracic
epidural block have been t r ie d . Volume expansion is an e ffe c t iv e way
to counteract hypotension following lumbar epidural block (BROMAGE
1967) but is not e f fe c t iv e by i t s e l f in high thoracic epidural block
33
(ENGBERG 1977). By administrating ephedrine p r io r to the thoracic
epidural block and using a local anaesthetic with adrenaline# ENGBERG
& WIKLUND (1978) were able to prevent a r t e r i a l hypotension. In the
present investigations# the e ffe c t of the card io se lec t ive ß^-adreno-
receptor agonist prenaltero l (CARLSSON et al 1977) on the induced
hypotension was studied. This drug normalized the systemic blood
pressure almost completely due to an increase in cardiac output to
above pre-epidural control values. The increase in cardiac output was
mainly due to increased stroke volume and in some patients to a
moderately increased heart ra te . The e ffec t on heart rate varied:
in 10 of the 12 patients there was an unchanged or only s l ig h t ly
increased heart rate and in the remaining two# there was a marked
decrease (more than 20 bpm). The unchanged pulmonary arte ry d ia s to l ic
pressure ( re f le c t in g l e f t ven tr icu lar f i l l i n g pressure) together with
an increase of the stroke volume indicate that prenaltero l had a d irec t
posit ive inotropic e ffec t and could abolish the negative inotropic
e ffe c t induced by the thoracic epidural block.
The e ffec ts of high thoracic epidural block on myocardial metabolism
and coronary hemodynamics have not been studied in man before. OTTESEN
et al (1978) investigated the cardiovascular e ffec ts of cardioselec
t i ve thoracic epidural block in sheep and found a reduction in myocar
d ia l blood flow measured by the hydrogen washout technique and a de
creased myocardial oxygen consumption. The changes of these variables
in the'present investigation were of the same magnitude. In addition#
myocardial lacta te extraction decreased secondary to a decreased
coronary sinus blood flow and increased coronary sinus lactate ad
mixture.
34
The major determinants of myocardial oxygen consumption are heart rate#
wall tension and myocardial c o n t r a c t i l i t y (BRAUNWALD 1971# PARMLEY &
TYBER6 1976). Coronary blood flow is largely determined by the coro
nary a r t e r io la r tone which is regulated by myocardial metabolic rate
(FOLKOW & NEIL 1971, BERNE & RUBIO 1974, KLOCKE 1976). The d irec t
autonomic nerve control of the coronary vascular tone which seems to be
of much less importance is regulated by alpha- and beta2 ~adrenoreceptors
(BERNE et al 1965# GRANATA et al 1965, KLOCKE et al 1965, PITT et al
1966, FEIGL 1967). The decrease in calculated coronary vascular re s is t
ance in the present investigation is probably due to a c r i t i c a l l y low
perfusion pressure as the d ia s to l ic a r t e r i a l pressure decreased to
below 50 mm Hg. In support of regional myocardial ischemia during the
hypotensive period is also the increased coronary sinus lactate ad
mixture. I t is also possible, that part of the coronary vasodilation
following the thoracic epidural block was due to alpha adrenoreceptor
blockade.
Administration of p renaltero l increased coronary sinus blood flow
in p a r a l le l to the increase in coronary perfusion pressure. Subse
quently, coronary vascular resistance was not a ffected . This is pro
bably due to the increased metabolic rate induced by the drug as de
monstrated by increased myocardial oxygen and lactate extractions.
I t is apparent, that prenaltero l had no d irec t e f fe c t on coronary
vascular smooth muscle.
