Table Of Content12 Update in Intensive Care
and Emergency Medicine
Edited by J. L. Vincent
Tissue Oxygen
Utilization
Edited by
G. Gutierrez and J. L. Vincent
With 108 Figures and 19 Tables
Springer-Verlag
Berlin Heidelberg New York London
Paris Tokyo Hong Kong Barcelona
Series Editor
Prof. Dr. Jean Louis Vincent
Clinical Director, Department of
Intensive Care, Erasme Hospital,
Free University of Brussels,
Route de Lennik 808,
1070 Brussels, Belgium
Volume Editors
Prof. Dr. Guillermo Gutierrez
Pulmonary Medicine, Health Science Center
6431 Fannin, Suite 1274
Houston, TX 77030, USA
and
Prof. Dr. Jean Louis Vincent
ISBN-13:978-3-540-52472-4 e-ISBN-13:978-3-642-84169-9
DOl: 10_1007/978-3-642-84169-9
Library of Congress Cataloging-in-Publication Data
Tissue oxygen utilization/edited by G. Gutierrez and J. L. Vincent -(Update in intensive care and
emergency medicine; 12) Includes index. ISBN-13:978-3-540-52472-4
1. Anoxemia - Pathophysiology. 2. Oxygen in the body. 3. Oxygen - Metabolism
- Disorders. I. Gutierrez, G. (Guillermo), 1946- . II. Vincent, 1. L. III. Series. [DNLM: 1. Oxygen
- metabolism. 2. Oxygen Consumption. WI UP66H V. 12/QV 312 T616] RB150.A67T57
1991 616.2 - dc20
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Contents
Intracellular Oxygen Supply: Implications for Intensive Care
(D. P. Jones, T. Y. Aw, and D. P. Kowalski) . ........ .
NMR Investigations of Cardiac Metabolism (A.-M. Seymour) 16
Evaluation of Tissue Hypoxia by Optical Methods (B. Chance) 33
Application of NIR Spectroscopy to Problems of Tissue Oxy
genation (c. A. Piantadosi, W. J. Parsons, and J. A. Griebel) 41
Principal Determinants of Tissue P0
2:
Clinical Considerations (T. E. Gayeski). 56
Cellular Metabolic Consequences of Altered Perfusion
(H. Haljamiie)................ . . . . . . . . 71
Vascular Response to Hypoxia
(J. Almirall and G. Hedenstierna). 87
Blood Rheology Factors and Capillary Blood Flow
(K. Messmer). . . . . . . . . . . . . . . . . . . . . . . . . . . .. 103
Physiological and Pathological Oxygen Supply Dependency
(S. M. Cain) . ............................ 114
Oxygen Delivery and Utilization in Acute and Chronic Disease
(D. R. Dantzker). . . . . . . . . . . . . . . . . . . . . . . . .. 124
Oxygen Transport and Uptake in Health and Disease
(P. T. Schumacker and R. W. Samsel). . . . . . . . .. . .. 132
Multiple Organ Oxygen Supply-Demand Relationships
and Redistribution of Flow
(R. Schlichtig, J. V. Snyder, and M. R. Pinsky). . . ... 143
The Determinants of Maximum Oxygen Utilization:
The Role of Hemoglobin Concentration (P. D. Wagner). .. 160
VI Contents
Oxygen Cost of Breathing (S. Zakynthinos and C. Roussos). 171
Myocardial Oxygen Metabolism in the Sepsis Syndrome
(w. J. Sibbald). . . . . . . . . . . . . . . . . . . . . . . . . . .. 185
Tissue Oxygen Utilization in Septic Shock
(L. G. Thijs and A. B. J. Groeneveld) . . " .......... 200
Oxygen Supply Dependency in Septic Shock
(J.-F. Dhainaut, G. Annat, and A. Armaganidis). 217
Cellular Metabolism in Sepsis (G. Gutierrez and A. Dubin). 227
Multiple Organ Failure: Is It Only Hypoxia? (F. B. Cerra). 242
Oxygen Demand/Supply Relationship: Role of Hormonal
Influences (P. M. Suter and M. G. Palazzo). . . . . . . . 252
The Value of Blood Lactate Monitoring in Clinical Practice
(J. L. Vincent). . . . . . . . . . . . . . . . . . . . . . . 260
Clinical Assessment of Tissue Oxygenation: Value of
Hemodynamic and Oxygen Transport Related Variables
(K. Reinhart). . . . . . . . . . . . . . . . . . . . . . . . . . . .. 269
Therapeutic Implications of Oxygen Transport in Critically III
Patients (J. D. Edwards and C. Clarke). . . . . . . . . . . .. 286
The Effects of Anesthesia on Tissue Oxygen Balance
(P. Van der Linden). . . . . . . . . . . . . . . . . . . . . . . .. 300
Clinical Use of Continuous Mixed Venous Oximetry
(L. D. Nelson) . ........................... 309
Tissue Oxygen Tension Monitoring: Relation to Hemodynamic
and Oxygen Transport Variables (F. Gottrup). . . . . . . .. 322
Measurement and Control of Tissue Oxygen Tension
in Surgical Patients (T. K. Hunt, B. J. Halliday,
H. W. Hop/, H. Scheuenstuhl, and J. M. West) . .. " .. 337
Conditions Associated with Impaired Oxygen Extraction
(J. Goris). . . 350
Subject Index. 371
List of Contributors
Almirall, J. Dantzker, D. R.
