Download hyperoxia - Anaesthetics

04 April 2014
No. 10
HYPEROXIA
J. Invernizzi
Moderator: L. Pillay
Discipline of Anaesthetics
CONTENTS
HYPEROXIA ......................................................................................................... 4
PATHOPHYSIOLOGY .......................................................................................... 4
Oxygen Delivery ................................................................................................ 4
Reactive Oxygen Species ................................................................................. 7
OXYGEN USE IN HOSPITALS ............................................................................. 8
Oxygen Use in Resuscitation ........................................................................... 8
OXYGEN USE PERI-OPERATIVELY ................................................................. 12
PROPOSED CHANGES TO CURRENT PRACTICE .......................................... 15
REFERENCES.................................................................................................... 17
Page 2 of 21
INTRODUCTION
The role of oxygen in the development and sustenance of life on earth is a hugely
complicated and diverse topic. The formation of an oxygen rich atmosphere and
the emergence of oxygen-dependant organisms are topics that encompass a lot
of the physical, philosophical and theological questions at the root of our existence
and are well beyond the scope of this lecture. It is sufficed to say that a
continuous supply of oxygen, a by-product of photosynthesis, is required by all
aerobic organisms in order to maintain cellular metabolism (1, 2).
All life on earth is based on reduction-oxidation reactions (reduction to store
energy and oxidation to release it). As an element, Oxygen is voracious electronacceptor. It can therefore react with most elements in a variety of manners
ranging from rapid and violent, as is seen in explosions and fires, to slow and
ceaselessly as is seen when metal rusts. In aerobic organisms, oxygen is reduced
to water as the final step of the electron transport chain within the mitochondria,
part of an overall process which encompasses the oxidation of glucose and other
substrates to carbon dioxide(2).
Fig. 1: Electron Transport Chain (3)
Oxygen is probably the most widely used drug within the hospital setting, with a
large proportion of patients receiving oxygen at some point during their admission.
Very few patients receiving anaesthesia, presenting with cardiac or respiratory
pathologies, or undergoing intensive care will not be given oxygen at some stage.
When considering also the number of patients that will receive oxygen during
transport to hospital by the emergency care practitioners, the scale of oxygen use
becomes apparent.
Page 3 of 21
HYPEROXIA
Definition: A higher than normal oxygen tension, such as that produced by
breathing air or oxygen at greater than atmospheric pressures (4)
PATHOPHYSIOLOGY
Oxygen Delivery
Supplemental oxygen is often administered with various presumptions. Firstly, it is
recognised that avoidance of hypoxia is one of the core goals in patient care.
However this is often achieved on the premise that excess oxygen is not harmful
(2)
. Furthermore it is also often presumed that the amount of oxygen available to
tissues in various parts of the body is directly proportional to the concentration of
oxygen supplied to the patient. In simple terms, a high concentration of
administered oxygen results in a high amount of oxygen available at tissue level.
Unfortunately while this is true in certain circumstances, the amount of oxygen
available at tissue level depends both on arterial oxygen content as well as the
perfusion of the tissues, as is demonstrated in the often quoted oxygen delivery
equation:
Fig. 2: Oxygen Delivery Equation (5)
Page 4 of 21
What is not widely considered is that hyperoxia causes vasoconstriction in the
cardiac, cerebral, renal and other key vasculatures both directly and via
hyperoxia-induced hypocapnia (6). This can result in a situation whereby perfusion
decreases more than arterial oxygen content increases, resulting in an overall
decrease in regional oxygen delivery and subsequently relative hypoxia at a tissue
level (6). This seemingly paradoxical situation can then easily be overlooked as
tissue hypoxia is prescribed to the underlying disease process, with few people
recognising the administration of supplementary oxygen as a contributory factor.
This process can be better understood when examining the oxygen delivery
equation in more detail, and fully appreciating the effects of the various factors on
the overall delivery of oxygen:
Arterial Oxygen Content (7)
Assuming the patient is not hypoxic and that the haemoglobin is fully saturated,
CaO2 increases only 0.003ml/l per mmHg rise in PaO2. This equates to roughly
only a 7.5% rise in CaO2 between a PaO2 of 100mmHg compared to a PaO2 of
600mmHg. However, when looking at research done on the brain for instance,
cerebral blood flow decreases between 11 and 33% in hyperoxic conditions (8, 9).
This would result in an overall decrease in the delivery of oxygen to tissues
despite (and in deed because of) the higher FiO2. This effect is also not confined
to the brain, with similar results being demonstrated in the renal (10) and cardiac (11,
12)
systems, as well as in organs such as the eye and skin (13, 14) . Normobaric
hyperoxia has been shown to decrease coronary blood flow by 8-29% in patients
with coronary artery disease or chronic heart failure resulting in a similar overall
effect in the heart as in the brain (11, 12).
Page 5 of 21
Fig. 3: Oxygen Haemoglobin Dissociation Curve(15)
The precise mechanism mediating hyperoxic vasoconstriction is still under debate.
Proposed mechanisms include the inhibition of vasodilators such as
prostaglandins and nitric oxide by reactive oxidative species (10, 16), an increased
production of vasoconstrictive substances such as endothelin-1 (13), and the
activation of brainstem respiratory neurons (17).
