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2016 ECLS

Respiratory Medicine
Series Editor: Sharon I.S. Rounds

Gregory A. Schmidt Editor

Life Support for

Respiratory Medicine
Series Editor :
Sharon I.S. Rounds

More information about this series at http://www.springer.com/series/7665

Gregory A. Schmidt

Extracorporeal Life Support
for Adults

Gregory A. Schmidt, MD
Division of Pulmonary Diseases, Critical Care,
and Occupational Medicine
Department of Internal Medicine
University of Iowa
Iowa City, IA, USA

ISSN 2197-7372
ISSN 2197-7380 (electronic)
Respiratory Medicine
ISBN 978-1-4939-3004-3
ISBN 978-1-4939-3005-0 (eBook)
DOI 10.1007/978-1-4939-3005-0
Library of Congress Control Number: 2015950466
Springer New York Heidelberg Dordrecht London
© Springer Science+Business Media New York 2016
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To William R. Lynch, MD, who built and

nurtured an outstanding program, exhibited
remarkable vision in how to advance ECLS
care, and opened my eyes to its new


Extracorporeal life support (ECLS) consists of using an external gas-exchanging
membrane to support oxygenation or carbon dioxide removal (or both), at times
including circulatory assistance. ECLS has been used in severe hypoxemic respiratory failure (ARDS, pneumonia); diseases dominated by ventilatory failure such as
status asthmaticus and COPD; cardiogenic shock; following cardiothoracic surgery
complicated by circulatory or gas exchange failure; and as a bridge to lung transplant. Historically, ECLS has been used sparingly, often as a last resort, and in few
centers with the requisite expertise. Three factors have combined to change this.
First, technological improvements in membranes, pumps, circuits, and cannulas
have led to more efficient and safer ECLS. Second, the CESAR trial has shown that,
for adults with severe ARDS, referral to an ECLS center improves outcomes.
Finally, the adverse consequences of conventional management of lung failure,
including ventilator-induced lung injury, ICU-acquired weakness, and nosocomial
infection, have become abundantly clear. Some of these may be ameliorated by
using ECLS in preference to conventional care. As perceptions of the role of ECLS
have evolved, more practitioners and more centers are developing ECLS capability
or positioning themselves to offer ECLS.
The aim of this book is to deliver a concise, evidence-based review of ECLS for
adult disease. Adult medicine (rather than neonatal and pediatric disease, where
ECLS has an established but limited role) represents the growth area for
ECLS. Chapters are devoted to describing the complex physiology and technology;
the evidence base in varied clinical conditions; how to obtain vascular access; daily
management of the circuit and patient; guidance regarding the weaning and decannulation process; and recommendations for crisis management and rehabilitation
related to ECLS. The text concludes with a fascinating historical review, showing
just how far we’ve come.
This text has been written for practicing physicians, nurses, perfusion specialists,
therapists, and critical care trainees who are considering whether to refer their
patients for ECLS, debating whether to offer ECLS capability to their patients, or
are already providing ECLS but seek a practical reference to best practices and
updated information. It could never have been completed without the inspiration



from my colleagues at Iowa who strive daily to save the sickest patients; the trainees
whose curiosity makes us all want to know more; my contributors who are at the
forefront of a truly challenging field; and our publisher at Springer-Link who pushed
for this important book. Finally, I recognize all those who do the hard work: the
nurses, perfusionists, and therapists who dedicate their lives to the critically ill. This
is an exciting time, ripe with change and opportunity. We seek a path forward for the
benefit of all our patients.
Iowa City, IA, USA

Gregory A. Schmidt, MD



Physiology of Extracorporeal Life Support (ECLS) ...........................
Matthew J. Brain, Warwick W. Butt, and Graeme MacLaren


Hypoxemic Respiratory Failure: Evidence, Indications,
and Exclusions .........................................................................................
Darryl Abrams, Matthew Bacchetta, and Daniel Brodie


Cardiogenic Shock: Evidence, Indications, and Exclusions................
Nicolas Bréchot and Alain Combes


ECCO2R in Obstructive Diseases: Evidence, Indications,
and Exclusions .........................................................................................
Lorenzo Del Sorbo and V. Marco Ranieri





ECLS as a Bridge to Lung Transplantation ......................................... 105
Christian Kuehn


Modes of ECLS ....................................................................................... 117
L. Keith Scott and Benjamin Schmidt


Vascular Access for ECLS ...................................................................... 133
Steven A. Conrad


