Table Of ContentADVANCES IN PHYSIOLOGICAL SCIENCES
Proceedings of the 28th International Congress of Physiological Sciences
Budapest 1980
Volumes
1 - Regulatory Functions of the CNS. Principles of Motion and Organization
2 - Regulatory Functions of the CNS. Subsystems
3 - Physiology of Non-excitable Cells
4 - Physiology of Excitable Membranes
5 - Molecular and Cellular Aspects of Muscle Function
6 - Genetics, Structure and Function of Blood Cells
7 - Cardiovascular Physiology. Microcirculation and Capillary Exchange
8 - Cardiovascular Physiology. Heart, Peripheral Cij;culation and Methodology
9 - Cardiovascular Physiology. Neural Control Mechanisms
10 - Respiration
11 - Kidney and Body Fluids
12 - Nutrition, Digestion, Metabolism
13 - Endocrinology, Neuroendocrinology, Neuropeptides - I
14 - Endocrinology, Neuroendocrinology, Neuropeptides - II
15 - Reproduction and Development
16 - Sensory Functions
17 - Brain and Behaviour
18 - Environmental Physiology
19 - Gravitational Physiology
20 - Advances in Animal and Comparative Physiology
21 - History of Physiology
Satellite symposia of the 28th International Congress of Physiological Sciences
22 - Neurotransmitters in Invertebrates
23 - Neurobiology of Invertebrates
24 - Mechanism of Muscle Adaptation to Functional Requirements
25 - Oxygen Transport to Tissue
26 - Homeostasis in Injury and Shock
27 - Factors Influencing Adrenergic Mechanisms in the Heart
28 - Saliva and Salivation
29 - Gastrointestinal Defence Mechanisms
30 - Neural Communications and Control
31 - Sensory Physiology of Aquatic Lower Vertebrates
32 - Contributions to Thermal Physiology
33 - Recent Advances of Avian Endocrinology
34 - Mathematical and Computational Methods in Physiology
35 - Hormones, Lipoproteins and Atherosclerosis
36 - Cellular Analogues of Conditioning and Neural Plasticity
(Each volume is available separately.)
ADVANCES IN
PHYSIOLOGICAL SCIENCES
Satellite Symposium of the 28th International Congress of Physiological Sciences
Budapest, Hungary 1980
Volume 26
Homeostasis in Injury and Shock
Editors
Zs. Biro
A. G. B. Kovαch
Budapest, Hungary
J. J. Spitzer
New Orleans, USA
H. B. Stoner
Manchester, UK
PERGAMON PRESS AKADΙMIAI KIADΣ
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Copyright C Akadémiai Kiadó, Budapest 1981
All rights reserved. Mo part of this publication may he reproduced,
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the publishers.
British Library CaUiloguiiig in Publicatioii Data
International Congress of Physiological Sciences.
Satellite Symposium (28th : 1980 : Budapest)
Advances in physiological sciences.
Vol. 26: Homeostasis in injury and shock
I. Physiology - Congresses
I. Tide II. Biro, Zs.
591.1 QPI 80-42104
Pergamon Press ISBN O 08 026407 7 (Series)
ISBN O 08 027347 5 (Volume)
Akadémiai Kiadó ISBN %3 05 2691 3 (Series)
ISBN %3 05 2752 9 (Volume)
In order to make this volume available as economically and as
rapidly as possible the authors" typescripts have been reproduced in
their original forms. This method unfortunately has its typographi
cal limitations but it is hoped that they in no way distract the reader.
Printed in Hungary
FOREWORD
This book records the proceedings of a symposium on "Homeostasis in
Injury and Shock" held on July 21-23, 1980 in the Technical University of
Budapest as a SateUite Symposium to the 28th International Congress of
Physiological Sciences. The last satellite symposium on this subject had been
held after the 1971 Munich Congress. On the present occasion there were
50 registrants from 13 different countries.
The morning and afternoon sessions of the Symposium were composed
of invited lectures and sessions of submitted posters. In the pages which
follow the seventeen invited lectures are printed in the order in which they
were given. The abstracts submitted with the posters have been printed in
alphabetical order. The object of all symposia is good discussion and this was
achieved. It has not been possible to give a verbatim account of the discus
sion which followed each invited lecture and of the general discussion after
the lecture and poster sessions. Short summaries have been included in order
to give some idea of its flavour. This mixture of lectures, posters and discus
sion proved, once again, the value of a symposium bringing together workers
from the many disciplines involved in research on this subject.