The theory of hyperoxia-induced-hypocapnia, or “reverse Haldane effect” also
needs to be examined. Oxygenated haemoglobin binds less CO2 (the Haldane
effect), therefore in the face of hyperoxia, in order to maintain CO2 transport,
bicarbonate and dissolved CO2 (PCO2) levels need to increase. This rise in PCO2
in turn stimulates chemoreceptors in the brainstem (indirectly via raised H+
levels), which result in an increase in the respiratory rate. This response often
exceeds the rise in PCO2 resulting in a hyperoxic-induced-hypocapnia, which in
turn can lead to vasoconstriction in CO2-responsice vascular beds (18, 19).
Regardless of the mechanism however, both hyperoxia and hypocapnia have
both independently been shown to result in vasoconstriction (9).
Page 6 of 21
Fig. 4: Effects of hyperoxia on minute-ventilation, ETCO2 levels and cerebral blood flow
Typical effects of hyperoxia on minute ventilation (V̇e), end-tidal Pco2 (PETCO2), and middle
cerebral artery velocity (MCAV), an index of cerebral blood flow, in one of five normal subjects.
Correction of the hyperoxia-induced hypocapnia by addition of CO2 to the inspired gas
(normocapnic hyperoxia) returned middle cerebral artery velocity back toward control.(18)
Reactive Oxygen Species
Reactive oxygen species (ROS) are oxygen molecules that contain an unpaired
electron and are considerably more reactive than their paired-electron
counterparts. They are produced in the mitochondria during partial metabolism of
oxygen, and include the superoxide anion (O2-), hydrogen peroxide (H2O2) and
the hydroxyl radical (OH-). Excess ROS are metabolised by the cell via various
enzyme systems including glutathione perioxidases, lactoperioxidases,
superoxide dismutases, and various catalases. Extracellularly, uric acid fulfils the
role as the biggest free radical scavenger (20).
Although responsible for many deleterious effects if their production exceeds their
breakdown by the cell, they are also used by the cell in various ways. It has long
been recognised that ROS are utilised by phagocytic cells as part of their host
defences. Recently however, they have also been recognised to have a role in a
myriad of other functions such as cell signalling, apoptosis, the expression or
suppression of genes, the activation of intracellular cascades such as those
involving mitogen activated protein kinases, and platelet aggregation (21). In
excess however, ROS can result in damage to DNA, oxidation of polyunsaturated
fatty acids (lipid peroxidation), oxidation of cellular amino acids as well as
inactivation of various enzymes via oxidation of cofactors. This damage is in turn
implicated in ageing, atherosclerosis, carcinogenesis, ototoxicity and
cardiovascular disease (20).
Page 7 of 21
Defence against hyperoxic damage associated with the ever-increasing
atmospheric oxygen levels is thought to be behind the endosymbiotic integration
of primitive bacteria into early organisms as they evolved. These bacterium, which
evolved into mitochondria, provided a dual service of metabolising ROS
(protecting the rest of the cell), while at the same time facilitating cellular
respiration and the formation of energy, paving the way to the evolution of
multicellular organisms (1).
It is thought that it is the combination of an impaired delivery of oxygen at tissue
level, as well as the reactive oxidative species produced by an excess of oxygen
that results in the various poor clinical outcomes associated with hyperoxia (6).
OXYGEN USE IN HOSPITALS
Supplemental oxygen is used in three main scenarios in the hospital setting. In
resuscitation, peri-operative care and critical care.
Oxygen Use in Resuscitation
Neonate
Approximately 10% of newborns require assistance to start breathing at birth with
around 1% of these requiring full resuscitation (22). In 2010 the new International
Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular
Care Science guidelines on neonatal resuscitation were published following a
review of the available literature. These guidelines in turn form the basis for the
American Heart association, European resuscitation Council and International
Liaison Committee on Resuscitation’s guidelines respectively (23).
A number of significant changes were made to the 2005 guidelines. These
included that for babies born at term, resuscitation should begin with air rather
than 100% oxygen, administration of supplemental oxygen should be a blend of
oxygen and air, and the concentration of oxygen delivered should be guided by
oximetry. These recommendations were based upon studies that had shown that
while resuscitation with 100% oxygen conferred no advantage to the child, an
increase time until first breath was exhibited. This recommendation was further
supported by 2 large meta-analyses which both demonstrated decreased mortality
in infants resuscitated with air instead of 100% oxygen (24, 25).
In preterm infants blended oxygen may be required, however the guidelines
caution against both hypoxia and hyperoxia in the infant, and suggest that if no
blended oxygen is available then air should be used for resuscitation in preterm
infants as well (22).
Page 8 of 21
Other studies have demonstrated other deleterious effects of 100% oxygen in
neonates. These include amongst others:
- Myocardial and renal injury (26)
- Oxidative stress persisting for at least 4 weeks after birth (27)
- Higher risk of childhood leukaemia and cancer(28, 29)
Furthermore, animal studies have demonstrated potential harm to other systems
including the neurologic, respiratory and central nervous system (23).
Adult
Oxygen is currently used in three main scenarios for adult resuscitation:
1) To treat established hypoxaemia
2) To prevent potential hypoxaemia in an ill patient
3) To alleviate dyspnoea
Only the use of oxygen to treat established hypoxaemia is evidence based, the
other two indications are not. There is no evidence to suggest that administration
of oxygen to an ill patient without hypoxaemia will be of any benefit to them, nor
that oxygen supply to a breathless normoxaemic patient will relieve the
breathlessness (30). If the potential for hypoxaemia exists then monitoring of the
patient should rather be instituted (31). As a result of the wanton application of
oxygen in the acute care setting, hyperoxia can be as common as hypoxia (32).
