Oxygen therapy for acute myocardial infarction-then and now. A century of uncertainty.
ABSTRACT For about 100 years, inhaled oxygen has been administered to all patients suspected of having an acute myocardial infarction. The basis for this practice was the belief that oxygen supplementation raised often-deficient arterial oxygen content to improve myocardial oxygenation, thereby reducing infarct size. This assumption is conditional and not evidence-based. While such physiological changes may pertain in some patients who are hypoxemic, considerable data suggest that oxygen therapy may be detrimental in others. Acute oxygen therapy may raise blood pressure and lower cardiac index, heart rate, cardiac oxygen consumption, and blood flow in the cerebral and renal beds. Oxygen also may lower capillary density and redistribute blood in the microcirculation. Several reports now confirm that these changes occur in humans. In patients with both acute coronary syndromes and stable coronary disease, oxygen administration may constrict the coronary vessels, lower myocardial oxygen delivery, and may actually worsen ischemia. There are no large, contemporary, randomized studies that examine clinical outcomes after this intervention. Hence, this long-accepted but potentially harmful tradition urgently needs reevaluation. Clinical guidelines appear to be changing, favoring use of oxygen only in hypoxemic patients, and then cautiously titrating to individual oxygen tensions.
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ABSTRACT: Oxygen is one of the most frequently-used therapeutic agents in medicine and the most commonly administered drug by prehospital personnel. There is increasing evidence of harm with too much supplemental oxygen in certain conditions, including stroke, chronic obstructive pulmonary disease (COPD), neonatal resuscitations, and in postresuscitation care. Recent guidelines published by the British Thoracic Society (BTS) advocate titrated oxygen therapy, but these guidelines have not been widely adapted in the out-of-hospital setting where high-flow oxygen is the standard. This report is a description of the implementation of a titrated oxygen protocol in a large urban-suburban Emergency Medical Services (EMS) system and a discussion of the practical application of this out-of-hospital protocol. Bosson N , Gausche-Hill M , Koenig W . Implementation of a titrated oxygen protocol in the out-of-hospital setting. Prehosp Disaster Med. 2014;28(4):1-6 .Prehospital and disaster medicine: the official journal of the National Association of EMS Physicians and the World Association for Emergency and Disaster Medicine in association with the Acute Care Foundation 07/2014;
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ABSTRACT: The aim of this study was to assess the effect on adherence to statin therapy and assess the effect of beneficial changes in behavior that resulted in weight loss in patients who underwent coronary artery calcium (CAC) scoring with cardiac computed tomography. Despite convincing data demonstrating the benefits of HmGCoA inhibitors for both primary and secondary prevention of coronary heart disease, they remain underused. Also, despite convincing data demonstrating the benefits of weight loss for both primary and secondary prevention of coronary heart disease, it remains difficult to motivate behavioral changes resulting in weight loss. In this study, we assess whether higher CAC scores are associated with increased compliance with statin medication and whether higher CAC scores are associated with beneficial lifestyle behaviors resulting in weight loss. We retrospectively analyzed patients that had undergone baseline CAC testing and returned for a follow-up scan. All patients had weight documented and were administered a questionnaire regarding compliance to medications. The primary endpoint was measurable weight loss between visit one and visit two and the self-reported compliance to statin use. The study population with data regarding statin compliance consisted of 2608 individuals (72% men, mean age 58±8 years) who were followed for a mean of 4.1±3.2 years after an initial CAC scan. Overall, statin compliance was lowest (27.4%) among those with CAC=0, and gradually increased with higher CAC scores (1-99, 39.2%; 100-399, 53.6%; ≥400, 58.8%; P<0.001 for trend). In the group analyzed for weight loss the study population consisted of 1078 individuals (68% men, mean age 60±8 years) who were followed for a mean of 4.1±3.2 years after an initial CAC scan. Overall, behavioral modification resulting in weight loss was lowest (19.8%) among those with CAC=0, and gradually increased with higher CAC scores (1-99, 23.4%; 100-399, 30.8%; ≥400, 33.6%; P<0.001 for trend). In addition to being a robust risk stratification tool, a higher rate of adherences with statin therapy was observed in patients with higher CAC scores.Coronary Artery Disease 12/2014; · 1.30 Impact Factor
