Oxygen Therapy in Critical Illness

1 UCL Centre for Altitude, Space and Extreme Environment Medicine, Portex Unit, Institute of Child Health, London, United Kingdom. 2 Intensive Care Unit and University College London Division of Surgery and Interventional Science, Royal Free Hospital, London, United Kingdom. 3 Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom. 4 Anaesthesia and Critical Care Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
Critical care medicine (Impact Factor: 6.31). 12/2012; 41(2). DOI: 10.1097/CCM.0b013e31826a44f6
Source: PubMed
ABSTRACT
OBJECTIVE:: The management of hypoxemia in critically ill patients is challenging. Whilst the harms of tissue hypoxia are well recognized, the possibility of harm from excess oxygen administration, or other interventions targeted at mitigating hypoxemia, may be inadequately appreciated. The benefits of attempting to fully reverse arterial hypoxemia may be outweighed by the harms associated with high concentrations of supplemental oxygen and invasive mechanical ventilation strategies. We propose two novel related strategies for the management of hypoxemia in critically ill patients. First, we describe precise control of arterial oxygenation involving the specific targeting of arterial partial pressure of oxygen or arterial hemoglobin oxygen saturation to individualized target values, with the avoidance of significant variation from these levels. The aim of precise control of arterial oxygenation is to avoid the harms associated with inadvertent hyperoxia or hypoxia through careful and precise control of arterial oxygen levels. Secondly, we describe permissive hypoxemia: the acceptance of levels of arterial oxygenation lower than is conventionally tolerated in patients. The aim of permissive hypoxemia is to minimize the possible harms caused by restoration of normoxemia while avoiding tissue hypoxia. This review sets out to discuss the strengths and limitations of precise control of arterial oxygenation and permissive hypoxemia as candidate management strategies in hypoxemic critically ill patients. DESIGN:: We searched PubMed for references to "permissive hypoxemia/hypoxaemia" and "precise control of arterial oxygenation" as well as reference to "profound hypoxemia/hypoxaemia/hypoxia," "severe hypoxemia/hypoxaemia/hypoxia." We searched personal reference libraries in the areas of critical illness and high altitude physiology and medicine. We also identified large clinical studies in patients with critical illness characterized by hypoxemia such as acute respiratory distress syndrome. SUBJECTS:: Studies were selected that explored the physiology of hypoxemia in healthy volunteers or critically ill patients. SETTING:: The data were subjectively assessed and combined to generate the narrative. RESULTS:: Inadequate tissue oxygenation and excessive oxygen administration can be detrimental to outcome but safety thresholds lack definition in critically ill patients. Precise control of arterial oxygenation provides a rational approach to the management of arterial oxygenation that reflects recent clinical developments in other settings. Permissive hypoxemia is a concept that is untested clinically and requires robust investigation prior to consideration of implementation. Both strategies will require accurate monitoring of oxygen administration and arterial oxygenation. Effective, reliable measurement of tissue oxygenation along with the use of selected biomarkers to identify suitable candidates and monitor harm will aid the development of permissive hypoxemia as viable clinical strategy. CONCLUSIONS:: Implementation of precise control of arterial oxygenation may avoid the harms associated with excessive and inadequate oxygenation. However, at present there is no direct evidence to support the immediate implementation of permissive hypoxemia and a comprehensive evaluation of its value in critically ill patients should be a high research priority.

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Critical Care Medicine www.ccmjournal.org 1
T
he current balance of clinical teaching emphasizes the
avoidance of hypoxemia over concerns about the possible
harm associated with hyperoxia. This would seem to be a
well-founded thesis when considering the necessity of maintain-
ing adequate oxygen delivery to cells to avoid cellular and organ
dysfunction. However, in critically ill patients, in whom arterial
oxygenation may remain persistently low despite efforts to resolve
it, ongoing attempts to restore normoxemia may be more harmful
than the acceptance of a degree of hypoxemia. The toxic effects of
breathing high concentrations of oxygen and the injury associated
with elevated levels of positive pressure ventilation are well recog-
nized (1, 2). However, the balance of benefit and harm at different
levels of oxygenation (inspired and arterial), and the interindividual
Objective: The management of hypoxemia in critically ill patients is
challenging. Whilst the harms of tissue hypoxia are well recognized,
the possibility of harm from excess oxygen administration, or other
interventions targeted at mitigating hypoxemia, may be inadequately
appreciated. The benefits of attempting to fully reverse arterial hypox-
emia may be outweighed by the harms associated with high concen-
trations of supplemental oxygen and invasive mechanical ventilation
strategies. We propose two novel related strategies for the manage-
ment of hypoxemia in critically ill patients. First, we describe precise
control of arterial oxygenation involving the specific targeting of arte-
rial partial pressure of oxygen or arterial hemoglobin oxygen satura-
tion to individualized target values, with the avoidance of significant
variation from these levels. The aim of precise control of arterial oxy-
genation is to avoid the harms associated with inadvertent hyperoxia
or hypoxia through careful and precise control of arterial oxygen lev-
els. Secondly, we describe permissive hypoxemia: the acceptance of
levels of arterial oxygenation lower than is conventionally tolerated in
patients. The aim of permissive hypoxemia is to minimize the possible
harms caused by restoration of normoxemia while avoiding tissue
hypoxia. This review sets out to discuss the strengths and limitations
of precise control of arterial oxygenation and permissive hypoxemia as
candidate management strategies in hypoxemic critically ill patients.
Design: We searched PubMed for references to “permissive hypoxemia/
hypoxaemia” and “precise control of arterial oxygenation” as well as
reference to “profound hypoxemia/hypoxaemia/hypoxia,” “severe hypox-
emia/hypoxaemia/hypoxia.” We searched personal reference libraries in
the areas of critical illness and high altitude physiology and medicine. We
also identified large clinical studies in patients with critical illness charac-
terized by hypoxemia such as acute respiratory distress syndrome.
Subjects: Studies were selected that explored the physiology of
hypoxemia in healthy volunteers or critically ill patients.
Setting: The data were subjectively assessed and combined to gen-
erate the narrative.
Results: Inadequate tissue oxygenation and excessive oxygen administra-
tion can be detrimental to outcome but safety thresholds lack definition
in critically ill patients. Precise control of arterial oxygenation provides a
rational approach to the management of arterial oxygenation that reflects
recent clinical developments in other settings. Permissive hypoxemia is a
concept that is untested clinically and requires robust investigation prior
to consideration of implementation. Both strategies will require accu-
rate monitoring of oxygen administration and arterial oxygenation. Effec-
tive, reliable measurement of tissue oxygenation along with the use of
selected biomarkers to identify suitable candidates and monitor harm will
aid the development of permissive hypoxemia as viable clinical strategy.
Conclusions: Implementation of precise control of arterial oxygenation
may avoid the harms associated with excessive and inadequate oxy-
genation. However, at present there is no direct evidence to support
the immediate implementation of permissive hypoxemia and a com-
prehensive evaluation of its value in critically ill patients should be a
high research priority. (Crit Care Med 2013; 41:0–0)
Key Words: critical care; hyperoxemia; hyperoxia; hypoxemia; hypoxia;
oxygen
Oxygen Therapy in Critical Illness: Precise Control of
Arterial Oxygenation and Permissive Hypoxemia
Daniel Stuart Martin, BSc, MBChB, PhD, FRCA, FFICM
1,2
;
Michael Patrick William Grocott, MBBS, MD, FRCA, FRCP, FFICM
1,3,4
1
UCL Centre for Altitude, Space and Extreme Environment Medicine, Portex
Unit, Institute of Child Health, London, United Kingdom.
2
Intensive Care Unit and University College London Division of Surgery and
Interventional Science, Royal Free Hospital, London, United Kingdom.
3
Integrative Physiology and Critical Illness Group, Clinical and Experimental Sci-
ences, Sir Henry Wellcome Laboratories, University of Southampton, University
Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
4
Anaesthesia and Critical Care Research Unit, University Hospital Southamp-
ton NHS Foundation Trust, Southampton, United Kingdom.
The authors have not disclosed any potential conflicts of interest.
For information regarding this article, E-mail: daniel.martin@ucl.ac.uk
Critical Care Medicine
0090-3493
10.1097/CCM.0b013e31826a44f6
41
2
00
00
2012
Copyright © 2013 by the Society of Critical Care Medicine and Lippincott
Williams & Wilkins
DOI: 10.1097/CCM.0b013e31826a44f6
Rajagopal
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Martin et al
2 www.ccmjournal.org February 2013 • Volume 41 • Number 2
variability in this balance, are not well defined. Successfully bal-
ancing the harms associated with hyperoxia and hypoxia may
result in improved patient outcomes. We, therefore, propose two
novel related strategies for the management of hypoxemia in criti-
cally ill patients. Precise control of arterial oxygenation (PCAO)
is an approach whereby the arterial partial pressure of oxygen
(PaO
2
), or arterial hemoglobin oxygen saturation (SaO
2
), is precise-
ly targeted and significant variation from the target level avoided.