Unfortunately the practice of administration of oxygen by healthcare practitioners
varies widely, with many strongly held beliefs but a relative paucity of randomised
control trials providing evidence on the matter.
In 2008 the British Thoracic Society (BTS) established a working group to address
this problem, which resulted in the formulation of an evidence-based guideline for
emergency oxygen use in the UK (33).
Some recommendations of the BTS are:
Assessment:
- High concentration oxygen should be administered immediately to all
critically ill patients.
- SPO2 should be monitored in all breathless or critically ill patients
- SPO2 monitoring should be available in all locations that emergency
oxygen is used
Prescription:
- Oxygen delivery should be prescribed and written on drug chart with
target saturation noted.
- Oxygen should be prescribed to achieve a target of 94-98% for most
acutely ill patients (including cardiac patients) or 88-92% for those at risk
of hypercapnic respiratory failure (Chronic obstructive airways disease,
cystic fibrosis, restrictive lung disorders, morbid obesity).
Page 9 of 21
Discontinuation:
- Oxygen should be weaned once target saturations are achieved, and
crossed off the drug chart once therapy is discontinued.
Fig. 5: British Thoracic Society oxygen administration guidelines (33)
Page 10 of 21
Acute Coronary Syndromes
Oxygen for treatment of ACS (acute coronary syndromes) was formally suggested
as early as the 1930’s (34). Since then it has become a mainstay of treatment with
the M.O.N.A. (morphine, oxygen, nitrates, aspirin) acronym being taught to most
med school graduates despite there only ever having been low-grade evidence
(level C) for its use in uncomplicated ST-elevation myocardial infarction (35). While
the effects of hypoxia on cardiac tissue are well understood, increasingly studies
are beginning to consistently show the detrimental effects of hyperoxia on cardiac
function, with decreased coronary blood flow, increased coronary resistance and
decreased myocardial oxygen consumption being demonstrated in both normal
patients and patients with cardiac pathology when exogenous oxygen is
administered in the absence of hypoxemia (11, 12, 36-39).
A Cochrane review in 2013 attempted to resolve the debate. It found twice the
increase in mortality in patients with acute myocardial infarction (AMI) who
received oxygen as opposed to air, however was limited by the lack of research
that directly addressed this topic (only four small randomised controlled trials). A
large randomised controlled trial, the AVOID (Air vs. Oxygen in Myocardial
Infarction) study, is currently underway in Australia and will hopefully provide more
clarity on this matter (40).
Currently American Heart Association recommendations include administration of
oxygen in AMI if there is dyspnoea and hypoxaemia as shown on pulse oximetry,
or if there are signs of heart failure. Oxygen should then be administered to titrate
to a SPO2 of greater or equal to 94%.
Cardiac arrest provides an even more contentious topic. During cardiopulmonary
resuscitation, delivery of 100% oxygen remains recommended protocol with
hypoxia being the predominant state in most resuscitations. There is however
compelling evidence from animal studies to suggest that hyperoxia may result in
worse outcomes due to ischaemic/reperfusion injury (41). This has been
corroborated by a large clinical review (over 6000 patients) which demonstrated a
significantly increased in-hospital mortality rate in hyperoxic patients following
cardiac arrest compared to normoxic patients (OR 1.8, 95%CI 1.5-2.2) even when
controlling for possible confounders such as age, preadmission functional status,
comorbid conditions, vital signs, and other physiological indices (42). This same
study also evaluated post-resuscitation PaO2 levels in ICU patients and found that
for every post resuscitation increase of 100mmHg in PaO2, there was an
associated 24% increase in relative risk of death (42).
A further large review (43) has subsequently questioned various aspects of the
methodology utilised in obtaining these results, however this study too contained
flaws in methodology and as yet no large randomised control trial has been
performed to corroborate the results of either review.
Page 11 of 21
Chronic Obstructive Airways Disease (COPD)
The risks of high concentration oxygen supplementation in COPD have long been
acknowledged. The use of high concentration oxygen in these patients may result
in hypercapnic ventilatory failure due to various mechanisms including the
Haldane effect, ventilation perfusion mismatching (due to loss of hypoxic
pulmonary autoregulation), atelectasis and inhibition of the patient’s hypoxic
drive(17). This has resulted in the recommendation for COPD patients of
supplemental oxygen being limited to 28%. Despite this, many COPD patients
receive higher concentrations of oxygen both pre-hospital and in-hospital. This
has been shown in numerous randomised controlled trials to adversely affect
patient outcomes including acidosis, hypercapnia and overall mortality (32).
Other Resuscitation scenarios
Hyperoxaemia has also been shown to adversely affect outcomes when used in
the acute treatment of many other conditions. These include congestive heart
failure where a decreased cardiac output, increased systemic vascular resistance,
increased left ventricular end diastolic pressures and increased isovolumic
relaxation times have been shown (12, 37, 44), and stroke where an increased stroke
severity score and overall mortality has been demonstrated (45, 46). The American
Heart Association has advised against the use of supplemental oxygen in
normoxaemic acute stroke patients in their guidelines for stroke management in
accordance with this research (47).