I35
Hemodynamic effects of aortic c lam p ing ( i l l )
Patients operated on for abdominal aort ic aneurysms constitute a high
in t r a - and postoperative r isk group. Almost a l l these patients have
overt or covert cardiac disease# thus making them vulnerable to rapid
changes in a fte r load as seen in association with cross clamping (PERRY
et al 1968, CARROLL et al 1976) or long hypotensive periods associated
with extensive bleeding or declamping of the aorta (CAMPBELL 1967#
THOMAS 1971, IMPARATO et a l 1972# BUSH et al 1977). Following in f r a -
renal aort ic cross clamping an extensive r ise in systemic blood
pressure accompanied by l e f t ven tr icu lar f a i lu r e has been reported
by several workers (ATTIA et al 1976#, MELOCHE et al 1977# BUSH et al
1977). Pharmacological interventions to modify these negative cardio
vascular changes have mainly been focused on reduction of a f te r - lo a d
(POTTECHER & MELOCHE 1977). However# systemically administered drugs
w i l l a f fec t the to ta l vascular system. A thoracic epidural block from
T1 to the level of cross'clamping (approximately T12) is from a theo
r e t ic a l point of view a more in te res t ing intervention# as the block
w i l l induce a decreased resistance in the vascular bed central to the
clamping leve l . However# to counteract the negative inotropic action of
the block i t s e l f the combined treatment with a drug with posit ive
inotropic action without vascular e f fec ts would be ju s t i f i e d .
The cardiovascular response to in frarena l aort ic cross clamping in a
group of patients pre-treated with thoracic epidural block and pren-
a l te r o l and ,then given general anaesthesia (group I ) was compared to
that of a group of patients who had general anaesthesia only (group I I ) .
36
C l in ica l ly# the two groups were comparable# but group I started the
investigation with a s l ig h t ly lower pulmonary arte ry d ia s to l ic pressure
than group I I (8 versus 11 mm Hg, 1.1 versus 1.5 kPa) before any in te r
vention. This d if ference was somewhat increased a f te r the epidural block
and p ren a lte ro l . The pre-treatment also induced a lower systemic vascu
la r resistance but higher cardiac output than seen in the control group.
There were no s ig n if ic a n t d ifferences in systemic blood pressure and
heart rate between the two groups. These hemodynamic dif ferences per
sisted during general anaesthesia u n t i l the aort ic cross clamping pro
cedure (Figure 6 ) .
Following cross clamping in group I I (control) the cardiovascular
response did not d i f f e r from that reported by other workers (ATTIA
et al 1976# MELOCHE et a l 1977). Within 30 s there was a marked in
crease in brachial a r te ry and pulmonary arte ry d ia s to l ic pressures
in p a r a l le l to a sharp increase in calculated systemic vascular re
sistance. In addition# mean r ight a t r i a l pressure and cardiac output
decreased. Heart rate did not change but premature supraventricular
and ven tr icu lar contractions were recorded in 7 of the 8 pat ients .
These changes indicate that aort ic cross clamping induced decreased
venous return and severe impairment of cardiac function. Furthermore#
the appearance of supraventricular and ventr icu lar arrythmias is
strongly suggestive of myocardial dysoxia.
Compared to the control patients# the patients in group I had an equal
rise in brachial a rte ry pressure and pulmonary ar te ry d ia s to l ic pressure
without change in heart rate 30 s a f t e r cross clamping. In contrast to
group I I# cardiac output increased s ig n i f ic a n t ly . Calculated systemic
37
vascular resistance did not increase s ig n i f ic a n t ly u n t i l 2 min a f te r
cross clamping and was also at th is time s ig n i f ic a n t ly lower than that
calculated for the control group. No arrythmias were recorded in any
p at ie n t . The results ind icate that venous return increased and cardiac
performance improved in association with cross clamping. The mechanisms
for the increased venous return are not p e r fe c t ly c lear . BAYLISS (1902)
demonstrated that vascular d is tent ion induced by an elevation of
a r t e r ia l pressure increased the tone of vascular smooth muscle. This
mechanism is also active in denervated blood vessels (BRAUNWALD 1974b).
I t is possible that the epidural block might create opening of physio
logical arterio-venous shunts within the splanchnic area and thereby
could f a c i l i t a t e re d is tr ib u t io n of blood flow and increase venous
return in association with cross clamping.