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ABSTRACT: The use of supplemental oxygen in the setting of suspected acute myocardial infarction (AMI) is recommended in international treatment guidelines and established in prehospital and hospital clinical routine throughout the world. However, to date there is no conclusive evidence from adequately designed and powered trials supporting this practice. Existing data are conflicting and fail to clarify the role of supplemental oxygen in AMI. A total of 6,600 normoxemic (oxygen saturation [SpO2] ≥90%) patients with suspected AMI will be randomly assigned to either supplemental oxygen 6 L/min delivered by Oxymask (MedCore Sweden AB, Kista, Sweden) for 6 to 12 hours in the treatment group or room air in the control group. Patient inclusion and randomization will take place at first medical contact, either before hospital admission or at the emergency department. The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry will be used for online randomization, allowing inclusion of a broad population of all-comers. Follow-up will be carried out in nationwide health registries and Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies. The primary objective is to evaluate whether oxygen reduces 1-year all-cause mortality. Secondary end points include 30-day mortality, major adverse cardiac events, and health economy. Prespecified subgroups include patients with confirmed AMI and certain risk groups. In a 3-month pilot study, the study concept was found to be safe and feasible. The need to clarify the uncertainty of the role of supplemental oxygen therapy in the setting of suspected AMI is urgent. The DETO2X-AMI trial is designed and powered to address this important issue and may have a direct impact on future recommendations.American heart journal 03/2014; 167(3):322-8. · 4.56 Impact Factor
Oxygen Therapy for Acute Myocardial Infarction—Then
and Now. A Century of Uncertainty
Richard Kones, MD, FAHA, FESC
Cardiometabolic Research Institute, Houston, Tex.
For about 100 years, inhaled oxygen has been administered to all patients suspected of having an acute
myocardial infarction. The basis for this practice was the belief that oxygen supplementation raised
often-deficient arterial oxygen content to improve myocardial oxygenation, thereby reducing infarct size.
This assumption is conditional and not evidence-based. While such physiological changes may pertain in
some patients who are hypoxemic, considerable data suggest that oxygen therapy may be detrimental in
others. Acute oxygen therapy may raise blood pressure and lower cardiac index, heart rate, cardiac oxygen
consumption, and blood flow in the cerebral and renal beds. Oxygen also may lower capillary density and
redistribute blood in the microcirculation. Several reports now confirm that these changes occur in humans.
In patients with both acute coronary syndromes and stable coronary disease, oxygen administration may
constrict the coronary vessels, lower myocardial oxygen delivery, and may actually worsen ischemia.
There are no large, contemporary, randomized studies that examine clinical outcomes after this interven-
tion. Hence, this long-accepted but potentially harmful tradition urgently needs reevaluation. Clinical
guidelines appear to be changing, favoring use of oxygen only in hypoxemic patients, and then cautiously
titrating to individual oxygen tensions.
© 2011 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2011) 124, 1000-1005
KEYWORDS: Acute coronary syndrome guidelines; Acute myocardial infarction; Coronary artery disease; Hyper-
oxia; Hyperoxic vasoconstriction; Hypoxemia; Myocardial oxygenation; Oxygen inhalation; Oxygen toxicity
In September 1955, President Eisenhower, who had been a
4-pack/day smoker and followed an atherogenic diet, sus-
tained an anterior myocardial infarction. He was placed in
an oxygen tent, given anticoagulants despite a friction rub,
and kept at strict bed rest for 4 weeks. Observers blamed
chronic low intensity exercise—golf—as an etiological fac-
tor in producing the episode. Dr Paul Dudley White was not
only criticized for mobilizing him “early,” allowing him to
begin walking at 6 weeks, but also for suggesting that
chronic exercise was cardioprotective.1The President’s per-
sonal experience may have led him to establish, by Execu-
tive Order, the President’s Council on Youth Fitness some
The management of acute coronary syndromes has
changed markedly from the 1950s, when medicine was
organized as a “cottage industry” and about to transition
from a descriptive discipline. During the 61 years since,
medicine has undergone a metamorphosis to an increasingly
quantitative science based upon the scientific method, physico-
chemical principles, and “evidence-based medicine.” One
of the holdovers from that era, when patients with acute
myocardial infarction (AMI) were treated with bed rest for
4-6 weeks and were relatively unmonitored, is the use of
Because heart muscle death during AMI is associated with
coronary blood flow, and hypoxemia, frequently observed in
such patients, reduces the ability of the blood to carry oxygen,
the belief evolved that oxygen inhalation raised oxygen deliv-
ery to ischemic myocardium, leading to reduced infarct size.