OXYGEN USE PERI-OPERATIVELY
Infection Rates
Several studies have been published that suggest a correlation between the use
of high intraoperative oxygen concentrations (FiO2) and decreased surgical site
infections. A recent meta-analysis provided mixed results on the topic concluding
that although there was no overall benefit, benefit was seen in the subgroups of
colorectal surgery and general anaesthesia (48). The PROXI trial however, the
largest randomised control trial to tackle this issue, failed to demonstrate any
reduction in surgical site infection with the use of an 80% FiO2 compared to a 30%
FiO2 for laparotomies for various indications of at least 2 hours duration in the
1400 patients included in the trial (49).
Wound Healing
High levels of oxygen have for many years been argued to increase the rate of
surgical and traumatic wound healing. Unfortunately the evidence directly
addressing this topic is poor and conflicting. A recent Cochrane review (2013)
concluded that due to the lack of evidence, further randomised controlled trials on
the topic were required (50).
Page 12 of 21
Pulmonary Atelectasis
Pulmonary atelectasis is a well-recognised sequlae of general anaesthesia being
present in 90% of patients regardless of whether they are spontaneously
breathing or paralysed (51). Atelectasis in turn increases shunt, increases
pulmonary vascular resistance, decreases compliance, may contribute to
perioperative hypoxaemia, and may increase the chance of post-operative
pneumonia (52, 53). One of the mechanisms of atelectasis occurs when the patient
is ventilated with 100% oxygen. The nitrogen in the alveoli is washed out and
replaced by oxygen, which in turn is quickly absorbed into the pulmonary
vasculature, not leaving enough gas in the alveoli to maintain patency.
Atelectasis, especially in the presence of pre-existing lung disease or limited
cardio-pulmonary reserve may in turn have a significant impact on perioperative
outcomes (54).
Recommendations to avoid perioperative atelectasis include preoxygenation with
an FiO2 of 0.8 in low airway-risk patients, or recruitment for 10 seconds following
preoxygenation with an FiO2 of 1.0 in higher risk patients (53). Intraoperatively the
use of PEEP (positive end expiratory pressure), and ventilation during
anaesthesia utilising only a moderate fraction of inspired oxygen (FiO2 e.g. 0.30.4) is recommended (51).
Fig. 6: CT in obese patients undergoing anaesthesia
Page 13 of 21
(55)
O2 Use in Critical Care
The problem of tissue hypoxia is central to the management of most patients in
the critical care setting. The current paradigm of critical care emphasises the
avoidance of tissue hypoxia over any risk associated with hyperoxia. Careful
evaluation is needed however to avoid the harmful effects of high concentrations
of FiO2 and invasive mechanical ventilation associated with the repeated attempts
to achieve normoxaemia in patients that may have a persistently low level of
arterial oxygenation despite the efforts to restore it to normal (56). Furthermore,
there has been little survival benefit shown in restoring normoxaemia in critical
care patients (57, 58).
Unfortunately little is known about the benefit vs. harm ratio between the
strategies to increase arterial oxygenation compared to the risks of relative arterial
hypoxaemia. This is further more complicated when trying to assess the benefit or
risk of smaller deviations from normal, as well as taking into account the various
underlying pathologies as well as inter-patient variability in response. Some
assistance in the management of hypoxia can be gained from analysis of factors
such as the arterial-alveolar oxygen partial pressure gradient:
P(A-a)O2
This enables a quick evaluation as to whether or not the cause of the hypoxia is
likely to respond to an increase in the FiO2. A normal gradient in the face of
arterial hypoxaemia will likely respond well to increasing the FiO2, while a
markedly raised gradient likely will not (56). Recent changes in the consideration of
hypoxia in critical care patients have emphasised the time-course of the onset of
the hypoxia in the management of the patient. The rationale behind this is that
hypoxia of an acute or sub-acute onset such as upper airway obstruction or
pneumonia, will most likely result in physiological responses that are aimed
towards the immediate augmentation of oxygen delivery (increased ventilation,
cardiac output), while hypoxia that is more chronic in onset may result in more of
an adaption at the cellular level (56).
Cellular hypoxia results in an exponential rise in the hetrodimeric protein, hypoxiainducible-factor 1 (HIF-1). This transcription factor in turn results in the
upregulation of erythropoietin, vasogenic mediators and angiogenic factors, as
well as stimulating the production of glycolytic enzymes which allow the
continuation of energy production in oxygen-poor environments. Importantly HIF-1
also depresses mitochondrial oxygen consumption and improves the efficiency of
mitochondrial ATP production via mitochondrial biogenesis deactivation and
down-regulation of mitochondrial uncoupling (59, 60). These considerations in turn
should be used to help determine the target arterial oxygenation levels, and
ventilator strategies for the patient (56).
Prolonged administrations of high concentrations of oxygen have long been
recognised as having adverse consequences in the critical care setting.
Page 14 of 21
One of the main affected sites is the lung, with high FiO2’s resulting in damage to
pulmonary tissue resembling the Acute Respiratory Distress Syndrome (ARDS)
clinical picture. This damage is proportional to the FiO2 and the duration of
exposure (61, 62), and independent of the mechanical effects of ventilation (63).
Oxygen toxicity has been shown to result in decreased mucocilliary transport (64),
atelectasis, inflammation, pulmonary oedema and interstitial fibrosis (62).