Permissive hypoxemia (PH) is an untested concept that describes
the tolerance of levels of arterial oxygenation considerably lower
than would conventionally be acceptable. If successfully evaluated
and implemented, PH could be considered in selected patients in
whom tolerance of hypoxemia is expected to be good and main-
tenance of normoxemia is likely to be associated with harm (3–5).
This review will explore ideas behind the concepts of PH and
PCAO in hypoxemic critically ill adult patients. Achieving optimal
arterial oxygenation for individual critically ill patients is an ambi-
tious goal due to the complex interaction of multiple harms and
benefit. The influences of different underlying disease processes
will have dramatic effects on the balance between oxygen supply
and demand at a cellular level. The aim of this review is to present
the limited clinical evidence base along with useful contributory
nonclinical data in order to explore the strengths and limitations
of the proposed strategies.
HYPOXEMIA
Hypoxemia is a common finding among critically ill patients ir-
respective of their underlying diagnosis (3, 6). It is defined as a
PaO
2
or SaO
2
that falls below what is conventionally considered to
be normal. Normal, while breathing air at sea level has been de-
scribed as a PaO
2
of between 80 and 100 mm Hg (10.7 and 13.3
kPa) (7) and SaO
2
of greater than 94% (8); however, considerable
interindividual variability may exist with respect to these quoted
values. For example, arterial oxygenation is inversely related to age
(9) due to the decline in ventilation–perfusion matching that oc-
curs over time (10). The PaO
2
at which clinicians choose to make a
diagnosis of hypoxemia varies widely, but typically is in the range
of 60 to 75 mm Hg (8–10 kPa) (11–13). In order to determine its
cause, hypoxemia can also been described in relation to fractional
inspired oxygen concentration (FIO
2
). In this instance the ratio of
PaO
2
to FIO
2
(PaO
2
/FIO
2
or P/F ratio) is used. A P/F ratio of less than
100 (when PaO
2
is measured in mm Hg) or 13.3 (when PaO
2
is mea-
sured in kPa) has been suggested for the diagnosis of refractory
hypoxemia (14) (e.g., a PaO
2
of 60 mm Hg [8 kPa] while receiving
60% oxygen). Perhaps it is the lack of evidence that maintaining
normoxemia in critically ill patients is beneficial (15) that explains
the wide variation in practice surrounding the management of hy-
poxemia in these patients (16–18).
The Cause and Time-Course of Hypoxemia
Potential mechanisms leading to hypoxemia should be kept in
mind when considering treatment strategies as some causes may
respond to specific therapies. Calculation of the alveolar-arterial
oxygen partial pressure gradient (P(A-a)O
2
) may assist in eluci-
dating the cause of hypoxemia; an example being that hypoven-
tilation with open lungs and no elevation of FIO
2
will result in a
normal P(A-a)O
2
that responds to simple oxygen therapy; whereas
a right-to-left shunt will produce a raised P(A-a)O
2
that will not
respond to additional oxygen (Table 1).
Regardless of its etiology, hypoxemia may also be defined in
terms of the duration of its evolution. However, the precise criteria
defining specific categories are open to subjective interpretation.
We, therefore, propose a structured approach to defining the time-
course of hypoxemia based on the changing physiological respons-
es and adaptations to declining arterial oxygenation that occur
over time (Table 2). As an example, acute hypoxemia occurring as
a consequence of abrupt upper airway obstruction or penetrating
chest injury evokes physiological responses that are limited to the
immediate augmentation of oxygen delivery through increases in
minute volume and cardiac output. Persistence of sublethal hypox-
emia results in alternative adaptive mechanisms, predominantly at
a cellular level. Critically ill patients tend to fall within the subacute
(6 hrs to 7 days) and sustained (7–90 days) categories (Table 2).
Sustained cross-generational hypoxic stress occurring in high al-
titude native populations can lead to modification of the genome.
The time-course of hypoxemia may influence decisions surround-
ing implementation of PCAO and PH for individual patients.
Clinical “Acclimatization” to Hypoxemia and
Cellular Hypoxia
Exposure to subacute and sustained hypoxemia permits a coor-
dinated process of adaptation, which outside of a clinical setting
is commonly referred to as acclimatization. For example, at alti-
tude the human response to hypobaric hypoxia is well described
and characterized by the restoration of convective oxygen delivery
through increases in alveolar ventilation, cardiac output, and red
TABLE 1. Causes of Hypoxemia and Their Effect on the Alveolar-Arterial Oxygen Difference
Cause of Hypoxemia Effect on P(A-a)O
2
Comment
Reduced FIO
2
(or PIO
2
) Unchanged or reduced Resolved by increasing FIO
2
(or PIO
2
)
Hypoventilation Unchanged Causes included pharmacological, neurological, and muscular
weakness. Alleviated by increasing FIO
2
Ventilation–perfusion mismatch Increased Commonest cause of hypoxemia in the critically ill. Alleviated to some
extent by increasing FIO
2
Right-to-left shunt Increased Anatomical or physiological. Cannot be alleviated by increasing FIO
2
Diffusion limitation Increased Rare cause of hypoxemia that can be alleviated by increasing FIO
2
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Clinical Investigation
Critical Care Medicine www.ccmjournal.org 3
blood cell mass (19, 20). It is unlikely that critically ill patients
mount such effective cardiorespiratory countermeasures to in-
crease oxygen delivery as a result of their underlying pathology.
However, there may be similarities in tissue and cellular responses
to hypoxia between patients and healthy volunteers at altitude
(21). In skeletal muscle biopsies of healthy volunteers exposed to
sustained hypoxia at high altitude, there is deactivation of mito-
chondrial biogenesis and down-regulation of mitochondrial un-
coupling, possibly resulting in improved efficiency of ATP pro-
duction (22). Comparable changes in mitochondrial biogenesis
also occur in critical ill patients and may reflect similar adaptive
responses (23, 24). The difficulty that arises in comparing acclima-
tization to high altitude and the physiological changes that occur
in the critically ill is that the degree of iatrogenic control over the
latter group may prevent some aspects of adaptation. For example,
patients in whom ventilation is controlled artificially by mechani-
cal means will be unable to mount a hypoxic ventilator response.
However, it is unlikely that cellular adaptation to hypoxia via hy-
poxia inducible factor will be inhibited by such interventions.
Severe and sustained tissue oxygen deprivation results in cellular
hypoxia and a decline in ATP production that triggers apoptosis,
a regulated energy-dependent process of programmed cell death.
The level of cellular hypoxia at which apoptosis is initiated is un-
clear and almost certainly varies between organs and individuals.
In isolated mitochondria, oxidative cellular metabolism fails when
the PO
2
falls less than 0.08 to 0.53 mm Hg (0.01–0.07 kPa) (25, 26),
while the corresponding values for cultured cells in vitro seem to be
in the range of 3.00 to 5.25 mm Hg (0.40–0.70 kPa) (25). Cellular
oxygen consumption (VO
2
) is governed by metabolic activity rather
than oxygen supply (27), but this relationship can be modified dur-
ing conditions of limited oxygen availability. Following exposure to
moderately prolonged hypoxia, cultured cells demonstrate a 40 to
60% reduction in VO
2
secondary to the down-regulation of non-
essential” cellular processes (28–30). This phenomenon is revers-
ible on re-exposure to normoxia (29) and is not associated with
demonstrable long-term cellular harm (28). Termed oxygen con-
formance, this reversible reduction in cellular metabolism and ATP
production represents a chronic adaptive response to hypoxia not
observed during acute hypoxic exposure. The coordinated reduc-
tion in VO
2
demonstrated by oxygen conformance not only attenu-
ates the depletion of scarce oxygen supplies, but may also render
cells less susceptible to hypoxic injury if oxygen delivery continues
to fall to a critical level. Strikingly similar mechanisms have been
demonstrated during multiple organ failure in critically ill patients,
and it has been proposed as an effective cellular survival strategy in
this context (31). These processes may be a manifestation of a more
generalized adaptive response to hypoxia that facilitates cellular sur-
vival under conditions of extreme physiological stress.