Circuits, Membranes, and Pumps ......................................................... 147
Bradley H. Rosen


Ventilator Management During ECLS ................................................. 163
Antonio Pesenti, Giacomo Bellani, Giacomo Grasselli,
and Tommaso Mauri


Daily Care on ECLS ............................................................................... 181
Giles J. Peek


Crises During ECLS ............................................................................... 193
Cara L. Agerstrand, Linda B. Mongero, Darryl Abrams,
Matthew Bacchetta, and Daniel Brodie




Mobilization During ECLS .................................................................... 211
Gregory A. Schmidt


ECMO Weaning and Decannulation ..................................................... 223
Sundar Krishnan and Gregory A. Schmidt


The Story of ECLS: History and Future .............................................. 233
J. Ann Morris, Robert Pollock, Brittany A. Zwischenberger,
Cherry Ballard-Croft, and Joseph B. Zwischenberger

Index ................................................................................................................. 261


Darryl Abrams, MD Division of Pulmonary, Allergy and Critical Care, New YorkPresbyterian Hospital/Columbia University Medical Center, New York, NY, USA
Cara L. Agerstrand, MD Division of Pulmonary, Allergy, and Critical Care
Medicine, Department of Medicine, Columbia University College of Physicians
and Surgeons/New York-Presbyterian Hospital, New York, NY, USA
Matthew Bacchetta, MD, MBA, MA Division of Thoracic Surgery, New YorkPresbyterian Hospital/Columbia University Medical Center, New York, NY, USA
Cherry Ballard-Croft, PhD Division of Cardiothoracic Surgery, Department of
Surgery, University of Kentucky College of Medicine, Lexington, KY, USA
Giacomo Bellani, MD, PhD Department of Health Sciences, University of
Milano-Bicocca, Monza, Italy
Department of Anesthesia and Critical Care, San Gerardo Hospital and MilanoBicocca University, Monza, Italy
Matthew J. Brain, MBBS (Hons), FRACP, FCICM, DDU School of Public
Health and Preventive Medicine, Monash University, Malvern East, VIC, Australia
The Alfred Intensive Care Unit, Melbourne, VIC, Australia
Department of Medicine, Launceston General Hospital, Launceston, TAS, Australia
Nicolas Bréchot, MD, PhD Service de Réanimation Médicale, Hospital
Pitié–Salpêtrière, Paris, France
Daniel Brodie, MD Division of Pulmonary, Allergy and Critical Care, New YorkPresbyterian Hospital/Columbia University Medical Center, New York, NY, USA
Warwick W. Butt, FRACP, FCICM ICU RCH, Department of Paediatrics UoM,
Clinical Sciences Theme MCRI, Royal Children’s Hospital, Melbourne, VIC, Australia
Paediatric Intensive Care Unit, Parkville, VIC, Australia




Alain Combes, MD, PhD Service de Réanimation Médicale, Institut de
Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, iCAN, Institute of
Cardiometabolism and Nutrition, Paris Cedex, France
Steven A. Conrad, MD, PhD, MCCM, FCCP Department of Medicine,
Emergency Medicine and Pediatrics, Louisiana State University Health Sciences
Center, Shreveport, LA, USA
Lorenzo Del Sorbo, MD Dipartimento di Anestesiologia e Rianimazione,
Azienda Ospedaliera Città della Salute e della Scienza di Torino, Università di Torino,
Torino, Italy
Inter-departmental Division of Critical Care Medicine, University Health Network,
University of Toronto, Toronto, ON, Canada
Giacomo Grasselli, MD Department of Anesthesia and Critical Care, San Gerardo
Hospital and Milano-Bicocca University, Monza, Italy
Sundar Krishnan, MBBS Department of Anesthesia, University of Iowa Hospitals
and Clinics, Iowa City, IA, USA
Christian Kuehn, MD Department of Cardiac, Thoracic, Transplantation and
Vascular Surgery, Privatdozent Dr. med., Hannover Medical School, Hannover,
Graeme MacLaren, MBBS, FRACP, FCICM, FRCP, FCCP, DipEcho ICU
RCH, Department of Paediatrics UoM, Clinical Sciences Theme MCRI, Royal
Children’s Hospital, Melbourne, VIC, Australia
Paediatric Intensive Care Unit, Parkville, VIC, Australia
Cardiothoracic ICU, National University Hospital, Singapore, Singapore
Tommaso Mauri, MD Department of Anesthesia and Critical Care, Fondazione
IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Linda B. Mongero, CCP, BS Department of Clinical Perfusion, New York
Presbyterian-Columbia University Medical Center, Locust Valley, NY, USA
J. Ann Morris, BS Division of Cardiothoracic Surgery, Department of Surgery,
University of Kentucky College of Medicine, Lexington, KY, USA
Giles J. Peek, MD, FRCS CTh, FFICM Heartlink ECMO Centre, Glenfield
Hospital, Leicester, UK
Antonio Pesenti, MD Department of Health Sciences, University of MilanoBicocca, Monza, Italy
Department of Anesthesia and Critical Care, San Gerardo Hospital and MilanoBicocca University, Monza, Italy
Robert Pollock, BS Division of Cardiothoracic Surgery, Department of Surgery,
University of Kentucky College of Medicine, Lexington, KY, USA