PROPOSED CHANGES TO CURRENT PRACTICE:
Currently much of the evidence of the deleterious effects of hyperoxia is based on
research which is still in its early stage. This combined with the fact that while we
may want to avoid the extremes of hypoxia and hyperoxia on either side, the risks
of smaller deviations from normoxia are largely still unknown, makes changes to
current practice hard to formulate.
Two stratagems have so far been proposed, “precise control of arterial
oxygenation” and “permissive hypoxaemia” (2, 56).
“Precise Control of Arterial Oxygenation”
This involves targeting the PaO2 or SaO2 to individualised values, taking into
account age, pathology, co-morbidities, chronicity of disease and clinical setting.
Values outside a tightly defined range would be avoided in order to minimise the
deleterious effects of both hypoxaemia and hyperoxaemia. This may be simplified
by formulating ranges for cohorts of patients, such as post-operative, acute
myocardial infarction etc. This approach essentially involves managing oxygen
application to patients the same as we manage most other aspects of patient
care such as the blood glucose level in diabetics, drug prescriptions, intravenous
fluids or temperature control (2, 56). The prescription of a patient specific oxygen
range is in-keeping with most of the current guidelines which deal with the
application of supplementary oxygen (22, 33, 47), however its usefulness is limited by
a poor knowledge and understanding of the correct application of oxygen therapy
by many junior doctors and nurses (65).
Page 15 of 21
“Permissive Hypoxaemia”
In critically ill patients, the hypoxia observed may be of sub-acute or chronic
duration. This in turn may be resulting in physiological adaptation at a cellular
level. It is hypothesised that these patients may benefit from targeting a lower
arterial oxygen level than would normally be accepted due to the increased
resilience to hypoxia that the adaptation provides, combined with the decreased
harm associated with chasing a normoxaemic level. This strategy at the moment
is still hypothetical as more work needs to be done in order to identify oxygenation
levels, biomarkers and patient cohorts that will allow its safe and effective
implementation (2, 56).
Fig. 7: Permissive Hypoxaemia (66)
Page 16 of 21
REFERENCES
1. Lane N. Oxygen: The Molecule that Made the World. Oxford: Oxford University Press; 2003.
2. Martin DS, Grocott MP. III. Oxygen therapy in anaesthesia: the yin and yang of O2. British
journal of anaesthesia. 2013 Dec;111(6):867-71. PubMed PMID: 24233308. Epub
2013/11/16. eng.
3. Muskopf S. Cellular Respiration: Biologycorner.com; 2014 [cited 2014 04/03/2014].
Available from:
http://www.biologycorner.com/APbiology/cellular/notes_cellular_respiration.html.
4. Dictionary TAHSsM. Hyperoxia 2014 [cited
http://dictionary.reference.com/browse/hyperoxia.
2014
19/03/14].
Available
from:
5. Quizlet.com. Delivery of Oxygen: www.Quizlet.com; 2014 [cited 2014]. Available from:
http://quizlet.com/3931436/ap13-ventilation-perfusion-flash-cards/.
6. Iscoe S, Beasley R, Fisher JA. Supplementary oxygen for nonhypoxemic patients: O2 much
of a good thing? Critical care (London, England). 2011;15(3):305. PubMed PMID:
21722334. Pubmed Central PMCID: PMC3218982. Epub 2011/07/05. eng.
7. Brown DW, Hadway J, Lee TY. Near-infrared spectroscopy measurement of oxygen
extraction fraction and cerebral metabolic rate of oxygen in newborn piglets. Pediatric
research. 2003 Dec;54(6):861-7. PubMed PMID: 12930911. Epub 2003/08/22. eng.
8. Johnston AJ, Steiner LA, Gupta AK, Menon DK. Cerebral oxygen vasoreactivity and
cerebral tissue oxygen reactivity. British journal of anaesthesia. 2003 Jun;90(6):774-86.
PubMed PMID: 12765894. Epub 2003/05/27. eng.
9. Floyd TF, Clark JM, Gelfand R, Detre JA, Ratcliffe S, Guvakov D, et al. Independent
cerebral vasoconstrictive effects of hyperoxia and accompanying arterial hypocapnia at 1
ATA. Journal of applied physiology (Bethesda, Md : 1985). 2003 Dec;95(6):2453-61.
PubMed PMID: 12937024. Epub 2003/08/26. eng.
10. Majid DS, Kopkan L. Nitric oxide and superoxide interactions in the kidney and their
implication in the development of salt-sensitive hypertension. Clinical and experimental
pharmacology & physiology. 2007 Sep;34(9):946-52. PubMed PMID: 17645645. Epub
2007/07/25. eng.
11. Farquhar H, Weatherall M, Wijesinghe M, Perrin K, Ranchord A, Simmonds M, et al.
Systematic review of studies of the effect of hyperoxia on coronary blood flow. American
heart journal. 2009 Sep;158(3):371-7. PubMed PMID: 19699859. Epub 2009/08/25. eng.
12. Haque WA, Boehmer J, Clemson BS, Leuenberger UA, Silber DH, Sinoway LI.
Hemodynamic effects of supplemental oxygen administration in congestive heart failure.