POTENTIALLY HARMFUL EFFECTS OF
EXCESSIVE OXYGEN AND HYPEROXEMIA
Eponymously named after Paul Bert and James Lorrain Smith, the
detrimental effects of hyperbaric oxygen on the central nervous
system (32) and pulmonary tissues (33) respectively, were well
described in the 19th century. More recently, it has become clear
that high concentrations of normobaric oxygen may also be
harmful. As the gas exchange interface of the body, it is logical
that pulmonary tissue would be one of the tissues at greatest
risk of damage from high-inspired oxygen concentrations, and
this has been demonstrated in numerous animal and healthy
human volunteer studies (34). The damage caused to pulmonary
tissue by excessive oxygen resembles the changes seen in acute
respiratory distress syndrome (ARDS); the magnitude of injury
is directly related to the concentration of oxygen and duration of
exposure (35, 36). Oxygen toxicity is rarely evident when the FIO
2
is less than 0.5 (1). As patients with ARDS frequently require an
FIO
2
greater than 0.5, they are potentially at risk of exacerbating
the underlying lung injury. It has been previously reported that
positive pressure ventilation with a high FIO
2
(0.61–0.93) resulted
in specific pathological findings independent of the detrimental
effects of the ventilator (37). Clinically, oxygen toxicity can result
in decreased mucociliary transport (38, 39), atelectasis (resulting
in ventilation–perfusion mismatching), inflammation, pulmonary
edema, and eventually interstitial fibrosis (35). These pathologies
may result in worsening lung function.
Excess oxygen administration is thought to damage tissue
through the production of reactive oxygen species (ROS). These
oxygen-containing molecules that form covalent bonds with oth-
er molecules through their unpaired electrons are produced by
the mitochondria during oxidative phosphorylation and serve a
number of important biological functions. In excessive concentra-
TABLE 2. Proposed Terms for the Categorization of Hypoxemia Based on Physiological
Responses to the Duration of Its Development
Term Description
Acute hypoxemia A rapid decline in arterial oxygenation developing over < 6 hrs (e.g., acute upper airway obstruction)
Subacute hypoxemia Reduced arterial oxygenation occurring in 6 hrs to 7 days (e.g., pneumonia)
Sustained hypoxemia Reduced arterial oxygenation for 7–90 days (e.g., prolonged acute respiratory distress syndrome, high
altitude climbing expeditions)
Chronic hypoxemia Prolonged reduction of arterial oxygenation for over 90 days (e.g., chronic obstructive pulmonary
disease)
Generational hypoxemia Cross-generational reduced arterial oxygenation (e.g., Tibetan highland residents)
In the absence of any universally accepted terminology describing the time-related differences in responses to hypoxemia, the proposed criteria are based upon human
physiological adaptations to hypoxemia.
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Martin et al
4 www.ccmjournal.org February 2013 • Volume 41 • Number 2
tions, ROS-mediated oxidative stress can lead to cellular necrosis
or apoptosis. Paradoxically, hypoxia can also result in an increase
in ROS production (40), and ROS are thought to be key players in
the pathobiology of reperfusion injury (41). An important feature
of pulmonary oxygen toxicity is that it is almost impossible to dis-
tinguish from damage caused by other lung injury processes (42).
Consequently, it is unclear whether deterioration of lung function
during high concentration oxygen therapy is due to worsening
of the primary disease process or to oxygen-free radical-induced
damage; the administration of high concentration oxygen may be
perpetuating lung injury in some patients.
Supranormal arterial oxygenation is also associated with a
number of cardiovascular responses such as reduced stroke vol-
ume and cardiac output (43, 44), increased peripheral vascular
resistance (43), coronary artery vasoconstriction, and reduced
coronary blood flow (45, 46), which may be undesirable in criti-
cally ill patients.
A growing body of clinical evidence points to the potential
harm of using high concentrations of inspired oxygen in clini-
cal situations where classical teaching and physiological intuition
might suggest a beneficial response. A number of examples are
outlined below:
1. Acute myocardial infarction. Two recently published system-
atic reviews of the use of supplemental oxygen during the
management of acute myocardial infarction came to the same
conclusion; there is no evidence that oxygen therapy (when
compared to air breathing) is of benefit in this setting (47), and
it may in fact be harmful, resulting in greater infarct size and
increased mortality (48). While the small number of included
studies limited the interpretation of these reviews and none
of the original studies obtained a statistically significant result
(49), they highlight provocative data that merits further urgent
investigation. The AVOID (Air Verses Oxygen In myocarDial
infarction) study (NCT01272713) is currently recruiting pa-
tients in order to answer this crucial clinical question (50).
2. Acute ischemic stroke. Clinical trial data evaluating the effects
of different inspired oxygen levels are even more sparse in acute
ischemic stroke. Oxygen therapy may be of benefit if adminis-
tered within the first few hours of onset, but evidence also ex-
ists that it may result in increased harm (higher 1-yr mortality)
with continued administration (51).
3. Neonatal resuscitation. During the past decade, the practice of
resuscitating neonates with 100% oxygen has been challenged
and many are now advocating that air should be used for initial
resuscitation (52). Several studies have demonstrated that the
use of 100% oxygen during the resuscitation of human neo-
nates may increase mortality, myocardial injury and renal inju-
ry, and even be associated with a higher risk of childhood leu-
kemia and cancer (53). Furthermore, in a manner comparable
to an ischemia-reperfusion injury, the use of 100% oxygen in
the new born following an asphyxiating perinatal event (54) is
thought to result in cerebral damage. Such is the evidence base
that resuscitation guidelines in neonates now advise that the
initial gas administered for ventilation should be air, and that
oxygen should be titrated into the mixture according to clinical
response so as to avoid hypoxemia (55).
4. Adult resuscitation following cardiac arrest. In a retrospective
cohort study of more than 6,000 patients following resusci-
tation from cardiac arrest, hyperoxemia (defined as a PaO
2
>
300 mm Hg [40 kPa]) was associated with a significantly worse
outcome than both normoxemia (60–300 mm Hg [8 to 40
kPa]) and hypoxemia (< 60 mm Hg [8 kPa]) (56). The authors
of this article concluded that excessive oxygen has harmful po-
tential during adult resuscitation post cardiac arrest, possibly
via ischemic reperfusion damage to central nervous tissue.
5. Critical illness. Limited data are available describing the rela-
tionship between arterial oxygenation, morbidity, and mortali-
ty in critically ill patients. The complexity of separating signal”
from “noise” in this heterogeneous patient cohort makes this
task challenging. Among acute medical emergency admissions
there is evidence that low SaO
2
is an independent predictor of
mortality (57); however, this relationship is more complicated
in established critical illness with sustained hypoxemia. Like-
wise, the degree to which a reduction in arterial oxygenation
can be tolerated in the critically ill is difficult to determine and
remains unclear (58).
The assumption that a higher PaO
2
is correlated with improved
long-term survival in critically ill patients has no robust evidence
in its support (15). A retrospective study of arterial oxygenation
in Dutch intensive care patients who were mechanically ventilated
within 24 hrs of admission demonstrated a biphasic relationship
between PaO
2
and in-hospital mortality (59). Mean PaO
2
in this co-
hort of more than 36,000 patients was 99.0 mm Hg (13.2 kPa), yet
the nadir for unadjusted hospital mortality was just below 150 mm
Hg (20 kPa). A similar study of patients in Australia and New Zea-
land reported a mean PaO
2
of 152.5 (±109.5) mm Hg (20.3 kPa),
representing supraphysiological levels of oxygenation, with 49.8%
of the 152,680 cohort being categorized as hyperoxemic (PaO
2
>
120 mm Hg [16 kPa]) (60). In contrast to the Dutch cohort, an as-
sociation between progressive hyperoxemia and in-hospital mor-
tality was not found after adjustment for disease severity, although
hypoxemia was associated with elevated mortality. These conflict-
ing data are limited by the methods used: both studies evaluat-
ed the association between the single “worst” (lowest P/F ratio)
blood gas within the first 24 hrs of admission to an intensive care
unit with in-hospital mortality, without quantifying oxygenation
during the rest of the patients’ critical illness. The difficulty in in-
ferring a clear message from these studies may, therefore, reflect
discordance between the severity of acute hypoxemia and subse-
quent changes in oxygenation along with the consequent adaptive
responses that may occur in critically ill patients. Using arterial
blood gas data beyond the first 24 hrs of admission may help more
clearly define any association between oxygenation and outcome.
Oxygenation in ARDS
The assumption that elevating arterial oxygenation improves
outcomes in patients with hypoxemia secondary to ARDS under-
pins many studies in this field (61). However, data from clinical
trials in patients with ARDS challenge this assumption and fre-
quently oxygenation and long-term outcome seem unrelated
(62–64). While some studies have reported a relationship be-
tween arterial oxygenation and mortality, a systematic review of
Page 4
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Clinical Investigation
Critical Care Medicine www.ccmjournal.org 5
101 clinical studies of ARDS concluded that P/F ratio was not a
reliable predictor of outcome (65). A variety of interventions in-
cluding high frequency oscillatory ventilation, prone positioning,
inhaled nitric oxide, and extracorporeal membrane oxygenation
have been shown to improve arterial oxygenation in patients with
ARDS without yielding an outcome benefit (14, 66). Further-
more, different strategies of mechanical ventilation have led to
1) improved oxygenation but unchanged outcome (67–69), 2)
improved outcome but unchanged oxygenation (70), and 3) de-
terioration in oxygenation but unchanged outcome (71). Taken
together, these data do not support the assumption that improved
oxygenation has a causative relationship with improved clinical
outcomes in patients with ARDS.
