Annals of Medicine and Surgery 81 (2022) 104393

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Annals of Medicine and Surgery

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Review

Hyperoxia in the management of respiratory failure: A literature review

Elvina Elizabeth Lius, Irmi Syafaah *
Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga – Dr. Soetomo General Academic Hospital, Surabaya, Indonesia

A R T I C L E I N F O A B S T R A C T

Keywords: Management of respiratory failure is closely related to oxygen supplementation. Thus, its administration needed
Hyperoxia special attention according to indications to avoid the toxic effect. Oxygen supplementation in conditions of
Oxygen respiratory failure aims to overcome hypoxemia. Excessive oxygen exposure can cause oxygen toxicity and lead
Respiratory failure
to hyperoxia. Hyperoxia is a condition in which there is an excess supply of oxygen in the tissues and organs.
Toxicity
Clinically, respiratory failure is diagnosed if the PaO2 is less than 60 mmHg with or without an increase in carbon
dioxide when the patient breathes room air. Respiratory failure is divided into acute (sudden) respiratory failure
and chronic (slow) respiratory failure. The basis for managing respiratory failure consists of supportive/non-
specific and causative/specific management. Oxygen should be prescribed wisely not to cause injury to organs
such as the heart, lungs, eyes, nervous system, and others. Hyperoxia often occurs in managing respiratory
failure, so it requires supervision, especially in administering oxygen. Oxygen should be given as needed to avoid
hyperoxia. In oxygen therapy, it is necessary to pay attention to the patient’s condition because each condition
requires different oxygen concentrations, so dose adjustments are necessary. These conditions can be divided into
critical, severe, and observation conditions. The target oxygen saturation in all these conditions is 94–98%.

1. Introduction mechanical ventilation) [8,9].

Patients with respiratory failure require oxygen as the primary
Oxygen is a vital and primary gas in sustaining human life. Oxygen therapy to treat hypoxemia. To avoid excessive oxygen, prescribing
has been available in the atmosphere since 5 billion years ago [1]. oxygen supplementation must be considered correct and according to
Priestley was the first to discover oxygen and pointed out the harmful indications. Excessive oxygen exposure can cause oxygen toxicity and
effects. Oxygen can be of good therapeutic value if used as indicated in hyperoxia [4,10]. Hyperoxia is a condition in which there is an excess
patients with respiratory failure [2–4]. Respiratory failure is a syndrome supply of oxygen to the tissues and organs. Oxygen toxicity occurs when
in which the respiratory system cannot maintain adequate gas exchange the alveolar partial pressure of O2 (PaO2) exceeds that inhaled under
at rest or with activity. Inability to adequately perform the essential normal conditions [10–12].
functions of respiration, namely sending oxygen to the blood and A non-indicated administration of oxygen supplementation exceeds
removing carbon dioxide. Clinically respiratory failure is diagnosed excessive use of antibiotics. This is often not realized and is considered
when the PaO2 is less than 60 mmHg with or without increased carbon good. Annually, the need for oxygen supplementation is projected to be
dioxide when the patient is breathing room air [5–7]. around 800,000 individuals at the cost of $1.8 billion [11]. Prolonged
Respiratory failure is the primary and most common cause of illness exposure to hyperoxia can cause HALI (hyperoxia-induced acute lung
and death. The mortality rate of respiratory failure is nearly 20% and injury). This is influenced by the increase in ROS (reactive O2 species),
costs about $54 million [7]. No data show the impact of respiratory causing disturbances in the balance of oxidants and antioxidants, and
failure, but in a study that observed 45 ICU patients for 2 months, the can disrupt homeostasis [10,13].
mortality rate was 34% with respiratory failure. The leading causes
include pneumonia (27%), neurological disorders (19%), sepsis (12%), 2. Management of respiratory failure
COPD (6%), and acute pulmonary oedema (6%). As many as 80% of
patients use mechanical ventilation, and 20% use NIV (non-invasive The respiratory center that controls breathing is located below the

* Corresponding author. Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga – Dr. Soetomo General Academic
Hospital, Jl. Mayjend Prof. Dr. Moestopo No. 6-8, Airlangga, Gubeng, Surabaya, East Java, 60286, Indonesia.
E-mail address: irmi-syafaah@fk.unair.ac.id (I. Syafaah).