When le f t v en tr icu lar stroke work index (LVSWI) is p lo tted against
pulmonary ar te ry d ia s to l ic pressure (PAp) fo r the ind iv idual patients
in the two groups (Figure 8) i t is apparent# that the control patients
(group I I ) are on the f l a t part of the function curve# whereas the
patients treated with thoracic epidural block and p renaltero l (group I )
are capable of increasing cardiac performance in association with the
rapid increase in a fte r load induced by the ao r t ic cross clamping.
Figure 8. Effects of in frarena l aortic clamping for the in d i vidual patients in groups I and I I . The patients with thoracic epidural block and prenaltero l (group I ) are on the upward slope of the function curve whereas the control patients (group I I ) are on the horizont a l p ar t . Note the d ifference in PAp scale between the groups.
-2GROUP I L V S W I (g -m .m ) GROUP II
PAd (mmHg)
38
Declamping hypotension ( IV )
From studies with microspheres in dogs i t is known that about 3% of
cardiac output only# is d irected to the lower extrem ities during the
clamping period (RUTHERFORD 1977). This w i l l result in dysoxia and
accumulation of acid metabolites in the lower limbs. When aort ic
dec lamping is performed# the proportion of cardiac output directed
to the lower extremit ies increases to about 21%. This occurs at the
expense of renal# hepatic and mesenteric blood flow and in p a r a l le l to
a decrease in cardiac output by 25% (RUTHERFORD Ì9 7 7 ) . "Central hypo
volemia" suggested by STRANDNESS et al (1961)# FRY et al (1963) and
BAUE & McCLERKIN (1965) seems to be by fa r the most important mechanism
for the development of the declamping hypotension. Other mechanisms#
l ike release of myocardial depressant factors from the post ischemic
lower limbs (SELBY et al 1964# BRANT et al 1970# RITTENHOUSE et al
1976) or the presence of acid metabolites in the systemic c ircu la t io n
(MAUSBERGER et al 1966# LIM et al 1969) have not been adequately proven.
BUSH et a l (1977) who were also in favour of central hypovolemia as the
major cause of declamping hypotension reported that a Left ventr icu lar
f i l l i n g pressure around 10 mm Hg (1 .3 kPa) completely abolished the
blood pressuré drop following declamping of the in frarena l aorta. As
th is was not our experience# we wanted to investigate the use of higher
l e f t ventr icu lar f i l l i n g pressure to prevent declamping hypotension.
Nineteen patients operated on for abdominal aort ic aneurysm under
general anaesthesia only# were therefore randomly assigned to two
groups. The control patients (group I ) were kept at a stable mean
pulmonary a r te ry occlusion pressure around 11 mm Hg (1 .5 kPa) t i l l
39
immediately before declamping. The patients in group I I were volume
loaded during the last 10 min before declamping to a mean pulmonary
a rte ry occlusion pressure around 16 mm Hg (2.1 kPa). Besides th is
there were no c l in ic a l or hemodynamic differences between the two
groups. Following declamping however, s tr ik in g differences between the
groups became apparent:
In contrast to what was postulated by BUSH et al (1977) the patients
in the control group had a substantial decrease in systemic blood
pressure coinciding with a 3 mm Hg drop in mean pulmonary a rte ry
occlusion pressure which was of the same magnitude as reported by BUSH
et a l . The volume loaded patients had an equal reduction in f i l l i n g
pressure following declamping, but the reduction in systemic blood
pressure was s ig n i f ic a n t ly smaller than that recorded in the control
p atients . In the control group, cardiac output decreased. In contrast,
cardiac output did not change in the volume loaded p at ients . Heart
rate was not affected by declamping in any of the groups, nor were
arrythmias recorded in any p at ien t . During deep general anaesthesia i t
is common that a decrease in stroke volume is not followed by a re f lexo -
genic increase in heart ra te . Furthermore, eight of the 19 patients
were under influence of beta-blockers which may also explain the
absence of heart rate response.