Department of Clinical Physiology, Uni Department of Internal Medicine, Univer
versity Hospital, 75185 Uppsala, Sweden sity of Texas, 6431 Fannin, Suite 1274,
Houston, TX 77030, USA
Annat, G.
Physiology Department, Grange Blanche Dhainaut, J.-F.
University, 8, avenue Rockefeller, 69373 Medical Intensive Care Unit, Cochin Port
Lyon Cedex 08, France Royal University Hospital, Pavilion Land
ouzy, 27, rue du Faubourg Saint Jacques,
Armaganidis, A. 75674 Paris Cedex 14, France
Medical Intensive Care Unit, Cochin Port
Royal University Hospital, 27, rue du Dubin, A.
Faubourg Saint Jacques, 75674 Paris Pulmonary and Critical Care Division,
Cede x 14, France University of Texas Health Science Center,
6431 Fannin, Suite 1274, Houston, TX
Aw, T. Y. 77030, USA
Department of Biochemistry and Winship
Cancer Center, Emory University School Edwards, J. D.
of Medicine, Atlanta, GA 30322, USA Department of Intensive Care, University
Hospital of South Manchester, Nell Lane,
Cain, S. M. Withington, Manchester M20 8LR, United
Department of Physiology and Biophysics, Kingdom
University of Alabama at Birmingham,
University Station, Birmingham, AL Gayeski, T. E.
35294, USA Department of Anesthesiology, University
of Rochester, School of Medicine and Den
tistry, 601 Elmwood Avenue, Rochester,
Cerra, F. B.
NY 14642, USA
Department of Surgery, University of
Minnesota Hospitals .a nd Clinics, Min
neapolis, MN 55455, USA Goris, J.
Department of General Surgery, Univer
sity Hospital St Radboud, 6500 HB Nij
Chance, B.
megen, The Netherlands
Department of Biochemistry and Bio
physics, University of Pennsylvania,
Gottrup, F.
Philadelphia, PA 19104, USA
Department of Surgical Gastroenterology
K, Odense University Hospital, 5000
Clarke, C. Odense C, Denmark
Department of Intensive Care, University
Hospital of South Manchester, Nell Lane, Griebel, J. A.
Withington, Manchester M20 8LR, United Department of Medicine, Duke University
Kingdom Medical Center, Durham, NC 27710, USA
Vlll List of Contributors
Groeneveld, A. B. J. Palazzo, M. G.
Medical Intensive Care Unit, Free Univer Division of Surgical Intensive Care, Uni
sity Hospital, De Boelelaan 1117, 1081 HV versity Hospital of Geneva, 1211 Geneva
Amsterdam, The Netherlands 4, Switzerland
Gutierrez, G. Parsons, W. J.
Department of Internal Medicine, Univer Department of Medicine, Duke University
sity of Texas, 6431 Fannin, Suite 1274, Medical Center, Durham, NC 27710, USA
Houston, TX 77030, USA
Piantadosi, C. A.
Haljamiie, H. Department of Medicine, P. O. Box 3315,
Department of Anesthesiology, Sahlgren's Duke University Medical Center, Dur
Hospital, 41345 Gothenburg, Sweden ham, NC 27710, USA
Pinsky, M. R.
Halliday, B. J.
Critical Care Medicine, Presbyterian Uni
Department of Surgery, University of
versity Hospital, 3471 Scaife Hall, 3550
California San Francisco, 513 Parnassus
Terrace Street, Pittsburgh, PA 15213, USA
Avenue, HSE 839, San Francisco, CA
94143-0522, USA
Reinhart, K.