Journal of the American College of Cardiology. 1996 Feb;27(2):353-7. PubMed PMID:
8557905. Epub 1996/02/01. eng.
13. Dallinger S, Dorner GT, Wenzel R, Graselli U, Findl O, Eichler HG, et al. Endothelin-1
contributes to hyperoxia-induced vasoconstriction in the human retina. Investigative
ophthalmology & visual science. 2000 Mar;41(3):864-9. PubMed PMID: 10711705. Epub
2000/03/11. eng.
14. Yamazaki F, Takahara K, Sone R, Johnson JM. Influence of hyperoxia on skin vasomotor
control in normothermic and heat-stressed humans. Journal of applied physiology
(Bethesda, Md : 1985). 2007 Dec;103(6):2026-33. PubMed PMID: 17885027. Epub
2007/09/22. eng.
Page 17 of 21
15. Focosi D. Physiology of Adult Homo Sapiens: Universidade Federal do Rio Grande do Sul;
2013 [cited 2014 19/02/2014]. Available from:
http://www.ufrgs.br/imunovet/molecular_immunology/blood.html.
16. Zhilyaev SY, Moskvin AN, Platonova TF, Gutsaeva DR, Churilina IV, Demchenko IT.
Hyperoxic vasoconstriction in the brain is mediated by inactivation of nitric oxide by
superoxide anions. Neuroscience and behavioral physiology. 2003 Oct;33(8):783-7.
PubMed PMID: 14635993. Epub 2003/11/26. eng.
17. Cornet AD, Kooter AJ, Peters MJ, Smulders YM. Supplemental oxygen therapy in medical
emergencies: more harm than benefit? Archives of internal medicine. 2012 Feb
13;172(3):289-90. PubMed PMID: 22231614. Epub 2012/01/11. eng.
18. Iscoe S, Fisher JA. Hyperoxia-induced hypocapnia: an underappreciated risk. Chest. 2005
Jul;128(1):430-3. PubMed PMID: 16002967. Epub 2005/07/09. eng.
19. Becker HF, Polo O, McNamara SG, Berthon-Jones M, Sullivan CE. Effect of different levels
of hyperoxia on breathing in healthy subjects. Journal of applied physiology (Bethesda, Md :
1985). 1996 Oct;81(4):1683-90. PubMed PMID: 8904587. Epub 1996/10/01. eng.
20. Poole R. SEB Bulletin Otober 2006 - ROS: A radical paradox: SE Biology; 2006 [cited 2014
19/02/2014]. Available from:
http://www.sebiology.org/publications/Bulletin/October06/Reactive_Oxygen.html.
21. Hancock JT, Desikan R, Neill SJ. Role of reactive oxygen species in cell signalling
pathways. Biochemical Society transactions. 2001 May;29(Pt 2):345-50. PubMed PMID:
11356180. Epub 2001/05/18. eng.
22. Wyllie J, Perlman JM, Kattwinkel J, Atkins DL, Chameides L, Goldsmith JP, et al. Part 11:
Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation
and Emergency Cardiovascular Care Science with Treatment Recommendations.
Resuscitation. 2010 Oct;81 Suppl 1:e260-87. PubMed PMID: 20956039. Epub 2010/10/20.
eng.
23. Saugstad OD, Ramji S, Vento M. Oxygen for newborn resuscitation: how much is enough?
Pediatrics. 2006 Aug;118(2):789-92. PubMed PMID: 16882835. Epub 2006/08/03. eng.
24. Davis PG, Tan A, O'Donnell CP, Schulze A. Resuscitation of newborn infants with 100%
oxygen or air: a systematic review and meta-analysis. Lancet. 2004 Oct 915;364(9442):1329-33. PubMed PMID: 15474135. Epub 2004/10/12. eng.
25. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic
review and meta-analysis. Resuscitation. 2007 Mar;72(3):353-63. PubMed PMID:
17240032. Epub 2007/01/24. eng.
26. Vento M, Sastre J, Asensi MA, Vina J. Room-air resuscitation causes less damage to heart
and kidney than 100% oxygen. American journal of respiratory and critical care medicine.
2005 Dec 1;172(11):1393-8. PubMed PMID: 16141440. Epub 2005/09/06. eng.
27. Vento M, Asensi M, Sastre J, Lloret A, Garcia-Sala F, Vina J. Oxidative stress in
asphyxiated term infants resuscitated with 100% oxygen. The Journal of pediatrics. 2003
Mar;142(3):240-6. PubMed PMID: 12640369. Epub 2003/03/18. eng.
28. Naumburg E, Bellocco R, Cnattingius S, Jonzon A, Ekbom A. Supplementary oxygen and
risk of childhood lymphatic leukaemia. Acta paediatrica (Oslo, Norway : 1992).
2002;91(12):1328-33. PubMed PMID: 12578290. Epub 2003/02/13. eng.
Page 18 of 21
29. Spector LG, Klebanoff MA, Feusner JH, Georgieff MK, Ross JA. Childhood cancer following
neonatal oxygen supplementation. The Journal of pediatrics. 2005 Jul;147(1):27-31.
PubMed PMID: 16027689. Epub 2005/07/20. eng.
30. Abernethy AP, McDonald CF, Frith PA, Clark K, Herndon JE, 2nd, Marcello J, et al. Effect of
palliative oxygen versus room air in relief of breathlessness in patients with refractory
dyspnoea: a double-blind, randomised controlled trial. Lancet. 2010 Sep 4;376(9743):78493. PubMed PMID: 20816546. Pubmed Central PMCID: PMC2962424. Epub 2010/09/08.
eng.