Three important considerations relate to this discussion. First,
supplemental oxygen is a supportive intervention serving to cor-
rect a consequence of the underlying pathophysiology, rather than
to treat a cause or reverse a disease process. Second, cellular hy-
poxia is not a prominent feature of ARDS. Third, death in these
studies is rarely due to intractable hypoxemia or respiratory fail-
ure, but commonly from the underlying cause of ARDS (e.g., sys-
temic inflammation due to sepsis) (72, 73). Taken together, these
data suggest that the underlying assumption that merits testing
through adequately powered well-designed clinical trials.
POTENTIALLY HARMFUL
EFFECTS OF HYPOXEMIA
Severe hypoxemia can result in cellular hypoxia, organ dysfunc-
tion, and death. The degree of organ dysfunction is determined by
the rapidity of onset, severity, and duration of hypoxemia and in-
dividual susceptibility. An extreme example of ischemia-hypoxia
tolerance is iatrogenically induced hypothermic circulatory arrest
during cardiothoracic surgery. Sudden exposure to severe atmo-
spheric hypoxia will cause rapid unconsciousness secondary to
cerebral hypoxia (74), while gradual acclimatization to a compa-
rable level of hypoxia can be well tolerated (75). In a report detail-
ing 22 clinical cases of profound hypoxemia (PaO
2
< 20.3 mm Hg
[2.7 kPa]), 13 of the patients survived, ten of whom were seem-
ingly unaffected by the event (76). The lowest reported PaO
2
was
7.5 mm Hg (1.0 kPa), in a 20-yr-old male patient breathing room
air following a heroin overdose yet he made an unremarkable re-
covery (76).
Much of the concern regarding extreme hypoxemia is
focused upon recovery of neurological function. It is difficult
to attribute cognitive deficits occurring after critical illness
directly to hypoxemia, when other factors such as hypotension,
infection, electrolyte abnormality, and drug effects may have
contributed. Whether hypoxemia reduces long-term cognitive
function after sustained exposure to extreme high altitude is
disputed (77–80). In a study of healthy volunteers breathing 7%
oxygen, no electroencephalogram abnormalities were detectable
(81). Furthermore, postmortem examinations of young adults
following severe and prolonged hypoxemia prior to death from
sudden cardiac failure revealed no specific pathological cerebral
changes that might be attributed to hypoxia (82). Hypoxemia tends
to increase blood flow to tissues (83) ensuring an adequate oxygen
supply for metabolism, and this has been clearly demonstrated
in the severely hypoxemic brain (83). Thus, when untangling the
literature it is important to differentiate the subtle but important
differences between hypoxemia and ischemia. “Hypoxic brain
injury” in the absence of hypoperfusion is a much-feared
consequence of a prolonged reduction in arterial oxygenation,
yet there is little evidence for its existence and it should not be
mistaken for ischemic cerebral injury that occurs post cardiac
arrest.
NOVEL CLINICAL STRATEGIES
FOR OXYGEN PRESCRIPTION
Moving away from targeting normal values as physiological goals
(84) for oxygen therapy in critically ill patients is consistent with
recent paradigm shifts in relation to other interventions. These
include hemoglobin concentration ([Hb]) (85) and arterial par-
tial pressure of carbon dioxide (86). For oxygen therapy, consider-
ation of how the balance of benefit and harm alters over time may
also be important. For example, specific oxygen delivery targets
seem to be effective in the resuscitation of acutely injured patients
(87–90), whereas elevating systemic oxygen delivery above normal
does not improve outcome in established critical illness and may
cause harm (91–93). The same may be true for maintenance of
PaO
2
as critical illness develops with time.
Precise Control of Arterial Oxygenation
PCAO involves targeting of PaO
2
or SaO
2
to individually specified
values, and avoiding significant fluctuation outside of a tightly
defined range, thereby minimizing the potential harms associ-
ated with hyperoxemia and hypoxemia (unnecessarily high or
low PaO
2
and/or PIO
2
). The traditional clinical approach to oxygen
therapy has been to prioritize the avoidance of hypoxemia while
being relatively tolerant of hyperoxemia. The possibility that “too
much oxygen may be as harmful as not enough should (94) lead
to a pragmatic rethinking of the practice of oxygen administra-
tion. Observational data suggests that current practice tends to
hyperoxemia (59, 60). This may be an inevitable consequence of
the widespread use of pulse oximetry that effectively detects hy-
poxemia but cannot be used to differentiate between normoxemia
and hyperoxemia (ceiling effect). The result of PCAO should be
oxygenation values that fall within a considerably narrower range
than is currently common, the midpoint of which is appropriately
targeted for a specific patient. Prescription of an achievable range
(e.g., “60 to 75 mm Hg” or 8 to 10 kPa) might replace the more
commonly observed prescription of “> 60 mm Hg” (8 kPa).
Founded upon physiological first principles, one can con-
struct a theoretical schema that depicts a patient’s target oxy-
genation zone (Fig. 1). The choice of values for a specific patient
will depend upon their age, the clinical setting, underlying dis-
ease (and its chronicity), and other comorbidities. Agreed tar-
get values may be suitable for cohorts of patients, for example
postoperatively or following a myocardial infarction. This ap-
proach to PCAO can be compared to other well-founded, evi-
dence-based practices in critical care medicine; for example, the
administration of intravenous fluids to optimize intravascular
volume status (95) is now commonly guided by measurable end
points such as stroke volume. In this instance, increased risks
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Martin et al
6 www.ccmjournal.org February 2013 • Volume 41 • Number 2
are encountered if physiological goals are ignored and fluid is
administered in a uniformly prescriptive style (e.g., volume per
hour or kilogram) rather than being tailored according to indi-
vidual’s requirements (96). Tight control of blood glucose again
endorses this approach, having a significant impact on mortality
and morbidity in the critically ill (97).
Permissive Hypoxemia
The concept of target defined arterial oxygenation described
above (PCAO) is echoed in a recently published guideline for
acutely ill patients which suggests normal or near normal oxy-
genation as the goal for oxygen therapy rather than unrestricted
administration of oxygen to hypoxemic patients (8). However,
while targeting normoxemia may be the best practice in acute
situations, it may be neither achievable nor beneficial in criti-
cally ill patients exposed to subacute or sustained hypoxemia. In
patients who have had sufficient time to be adapting or adapt-
ed to a subacute or sustained hypoxemia (Table 2), a strategy
of PH may improve outcomes because of the marginal benefit
(and potential increased harm) that arises from increasing arte-
rial oxygenation to normal. In other words, the goal of PH is to
reduce morbidity and mortality in selected hypoxemic patients
who have had sufficient time to adapt this state, by targeting low-
er levels of arterial oxygenation than are currently acceptable.
Conceptually, this can be presented as a shift to the left of the
PCAO curve in Figure 1 (lower PaO
2
), with the consequence that
the zone of optimal outcome lies within the sector convention-
ally described as hypoxemia: hence PH (Fig. 2). The corollary
of this is that normoxemia may be associated with worse out-
come in these individuals. Within the oxygenation target zone
(left of center) in Figure 2, adaptation to hypoxemia may facili-
tate a reduction of risk, in a similar way to the acclimatization
process that occurs on ascent to high altitude permits contin-
ued functioning even under conditions where inspired oxygen
is profoundly reduced (75). This rationale for PH is in part a
reflection of the fact that humans posses a variety of effective
adaptive mechanisms that support hypoxia tolerance, whereas
hyperoxia seems to be consistently harmful due to the absence of
known defensive adaptations.
The two proposed strategies (PH and PCAO) could be used
in combination; the application of PH without PCAO risks the
unintended consequence of unacceptably low PaO
2
.
Individualizing Oxygen Therapy in Critical Illness
There is wide variability in human responses to a hypoxic stimulus,
strikingly demonstrated by dramatic interindividual differences in
performance at high altitude (98). Prediction of an individual’s
response to hypoxemia is very poor, and neither isolated variables
relating to an ability to improve oxygen transport (e.g., hypoxic
ventilatory response), nor measures of physiological reserve relat-
ing to overall oxygen flux (e.g., peak oxygen consumption), are
predictive of subsequent hypoxia tolerance (21). That said, predic-
tor variables for acute mountain sickness were recently identified
in a large cohort of subjects ascending to high altitude, and these
consisted of marked desaturation and low ventilatory response to
hypoxia during exercise (99). Comparable predictor variables in
critically ill patients are largely unknown, and although individual
risk stratification according to exercise capacity perioperatively
is now commonplace (100), a one-size fits all” approach is still
commonly adopted.