https://doi.org/10.1016/j.amsu.2022.104393
Received 4 June 2022; Received in revised form 1 August 2022; Accepted 12 August 2022
Available online 18 August 2022
2049-0801/© 2022 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
E.E. Lius and I. Syafaah Annals of Medicine and Surgery 81 (2022) 104393

brainstem (pons and medulla). Respiratory failure can occur if the res­ and others if it is deficient or excessive (Fig. 1) [22].
piratory center is disturbed. Respiratory failure can be caused by ab­ In general, oxygen can be provided in two ways: low-flow systems
normalities in the lungs, heart, chest wall, respiratory muscles and the and high-flow systems. The nasal cannula is a widely used low-flow
central control mechanism of ventilation in the medulla oblongata. system. A low-current nasal cannula delivers oxygen to the naso­
Although not considered a direct cause, dysfunction of the heart, pul­ pharynx at a 1–6 L/min flow, with a FiO2 of 0.24–0.44 (24%–44%).
monary circulation, systemic circulation, hemoglobin oxygen transport Higher flow does not increase FiO2 significantly above 44% and can
and systemic capillary dysfunction are essential in respiratory failure [7, cause mucous membranes to dry. High-flow oxygen devices include
14,15]. venturi masks and reservoir nebulizer blenders [15]. These high-flow
Respiratory failure is divided into acute (sudden) respiratory failure systems can deliver 20–40 L/min of oxygen through the mask, gener­
and chronic (slow) respiratory failure. Acute respiratory failure is res­ ally sufficient for the total respiratory requirement. Two clinical in­
piratory failure that occurs in patients who have typical lung structure dications for the use of high-flow oxygen are patients requiring FiO2
and function before the onset of the disease. On the other hand, chronic control and hypoxic patients with abnormal ventilation [15,21].
respiratory failure is respiratory failure that occurs in patients with Guidelines for oxygen administration aim to achieve normal or near-
chronic lung diseases such as chronic bronchitis and emphysema. Pa­ normal oxygen saturation in all acutely ill patients, patients at risk for
tients tolerate hypoxia and hypercapnia, which worsens gradually [7, hypercapnic respiratory failure or patients on palliative care [23]. Pul­
14]. Intrapulmonary and extrapulmonary abnormalities can cause acute monary oximetry should check oxygen saturation in all shortness of
respiratory failure. Intrapulmonary disorders include abnormalities in breath and acutely ill patients. Vital signs must be checked oxygen
the lower respiratory tract, pulmonary circulation, interstitial tissue, saturation, pulse, blood pressure, temperature and respiratory rate. A
and alveolar capillaries. Extrapulmonary abnormalities occur in the clinical assessment is recommended if saturation falls by 3% or below
respiratory center, neuromuscular, pleura and upper airway [7,15]. the target range. All critically ill patients outside the critical care area (e.
Other respiratory failure classifications include hypoxemic, hyper­ g. ICU, HCU) should be assessed and monitored using the NEWS (Na­
capnic, and mixed respiratory failure. The criteria for respiratory failure tional Early Warning Score) system [23,24].
are included type I a hypoxemic respiratory failure if the PaO2 is less In critically ill patients (Table 1), high-concentration oxygen should
than 60 mmHg (SaO2 <91%) with room air or the ratio of partial be administered immediately with a 15 L/min reservoir mask while
pressure of oxygen/inspired oxygen fraction (P/F) <300 or a decrease in waiting for an oximetry device. Critical conditions requiring oxygen
PaO2 of 10 mmHg from previous data if known; type II hypercapnic include cardiac arrest, resuscitation, carbon monoxide poisoning, severe
respiratory failure if PaCO2 >50 mmHg with Ph <7.35 or a PaCO2 in­ head injury, shock, sepsis, drowning, anaphylaxis, pulmonary hemor­
crease of 10 mmHg from the previous data if known [10,16]. Classifi­ rhage or status epilepticus [23,25]. Administration of supplemental
cation based on the results of blood gas analysis is divided into 3, such as oxygen to improve oxygenation does not treat the underlying cause of
respiratory failure types I, II, and III or combined. Respiratory failure hypoxemia. If the patient is well-circulated and the oximetry is
types I and II are similar as described above. Type III respiratory failure measurable, the oxygen concentration can be reduced with a saturation
is a combination of the failure of oxygenation and ventilation charac­ target of 94–98%. If oximetry is unavailable, continue to use a reservoir