V. Marco Ranieri, MD Dipartimento di Anestesiologia e Medicina degli Stati
Critici, Ospedale S. Giovanni Battista-Molinette, Università di Torino, Torino, Italy
Dipartimento di Anestesiologia e Rianimazione, Azienda Ospedaliera Città della
Salute e della Scienza di Torino, Università di Torino, Torino, Italy
Bradley H. Rosen, DO Division of Pulmonary, Critical Care, and Occupational
Medicine, Department of Internal Medicine, Carver College of Medicine, University
of Iowa Hospitals and Clinics, Iowa City, IA, USA
Benjamin Schmidt, MD Department of Surgery, Wake Forest University, Medical
Center Boulevard, Winston-Salem, NC, USA
Gregory A. Schmidt, MD Division of Pulmonary Diseases, Critical Care, and
Occupational Medicine, Department of Internal Medicine, University of Iowa, Iowa
City, IA, USA
L. Keith Scott, MD Department of Anesthesiology, Wake Forest University,
Medical Center Boulevard, Winston-Salem, NC, USA
Brittany A. Zwischenberger, MD Division of Cardiothoracic Surgery, Department
of Surgery, University of Kentucky College of Medicine, Lexington, KY, USA
Joseph B. Zwischenberger, MD Division of Cardiothoracic Surgery, Department
of Surgery, University of Kentucky College of Medicine, Lexington, KY, USA

Chapter 1

Physiology of Extracorporeal
Life Support (ECLS)
Matthew J. Brain, Warwick W. Butt, and Graeme MacLaren

Extracorporeal life support (ECLS) and related implantable circulatory assistance
devices describe several advancing technologies with broadening scope that are
being increasingly incorporated into management of critically ill patients.
ECLS may be provided in several configurations to support or replace cardiorespiratory function (Fig. 1.1). In veno-venous extracorporeal membrane oxygenation
(VV-ECMO) the objective is to maintain systemic oxygen delivery by oxygenating
venous blood returning to the right heart. In veno-arterial mode (VA-ECMO),
M.J. Brain, MBBS (Hons), FRACP, FCICM, DDU (*)
School of Public Health and Preventive Medicine, Monash University,
Malvern East, VIC, Australia
The Alfred Intensive Care Unit, Melbourne, VIC, Australia
Department of Medicine, Launceston General Hospital,
274-280 Charles St, Launceston, TAS 7250, Australia
e-mail: m.brain@iinet.net.au
ICU RCH, Department of Paediatrics UoM, Clinical Sciences Theme MCRI,
Royal Children’s Hospital, Melbourne, VIC, Australia
Paediatric Intensive Care Unit, 50 Flemington Road, Parkville, VIC 3052, Australia
e-mail: Warwick.butt@rch.org.au
ICU RCH, Department of Paediatrics UoM, Clinical Sciences Theme MCRI,
Royal Children’s Hospital, Melbourne, VIC, Australia
Paediatric Intensive Care Unit, 50 Flemington Road, Parkville, VIC 3052, Australia
Cardiothoracic ICU, National University Hospital,
5 Lower Kent Ridge Rd, Singapore 119074, Singapore
e-mail: graeme_maclaren@nuhs.edu.sg
© Springer Science+Business Media New York 2016
G.A. Schmidt (ed.), Extracorporeal Life Support for Adults,
Respiratory Medicine 16, DOI 10.1007/978-1-4939-3005-0_1



M.J. Brain et al.