The thanks of the Organizing Committee, and of the participants, are
due to Dr. Zsuzsanna Biro, the Symposium Secretary, and all who assisted
her (most of all: Mrs. Anna Schmidt, Miss Klara Szuchanek and Miss Edit
Fαklya) in the excellent conduct of the meeting and to Dr. H. I. Miller for
organizing the poster sessions.
A, G. B. Kovαcs
J. J. Spitzer
Η. Β. Stoner
XI
ACKNOWLEDGEMENTS
The Organizing Committee of the Symposium expresses its gratitude to
the following organizations for their financial support:
Welcome Trust
Upjohn Limited
British Petroleum
Imperial Chemical Industries Limited
Smith Kline and French
Geistlich Sons Limited
Janssen Pharmaceutical
Heinz and Anna Kroch Foundation
International Trauma Foundation
Medical Commision for Accident Prevention
Wyeth Laboiatories
V/0 MEDEXPORT
OMKER Commercial Company for Medical Instruments
IKARUS Body and Coach Building Works
TAURUS Hungarian Rubber Works
xu
^dv. Physiol. Sei. Vol. 26. Homeostasis in Injury and Shock
Zs. Biro, A. G. B. Kovách, J. J. Spitzer. Η. Β. Stoner (eds)
THE BRAIN IN SHOCK
Arisztid G. B. Kovách
Experimental Research Department and 2nd Institute of Physiology, Semmelweis Medical University,
Budapest, Hungary
The integrity of the nervous system is necessary for the
proper adjustment of the living organism to the reduction of
blood volume and to other forms of injury. It was generally
assumed that owing to its appropriate blood flow autoregulatory
mechanisms, the brain's vital functions are protected during
hypotension in hypovolemic and other types of shock.
However, observations made in our and other laboratories
have established that the CNS is in fact vulnerable in pro
longed haemorrhagic hypotension and shock.
It has been demonstrated that spontaneous electrocortical
activity 1121 and somatosensory evoked potentials /13/ dis
appear during hypovolemia and do not return after reinfusion.
Metabolic /23/ and functional /8/ alterations also suggest
that the CNS is seriously affected in shock.
The deterioration of cerebral electrical activity during
haemorrhagic shock can be explained by the diminution of
regional cerebral blood flow /8,12/ and also by the primary
defect of cerebral energy metabolism /lO,11,12,13/. McShan et
al. /60/ ascribed the development of irreversible shock and of
the tissue metabolic disturbances that are characteristic of
shock to the reduction of ATP and CrP concentrations. Since
the concentrations of the energy rich compound in traumatic
/II,12,13/ and ischaemic /23/ shock diminishes only in the
late phase of shock, the validity of the "energy depletion"
hypothesis has been questioned by many authors /31/.
In contrast, Kovách et al. /47/ attributed the stability
of cerebral ATP and CrP concentrations in the early phase of
shock to the reduced ATP consumption and to the decelerated
ATP and CrP synthesis. The decreased capacity for oxidative
phosphorylation of mitochondria isolated from the brain of
animals in shock was also demonstrated in vitro /27,32,25/.
In this survey the results obtained in baboons - the
changes in cerebral blood flow were measured by ^^-^Xe and ^^C
antipyrene - and in cats - the alterations in intracellular
oxygen tension and in the tightness of coupling of oxidative
phosphorylation in the brain cortex were determined in vivo
by surface fluororefleetometry - will be encountered.
Changes in cerebrocortical intracellular oxygen tension
were assessed by alterations of the maximal NAD reduction
obtained during transient nitrogen gas inhalation 12,9,111.
The changes in the tightness of coupling between mitochondrial
respiration and oxidative phosphorylation were estimated from
the kinetics of cortical NADH reoxidation which appears
subsequent to the termination of nitrogen gas inhalation /57,
70/. These results have been*reported earlier /14,45,64/.
Material and methods
Cerebral blood flow studies in baboon
Experiments were carried out on baboons of both sexes,
anaesthetized with Sernylan / 1 ml/kg /. The animals were
ventilated artificially and immobilized with Flaxedyl.