The etiology and time-course of hypoxemia will affect the
optimal level of arterial oxygenation for an individual patient
(Table 2). Our current understanding of the transition from acute
response to a more adapted phenotype is limited in critically
ill patients and there is likely to be substantial interindividual
variation in the magnitude and time-course of these processes.
For example, the targets for arterial oxygenation, [Hb] and blood
Figure 1. Schematic diagram of the precise control of arterial oxygenation
concept. A target arterial partial pressure of oxygen or arterial hemoglobin
oxygen saturation is selected for each patient (thick dashed, arrowed line in
the center of curve) around which tight boundaries are delineated that create
the therapeutic target range for oxygenation (thin dashed lines). Harm is pos-
sible if oxygenation strays outside of this selected range. The optimal range
for individuals will be dependent upon their specific clinical situation.
Figure 2. The precise control of arterial oxygenation concept demonstrating
the potential risk reduction presented by permissive hypoxemia. Shifting the
therapeutic target range for oxygenation (area between thin dashed lines)
to the left on this conceptogram could potentially reduce harm to selected
patients by tolerating increasing degrees of hypoxemia and avoiding interven-
tions that pursue normoxemia or lead to hyperoxemia. Cellular and organ
“acclimatization” may occur during subacute and sustained hypoxemia that
facilitates survival without increased harm, which occurs during prolonged
ascent to high altitude.
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Clinical Investigation
Critical Care Medicine www.ccmjournal.org 7
pressure in a patient with a traumatic chest injury may well be
different from those in a patient with long-standing multiple
organ failure secondary to sepsis. Clinical decisions should be
driven by a pragmatic approach to individual patients guided by
the best available clinical evidence.
Patient Selection for PCAO and PH
Although most patients are likely to benefit from PCAO, not all
patients will tolerate profound hypoxemia. Hypoxemia is cur-
rently contraindicated in patients with severe brain injuries and
evidence exists that increasing systemic oxygenation with supple-
mental oxygen following major surgery reduces postoperative
wound infection rates (101). Given that even in these patients ex-
cessive oxygenation is likely to be harmful, and PCAO is likely to
be beneficial, the identification of “susceptibility” biomarkers for
hypoxia tolerance or intolerance is imperative and would facili-
tate individualized implementation of PCAO and PH to patients.
Such biomarkers might include physiological variables, biochemi-
cal signals in plasma or other compartments, genetic loci, and epi-
genetic modifications (102). Rapid diagnostic technologies cur-
rently being developed might permit bedside characterization of
the likely rate and degree of adaptation to hypoxemia and thereby
guide management.
Patient Responses and Targeting of Treatments
Should a distinct group of “response biomarkers be identified
that indicate hyperoxic or hypoxic tissue damage, they could
also be used to monitor treatment and modify therapeutic strat-
egies for individual patients. Markers of cellular damage (e.g.,
S100) (103), beneficial adaptation (nitrogen oxides) (104), or
oxidative stress (105) may be useful for this purpose. In addi-
tion , continuous monitoring of tissue oxygenation to provide
a real-time readout of the balance between oxygen delivery and
consumption is also likely to be imperative to successful PH.
Technologies such as near infrared spectroscopy (106), real-
time in vivo speckle laser (107), Clarke electrodes, microdialysis,
and fluorescence quenching (108) offer the potential of moni-
toring oxygenation in a variety of tissues and the potential for
generating organ-specific oxygen toxicity profiles. It is difficult
to pinpoint the threshold for oxygen-related tissue damage in
humans; the precise FIO
2
is likely to differ between individuals
and depend upon their degree of underlying lung injury. The
consequences of ROS-mediated oxidative damage due to high
FIO
2
in the lung may be identified through analysis of pulmo-
nary surfactant with characterization of phospholipid oxidative
damage using high precision modern diagnostics such as bed-
side mass spectrometry. The identification of such markers is
an unmet research need with the potential to improve the safety
and efficacy of oxygen therapy.
Taken further, perhaps the ultimate goal, as with other con-
texts in medicine where precise control of a monitored variable
is required, would be the introduction of “servo control” systems
to permit the automated control of arterial oxygenation. With
appropriate monitoring and safety structures in place, systems
based on high quality input variables, such as that derived from
a reliable pulse oximetry source or continuous intra-arterial oxy-
gen tension monitoring (109), could be linked to variable oxygen
administration systems, to allow real-time management of hy-
poxemia.
Oxygen Delivery and PH
When implementing PH, it may necessary to manipulate [Hb]
and cardiac output in subgroups of patients to ensure adequate
convective oxygen delivery to tissues (5). Patients with reduced
oxygen delivery due to low [Hb] (e.g., Jehovahs Witness post
surgery) or low cardiac output (e.g., end-stage heart failure) may
therefore not be suitable candidates for PH but may still benefit
from modified target values for PaO
2
. Determination of the pre-
cise thresholds for [Hb] and cardiac output in the context of a
selected oxygenation target will depend on basal metabolic oxy-
gen requirements and should be guided by the use of biomark-
ers and monitors of tissue oxygenation/hypoxia. While it may be
necessary to reduce metabolic requirements in patients in whom
hypoxemia is severe and oxygenation targets are low, for example
through the use of sedatives, muscle relaxants, or therapeutic hy-
pothermia, tissue oxygen extraction might also be amenable to
manipulation via matching of microvascular blood flow to local
tissue demands (110).
CONCLUSIONS
The selection of optimum arterial oxygenation goals is essen-
tial if cellular hypoxia and unnecessarily excessive oxygenation
(and ventilation) are to be avoided. It is imperative that balanc-
ing the risks associated with hypoxemia and hyperoxemia forms
part of the daily assessment of critically ill patients. Oxygen
administration should be considered in the same way as other
drugs, being titrated to a measured end point to avoid exces-
sive and inadequate dosage. While the signs of excessive oxygen
administration are often difficult to tease apart from a patient’s
underlying lung injury, limiting the dose administered and the
mechanical means to achieve oxygenation may reduce harm in
some individuals. There are no generally acceptable thresholds
for the lower limit of oxygenation that can be tolerated and in-
dividual evaluation is crucial when determining prescribed tar-
gets. The development of new technologies and biomarkers may
aid patient selection, and provide an umbrella of safety with
regards to tissue oxygenation.
At present, any immediate change in clinical practice toward
PH is not justified in the absence of experimental data in critical-
ly ill patients. However, greater attention to both the concentra-
tion of oxygen received by patients and the arterial oxygenation
achieved is likely to be beneficial. Implementation of the PCAO
method of oxygen prescription may assist in this process, provid-
ing a safe oxygenation range for the patient.
The weight of clinical experimental data coupled with obser-
vational and basic science studies suggest that a comprehensive
evaluation of PH in critically ill patients should be a high research
priority.
ACKNOWLEDGMENT
NIHR funding supports the UCL/UCLH Biomedical Research
Centre and the Southampton Biomedical Research Unit.
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Martin et al
8 www.ccmjournal.org February 2013 • Volume 41 • Number 2
REFERENCES
1. Clark JM, Lambertsen CJ: Pulmonary oxygen toxicity: A review. Pharmacol
Rev 1971; 23:37–133
2. Sinclair SE, Altemeier WA, Matute-Bello G, et al: Augmented lung injury due
to interaction between hyperoxia and mechanical ventilation. Crit Care Med
2004; 32:2496–2501
3. Abdelsalam M: Permissive hypoxemia: Is it time to change our approach?
Chest 2006; 129:210–211
4. Cheifetz IM, Hamel DS: Is permissive hypoxemia a beneficial strategy
for pediatric acute lung injury? Respir Care Clin N Am 2006; 12:359–69, v
5. Abdelsalam M, Cheifetz IM: Goal-directed therapy for severely hypoxic
patients with acute respiratory distress syndrome: Permissive hypoxemia.