Based upon this assumption, it appeared reasonable to admin-
ister oxygen by nasal cannula, mask, or tent, and this practice
has continued rather routinely for all patients suspected of
having an AMI for about 100 years. In 2011, however, with
Conflict of Interest: None.
Authorship: The author is solely responsible for the entire content of
Requests for reprints should be addressed to Richard Kones, MD,
FAHA, FESC, Cardiometabolic Research Institute, 8181 Fannin St, U314,
Houston, TX 77054.
E-mail address: firstname.lastname@example.org
0002-9343/$ -see front matter © 2011 Elsevier Inc. All rights reserved.
Published in the Nov 2011 issue. Abstract available at
http://www.ncbi.nlm.nih.gov/pubmed/22017777. Full access
available through MDconsult.com, OVID, or Science Direct.
more sophisticated and rigorous criteria, advanced technology,
and relying more upon demonstrable clinical outcomes than
translating directly from the laboratory to the bedside, the use
of inhaled oxygen in patients with uncomplicated acute
coronary syndromes is being questioned. Closer examinat-
ion reveals that the long-standing
assumption upon which oxygen
therapy is based is conditional, and
is not evidence-based. There is no
better example of being misled by
observational reports than the past,
overzealous use of prophylactic in-
travenous lidocaine in such patients,
only to discover that actual out-
comes were convincingly detrimen-
tal.2Similarly, because evidence of
harm was not striking during tradi-
tional oxygen use in AMI during
these many years, a laissez-faire
attitude prevailed. In hypoxemic pa-
tients with complicated AMI, oxy-
gen therapy was, and remains,
EARLY LABORATORY AND
After Steele successfully used inhaled oxygen to relieve
angina in 1900,4the practice endured, based upon the pop-
ular notion that administered oxygen increased oxygen de-
livery to the myocardium and reduced infarct size.5,6Fifty
years later Russek et al7found that 100% oxygen given by
mask not only failed to relieve or modify angina, but ac-
centuated and prolonged some electrocardiographic changes
of ischemia. They postulated that hyperoxic blood pre-
vented reactive hyperemia in ischemic myocardium and
might be contraindicated during normoxemia but not during
hypoxia. Two decades later, when techniques capable of
decreasing infarct size were being explored, Maroko et al8
showed that 40% oxygen administration reduced the extent
of myocardial ischemic injury assessed by ST-segment and
biochemical marker elevations in a canine model. Madias
and Hood9also reported reductions in ST-segment eleva-
tions on precordial mapping in patients inhaling 16% oxy-
gen through masks, which was again attributed to a decrease
in the volume of ischemic myocardium. Both of these stud-
ies, however, had significant methodological limitations. A
trial by Horvat et al10in 11 patients with coronary heart
disease (CHD) found that oxygen supplementation raised
the threshold to pacing-induced angina, that is, at a greater
rate-pressure product associated with a higher left ventric-
ular oxygen consumption.
Rawles and Kenmure11conducted a double-blind study
of the effects of oxygen in 200 consecutive patients with
suspected myocardial infarction who were randomized to
receive either oxygen 6 L/min by mask or compressed air
during their first 24 hours in the hospital. After 43 patients
were excluded who proved not to have a myocardial infarc-
tion, both groups were comparable except for higher serum
aspartate aminotransferase and PaO2levels in the oxygen
group. The incidence of arrhythmias and mortality was no
better in the oxygen group than in the nontreated subjects.
Although not statistically signifi-
cant, 9 of 80 (11.25%) patients in
the oxygen group died, compared
with 3 of 77 (3.8%) in the com-
pressed air group.