systemic blood flow is augmented by the extracorporeal blood pump, while
VPA-­ECMO describes augmentation of pulmonary arterial flow. Both of the latter
configurations can also incorporate support of oxygenation.
Configurations can also be classified by the site of vascular access, with cannulas
being either peripherally placed via the great vessels or centrally placed via thoracotomy. Rotary pumps (without oxygenators) have been miniaturised, allowing development of left and right ventricular assist devices (LVAD and RVAD) respectively.
A basic ECMO circuit consists of a blood pump and oxygenator connected by conduits (Fig. 1.1). Other components may be added to this basic configuration, in particular other extracorporeal circuits such as renal replacement devices. However,
maintaining simplicity is important for safety, infection control and troubleshooting.
Each configuration creates a unique interaction with the cardiorespiratory
system. Sound understanding of the physiology and limitations of each mode is

Fig. 1.1  Schematic of ECMO configurations, circles represent pumps, diamonds represent
oxygenators. VA-ECMO: veno-arterial extracorporeal membrane oxygenation demonstrating
cavo-­aortic flow. VV-ECMO: veno-venous cannulation demonstrating cavo-atrial flow from the
inferior vena cava to the right atrium via the oxygenator and pump. VV-ECMO may also require a
second cannula taking blood from the superior vena cava, or dual lumen cannulas that access blood
from the inferior and superior vena cava, while returning blood to the right atrium. VPA-ECMO:
veno-­pulmonary artery cannulation may be configured as atrial to pulmonary artery flow with or
without oxygenation support. LVAD: left ventricular assist device (usually implanted) taking left
ventricular blood and returning it to the proximal aorta. RVAD: a right ventricular assist device is
not shown but may be implanted or external and can be configured identically to VPA-ECMO
without an oxygenator, or may directly drain the right ventricle as per the LVAD. Extracorporeal
carbon dioxide removal (ECCO2R) is commonly performed with a VV-ECMO configuration,
usually with a single dual-lumen catheter. Intravascular membrane oxygenators have also been
developed [1] but are not currently in clinical use

1  Physiology of Extracorporeal Life Support (ECLS)


required to prescribe, manage and wean this support and recognise evolving
complications of the therapy. Although designed primarily to replace cardiorespiratory function, the interaction of ECLS with several other physiologic systems must
be considered. For example, most patients who require ECLS will have sustained a
major insult such as severe sepsis, trauma or surgery, or have suffered from progressive cardiac or pulmonary disease. The systemic inflammatory response syndrome
(SIRS) may arise from the underlying disease or as a reaction to the non-biological
material of the ECLS circuit. The metabolic response to critical illness has direct
implications for oxygenation and CO2 removal, as well as nutritional supplementation
to facilitate later weaning.
In order to comprehensively understand ECLS and its effects on human physiology,
it is necessary to first review cellular metabolism and oxygen transport.

Cellular Metabolism
The fundamental role of tissue perfusion is to provide sufficient substrate delivery
to match the metabolic demand of aerobic cellular metabolism. While anaerobic
metabolism can support cellular energy requirements for brief periods, only oxidative
metabolism can maintain proper cellular and organ function.
Cardiorespiratory physiology and any mechanical support must provide an
adequate hydrostatic pressure gradient across capillary beds to support blood flow,
as well as maintain concentration gradients by which substrates, including oxygen,
diffuse into the immediate environment of cells. Likewise, a concentration gradient
must be maintained from the cell to the blood path for the waste products of metabolism, primarily CO2, or lactate in the case of anaerobic metabolism. These functions
are interlinked as the waste products of energy production are generally weak acids
and influence local perfusion and oxygen carriage.
The quantities of substrate required per unit time will depend on the supported
cell mass and its level of metabolic activity as influenced by demand (or stress),
temperature, inflammation and hormonal regulation.

Glycolysis and Aerobic and Anaerobic Metabolism
Glucose and other simple carbohydrates enter cells down a concentration gradient
through glucose transporters that allow for tissue-specific behaviour such as preferential basal uptake by the brain, concentration-dependent uptake by the liver,
sensing by the insulin-secreting pancreatic β-cells and insulin-­
dependent uptake in skeletal muscle and fat [2].
Intracellular glucose is rapidly phosphorylated in the cytosol by hexokinases,
after which it becomes the primary substrate for energy production or biosynthetic
reactions including glycogen storage (Fig. 1.2). Utilisable intracellular energy is