Respir Care 2010; 55:1483–1490
6. White AC: The evaluation and management of hypoxemia in the chronic
critically ill patient. Clin Chest Med 2001; 22:123–34, ix
7. Kratz A, Lewandrowski KB: Case records of the Massachusetts General
Hospital. Weekly clinicopathological exercises. Normal reference laboratory
values. N Engl J Med 1998; 339:1063–1072
8. O’Driscoll BR, Howard LS, Davison AG: BTS guideline for emergency
oxygen use in adult patients. Thorax 2008; 63(Suppl 6):1–68
9. Crapo RO, Jensen RL, Hegewald M, et al: Arterial blood gas reference val-
ues for sea level and an altitude of 1,400 meters. Am J Respir Crit Care
Med 1999; 160(5 Pt 1):1525–1531
10. Lumb A: Nunn’s Applied Respiratory Physiology. Sixth Edition. Oxford, But-
terworth-Heinemann, 2005
11. Waldmann C, Soni N, Rhodes A: Oxford Desk Reference. Critical Care.
Oxford, Oxford University Press, 2008
12. Webb A, Shapiro M, Singer M, et al: Oxford Textbook of Critical Care.
Oxford, Oxford University Press, 1999
13. Fink MP, Abraham E, Vincent JL, et al: Textbook of Critical Care. Philadel-
phia, Elsevier Saunders, 2005
14. Esan A, Hess DR, Raoof S, et al: Severe hypoxemic respiratory failure: Part
1–ventilatory strategies. Chest 2010; 137:1203–1216
15. Young JD: Hypoxemia and mortality in the ICU. In: Yearbook of Intensive Care
and Emergency Medicine. Vincent J-L (Ed). Berlin, Springer-Verlag, 2000, pp
239–246
16. Mao C, Wong DT, Slutsky AS, et al: A quantitative assessment of how
Canadian intensivists believe they utilize oxygen in the intensive care unit.
Crit Care Med 1999; 27:2806–2811
17. Eastwood GM, Reade MC, Peck L, et al: Intensivists’ opinion and self-reported
practice of oxygen therapy. Anaesth Intensive Care 2011; 39:122–126
18. Eastwood GM, Reade MC, Peck L, et al: Critical care nurses’ opinion and
self-reported practice of oxygen therapy: A survey. Aust Crit Care 2012;
25:23–30
19. West JB, Schoene B, Milledge JS: High Altitude Medicine and Physiology.
Third Edition. London, Arnold, 2007
20. Hornbein TF, Schoene RB: High Altitude: An Exploration of Human Adapta-
tion. New York, Marcel Dekker, 2001
21. Grocott M, Montgomery H, Vercueil A: High-altitude physiology and
pathophysiology: Implications and relevance for intensive care medicine.
Crit Care 2007; 11:203
22. Levett DZ, Radford EJ, Menassa DA, et al; Caudwell Xtreme Everest
Research Group: Acclimatization of skeletal muscle mitochondria to
high-altitude hypoxia during an ascent of Everest. FASEB J 2012; 26:
1431–1441
23. Levy RJ, Deutschman CS: Deficient mitochondrial biogenesis in critical
illness: Cause, effect, or epiphenomenon? Crit Care 2007; 11:158
24. Ruggieri AJ, Levy RJ, Deutschman CS: Mitochondrial dysfunction and
resuscitation in sepsis. Crit Care Clin 2010; 26:567–575, x
25. Wilson DF, Rumsey WL, Green TJ, et al: The oxygen dependence of mito-
chondrial oxidative phosphorylation measured by a new optical method for
measuring oxygen concentration. J Biol Chem 1988; 263:2712–2718
26. Connett RJ, Honig CR, Gayeski TE, et al: Defining hypoxia: A systems view
of VO2, glycolysis, energetics, and intracellular PO2. J Appl Physiol 1990;
68:833–842
27. Wilson DF, Erecinska M: The oxygen dependence of cellular energy metabo-
lism. Adv Exp Med Biol 1986; 194:229–239
28. Schumacker PT, Chandel N, Agusti AG: Oxygen conformance of cellular
respiration in hepatocytes. Am J Physiol 1993; 265(4 Pt 1):L395–L402
29. Subramanian RM, Chandel N, Budinger GR, et al: Hypoxic conformance
of metabolism in primary rat hepatocytes: A model of hepatic hibernation.
Hepatology 2007; 45:455–464
30. Budinger GR, Chandel N, Shao ZH, et al: Cellular energy utilization and
supply during hypoxia in embryonic cardiac myocytes. Am J Physiol 1996;
270(1 Pt 1):L44–L53
31. Singer M, De Santis V, Vitale D, et al: Multiorgan failure is an adaptive, en-
docrine-mediated, metabolic response to overwhelming systemic inflamma-
tion. Lancet 2004; 364:545–548
32. Bert P: La Pression Barométrique: Recherches de Physiologie Expérimen-
tale. Paris, Masson, 1878
33. Smith JL: The influence of pathological conditions on active absorption of
oxygen by the lungs. J Physiol (Lond) 1898; 22:307–318
34. Jackson RM: Pulmonary oxygen toxicity. Chest 1985; 88:900–905
35. Crapo JD: Morphologic changes in pulmonary oxygen toxicity. Annu Rev
Physiol 1986; 48:721–731
36. Fisher AB: Oxygen therapy. Side effects and toxicity. Am Rev Respir Dis
1980; 122(5 Pt 2):61–69
37. Nash G, Blennerhassett JB, Pontoppidan H: Pulmonary lesions associat-
ed with oxygen therapy and artificial ventilation. N Engl J Med 1967; 276:
368–374
38. Sackner MA, Landa J, Hirsch J, et al: Pulmonary effects of oxygen breathing.
A 6-hour study in normal men. Ann Intern Med 1975; 82:40–43
39. Fox RB, Hoidal JR, Brown DM, et al: Pulmonary inflammation due to oxygen
toxicity: Involvement of chemotactic factors and polymorphonuclear leuko-
cytes. Am Rev Respir Dis 1981; 123:521–523
40. Duranteau J, Chandel NS, Kulisz A, et al: Intracellular signaling by reac-
tive oxygen species during hypoxia in cardiomyocytes. J Biol Chem 1998;
273:11619–11624
41. Ambrosio G, Tritto I, Chiariello M: The role of oxygen free radicals in precon-
ditioning. J Mol Cell Cardiol 1995; 27:1035–1039
42. Deby-Dupont GDC, Lamy M: Oxygen therapy in intensive care patients:
A vital poison? In: Yearbook of Intensive Care and Emergency. Vincent J-L
(Ed). Berlin, Springer-Verlag, 1999, pp 417–432
43. Milone SD, Newton GE, Parker JD: Hemodynamic and biochemical effects
of 100% oxygen breathing in humans. Can J Physiol Pharmacol 1999;
77:124–130
44. Lodato RF: Decreased O2 consumption and cardiac output during normo-
baric hyperoxia in conscious dogs. J Appl Physiol 1989; 67:1551–1559
SUMMARY
•  The safe lower limit of arterial oxygenation in critically ill
patients is unknown, but may be less than accepted in
clinical practice.
•  High fractional inspired concentrations of oxygen cause
pulmonary damage, possibly more so in patients with
injured lungs, but this damage is difficult to identify
clinically and knowledge of safety thresholds for oxygen
administration are unclear.
•  Precise control of arterial oxygenation in critically ill
patients is a novel treatment strategy that we propose may
improve outcomes by reducing the harm associated with
unnecessary extremes of arterial oxygenation.
•  For selected critically ill patients, permissive hypoxemia
(the tolerance of lower arterial oxygenation levels) may
better balance the harms and benefits of oxygen therapy
than attempting to achieve normoxemia.
•  Clinical evidence supporting permissive hypoxemia is
not currently available and robust studies are required to
evaluate safety and efficacy before implementation can be
advocated.