Wilson and Channer12
veyed coronary care units in Eng-
land regarding use of pulse oxim-
etry to guide oxygen therapy after
AMI. They randomized 50 pa-
tients who presented within 24
hours of AMI to either inhaled ox-
ygen or room air. Among patients
breathing room air, 70% had an
oxygen saturation (SpO2) ?90%,
and 35% of them had an SpO2
?35%, compared with 27% and
4%, respectively, among patients
who received oxygen. There were
no differences between groups in
the incidence of arrhythmias or
therapy was easily guided by pulse oximetry, although un-
common at that time.
HEMODYNAMIC EFFECTS OF OXYGEN AND
MYOCARDIAL OXYGEN AVAILABILITY
Oxygen is a vasoactive substance, and the hemodynamic
effects upon healthy subjects and patients with AMI are
fairly well known. Acute oxygen administration may raise
blood pressure13and lower cardiac index, heart rate, and
cardiac oxygen consumption.14,15Coronary blood flow falls
in response to hyperoxia-induced vasoconstriction regard-
less of initial saturation.16Oxygen-induced vasoconstriction
may similarly lower cerebral17and renal blood flow.18
Thomas et al19found that 40% oxygen given to patients
within a few days of onset of AMI increased arterial blood
pressure with a fall in cardiac output, later confirmed by
Kenmure et al.20Foster et al21were able to document a
continuous increase in systemic vascular resistance and ar-
terial pressure as arterial oxygen tension increased, but not
a fall in cardiac output.
Preclinical studies show that hyperoxia may lower myo-
cardial oxygen consumption for reasons unrelated to cardiac
output or heart rate. Because high oxygen tensions lower
capillary density, thereby reducing oxygen transport into
muscle, hyperoxia may decrease myocardial oxygen con-
sumption.22,23In addition, high-flow oxygen administration
may disturb blood distribution in the microcirculation, lead-
ing to functional oxygen shunting and lowered total-body
● The practice of administering inhaled
oxygen to patients suspected of having
an acute myocardial infarction is wide-
spread, has been followed for about a
century, and is advised in major text-
books of emergency care, general med-
icine, and cardiology.
● A review of the evolution of supplemen-
tal oxygen therapy reveals that it is not
evidence-based, and in fact, guidelines
appear to be changing.
● Based upon available data, a revision of
this practice is suggested.
1001 Kones Oxygen Therapy for Acute Myocardial Infarction
oxygen consumption,24perhaps teleologically to protect tis-
sues from toxic effects of high oxygen tensions.
Indeed, Sukumalchantra et al25reported that in AMI
patients whose arterial oxygen saturation was over 90%,
oxygen administration did not produce a net increase in
oxygen transport in the myocardium because the effects of
lowered cardiac output, associated with decreases in coro-
nary blood flow and higher coronary vascular resistance,26
overcame the increase in oxygen content. However, when
arterial oxygen saturation was ?90%, the resulting increase
in both cardiac output and oxygen content after oxygen
supplementation increased net oxygen transport. By mea-
suring lactate/pyruvate ratios in coronary venous blood,
Neill27demonstrated that in patients with CHD, anaerobic
metabolism, reflecting ischemia, occurred when arterial ox-
ygen saturation was between 70% and 85%, but in healthy
subjects, hypoxia did not cause such changes until oxygen
saturation was about 50%. Hyperoxia did not raise myocar-
dial oxygen availability or reverse ischemia in patients with
heart disease. Bourassa and associates28noted further that in
patients with advanced triple vessel disease, abnormal lac-
tate values were associated with 100% oxygen therapy.
Thus, while high-flow oxygen may increase oxygen content,
a simultaneous fall in coronary blood flow may not only fail
to improve overall myocardial oxygenation, but actually
worsen the effects of ischemia. Oxidant stress is also asso-
ciated with endothelial dysfunction and a cascade of subse-
quent deleterious molecular events.