Fig. 1.2  Key intermediates in intracellular metabolism: After entering cells, glucose is phosphorylated (-P) and can then be incorporated into glycogen, enter synthetic reactions (not shown), or be
metabolised to two three-carbon pyruvate molecules (glycolysis). The conversion of pyruvate to
acetyl-CoA, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation only occur in mitochondria and depend on oxygen to restore nicotinamide adenine dinucleotide to its oxidised form
(NAD+) for continued cycling. The number of ATP generated depends on the source of reduction
power; a single mitochondrial NADH produces 2.5 ATP; however, electrons from cytosolic NADH
must be transferred to mitochondrial FADH2 which yields only 1.5 ATP each [3]. Different amino
acids can enter or be synthesised from the pathway at several points. Acetyl-CoA is a key junction
molecule providing the TCA cycle with two-carbon acetyl groups, not only from glycolysis but
also from fatty acids and some amino acids. In glucose excess, acetyl-CoA is the starting point for
fatty acid synthesis and, in the starvation state, ketone body production when insufficient oxaloacetate exists for acetyl groups to enter the TCA cycle. Ketone bodies are produced predominantly
in the liver from fatty acid breakdown and constitute a glucose-sparing fuel for the brain and heart.
Humoral promoters and inhibitors of reactions are shown

1  Physiology of Extracorporeal Life Support (ECLS)


stored in the phosphate bonds of adenosine triphosphate (ATP) and it is the breaking
of chemical bonds within glucose that powers ATP regeneration from adenosine
diphosphate (ADP) and inorganic phosphate (Pi).
Glycolysis describes the fracturing of the six-carbon glucose molecule into
two three-carbon pyruvate molecules with the net generation of two ATP molecules.
For glycolysis to continue, oxidative power (NAD+ concentration) must be continually restored. Under anaerobic conditions, this occurs by conversion of pyruvate to
lactate. Under aerobic conditions, pyruvate loses a carbon dioxide molecule to yield
acetyl coenzyme-A. This two-carbon acetyl group can be incorporated into fatty
acids for storage or can enter the tricarboxylic acid (TCA) cycle to complete the
chemical breakdown of glucose to CO2. This yields 38 ATP molecules, significantly
more than glycolysis, but generates NADH in such quantities that a powerful electron acceptor is required for efficient restoration of NAD+ so that the cycle can
continue. This electron acceptor is oxygen.
Oxidative phosphorylation describes the process of restoring NAD+ to perpetuate
the TCA cycle. Although oxygen is utilised as an electron acceptor in many enzyme
systems, its highest consumption is in this process. Oxidative phosphorylation
occurs in the inner mitochondrial matrix and it is to this intracellular destination that
oxygen must diffuse in sufficient quantities to sustain ATP generation for normal
cellular processes.
When oxygen is not available in sufficient quantities, ATP generation from ADP
can only continue in the cytosol by glycolysis. This process is inefficient, as not
only is less ATP produced but the resulting lactic acid is not as readily cleared from
the tissues or body as carbon dioxide. Lactic acid is thus a marker of glycolysis
activity in a hypoxic environment and usually indicates inadequate tissue perfusion
or global hypoxemia of the organism.

Carbon Dioxide Production and the Respiratory Quotient
The respiratory quotient (RQ) describes the ratio of the amount of carbon dioxide
( VCO 2 ) produced per unit time to the amount of oxygen consumed ( VO 2 ).
RQ =




The respiratory quotient depends on the sources of fuel being used. For glucose
metabolism, the six carbon atoms result in production of six molecules of carbon
dioxide while consuming six molecules of oxygen; it thus has a respiratory quotient
of 1. The reactions for oxidation of some amino acids and fatty acids (lipolysis)
produce less CO2 (by not including the pyruvate to acetyl-CoA reaction, Fig. 1.2)
and hence have respiratory quotients of less than 1.
In contrast, each acetyl-CoA molecule utilised for fatty acid synthesis (lipogenesis)
results in production of a molecule of CO2 (from pyruvate to acetyl-CoA, Fig. 1.2)


M.J. Brain et al.

without increasing mitochondrial NADH. As the rate of oxygen consumption
depends on the mitochondrial concentration of NADH, lipogenesis results in CO2
production which exceeds oxygen consumption. Some oxygen consumption still
occurs as the synthetic reaction also consumes ATP; however, the RQ will be
greater than 1. Examples of respiratory quotients based on theoretical stoichiometry
include [4, 5]:

Glucose Oxidation : C6 H12 O6 + 6O2 ® 6CO2 + H 2 O RQ = 1
Lipolysis of glycerol triestearate : C57 H110 O6 + 80.25O2 + 57CO2