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Copyright (c) Society of Critical Care Medicine and Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited
Clinical Investigation
Critical Care Medicine www.ccmjournal.org 9
45. Farquhar H, Weatherall M, Wijesinghe M, et al: Systematic review of stud-
ies of the effect of hyperoxia on coronary blood flow. Am Heart J 2009;
158:371–377
46. McNulty PH, King N, Scott S, et al: Effects of supplemental oxygen admin-
istration on coronary blood flow in patients undergoing cardiac catheteriza-
tion. Am J Physiol Heart Circ Physiol 2005; 288:H1057–H1062
47. Cabello JB, Burls A, Emparanza JI, et al: Oxygen therapy for acute myocar-
dial infarction. Cochrane Database Syst Rev 2010; 6:CD007160
48. Wijesinghe M, Perrin K, Ranchord A, et al: Routine use of oxygen in the treat-
ment of myocardial infarction: Systematic review. Heart 2009; 95:198–202
49. Atar D: Should oxygen be given in myocardial infarction? BMJ 2010;
340:c3287
50. Stub D, Smith K, Bernard S, et al; AVOID Study: A randomized controlled trial
of oxygen therapy in acute myocardial infarction Air Verses Oxygen In myocar-
Dial infarction study (AVOID Study). Am Heart J 2012; 163:339–345.e1
51. Rønning OM, Guldvog B: Should stroke victims routinely receive sup-
plemental oxygen? A quasi-randomized controlled trial. Stroke 1999;
30:2033–2037
52. Davis PG, Tan A, O’Donnell CP, et al: Resuscitation of newborn infants with
100% oxygen or air: A systematic review and meta-analysis. Lancet 2004;
364:1329–1333
53. Saugstad OD, Ramji S, Vento M: Oxygen for newborn resuscitation: How
much is enough? Pediatrics 2006; 118:789–792
54. Munkeby BH, Børke WB, Bjørnland K, et al: Resuscitation with 100% O2 in-
creases cerebral injury in hypoxemic piglets. Pediatr Res 2004; 56:783–790
55. Wyllie J, Perlman JM, Kattwinkel J, et al; Neonatal Resuscitation Chapter
Collaborators: Part 11: Neonatal resuscitation: 2010 International Con-
sensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular
Care Science with Treatment Recommendations. Resuscitation 2010; 81
(Suppl 1):e260–e287
56. Kilgannon JH, Jones AE, Shapiro NI, et al; Emergency Medicine Shock
Research Network (EMShockNet) Investigators: Association between ar-
terial hyperoxia following resuscitation from cardiac arrest and in-hospital
mortality. JAMA 2010; 303:2165–2171
57. Goodacre S, Turner J, Nicholl J: Prediction of mortality among emergency
medical admissions. Emerg Med J 2006; 23:372–375
58. Gøthgen IH: What is the lower limits of arterial pO2? Acta Anaesthesiol
Scand 2007; 51:393–394
59. de Jonge E, Peelen L, Keijzers PJ, et al: Association between administered
oxygen, arterial partial oxygen pressure and mortality in mechanically
ventilated intensive care unit patients. Crit Care 2008; 12:R156
60. Eastwood G, Bellomo R, Bailey M, et al: Arterial oxygen tension and mortal-
ity in mechanically ventilated patients. Intensive Care Med 2012; 38:91–98
61. McIntyre RC Jr, Pulido EJ, Bensard DD, et al: Thirty years of clinical trials in
acute respiratory distress syndrome. Crit Care Med 2000; 28:3314–3331
62. Suchyta MR, Clemmer TP, Elliott CG, et al: The adult respiratory dis-
tress syndrome. A report of survival and modifying factors. Chest 1992;
101:1074–1079
63. Ferring M, Vincent JL: Is outcome from ARDS related to the severity of respi-
ratory failure? Eur Respir J 1997; 10:1297–1300
64. Abel SJ, Finney SJ, Brett SJ, et al: Reduced mortality in association with the
acute respiratory distress syndrome (ARDS). Thorax 1998; 53:292–294
65. Krafft P, Fridrich P, Pernerstorfer T, et al: The acute respiratory distress syn-
drome: Definitions, severity and clinical outcome. An analysis of 101 clinical
investigations. Intensive Care Med 1996; 22:519–529
66. Raoof S, Goulet K, Esan A, et al: Severe hypoxemic respiratory failure: Part
2–nonventilatory strategies. Chest 2010; 137:1437–1448
67. Gattinoni L, Tognoni G, Pesenti A, et al; Prone-Supine Study Group: Effect
of prone positioning on the survival of patients with acute respiratory failure.
N Engl J Med 2001; 345:568–573
68. Dellinger RP, Zimmerman JL, Taylor RW, et al: Effects of inhaled nitric oxide
in patients with acute respiratory distress syndrome: Results of a random-
ized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med
1998; 26:15–23
69. Hodgson C, Keating JL, Holland AE, et al: Recruitment manoeuvres for
adults with acute lung injury receiving mechanical ventilation. Cochrane Da-
tabase Syst Rev 2009; CD006667
70. Ventilation with lower tidal volumes as compared with traditional tidal vol-
umes for acute lung injury and the acute respiratory distress syndrome.
The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;
342:1301–1308
71. Stewart TE, Meade MO, Cook DJ, et al: Evaluation of a ventilation strategy to
prevent barotrauma in patients at high risk for acute respiratory distress syn-
drome. Pressure- and Volume-Limited Ventilation Strategy Group. N Engl J
Med 1998; 338:355–361
72. Montgomery AB, Stager MA, Carrico CJ, et al: Causes of mortality in pa-
tients with the adult respiratory distress syndrome. Am Rev Respir Dis
1985; 132:485–489
73. Stapleton RD, Wang BM, Hudson LD, et al: Causes and timing of death in
patients with ARDS. Chest 2005; 128:525–532
74. Ernsting J, Sharp GR, Harding RM: Hypoxia and hyperventilation. In: Sec ond
Aviation Medicine. Ernsting J (Ed). London, Butterworths, 1988, pp 46–59
75. Grocott MP, Martin DS, Levett DZ, et al; Caudwell Xtreme Everest Research
Group: Arterial blood gases and oxygen content in climbers on Mount Ever-
est. N Engl J Med 2009; 360:140–149
76. Gray FD Jr, Horner GJ: Survival following extreme hypoxemia. JAMA 1970;
211:1815–1817
77. Bjursten H, Ederoth P, Sigurdsson E, et al: S100B profiles and cognitive
function at high altitude. High Alt Med Biol 2010; 11:31–38
78. Jason GW, Pajurkova EM, Lee RG: High-altitude mountaineering and brain
function: Neuropsychological testing of members of a Mount Everest expe-
dition. Aviat Space Environ Med 1989; 60:170–173
79. Regard M, Oelz O, Brugger P, et al: Persistent cognitive impairment in
climbers after repeated exposure to extreme altitude. Neurology 1989;
39(2 Pt 1):210–213
80. Nelson TO, Dunlosky J, White DM, et al: Cognition and metacognition at ex-
treme altitudes on Mount Everest. J Exp Psychol Gen 1990; 119:367–374
81. Cohen PJ, Alexander SC, Smith TC, et al: Effects of hypoxia and normocar-
bia on cerebral blood flow and metabolism in conscious man. J Appl Physiol
1967; 23:183–189
82. Rie MA, Bernad PG: Prolonged hypoxia in man without circulatory compro-
mise fail to demonstrate cerebral pathology. Neurology 1980; 30:443
83. Wilson MH, Edsell ME, Davagnanam I, et al; Caudwell Xtreme Everest
Research Group: Cerebral artery dilatation maintains cerebral oxygenation
at extreme altitude and in acute hypoxia—An ultrasound and MRI study.
J Cereb Blood Flow Metab 2011; 31:2019–2029
84. Kavanagh BP: Goals and concerns for oxygenation in acute respiratory dis-
tress syndrome. Curr Opin Crit Care 1998; 4:16–20
85. Hébert PC, Wells G, Blajchman MA, et al: A multicenter, randomized, con-
trolled clinical trial of transfusion requirements in critical care. Transfusion
Requirements in Critical Care Investigators, Canadian Critical Care Trials
Group. N Engl J Med 1999; 340:409–417
86. Hickling KG, Henderson SJ, Jackson R: Low mortality associated with low
volume pressure limited ventilation with permissive hypercapnia in severe
adult respiratory distress syndrome. Intensive Care Med 1990; 16:372–377
87. Shoemaker WC, Appel PL, Kram HB, et al: Prospective trial of supranor-
mal values of survivors as therapeutic goals in high-risk surgical patients.
Chest 1988; 94:1176–1186
88. Fleming A, Bishop M, Shoemaker W, et al: Prospective trial of supranor-
mal values as goals of resuscitation in severe trauma. Arch Surg 1992;
127:1175–1179; discussion 1179
89. Velmahos GC, Demetriades D, Shoemaker WC, et al: Endpoints of resus-
citation of critically injured patients: Normal or supranormal? A prospective
randomized trial. Ann Surg 2000; 232:409–418
90. Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collab-
orative Group: Early goal-directed therapy in the treatment of severe sepsis
and septic shock. N Engl J Med 2001; 345:1368–1377
91. Gattinoni L, Brazzi L, Pelosi P, et al: A trial of goal-oriented hemodynamic
therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med
1995; 333:1025–1032
92. Hayes MA, Timmins AC, Yau EH, et al: Elevation of systemic oxygen
delivery in the treatment of critically ill patients. N Engl J Med 1994;
330:1717–1722
93. Alía I, Esteban A, Gordo F, et al: A randomized and controlled trial of the
effect of treatment aimed at maximizing oxygen delivery in patients with
severe sepsis or septic shock. Chest 1999; 115:453–461
94. Schumacker PT: Is enough oxygen too much? Crit Care 2010;
14:191
Page 9
Copyright (c) Society of Critical Care Medicine and Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited
Martin et al
10 www.ccmjournal.org February 2013 • Volume 41 • Number 2
95. Sinclair S, James S, Singer M: Intraoperative intravascular volume optimi-
sation and length of hospital stay after repair of proximal femoral fracture:
Randomised controlled trial. BMJ 1997; 315:909–912
96. Bellamy MC: Wet, dry or something else? Br J Anaesth 2006; 97:755–757
97. van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in
critically ill patients. N Engl J Med 2001; 345:1359–1367
98. Martin DS, Levett DZ, Grocott MP, et al: Variation in human performance in
the hypoxic mountain environment. Exp Physiol 2010; 95:463–470
99. Richalet JP, Larmignat P, Poitrine E, et al: Physiological risk factors for
severe high-altitude illness: A prospective cohort study. Am J Respir Crit
Care Med 2012; 185:192–198
100. Hennis PJ, Meale PM, Grocott MP: Cardiopulmonary exercise testing for
the evaluation of perioperative risk in non-cardiopulmonary surgery. Post-
grad Med J 2011; 87:550–557
101. Greif R, Akça O, Horn EP, et al; Outcomes Research Group: Supplemental
perioperative oxygen to reduce the incidence of surgical-wound infection.