Department of Anesthesiology and Inten
Hedenstierna, G.
sive Operative Care Medicine, The Steglitz
Department of Clinical Physiology, Uni
Medical Center of the Free University of
versity Hospital, 75185 Uppsala, Sweden
Berlin, Hindenburgdamm 30, 1000 Berlin
45, Germany
HopI, H. W.
Department of Surgery, University of
Roussos, C.
California San Francisco, 513 Parnassus
Department of Critical Care, Evangelis
Avenue, HSE 839, San Francisco, CA
mos Hospital, 45 Ipsilandou Street, 11521
94143-0522, USA
Athens, Greece
Hunt, T. K. Samsel, R. W.
Department of Surgery, University of Pulmonary and Critical Care Medicine,
California San Francisco, 513 Parnassus The University of Chicago, Chicago, IL
Avenue, HSE 839, San Francisco, CA 60637, USA
94143-0522, USA
Scheuenstuhl, H.
Jones, D. P. Department of Surgery, University of
Depanment of Biochemistry and Winship California San Francisco, 513 Parnassus
Cancer Center, Emory University School Avenue, HSE 839, San Francisco, CA
of Medicine, Atlanta, GA 30322, USA 94143-0522, USA
Kowalski, D. P. Schlichtig, R.
Department of Biochemistry and Winship Department of Anesthesiology, Oakland
Cancer Center, Emory University School V. A. Medical Center, University Drive C,
of Medicine, Atlanta, GA 30322, USA Pittsburgh, PA 15240, USA
Messmer, K. Schumacker, P. T.
Department of Experimental Surgery, Sur Department of Medicine Box 83, The Uni
gical Clinic, University Hospital, 1m versity of Chicago, Chicago, II:: 60637,
Neuenheimer Feld 347, 6900 Heidelberg, USA
Germany
Seymour, A.-M.
Nelson, L. D. Department of Biochemistry, University of
Department of Surgery, Vanderbilt Uni Oxford, South Parks Road, Oxford OXI
versity, Nashville, TN 37232, USA 3QU, United Kingdom
List of Contributors IX
Sibbald, W. J. Van der Linden, P.
Critical Care Trauma Centre, Victoria Department of Anesthesiology, Erasme
Hospital Corporation, 375 South Street, University Hospital, Free University of
Room 482 NW, London, Ontario N6A Brussels, Route de Lennik 808, 1070
4G5, Canada Brussels, Belgium
Vincent, J. L.
Department of Intensive Care, Erasme
Snyder, J. V.
University Hospital, Free University of
Department of Anesthesiology and Criti
Brussels, Route de Lennik 808, 1070
cal Care Medicine, Oakland V. .A. Medical
Brussels, Belgium
Center, University Drive C, Pittsburgh,
PA 15240, USA
Wagner, P. D.
Department of Medicine M-023A, Univer
sity of California San Diego, La Jolla, CA
92093, USA
Suter, P. M.
Division of Surgical Intensive Care, Uni
versity Hospital of Geneva, 1211 Geneva West, J. M.
Department of Surgery, University of
4, Switzerland
California San Francisco, 513 Parnassus
Avenue, HSE 839, San Francisco, CA
94143-0522, USA
Thijs, L. G.
Department of Medical Intensive Care, Zakynthinos, S.
Free University Hospital, De Boelelaan Department of Critical Care, Evangelis
1117, 1081 HV Amsterdam, The Nether mos Hospital, 45 Ipsilandou Street, 11521
lands Athens, Greece
Intracellular Oxygen Supply:
Implications for Intensive Care*
D. P. Jones, T. Y. Aw, and D. P. Kowalski
Introduction
The interruption of O supply accompanying traumatic lflJuries, infarctions,
2
cerebrovascular accidents and other common emergencies is of extreme import
ance because O deficiency is a major cause of human morbidity and mortality.
2
Oxygen deficiency is an extensively studied subject, yet the molecular mechanisms
of irreversible injury remain incompletely defined.
In the current presentation, we discuss emerging concepts of hypoxia, anoxia
and ischemia that are especially relevant to emergency medicine. The focus is on
information obtained from studies with freshly isolated adult mammalian cells.