In Figure 9, l e f t ven tr icu lar stroke work index (LVSWI) has been plotted
against mean pulmonary a r te ry occlusion pressure (MPAOP) for the two
groups. I t is apparent, that the volume expansion has transferred the
patients in group I I to the horizontal part of the function curve,
where a moderate reduction of pre-load does not a f fe c t cardiac per-
40
formance# whereas the same réduction of pre-load in the control
patients w i l l induce a substantial drop in cardiac performance.
LVSWI (g-m.rrf2)
60
40
30
20
GROUP I GROUP II
-i— I-
Figure 9. Relationship between LVSWI and MPAOP. Note the s ign if ican t difference» (p < 0.001) in the reduction in mean LVSWI following declamp- i ng.Group I (control# n = 9 ) . Group I I (volume loaded# n = 10)
MPAOP (mm Hg)
In the volume loaded patients the systemic vascular resistance de
creased# which is regarded as an e ffe c t of decreased vascular tone
in the reperfused lower extrem ity (ies) and may well explain the
moderate decrease in systemic blood pressure in these patients as
cardiac output was unchanged. In contrast# systemic vascular re s is t
ance did not change in the control patients suggesting vasoconstriction
in central vascular beds to compensate for reduction in central blood
volume.
When comparing the two groups# no d if ference in myocardial oxygen or
lacta te extraction was found before declamping implying that the
volume loading did not a f fe c t cardiac work. In p a r a l le l to the de
crease in a fte r load and preload and thereby cardiac work in the control
patients# there was a decreased myocardial oxygen and lactate u t i l i z a
t io n . Myocardial ischemia could not be demonstrated following declamping
despite a reduced coronary a r te ry perfusion pressure. In group I I no
41
s ig n if ic a n t changes in myocardial substrate u t i l i z a t io n could be de
monstrated a f te r declamping.
I t is apparent from the findings in the present study# that the results
from animal studies by RUTHERFORD are also relevant in the c l in ic a l
s itu a t io n . Even with a normal l e f t ven tr icu lar f i l l i n g pressure imme
d ia te ly before aort ic declamping# venous return and thereby cardiac out
put and systemic blood pressure cannot be adequately maintained a f te r
declamping. However# a compensatory vasoconstriction# probably in the
splanchnic area# w i l l prevent a profound blood pressure drop and there
by preserve coronary perfusion. Volume expansion to s l ig h t ly supra-
normal l e f t v en tr icu lar f i l l i n g pressure shortly before declamping did
not induce any adverse cardiometabolic changes and almost completely
abolished the negative cardiovascular e f fec ts of declamping seen in the
control pat ients .
From the present investigations i t is obvious# that the cardiovascular
system can be extensively manipulated and that the hazardous in t r a -
operative events of abdominal aort ic aneurysm surgery can be e f fe c t iv e ly
eliminated. Thoracic epidural blockade from T1 to T12 supported by
c a rd iose lec t ive beta^-receptor stimulation with prenaltero l t ransferred
the patients to a more favourable myocardial function curve and pro
bably also f a c i l i t a t e d re d is tr ib u t io n of blood flow in association with
in frarena l aort ic cross clamping. However# the local anaesthetic used
for the thoracic epidural block has to be short acting not to in te r fe re
with the declamping. Apparently# declamping hypotension is induced by a
mismatching between vascular volume and blood volume# where well pre
served venous return is essential for cardiovascular equilibrium. A
42
thoracic epidural block» s t i l l e f fective» in association with declamping»
might therefore potentiate the hypotension by i t s e f fec t on vascular
volume and also block a compensatory splanchnic vasoconstrictor response
to central hypovolemia. I t would therefore appear» that the b enefic ia l
e ffec ts of a thoracic epidural block are res tr ic ted to modify the adverse
cardiovascular response to cross clamping but should id e a l ly be over at
the time of declamping.