Regional cerebral blood flow /rCBF/ was registered by two
methods. Repeated measurements were taken by monitoring the
cerebral clearance of ^^^Xe using a multi-channel, computer
based system. At the end of each experiment local blood flow
was also determined by an autoradiographic technique employing
l^C-antipyrine /67/. Arterial and central venous pressures,
end-tidal CO2 content of expired air, cortical electric
activity and EGG were monitored continuously, while arterial
and cerebral venous /sagittal sinus/ blood samples were taken
and analysed for pH, blood gases, haematocrit and metabolites.
Cardiac output was determined by thermal dilution.
Haemorrhagic shock was induced by using a pressure-buffered
reservoir system. Mean arterial blood pressure /MABP/ was
first set at 55-6 0, then at 35-40 mm Hg. Each hypotensive
period lasted for 90 min and at the end of the second bleeding
phase the shed blood was reinfused. Measurements were taken
one hour after reinfusion. In another group, experimental
animals were sacrificed at the end of the second bleeding
before reinfusion in order to obtain autoradiograms during
the hypotensive state.
Fluororeflectometric studies in cat
The experiments were carried out on 15 cats weighing
2.5-3.5 kg anaesthetized with 60 mg/kg alpha-D-glucochloralose,
immobilized with 2-4 mg/kg gallamine trietyliodide and
ventilated artificially. The trachea, femoral arteries, one
of the lingual arteries and femoral veins were prepared and
cannulated with cannulae filled with heparinized physiological
saline.
The head of the animals was mounted in a stereotaxic
stand and the skin and muscles were removed from both sides
of the skull. A hole 12 mm in diameter was drilled in the
left parietal bone and the dura was carefully removed.
Subsequent to this a glass windpw was placed and cemented
into the bored hole /45/
The electrocorticogram was recorded via the electrodes
attached into the wall of the plastic ring, in other cases
by means of copper screws fixed into the frontal and occipital
cranial bones /57/.
Cerebrocortical NADH fluorescence and UV reflectance were
measured by the modified microfluororeflectometer originally
developed by Chance et al. /3,40/.
The alterations of the NADH fluorescence caused by
changes in cerebral cortical blood content were eliminated
by the correction method of Harbig et al. /27,42/. The so
called corrected fluorescence demonstrates the true changes
of NADH concentration that were caused by the various inter
ventions /8,27,40/.
Haemorrhagic shock was brought about by bleeding the
cats to 30-35 mra Hg mean arterial blood pressure /MABP/,
by means of a buffer system attached to the femoral artery.
MABP was maintained at that level until 50-70% of the shed
blood had spontaneously returned into the animal. The blood
remaining in the tank was reinfused.
Arterial blood gas data and Hb were determined by an
ABL-1 blood gas analyzer /Radiometer/. The rectal temperature
of the ankmals was kept between 37-39 using an infrared
lamp.
Nitrogen gas inhalation and electrical stimulation of the
cerebral cortex as tests were applied once in the control
period, every hour during the bleeding and at half hour inter
vals after reinfusion. The correction factor was determined
in every single case for the assessment of the NADH changes
occurring as a result of the above interventions.
Results
Cerebral blood flow studies
Table 1 summarizes the haemodynamic data. There was a
substantial and significant decrease in cardiac output during
haemorrhage. To a much lesser degree, mean cerebral blood
flow also declined, especially during the second bleeding.
Table 1
Control Bleeding I Bleeding II Reinfusion
90' 90' 60'
+ + +
MABP 112 9 56 1 33 1 98 15
/mm Hg/
+ +
CO 2 07 13 90 5 56 7 175 34
/ml/min/kg/
+
CBF 39 2.1 34 1.5 22 1.6 78 18
/ml/lOOg/min/
+ + + +
FAST FLOW 55 2.2 50 2.6 35 5.7 112 32
/ml/lOOg/min/
+
SLOW FLOW 17 1.7 25 1.6 17 2.6 52 19
/ml/lOOg/min/
+
HTC 37 2 28 2 28 2 32 2
/per cent/
MABP=mean arterial blood pressure; CO=cardiac output;
CBF=mean cerebral blood flow; HTC=hematocrit
Comparison of percent changes revealed that cardiac output
dropped to 27% of its initial level while mean CBF decreased
to 56% during bleeding II. Diminution of the brain blood flow
could be attributed mainly to the decreased flow in the gray
matter as revealed by compartmental analysis, while the slow
flow /flow in the white matter/ remained rather unchanged if
not augmented. A marked haemodilution also occurred during
haemorrhage. There was a fairly uniform decrease in blood
flow due to haemorrhage in all of the brain regions studied
/Fig. 1/.