These cells retain metabolic characteristics similar to cells in vivo and allow direct
assessment of cell injury due to changes in 02 supply. Studies with these cells have
provided important new information on the definition of hypoxia at the cellular
level, the regulation of mitochondrial function during short-term anoxia, and the
sensitivity of post-anoxic cells to oxidative injury. The research indicates that
normoxic cells in vivo are on the verge of hypoxia and that mitochondrial functions
can be rapidly suppressed to provide protection against short-term 02 deficiency.
This protection is not without costs; hypoxic and post-hypoxic cells have enhanced
sensitivity to oxidant injury. Of particular relevance to medical care, both sodium
lactate and acidosis protect against post-anoxic oxidative injury in liver.
Mitochondrial O Dependence and the Definition
2
of Cellular Hypoxia
Many studies have focussed on the sequence of events that are responsible for
irreversible hypoxic injury. These have included attempts to identify the first and
most sensitive changes of hypoxia as early indicators of injury. The 02 tension at
which the first detectable change from normoxia occurred was termed the critical
O tension [1], and techniques were developed to measure rapid changes in
2
mitochondrial function [2, 3]. These studies provided fundamentally important
information on the changes accompanying O deficiency.
2
However, the critical issues of hypoxic injury may not involve the earliest or
most sensitive changes of hypoxia. All cells can survive and recover from periods of
* Supported by NIH Grants GM-36538, HL-30286, and GM-28176.
2 D. P. Jones et al.
anoxia in which dramatic changes occur in cellular energetics. In addition, physio
logical adaptations allow cells and organisms to adapt to hypoxia. Conditions in
which reversible changes in function occur in response to 02 deficiency are termed
neahypoxia (from "near hypoxia") [4]. The critical questions are: "How low of an
02 concentration can cells tolerate without irreversible injury?", "When do irre
versible changes occur?", and "What can be done to increase the tolerance and
lengthen the period of survival?"
The biochemical events responsible for irreversible injury are a result of the
failure of function of enzymes that use 02 as substrate, namely, the oxidases and
oxygenases [5]. Over 100 of these enzymes occur in mammals; many have high
Km02 values relative to physiological 02 concentrations and are 02 dependent in
cells even at normoxic 02 concentrations [4, 6-8]. However, the function of only
one enzyme, cytochrome oxidase, appears to be critical in determining irreversible
injury under most conditions. This enzyme is present in the mitochondria and uses
most of the O2 consumed by cells to support synthesis of ATP.
Warburg [9] recognized that this terminal oxidase has a very great affinity for
02' and later studies showed that its apparent Km02 in isolated mitochondria is in
the range of 0.2 IlM or lower [10, 11]. This is in contrast to in vivo conditions,
where the physiological effects of hypoxia occur when arterial P02 drops below
about 75 torr (105 IlM) [12]. The basis for the difference between the O2 depend
ence of the terminal oxidase and in vivo 02 dependence has been a matter of
controversy and speculation for decades. However, studies with freshly isolated
cells from adult animals show that much of the difference is due to the 02
concentration dependence of cellular respiration [4, 13-15].
Microelectrode measurements of 02 in tissues show that a distribution of P02
occurs, ranging from below 1 torr up to the P02 of arterial blood [16]. The median
P02 varies for different tissues, ranging from relatively low values for beating heart
to relatively high values for adrenals [17], apparently adapted to some optimal
range for each tissue. For the liver, the median P02 is about 25 torr [18]. This is an
important value because cellular bioenergetics change in isolated hepatocytes
when P02 is below about 25 torr [14]. Thus, at least some of the cells normally
function at less than maximal O2 consumption rate. This means that normoxic
cells are on the verge of hypoxia; there is little, if any, reserve in 02 supply before
functional changes occur. This appears to be a general conclusion that applies to
brain, heart, kidneys and other tissues [19, 20].
The relatively high 02 concentration required for cytochrome oxidase function
in adult mammalian cells is largely a result of diffusion gradients due to heterogen
eous distribution and high density of mitochondria in cells [13, 21]. Earlier
modeling of 02 diffusion into cells, where 02 consumption was assumed to be
uniform throughout the cell, indicated that significant inhomogeneities in 02
concentration should not occur in cells [22] and that significant gradients of 02
should not occur near an individual mitochondrion [23]. However, this modeling,
as well as recent analyses [24], used values for the intracellular diffusion coefficient
(Dc) of 02 that appear to be too high.
The effective diffusion of solutes within cells is impeded by immobile structures
that reduce the diffusional volume, bind a significant fraction of the cell water [25],