Gram negative septic shock (V )
Acute p e r i to n i t is associated with gram negative bacteremia» is character
ized by an inflammatory vasodilation with increased blood flow with in the
infected tissues (SHAL'KOV et al 1975» SILL 1976, ARCHIE 1977, WEIL 1977,
LUTSENKO 1978). Vascular resistance is decreased and a large portion of
cardiac output is directed to the peritoneal cavity which could lead to
t issue dysoxia in other organs. To meet the basal peripheral demand,
cardiac output must increase, which occurs mainly by an increase in
heart rate (WEIL 1977). In c ircu la to ry shock associated with gram nega
t iv e p e r i to n i t is there is , subsequently, a c r i t i c a l perfusion d e f ic i t
demonstrated by lactacidemia (WEIL et al 1975). The primary treatment
of the hypotension thus consists of volume expansion in order to in
crease cardiac output fu r th er (LOEB et al 1971, GOLDBERG 1971, WEIL
1977). However, volume expansion is often not followed by fur th er in
crease in cardiac output, ind icating impaired cardiac function (LOEB
et al 1967). Under these circumstances, pharmacological intervention
with inotropic drugs can be used to increase cardiac output (WINSLOW
et a l 1973).
43
The endogenous catecholamine# dopamine# is the most commonly used drug
fo r th is purpose today# due to i t s inotropic and renal c o r t ic a l vaso
d i la t in g action which tends to maintain urinary output (GOLDBERG 1972).
The drug exerts a mixed# dose dependent action on the cardiovascular
system. In dosages from 1 to 10 microgram/kg/min the drug is a dopamine-
and beta^-receptor agonist# whereas i t predominantly w i l l stimulate
beta2 ~ and alpha-adrenoreceptors at higher dose levels (GOLDBERG 1977).
As unwanted e ffec ts l ike tachycardia and arrythmias can be seen during
dopamine infusion at high dose levels# we wanted to investigate the
effec ts of a se lect ive ß ^ a d r e n o r e c e p t o r agonist# prenalterol# in
patients with low resistance# d is t r ib u t iv e shock caused by gram negative
bacteremias. A c r i t e r i a in the present investigation to in s t i tu te th is
treatment was that the patients had been adequately volume loaded and
did not increase cardiac output fu r th er at higher levels of l e f t v e n r i -
cular f i l l i n g pressure# ind icating the need for inotropic support.
Ten patients with p e r i to n i t is and gram negative bacteremia(s) associated
with c l in ic a l# metabolic and hemodynamic signs of c ircu la to ry shock were
included. In a l l but one patient the time from onset of shock t i l l pren
a l te r o l treatment was less than 8 hours (Table 4 ) . Prenalterol admini
s tra t io n increased systemic blood pressure by 30% and cardiac output
by 44% with in 15 minutes from termination of the infusion of the drug.
These e ffec ts persisted throughout the rest of the invest igat ion period.
Systemic vascular resistance and heart rate did not change s ig n i f ic a n t ly
during the 60 min observation period a f te r p rena lte ro l . Mean pulmonary
arte ry occlusion pressure declined slowly to reach a level of s i g n i f i
cance 60 min a f te r the drug administrat ion. The hemodynamic changes in
the present study were of the same magnitude as reported for dopamine
44
in septic shock by REGNIER et al (1977) and support previous observa
tions that prenaltero l is a se lective beta^-adrenoreceptor agonist which
compared with for instance isoprenaline has a higher inotropic than
chronotropic action (CARLSSON et al 1977). In p a r a l le l to the increased
cardiac work an increase in myocardial oxygen consumption and lactate
extraction was demonstrated. Total body oxygen consumption increased a f te r
prenaltero l concomitant with a decrease in a r t e r i a l lactate concentra
tion# suggesting improved tissue perfusion. The increase in to ta l oxygen
consumption might in part be due to increased l ipo ly s is and metabolic
rate a f te r administration of p renaltero l (RÖNN et al 1979). Urinary out
put increased s ig n i f ic a n t ly a f te r p ren a lte ro l . There is as yet no e v i
dence that the drug exerts any action on the dopaminergic receptors in
the kidney and we therefore regard the increased urinary output as an
e ffe c t of improved renal perfusion pressure.