terized by hypoxemia and hypercarbia, namely a decrease in PaO2 and mask until definitive treatment is available. Patients with COPD and
an increase in PaCO2 [10,17,18]. other conditions are at risk of hypercapnia with respiratory acidosis, if
The pathophysiology of respiratory failure is fundamental in terms of they are in a critical condition, the initial target for oxygen saturation
its management. There are four primary mechanisms of gas exchange will be the same as for patients with other critical conditions, pending
disturbances in the respiratory system: hypoventilation, ventilation or the results of blood gas analysis. If the blood gas analysis results show
perfusion imbalance, right to left blood shunt, and diffusion disorders. hypercapnia, the target oxygen saturation is 88–92% [23,24].
Extrapulmonary abnormalities cause hypoventilation, whereas intra­ Patients with severe conditions (Table 1) require moderate supple­
pulmonary abnormalities may encompass all these mechanisms [7,15, mental oxygen, such as (1) acute hypoxemia; (2) acute asthma; (3)
19]. The management of respiratory failure consists of pneumonia; (4) lung cancer; (5) pneumothorax; (6) pleural effusion; (7)
supportive/non-specific and causative/specific management. They are pulmonary embolism; (8) acute heart failure; (9) severe anemia; or (10)
generally carried out simultaneously [5,20]. Non-specific management postoperative shortness of breath. In patients with severe conditions,
is an indirect action aimed at improving gas exchange that includes: initial oxygen therapy involves a nasal cannula at 2–6 L/min (preferred)
overcoming hypoxemia with oxygen supplementation; overcoming hy­ or a simple face mask at 5–10 L/min [23]. For patients not at risk of
percapnia by improving ventilation, namely improving the airway, hypercapnic respiratory failure and who have a saturation below 85%,
additional ventilation such as face masks, bag valve masks, mechanical oxygen administration is initiated with a 15 L/min reservoir mask with
ventilation; chest physiotherapy [5,21]. an initial target oxygen saturation of 94–98%. Suppose the patients have
When the PaO2 drops acutely, immediate action is needed to raise COPD or other risk factors for hypercapnic respiratory failure, target
the PaO2 to be expected. This is inversely proportional to respiratory saturation of 88–92% pending results of blood gas analysis but adjust to
failure due to chronic disease that becomes acute again. The patient is 94–98% if PCO2 is expected (unless there is a history of previous hy­
used to hypercarbia, so the respiratory center is not stimulated by percapnic respiratory failure requiring NIV) and recheck analysis blood
hypercarbia drive but by hypoxemia drive. Due to the rapid rise in PaO2, gas after 30–60 min later [23,24].
the patient may become apnea [5,21]. The administration of oxygen Observational conditions are when the patient should be closely
must be considered whether the patient needs oxygen. Indications for monitored (Table 1), but oxygen therapy is not required unless the pa­
oxygen administration should be clear. Oxygen must be administered tient is hypoxemic, such as (1) stroke; (2) myocardial infarction, (3)
appropriately evaluated for therapeutic benefit and to avoid toxicity acute coronary syndrome; (4) drug overdose; (5) bleomycin poisoning;
[15]. (6) metabolic and kidney disorders; (7) nervous system disorders or (8)
Short-term oxygen therapy is required therapy in patients with acute pregnancy emergencies. Suppose the condition that needs to be moni­
hypoxemia. Oxygen must be given immediately and adequately because tored is hypoxemic. In that case, initial oxygen therapy is given in a nasal
it will cause permanent disability and death if it is not given. In this cannula of 2–6 L/min or a simple face mask of 5–10 L/min unless
condition, oxygen should be given with a FiO2 of 60–100% in a short saturation is below 85% (use a reservoir mask) or if there is a risk of
time, and specific therapy should be given. Furthermore, oxygen is given hypercapnia [23]. The recommended initial target oxygen saturation is
at a dose that can overcome hypoxemia and minimize side effects [5,21]. 94–98%. If oximetry is not available, administer oxygen until oximetry
Oxygen should be administered by considering the concentration of or blood gas analysis results are available. If the patient has COPD or
PaO2 because it can affect organs such as lungs, blood vessels, cell death, other risk factors for hypercapnic respiratory failure, target oxygen

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Fig. 1. Relationship of PaO2 concentration to organ [22].