70 Γ
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O
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<
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o
ο:
"If"
.30' 60' 90'.
CONTROL BLEEDING I BLEEDING I REINFUSION
Fig. 1
In the control animals mean CBF did not change signifi
cantly during the 5-6 hr of observation. After reinfusion a
marked increase in CBF occurred involving both the fast and
slow compartment /Table 1, Fig. 1/.
There was a slight but significant decrease in cerebral
oxygen consumption /CMR03^2/ from 3.28 ml/lOOg/min to
2.74 ml/lOOg/min, but a return to the initial level after re
infusion /3.53 ml/lOOg/min/ also occurred. A similar change
was seen in the cerebral uptake of glucose.
Cerebral venous ρθ2, which is thought to be an important
indicator of gross tissue hypoxia, did not fall below the
critical level of 20 mm Hg.
All other blood and metabolic parameters /blood gases,
plasma levels of lactate and pyruvate, and lactate and pyruvate
output of the brain/ displayed basically the same changes
during haemorrhage as published earlier /67,68/ and tended
toward prebleeding values following reinfusion.
Analysis of the autodiograms revealed an uneven perfusion
as a consequence of prolonged haemorrhage. Besides reduction
of perfusion rates in all brain regions, areas without any
uptake of the tracer l^c-antipyrine, indicating no flow at all,
also occurred. It was even more striking that ischemic areas
persisted after reinfusion when mean CBF was twice as much as
before bleeding.
Phenoxybenzamine pretreatment / 5 mg/kg / in baboon pro
tected against the cerebral blood flow decrease during shock
and the ischemic areas did not develope. Electrocorticogram
was much less affected during hypovolemia and total recovery
was found after retransfusion.
Cerebrocortical reflectance and corrected fluorescence
reactions elicited by transient nitrogen gas inhalation
In normotension the nitrogen anoxia led to a 12.2-1.94%
reflectance decrease and to a 25.9-2.13% corrected fluorescence
increase in the brain cortex. The value of the correction
factor in the control period was 1.26^0.21.
In the first period of bleeding, the cerebrocortical re
flectance and corrected fluorescence reactions evoked by
nitrogen gas inhalation decreased significantly. In the next
period of bleeding /B. 90' - 120'/ nitrogen inhalation resulted
in an 0.9*0.6% reflectance decrease and a 2.6*1.51% corrected
fluorescence increase. In the last phase of bleeding nitrogen
inhalation did not bring about changes in cerebrocortical
reflectance and corrected fluorescence in any of the experi
ments .
The severity of the changes of the cerebrocortical oxygen
supply during hypovolemic shock is clearly indicated by the
fact that nitrogen anoxia after reinfusion failed to bring
about the changes in the cortical NAD/NADH redox state in 5
out of the 9 experiments /R. 30'-60'/·
The changes of the reflectance and corrected fluorescence
reactions elicited by nitrogen gas inhalation are demonstrated
on the basis of a tipical experiment in Figs 2 and 3.
Nitrogen anoxia applied in the control period led to a
considerable decrease of reflectance which became more pro
nounced for á short time after the readministration of oxygen
into the inspired gas mixture /Fig. 2/. Subsequently the
reflectance gradually increased and 10 min after the cessation
of nitrogen inhalation it returned to the initial level.
In the first period of bleeding there was a smaller de
crease in reflectance during nitrogen inhalation than in the
control period and the reflectance transiently overshot on
the readministration of oxygen into the inspired gas mixture.
During the next phases of bleeding, the reflectance reactions
evoked by nitrogen anoxia gradually vanished and failed to
reappear after reinfusion.
In this experiment the nitrogen inhalation applied in the
control period increased the cerebrocortical corrected fluor
escence by about 34% /Fig. 3/.
After the anoxic period, reoxidation of NADH was rapid
cmd the redox state of the cerebral cortex did not show any
overshot towards oxidation, in spite of the higher oxygen