The m o rta l i ty in the present investigation was considerably lower than
that reported in most other studies of septic shock (LOEB et al 1967,
WINSLOW et al 1973# DRUECK et al 1978). There are probably several reasons
for th is . Early# correct diagnosis and c la s s i f ic a t io n of the shock state
by the use of invasive hemodynamic studies# aggresive treatment of the
hypotension together with early surgical intervention and appropriate
treatment with ant ib io tics# was the combined b en efic ia l therapy for
most of these pat ients .
Conclusions
45
Thoracic epidural block from T1 to T12 induced marked decrease in syste
mic blood pressure due to vasodilation and impairment of cardiac perfor
mance. Prenalterol administration e f fe c t iv e ly abolished the low blood
pressure by i t s marked inotropic action# having no e f fe c t on systemic
vascular resistance. Myocardial oxygen consumption changed in p a ra l le l
with the changes in cardiac work following both thoracic epidural block
and p ren a lte ro l . Coronary vascular resistance was markedly decreased by
the block and was not affected by p rena lte ro l . I t is suggested# that the
c r i t i c a l l y low perfusion pressure is the main cause of the coronary vaso
d i la t io n and that alpha-blockade induced by the thoracic epidural block
is of less importance.
The combination of a thoracic epidural block from T1 to T12 and selec
t iv e -s t im u lâ t ion with prenaltero l was an e f fe c t iv e way to modify the
cardiovascular response to in frarena l aort ic cross -clamping. This t r e a t
ment transferred the patients to a more favourable cardiac function
curve and possibly f a c i l i t a te d the re d is tr ibu t io n of blood flow in as
sociation with clamping.
In association with declamping of the in frarena l aorta or the common
i l i a c arteries# volume loading to a s l ig h t ly elevated le f t ventr icu lar
f i l l i n g pressure shortly before declamping was an e f fe c t iv e way to
counteract the expected blood pressure drop. A normal l e f t ventr icu lar
f i l l i n g pressure p r io r to declamping did not prevent the blood pressure
drop following declamping. I t is suggested# that mismatching between
vascular volume and blood volume is the main cause of declamping hypo
46
tension.
In patients with low resistance» d is t r ib u t iv e septic shock caused by
gram negative bacteremias and signs of impaired cardiac function» pre-
n a lte ro l e f fe c t iv e ly reversed the hypotension and improved tissue per
fusion by se lec t ive ly increasing cardiac output. In p a r a l le l to the in
creased cardiac work» an increase in myocardial metabolic demand was
demonstrated.
47
Acknowledgements
I want to thank my co-authors» collaborators» patients and friends
who helped me to accomplish the present research work.
There are some people who have given me outstanding support:
Anne-Marie Thorn-Alquist who gave me enviable research f a c i l i t i e s .
Sören Häggmark and B r it t -M a r ie Magnusson who gave s k i l fu l technical
assistance during the course of many long working days.
E l la Blad» Monica Edwall» Ulla -Greta Gidlund» Inger Larsfeit» Lena
Wiberger and Debbie Wolf who typed a l l the manuscripts.
G i l l i s Johnsson» Per Olov Wester and Hans Sström who guided me through
the stony archipelago of research.
Ske Hjalmarson and Garner King» who gave insp ira t ion and valuable
c r i t ic ism throughout the work.
Gunnel» Anna and Fredrik who could stand a l l the lonely nights and
long working days.
The work was supported by grants from the Swedish Anaesthetists'
Society» the University of Ume§ and AB Hässle» Gothenburg» Sweden.
48
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