+ 55.5H 2 O RQ = 0.667

Amino Acid ( Glycine ) Oxidation : NC2 H 5 O2 + 2.25O2 ® 2CO2
+ 2.5H 2 O RQ = 0..88

Lipogenesis from Glucose* : 4C6 H12 O6 + O2 ® C16 H 32 O2
+ 8CO2 + 8H 2 O RQ = 8
Lipogenesis* : 13.83C6 H12 O6 + 5O2 ® C55 H104 O6 + 28CO2 + 31H 2 O RQ = 5.6
*Note that the RQ of lipogenesis depends on the fatty acid being produced and
the carbohydrate that is utilised. C16H32O2 palmitic acid. C55H104O6 palmitoylstearoyl-2-oleoyl-glycerol.
A normal adult has a whole body RQ measured by indirect calorimetry of
around 0.8, reflecting utilisation of mixed fuel sources. This value will alter in
critically ill patients, depending on the nutrient availability and humoral control of
metabolism. While glycolysis reflects enzymatic processing of glucose, complete
aerobic metabolism is coupled to TCA intermediate availability and, when carbohydrate loads are excessive (such as with glucose supplementation exceeding
4 mg·kg−1·min−1 [5.8 g·kg−1·day−1]), lipogenesis occurs with a respiratory quotient as
high as 8 [5–7] resulting in a high CO2 burden.

Metabolism in the Stressed State
Key hormones coordinate the response to nutrition supply and stress. Insulin marks
the fed state, promoting hepatic glucose uptake, glycogen and amino acid synthesis
and conversion of acetyl-CoA to free-fatty acid production while in the peripheral
tissues stimulating myocyte synthesis of contractile elements and adipocyte
triglyceride deposition.
Glucagon is secreted by pancreatic α-cells in response to low blood glucose
levels and promotes glycogen breakdown and conversion of amino acids

1  Physiology of Extracorporeal Life Support (ECLS)


(from muscle breakdown), lactate and glycerol. Glycerol results from adipocyte
triglyceride metabolism and the released free fatty acids are converted to ketone
bodies by the liver for use as a secondary fuel source when glucose is scarce.
The catecholamines epinephrine and norepinephrine are released in response to
physiologic stress. By increasing intracellular cyclic AMP, they promote glycogenolysis in muscles and catabolism of protein to release amino acids. In the liver,
epinephrine promotes gluconeogenesis, glycogenolysis and inhibits glycolysis.
These responses result in the hyperglycaemia that characterises the stress state
and is exacerbated by exogenous administration of catecholamines and glucose.
The adverse effects of hyperglycaemia include osmotic diuresis, fat deposition in
the liver and impaired immune function.
The metabolic profile of patients receiving ECLS is typical of the stressed state
but the differences between this and the starvation state are important. In starvation
there is an overall decrease in energy expenditure with maximal use of triglycerides
and ketoacids promoting conservation of muscle bulk. The brain, heart and renal
cortex adapt to utilising ketoacids for significant proportions of their metabolic
requirements. In contrast, the chronic stressed state is characterised by increased
resting energy expenditure, accelerated catabolism of lean body mass—primarily
amino acids from muscle catabolism [3]—and the immunosuppressive effects of
hyperglycaemia and persistently elevated humoral mediators, including catecholamines and cortisol.
In those requiring ECLS, particularly those needing prolonged periods of heavy
sedation, the combination of muscle catabolism, disuse atrophy, critical illness
myopathy and myopathy associated with muscle relaxants can result in profound
weakness. The respiratory musculature is not spared from this process, with the
result being prolonged weaning, a requirement for tracheostomy and the risk of
secondary infection.

Erythrocyte Metabolism
Being a specialised organ for oxygen transport, erythrocytes are nearly 90 %
haemoglobin-­by-weight, with very few other organelles. Nevertheless, they require
an ongoing energy source to maintain membrane integrity, cytoskeleton structure,
intracellular electrolyte and osmotic equilibrium and to keep the iron moieties of
haemoglobin in a reduced state (Fe2+).
Erythrocytes lack mitochondria and do not store glycogen and thus depend on
anaerobic glycolysis of plasma glucose to lactate for ATP production. However,
glycolysis in erythrocytes is also utilised for reactions that do not produce ATP, such
as reducing power to correct oxidised haemoglobin (methaemoglobin carrying a
Fe3+ iron atom that cannot carry oxygen), glutathione production (protecting the cell
membrane against oxidative damage) and the production of 2,3-diphosphoglycerate
(2,3-DPG) that modulates the affinity of haemoglobin for oxygen [8].