N Engl J Med 2000; 342:161–167
102. Grocott M, Montgomery H: Genetophysiology: Using genetic strategies to
explore hypoxic adaptation. High Alt Med Biol 2008; 9:123–129
103. Büttner T, Weyers S, Postert T, et al: S-100 protein: Serum marker of fo-
cal brain damage after ischemic territorial MCA infarction. Stroke 1997;
28:1961–1965
104. Levett DZ, Fernandez BO, Riley HL, et al; Caudwell Xtreme Everest Re-
search Group: The role of nitrogen oxides in human adaptation to hypoxia.
Sci Rep 2011; 1:109
105. Sies H (Ed): Oxidative Stress. London, Academic Press, 1985
106. Boushel R, Langberg H, Olesen J, et al: Monitoring tissue oxygen availabil-
ity with near infrared spectroscopy (NIRS) in health and disease. Scand J
Med Sci Sports 2001; 11:213–222
107. Bezemer R, Legrand M, Klijn E, et al: Real-time assessment of renal cortical
microvascular perfusion heterogeneities using near-infrared laser speckle
imaging. Opt Express 2010; 18:15054–15061
108. Kiyose K, Hanaoka K, Oushiki D, et al: Hypoxia-sensitive fluorescent
probes for in vivo real-time fluorescence imaging of acute ischemia. J Am
Chem Soc 2010; 132:15846–15848
109. Venkatesh B, Clutton-Brock TH, Hendry SP: Evaluation of the Paratrend
7 intravascular blood gas monitor during cardiac surgery: Comparison
with the C4000 in-line blood gas monitor during cardiopulmonary bypass.
J Cardiothorac Vasc Anesth 1995; 9:412–419
110. Trzeciak S, Cinel I, Phillip Dellinger R, et al; Microcirculatory Alterations in
Resuscitation and Shock (MARS) Investigators: Resuscitating the micro-
circulation in sepsis: The central role of nitric oxide, emerging concepts for
novel therapies, and challenges for clinical trials. Acad Emerg Med 2008;
15:399–413
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    • "Much of our understanding is derived from assessment of gas exchange and from the morphological and biochemical analysis of biopsies [9] [10] [11] [12] [13] [14] [15]. When evaluating such studies, it is important to take into account both degree of hypoxia and exposure duration, as the adaptive response differs following initial acute, sub-acute or sustained hypoxia [16]. To our knowledge the first comprehensive study on the effects of chronic hypoxia on muscle morphologic adaptations and enzyme activities dates back to 1990. "
    [Show abstract] [Hide abstract] ABSTRACT: This study employed differential proteomic and immunoassay techniques to elucidate the biochemical mechanisms utilized by human muscle (vastus lateralis) in response to high altitude hypoxia exposure. Two groups of subjects, participating in a medical research expedition (A, n = 5, 19d at 5300m altitude; B, n = 6, 66d up to 8848m) underwent a ≈ 30% drop of muscular creatine kinase and of glycolytic enzymes abundance. Protein abundance of most enzymes of the tricarboxylic acid cycle and oxidative phosphorylation was reduced both in A and, particularly, in B. Restriction of α-ketoglutarate toward succinyl-CoA resulted in increased prolyl hydroxylase 2 and glutamine synthetase. Both A and B were characterized by a reduction of elongation factor 2alpha, controlling protein translation, and by an increase of heat shock cognate 71 kDa protein involved in chaperone-mediated autophagy. Increased protein levels of catalase and biliverdin reductase occurred in A alongside a decrement of voltage-dependent anion channels 1 and 2 and of myosin-binding protein C, suggesting damage to the sarcomeric structures. This study suggests that during acclimatization to hypobaric hypoxia the muscle behaves as a producer of substrates activating a metabolic reprogramming able to support anaplerotically the TCA cycle, to control protein translation, to prevent energy expenditure and to activate chaperone-mediated autophagy. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jan 2015 · Proteomics
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    • "The accuracy of SpO2 measurement can be of great significance for critically ill patients undergoing oxygen therapy. Lately, evidence has accumulated to support the need for precise control of arterial oxygenation in order to avoid hyperoxemia and the ill effects of oxygen toxicity associated with it.27 The detection of hyperoxemia in these patients is especially problematic, because the dissociation curve is almost flat in the high SaO2 range, ie, greater than 95%, and thus relatively small changes in SaO2 are associated with large changes in PaO2. "
    [Show abstract] [Hide abstract] ABSTRACT: Oxygen saturation in the arterial blood (SaO2) provides information on the adequacy of respiratory function. SaO2 can be assessed noninvasively by pulse oximetry, which is based on photoplethysmographic pulses in two wavelengths, generally in the red and infrared regions. The calibration of the measured photoplethysmographic signals is performed empirically for each type of commercial pulse-oximeter sensor, utilizing in vitro measurement of SaO2 in extracted arterial blood by means of co-oximetry. Due to the discrepancy between the measurement of SaO2 by pulse oximetry and the invasive technique, the former is denoted as SpO2. Manufacturers of pulse oximeters generally claim an accuracy of 2%, evaluated by the standard deviation (SD) of the differences between SpO2 and SaO2, measured simultaneously in healthy subjects. However, an SD of 2% reflects an expected error of 4% (two SDs) or more in 5% of the examinations, which is in accordance with an error of 3%-4%, reported in clinical studies. This level of accuracy is sufficient for the detection of a significant decline in respiratory function in patients, and pulse oximetry has been accepted as a reliable technique for that purpose. The accuracy of SpO2 measurement is insufficient in several situations, such as critically ill patients receiving supplemental oxygen, and can be hazardous if it leads to elevated values of oxygen partial pressure in blood. In particular, preterm newborns are vulnerable to retinopathy of prematurity induced by high oxygen concentration in the blood. The low accuracy of SpO2 measurement in critically ill patients and newborns can be attributed to the empirical calibration process, which is performed on healthy volunteers. Other limitations of pulse oximetry include the presence of dyshemoglobins, which has been addressed by multiwavelength pulse oximetry, as well as low perfusion and motion artifacts that are partially rectified by sophisticated algorithms and also by reflection pulse oximetry.
    Full-text · Article · Jul 2014 · Medical Devices: Evidence and Research
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    • "The top 5 most common pathogenic microorganisms included Staphylococcus epidermidis, Staphylococcus aureus, Enterococcus, Pseudomonas aeruginosa, and Candida albicans. The detection rates of Gram-positive bacteria exceeded those of Gram-negative ones, which may be associated with thymic hypoplasia, low immunity, and fragile barrier function, etc. S. epidermidis, an opportunistic pathogen, hides in sebaceous glands, sweat glands and skin folds under normal conditions and invades blood after puncture, leading to nosocomial infections eventually.14 S. aureus results in severe complications such as endocarditis, osteomyelitis and arthritis, as well as brings about dysbiosis by inhibiting normal microorganisms in human body. Gram-positive bacteria were highly resistant to penicillin, azithromycin and erythromycin, moderately susceptible to levofloxacin and cefazolin, and completely susceptible to vancomycin. "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: To study the pathogen distribution, antimicrobial susceptibility and risk factors of postoperative nosocomial infections among children with congenital heart disease. Methods: Three hundreds children with congenital heart disease admitted to our hospital to receive surgeries from February 2010 to February 2013 were selected. Results: A total of 120 children were tested as positive by sputum culture, with the infection rate of 40.0%. The top five most common pathogenic microorganisms included Staphylococcus epidermidis, Staphylococcus aureus, Enterococcus, Pseudomonas aeruginosa, and Candida albicans. S. epidermidis, S. aureus and Enterococcus were highly resistant to penicillin, azithromycin and erythromycin, moderately susceptible to levofloxacin and cefazolin, and completely susceptible to vancomycin. Multivariate Logistic regression analysis showed that hospitalization stay length, combined use of antibiotics, systemic use of hormones, mechanical ventilation and catheter indwelling were the independent risk factors of postoperative nosocomial infections (P<0.05). Conclusion: Nosocomial infection, which was the most frequent postoperative complication of pediatric congenital heart disease, was predominantly induced by Gram-positive bacteria that were highly susceptible to cephalosporins and vancomycin. Particular attention should be paid to decrease relevant risk factors to improve the prognosis.
    Full-text · Article · May 2014 · Pakistan Journal of Medical Sciences Online
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