31. O'Driscoll BR, Howard LS, Davison AG. Emergency oxygen use in adult patients: concise
guidance. Clinical medicine (London, England). 2011 Aug;11(4):372-5. PubMed PMID:
21853838. Epub 2011/08/23. eng.
32. Branson RD, Johannigman JA. Pre-hospital oxygen therapy. Respiratory care. 2013
Jan;58(1):86-97. PubMed PMID: 23271821. Epub 2012/12/29. eng.
33. O'Driscoll BR, Howard LS, Davison AG. BTS guideline for emergency oxygen use in adult
patients. Thorax. 2008 Oct;63 Suppl 6:vi1-68. PubMed PMID: 18838559. Epub 2008/10/22.
eng.
34. AL. B. Therapeutic use of oxygen in heart disease. Annals of Internal Medicine.
1931;5(10):428.
35. Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasyamani LK, et al. 2007
focused update of the ACC/AHA 2004 guidelines for the management of patients with STelevation myocardial infarction: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines. Journal of the American College of
Cardiology. 2008 Jan 15;51(2):210-47. PubMed PMID: 18191746. Epub 2008/01/15. eng.
36. Ganz W, Donoso R, Marcus H, Swan HJ. Coronary hemodynamics and myocardial oxygen
metabolism during oxygen breathing in patients with and without coronary artery disease.
Circulation. 1972 Apr;45(4):763-8. PubMed PMID: 5016013. Epub 1972/04/01. eng.
37. Mak S, Azevedo ER, Liu PP, Newton GE. Effect of hyperoxia on left ventricular function and
filling pressures in patients with and without congestive heart failure. Chest. 2001
Aug;120(2):467-73. PubMed PMID: 11502645. Epub 2001/08/15. eng.
38. McNulty PH, King N, Scott S, Hartman G, McCann J, Kozak M, et al. Effects of
supplemental oxygen administration on coronary blood flow in patients undergoing cardiac
catheterization. American journal of physiology Heart and circulatory physiology. 2005
Mar;288(3):H1057-62. PubMed PMID: 15706043. Epub 2005/02/12. eng.
39. McNulty PH, Robertson BJ, Tulli MA, Hess J, Harach LA, Scott S, et al. Effect of hyperoxia
and vitamin C on coronary blood flow in patients with ischemic heart disease. Journal of
applied physiology (Bethesda, Md : 1985). 2007 May;102(5):2040-5. PubMed PMID:
17303710. Epub 2007/02/17. eng.
40. Stub D, Smith K, Bernard S, Bray JE, Stephenson M, Cameron P, et al. A randomized
controlled trial of oxygen therapy in acute myocardial infarction Air Verses Oxygen In
myocarDial infarction study (AVOID Study). American heart journal. 2012 Mar;163(3):33945 e1. PubMed PMID: 22424003. Epub 2012/03/20. eng.
41. Pilcher J, Weatherall M, Shirtcliffe P, Bellomo R, Young P, Beasley R. The effect of
hyperoxia following cardiac arrest - A systematic review and meta-analysis of animal trials.
Resuscitation. 2012 Apr;83(4):417-22. PubMed PMID: 22226734. Epub 2012/01/10. eng.
Page 19 of 21
42. Kilgannon JH, Jones AE, Shapiro NI, Angelos MG, Milcarek B, Hunter K, et al. Association
between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital
mortality. JAMA : the journal of the American Medical Association. 2010 Jun
2;303(21):2165-71. PubMed PMID: 20516417. Epub 2010/06/03. eng.
43. Bellomo R, Bailey M, Eastwood GM, Nichol A, Pilcher D, Hart GK, et al. Arterial hyperoxia
and in-hospital mortality after resuscitation from cardiac arrest. Critical care (London,
England). 2011;15(2):R90. PubMed PMID: 21385416. Pubmed Central PMCID:
PMC3219350. Epub 2011/03/10. eng.
44. Park JH, Balmain S, Berry C, Morton JJ, McMurray JJ. Potentially detrimental
cardiovascular effects of oxygen in patients with chronic left ventricular systolic dysfunction.
Heart (British Cardiac Society). 2010 Apr;96(7):533-8. PubMed PMID: 20350990. Epub
2010/03/31. eng.
45. Rusyniak DE, Kirk MA, May JD, Kao LW, Brizendine EJ, Welch JL, et al. Hyperbaric oxygen
therapy in acute ischemic stroke: results of the Hyperbaric Oxygen in Acute Ischemic Stroke
Trial Pilot Study. Stroke; a journal of cerebral circulation. 2003 Feb;34(2):571-4. PubMed
PMID: 12574578. Epub 2003/02/08. eng.
46. Ronning OM, Guldvog B. Should stroke victims routinely receive supplemental oxygen? A
quasi-randomized controlled trial. Stroke; a journal of cerebral circulation. 1999
Oct;30(10):2033-7. PubMed PMID: 10512903. Epub 1999/10/08. eng.
47. Adams HP, Jr., del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. Guidelines for
the early management of adults with ischemic stroke: a guideline from the American Heart
Association/American Stroke Association Stroke Council, Clinical Cardiology Council,
Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral
Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working
Groups: The American Academy of Neurology affirms the value of this guideline as an
educational tool for neurologists. Circulation. 2007 May 22;115(20):e478-534. PubMed
PMID: 17515473. Epub 2007/05/23. eng.