More recently, McNulty et al26measured the effects of
breathing 100% oxygen by face mask for 15 minutes on
coronary blood flow (via coronary Doppler flow wire) in 18
patients with stable CHD. Breathing 100% oxygen
promptly decreased coronary blood flow by 29% and raised
coronary vascular resistance by 41% without changing the
diameter of large-conduit coronary arteries, suggesting in-
volvement of the microcirculation. Momen et al29used
duplex ultrasound to measure coronary blood velocity, an
index of coronary blood flow, in 7 healthy volunteers
breathing room air and 100% oxygen for 5 minutes. Com-
pared with room air, coronary blood velocity fell ?15%
while coronary vascular resistance rose by ?20%. Because
similar changes also were observed in patients who received
cardiac transplants several months before, hyperoxia appar-
ently produced vasoconstriction of the coronary arteries
through a direct effect, rather than through autonomic
Several systematic reviews of the effects of oxygen in
patients with CHD are available. In 2004, a review of 9
trials failed to demonstrate effectiveness because of insuf-
ficient evidence.30In 2008, Wijesinghe et al31identified 51
studies, but only 2 met inclusion criteria of substantive
clinical outcomes. It was concluded that evidence was lim-
ited, but primarily using the trial results of Rawles and
Kenmure,11support for oxygen therapy in all patients with
uncomplicated AMI was lacking, and oxygen may in fact
have resulted in a larger infarct size, as reflected by the
increase in aspartate aminotransferase levels observed.
A Cochrane study32reviewed bibliographic databases for
randomized controlled trials of patients with suspected or
proven AMI in which oxygen was administered within 24
hours after onset, and outcomes—particularly pain and
death—were compared with patients breathing room air. Of
2228 articles screened, only 3 trials qualified: Rawles and
Kenmure,11Wilson and Channer,12both older studies con-
ducted in the UK, and a Russian study, Ukholkina et al.33,34
Caution was urged because of the differences in current
management of AMI and, during the study periods, high
risk of bias for the main outcomes, and the curiously low
death rate among control participants, which averaged just
1.7%. A total of 387 patients were included, with a total of
14 deaths, about 3 times as many in patients randomized to
oxygen treatment than room air, not statistically significant,
and no benefit regarding pain relief, as assessed by analgesic
use. The pooled relative risk of death was 2.88 (95% con-
fidence interval [CI], 0.88-9.39) in an intention-to-treat
analysis, and 3.03 (95% CI, 0.93-9.83) in patients with
proven AMI. The pooled relative risk for analgesic use was
0.97 (95% CI, 0.78-1.20). Noting the paucity and poor
quality of the evidence, the authors concluded certainly no
benefit accrued from oxygen therapy in uncomplicated AMI
patients, but their analysis could not demonstrate any harm.
A definitive randomized controlled trial was deemed of
A commentary accompanying the Cochrane study35la-
mented the continuation of oxygen therapy in uncompli-
cated AMI patients, including use of oxygen in ambulances
before evaluation. The expense and difficulty of organizing
and performing a large randomized trial, especially without
funding and impetus of the pharmaceutical industry, were
cited. Another obstacle noted was the entrenchment of a
practice which was believed to be reasonable, simple, inex-
pensive, convenient, and apparently innocuous, together
with the psychological benefit to the paramedic, patient, and
physician by “doing something.”
An editorial in the British Medical Journal surprised
many readers by arguing in favor of routine use of supple-
mental oxygen, given the “positive physiological reasons”
and no trial evidence of harm.36To be sure, the methodol-
ogy was poor in all 3 trials analyzed by Cochrane; 2 studies
were performed unblinded and the third was accessible only
in abstract form in English.33The editorialist opined that
these limitations, combined with absence of demonstrable
harm, suggested the practice should continue. A flurry of
letters contesting this view followed.37
Of interest is the report by Kilgannon et al,38who ana-
lyzed data collected for the Project IMPACT database in-
volving 6326 adults with nontraumatic cardiac arrest admit-
ted to 120 US intensive care units after resuscitation.