M.J. Brain et al.

The Rapoport–Luebering shunt (Fig. 1.2) describes the pathway for 2,3-DPG
synthesis from the glycolytic pathway. In most cells, 1,3-DPG is rapidly converted
to 3-phosphoglycerate with the phosphate molecule transferred to ATP; however,
in erythrocytes up to 20 % of glycolytic flux occurs through the shunt, with the
value dependent on ATP requirements [9]. Oxygen depletion (resulting in fewer
haemoglobin-­binding sites for 2,3-DPG), acidotic conditions that inhibit 2,3-DPG
synthesis and the accumulation of inorganic phosphate (Pi) which increases 2,3-DPG
breakdown [8], result in decreased intracellular 2,3-DPG concentrations. This is most
relevant under conditions of red cell storage where lower glycolysis rates and accumulation of lactic acid can result in minimal 2,3-DPG concentrations at the time of
transfusion. Transfused red cells do not restore normal 2,3-DPG concentrations for
some time and, given the relatively high transfusion requirements of patients receiving ECLS, this effect may have significant implications for oxygen carriage. The role
of 2,3-DPG will be further discussed below when considering oxygen carriage.

Biophysics of Membrane Gas Exchange
Mitochondria can couple ATP production to NADH oxidation only if sufficient oxygen exists in the environment of cells. Similarly, carbon dioxide diffuses from the
mitochondria, through intracellular membranes, and away from the cell. The flux of
oxygen into the environment of cells and the reverse movement of carbon dioxide
can be divided into two components:
1 . Diffusion of gas molecules into and between liquid phases
2. The carriage of oxygen and carbon dioxide in blood
When considering pulmonary gas exchange a third component must be considered:
the convective transport of the gas to the alveolar epithelium. However, exposure of
the extracorporeal membrane to fresh gas flow is somewhat simpler in ECLS and
will be considered later in the context of carbon dioxide transport.

Membrane Oxygenator Construction
Extracorporeal membrane oxygenators consist of a high surface area blood path
separated by a membrane from a path for fresh gas flow (sweep gas). The devices
are in continual evolution to optimise the efficiency of gas transfer, minimise
untoward biological responses, reduce priming volumes, avoid plasma leakage and
increase their simplicity and integration as systems. Materials and construction of
gas exchange membranes will be discussed in later chapters; however, a brief introduction is important to understand their operation.
Membranes may be arranged in folded sheets or, more commonly, as tubes
known as hollow fibre oxygenators (Fig. 1.3). The pores of earlier polypropylene

1  Physiology of Extracorporeal Life Support (ECLS)


Fig. 1.3  Schematic detail of hollow fibre oxygenator construction demonstrating extra-capillary
flow of blood around the gas-carrying hollow fibres. Cross current flow exists between gas and
blood. Heated water tubules are also demonstrated. The diffusion path for gas exchange is shown
(top-right) consisting of the porous membrane, and the boundary layer of adsorbed proteins.
Parameters of effective diffusivity from Eq. (1.9) are demonstrated with ε being the porosity—the
area of membrane occupied by gas, τ the tortuosity, an index of effective path length for gas to
traverse the membrane (a path length is shown but in reality will be unknown), and δ the constrictivity—the resistance to passage

microporous membranes theoretically allow contact between plasma and the sweep
gas; however, more recent materials such as poly-4-methyl-1-pentene utilise closed
fibres and are thus considered true membranes [10]. Most systems direct fresh gas
through the lumen of the hollow fibres, while blood flows between the tubules
(termed extra-capillary flow). The reverse configuration is also sometimes utilised,
however, and overall characteristics such as total surface area for gas exchange,
resistance to flow and trauma to formed blood components will be determined by
factors such as membrane material, fibre diameter and length, fibre density and the
velocity of the blood [11].


M.J. Brain et al.

Heat loss over the extracorporeal circuit into the environment can be substantial
and heat exchangers are commonly incorporated into the oxygenator. Figure 1.3
demonstrates one such design where the microporous membrane fibres are laid
perpendicularly to impermeable capillaries that circulate heated water, allowing
heat to be regulated.