48. Al-Niaimi A, Safdar N. Supplemental perioperative oxygen for reducing surgical site
infection: a meta-analysis. Journal of evaluation in clinical practice. 2009 Apr;15(2):360-5.
PubMed PMID: 19335497. Epub 2009/04/02. eng.
49. Meyhoff CS, Wetterslev J, Jorgensen LN, Henneberg SW, Hogdall C, Lundvall L, et al.
Effect of high perioperative oxygen fraction on surgical site infection and pulmonary
complications after abdominal surgery: the PROXI randomized clinical trial. JAMA : the
journal of the American Medical Association. 2009 Oct 14;302(14):1543-50. PubMed PMID:
19826023. Epub 2009/10/15. eng.
50. Eskes A, Vermeulen H, Lucas C, Ubbink DT. Hyperbaric oxygen therapy for treating acute
surgical and traumatic wounds. The Cochrane database of systematic reviews.
2013;12:CD008059. PubMed PMID: 24343585. Epub 2013/12/18. eng.
51. Hedenstierna G, Rothen HU. Atelectasis formation during anesthesia: causes and
measures to prevent it. Journal of clinical monitoring and computing. 2000;16(5-6):329-35.
PubMed PMID: 12580216. Epub 2003/02/13. eng.
52. O'Brien J. Absorption atelectasis: incidence and clinical implications. AANA journal. 2013
Jun;81(3):205-8. PubMed PMID: 23923671. Epub 2013/08/09. eng.
53. Hedenstierna G. Oxygen and anesthesia: what lung do we deliver to the post-operative
ward? Acta anaesthesiologica Scandinavica. 2012 Jul;56(6):675-85. PubMed PMID:
22471648. Epub 2012/04/05. eng.
Page 20 of 21
54. Duggan M, Kavanagh BP. Atelectasis in the perioperative patient. Current opinion in
anaesthesiology. 2007 Feb;20(1):37-42. PubMed PMID: 17211165. Epub 2007/01/11. eng.
55. Thomas D. Oxygen, Atelectais and Anaesthesia: Scancrit.com; 2013 [cited 2014
10/03/2014]. Available from: http://www.scancrit.com/2013/07/08/oxygen-atelectasisanaesthesia/.
56. Martin DS, Grocott MP. Oxygen therapy in critical illness: precise control of arterial
oxygenation and permissive hypoxemia. Critical care medicine. 2013 Feb;41(2):423-32.
PubMed PMID: 23263574. Epub 2012/12/25. eng.
57. Abel SJ, Finney SJ, Brett SJ, Keogh BF, Morgan CJ, Evans TW. Reduced mortality in
association with the acute respiratory distress syndrome (ARDS). Thorax. 1998
Apr;53(4):292-4. PubMed PMID: 9741374. Pubmed Central PMCID: PMC1745195. Epub
1998/09/19. eng.
58. Suchyta MR, Clemmer TP, Elliott CG, Orme JF, Jr., Weaver LK. The adult respiratory
distress syndrome. A report of survival and modifying factors. Chest. 1992 Apr;101(4):10749. PubMed PMID: 1555423. Epub 1992/04/11. eng.
59. Levett DZ, Radford EJ, Menassa DA, Graber EF, Morash AJ, Hoppeler H, et al.
Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of
Everest. FASEB journal : official publication of the Federation of American Societies for
Experimental Biology. 2012 Apr;26(4):1431-41. PubMed PMID: 22186874. Epub
2011/12/22. eng.
60. Martin DS, Khosravi M, Grocott MP, Mythen MG. Concepts in hypoxia reborn. Critical care
(London, England). 2010;14(4):315. PubMed PMID: 20727228. Pubmed Central PMCID:
PMC2945079. Epub 2010/08/24. eng.
61. Fisher AB. Oxygen therapy. Side effects and toxicity. The American review of respiratory
disease. 1980 Nov;122(5 Pt 2):61-9. PubMed PMID: 7458051. Epub 1980/11/01. eng.
62. Crapo JD. Morphologic changes in pulmonary oxygen toxicity. Annual review of physiology.
1986;48:721-31. PubMed PMID: 3518622. Epub 1986/01/01. eng.
63. Nash G, Blennerhassett JB, Pontoppidan H. Pulmonary lesions associated with oxygen
therapy and artifical ventilation. The New England journal of medicine. 1967 Feb
16;276(7):368-74. PubMed PMID: 6017244. Epub 1967/02/16. eng.
64. Fox RB, Hoidal JR, Brown DM, Repine JE. Pulmonary inflammation due to oxygen toxicity:
involvement of chemotactic factors and polymorphonuclear leukocytes. The American
review of respiratory disease. 1981 May;123(5):521-3. PubMed PMID: 7235375. Epub
1981/05/01. eng.
65. Ganeshan A, Hon LQ, Soonawalla ZF. Oxygen: Can we prescribe it correctly? European
journal of internal medicine. 2006 Aug;17(5):355-9. PubMed PMID: 16864012. Epub
2006/07/26. eng.
66. Martin D, Grocott, M. Oxygen Therapy in Critical Illness: Crit Care Med.; 2013 [cited 2014
19/02/2014]. Available from: http://www.medscape.com/viewarticle/778505_5.
Page 21 of 21