Hyperoxia was present in 18% of the patients, hypoxia
present in 63%, and normoxia in 19%. The presence of
hyperoxia conferred an odds ratio for death of 1.8 (95% CI,
1002 The American Journal of Medicine, Vol 124, No 11, November 2011
1.5-2.2), indicating that arterial hyperoxia was indepen-
dently associated with increased in-hospital mortality com-
pared with either normoxia or hypoxia. Extension of this
work suggested a dose-dependent, linear relationship be-
tween supranormal oxygen tension and risk of in-hospital
death in postresuscitation patients.51
WHAT THE GUIDELINES SAY
Of guidelines that no longer recommend oxygen for all
AMI patients, one of the first was the British Thoracic
Society Guideline for Emergency Oxygen use, in which
oxygen was recommended only for hypoxemic patients.39
The National Institute for Health and Clinical Excellence
(NICE) Guideline on the management of chest pain of
suspected cardiac origin, the UK Ambulance Service
oxygen guideline, and a number of other societies sub-
sequently adopted similar advice.40-42The NICE guide-
line specifies the level of hypoxia that needs attention
with lower levels for patients with chronic obstructive
pulmonary disease (COPD).43Specifically, recommenda-
● Do not routinely administer oxygen, but monitor oxygen
saturation using pulse oximetry as soon as possible, ide-
ally before hospital admission. Only offer supplemental
oxygen to people with oxygen saturation (SaO2) of
?94% who are not at risk of hypercapnic respiratory
failure, aiming for SaO2of 94%–98%.
● In patients with COPD who are at risk of hypercapnic
respiratory failure, try to achieve a target SpO2of 88%–
92% until blood gas analysis is available.40
The American College of Cardiology/American Heart
Association (ACC/AHA) guideline on ST-elevation myo-
cardial infarction (STEMI)43assigned a class IIa, level of
evidence (LOE) C recommendation to the use of oxygen,
considering it reasonable to give supplemental oxygen to all
patients with uncomplicated STEMI during the first 6 hours.
The ACC/AHA guidelines for unstable angina (UA)/non-
STEMI (NSTEMI)44gave a class I, LOE B recommenda-
tion for administration of oxygen to all patients with UA/
NSTEMI with SaO2?90%, respiratory distress, or other
risk-risk features for hypoxemia, also recommending con-
tinuous monitoring with pulse oximetry. They also assigned
a class IIa, LOE C recommendation for supplemental oxy-
gen to all patients with UA/NSTEMI during the first 6 hours
The current European Society of Cardiology (ESC)
guideline on STEMI advises that in patients presenting with
chest pain, “oxygen 2-4 L/min by mask or nasal prongs
should be administered to those who are breathless or who
have any features of heart failure or shock.”45Members of
the ESC AMI-STEMI task force are aware of the issue and
a review is planned for the new ESC Clinical Practice
Guidelines due in 2012.
In addition to the variation in guidelines, there is some
further evidence that oxygen is inconsistently and casually
prescribed.46-48Garg and Lagan46audited 20 patients on
cardiology wards with respect to oxygen indication, mode
of delivery, documentation, and prescriptions written over a
2-month period. Numerous defects and issues were identi-
fied; prescriptions for oxygen were described as “very
poor,” resulting in significant potential for patient harm. A
call for greater quality and appropriateness in prescribing
oxygen was made. Most crucial was the need to improve
assessment for oxygen therapy and adequate titration to
individual patient requirement.49
Oxygen is a vasoactive drug and should be prescribed
only when indicated. The burden of proof properly falls
on the intervention, and there is no large, contemporary,
randomized study available. Evidence supporting use of
oxygen in patients suspected of having an AMI who are
normoxemic is of poor quality and now old, predating
modern trial methods, reperfusion, and other advances in
management. Recent data suggest that physiological ev-
idence of harm is strong, clinical evidence of harm is
weak, and there is no evidence for benefit. A large ran-
domized clinical trial is urgently needed. Currently, the
Air Versus Oxygen in myocardial Infarction Study
(AVOID) is in progress, a randomized trial with a pri-
mary end-point of infarct size as assessed with cardiac
troponin I and creatine kinase.50
In the interim, and consistent with the doctrine of
primum non nocere, it is suggested that in patients with
acute myocardial infarction who are hypoxemic, oxygen
is indicated to maintain arterial oxygen saturation from
94% to 96%. Sufficient evidence now exists that hyper-
oxia has the potential to induce unfavorable hemody-
namic and metabolic changes and should be avoided. In
patients with comorbidities, adjustments may be pro-
vided by proven therapies for those conditions. In pa-
tients at risk of hypercapnic respiratory failure, for in-
stance, a target oxygen saturation of 88% to 92% might
be appropriate until arterial blood gas results are avail-
able, with possible revision upward if PaCO2is not
elevated and there is no prior history of blunting hypox-
emia-driven respiratory drive with oxygen.
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