Diffusion of Gas Molecules into a Liquid Phase
Concentration of Gases in Solutions
Unlike most solutes dissolved in body fluids that are quantified in moles, gas concentrations are reported in units of pressure. The universal gas law describes the
relationship between the partial pressure of an ideal gas and its container, with ideal
gas molecules best summarised as having minimal mass and intermolecular
P = nRT



The universal gas equation: P = the partial pressure, n = number of molecules of gas
measured in moles, T is temperature in degrees Kelvin and V is volume of the container in litres. R is the ideal gas constant which in SI units is 8.314 J·K−1·mol−1 or
in conventional units: 62.36 mmHg·K−1·mol−1
At a constant temperature, Eq. (1.2) simplifies to P µ n / V . Concentration is
defined as moles/unit volume, i.e. n/V; hence pressure is proportional to gas concentration, i.e. the greater the number of gaseous molecules in a given volume, the
more force those gas molecules will exert on the walls of the container. The physical
reaction of dissolving in solution is also proportional to the partial pressure of the
gas above the solution, so that for oxygen dissolution [12]:
O2 ( gas )

K Forward
K Reverse

O2 ( dissolved )


[O2 ](gas) ´ K Forward = [O2 ](dissolved ) ´ K Reverse

[O2 ](dissolved ) = SC ´ [O2 ](gas)


The rate constant KForward in Eq. (1.4) describes the proportion of oxygen gas that
dissolves per unit time, while KReverse describes the proportion of the dissolved concentration that leaves the solution to the gas phase. When the system described
in Eq. (1.4) is at thermodynamic equilibrium, the concentrations in the gas and
liquid phases are stable and the constants may then be combined, resulting in
Eq. (1.5), also known as Henry’s Law. SC is the Bunsen solubility coefficient where
SC = KForward/KReverse and is gas- and solvent-specific. SC is affected by other dissolved

1  Physiology of Extracorporeal Life Support (ECLS)


solutes and falls with increasing temperature (i.e. KForward becomes smaller and
KReverse larger).
Due to difficulties in measuring the molar concentration of oxygen compared to
measuring a volume of 100 % oxygen at standard conditions (STPD: 0 °C, 760 mmHg,
dry gas), it is customary to report oxygen content in mL·dL−1. Under these conditions,
oxygen approximates an ideal gas such that 6.02 × 1023 gas molecules (i.e. 1 mol)
occupy 22.414 L at 0 °C. Quantification of human oxygen consumption is performed
using STPD rather than BTPS (body temperature and pressure, saturated: Eq. (1.7))
[13] as water vapour in the latter partially condenses with increasing pressure. This
vapour results in a significant deviation from an ideal gas and invalidates the relationship between the number of molecules and volume defined in Eq. (1.2).

The Solubility of Respiratory Gases in Solution
The Bunsen solubility coefficient of oxygen is 0.003082 mL·dL−1·mmHg−1 and
describes the measured solubility corrected to STPD. Utilising this conversion, the
solubility coefficient of oxygen in normal plasma is 1.38 × 10−3 mmol·L−1·mmHg−1
while carbon dioxide is nearly 22 times more soluble at 3.08 × 10−2 mmol·L−1·mmHg−1
[14]. Thus, using Henry’s Law (Eq. 1.5) in normal arterial blood the concentration
of dissolved carbon dioxide is nearly ten times that of dissolved oxygen:

[O2 ] = 1.38 ´ 10-3 ´ 90 mmHg
= 0.1242 mmolL-1 Or 0.0278 mLdL-1


[CO2 ] = 3.08 ´ 10-2 ´ 40 mmHg

= 1.232 mmolL-1 Or 2.7 mLdL-1

It should be noted that this does not include oxygen and CO2 in chemical equilibrium
with the dissolved gas such as that combined with haemoglobin or in reaction with
water. The significantly higher plasma concentration of dissolved carbon dioxide
(Eq. 1.6) resulting from its greater solubility allows for more rapid elimination by gas
exchange membranes when compared to oxygen under the same flow conditions.
In the gaseous phase, the partial pressures of individual gases combine to equal the
total ambient pressure that the gas mixture exerts on its container, allowing each gas
to be reported as a fraction of the total. For example, the partial pressure of oxygen in
inhaled 37 °C air that is fully saturated with water vapour at 1 atm. (i.e. BTPS) is:
PIO2 = ( 760 mmHg - 47 mmHg ) ´ FiO2

= 149.7 mmHg for an FiO2 of 21%


This summative requirement is only met when the solution is exposed to a gas phase.
As solubility coefficients vary between gases, the number of moles of dissolved gas
in a given quantity of solution that is in contact with a gas phase has no such equivalent summation, i.e. the summation of the partial pressures in solution will not equal
atmospheric pressure.

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