Oxygen toxicity can manifest in the central nervous system, lung and
Table 1
ocular, especially in premature infants. The onset and degree of toxicity
Conditions of patients requiring oxygen [23].
vary depending on oxygen concentration and duration of oxygen
Conditions of patients requiring oxygen administration. Prevention and early detection of oxygen toxicity
Critical Serious condition Observation require symptomatic treatment [1,28].
condition conditions Hyperoxia is a condition in which there is an excess supply of oxygen
Initial oxygen Reservoir Nasal cannula 2–6 L/ Nasal cannula 2–6 in the tissues and organs. Oxygen toxicity occurs when the alveolar
administration mask 15 L/ min or simple face L/min or simple partial pressure of O2 (PaO2) exceeds that of inhaled under normal
(L/min) min mask 5–10 L/min face mask 5–10 L/ conditions. In hyperoxia’s pathological condition, an influx of ROS
min
produced in large quantities. In reducing oxygen to water (Fig. 2), four
Oxygen targets 94–98% 94–98% 94–98%
Examples Heart attack Acute hypoxemia Stroke additional electrons produce three types of ROS: superoxide anion,
Poisoning acute asthma Myocardial hydrogen peroxide and hydroxyl radical. In intracellular and extracel­
Carbon Pneumonia infarction lular systems, the increase in ROS is due to overexposure to O2, thereby
monoxide Lung cancer Acute coronary
disrupting the balance between oxidants and antioxidants. This
Severe head Pneumothorax syndrome
injury Pleural effusion Drug overdose
disruption of homeostasis can cause damage to cells and tissues. The
Shock Pulmonary Bleomycin lung response to hyperoxia involves many immune cells [10,11].
Sepsis embolism addiction Hyperoxia induces NF-κB activation, which results in nuclear trans­
Drowning Acute heart failure Metabolic and locations that play a role in the occurrence of HALI. NF-κB has two
Anaphylaxis Severe anemia renal disorders
crucial roles: (1) regulating genes involved in inflammation such as IL-8
Lung bleeding Nervous system
Status disorders and TNFα; (2) regulating the survival of genes such as Bcl-2, Akt and
epilepticus Emergency MnSOD enzyme (manganese superoxide dismutase) that protect against
conditions in cell death due to hyperoxia (Fig. 3) [29,30]. The duration of exposure,
pregnancy
atmospheric pressure and fraction of inspired oxygen (FiO2) are the
basis for determining the dose of accumulated oxygen that causes
saturation of 88–92% [24,26]. Oxygen should be reduced in stable pa­ toxicity. Oxygen becomes toxic to the lungs when the FiO2 is high
tients whose oxygen saturation has reached the target. Oxygen should be (>0.60), administered over 24 h at standard barometric pressure (1
discontinued once the patient can maintain saturation within or above atmosphere absolute/ATA). Prolonged oxygen exposure of about 12 h
the target range of respiratory air [23,25]. can cause airway congestion, pulmonary oedema and atelectasis caused
by damage to the lining of the bronchi and alveoli [10,22].
3. Hyperoxia Paul Bert was the first to make an essential contribution to oxygen
toxicity. In 1878, Paul Bert conducted a study that found seizures in
Oxygen has a toxic effect at high partial pressures due to increased birds exposed to air 15–20 ATA. The CNS toxic effect of oxygen is called
oxygen concentration on inspiration, ambient pressure or both [1,27]. the ’Bert effect’. In 1899, J Lorain Smith, trying to reproduce the ’Bert

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Fig. 2. Stages of reducing oxygen to water [11].

Fig. 3. Schematic diagram illustrating the effects of NF-κB under hyperoxia conditions [29].

effect’, found fatal pneumonia in mice after 4 days of exposure to 73% by ROS that produces additional ROS; (4) The primary source of ROS
oxygen at 1 ATA [28]. The pulmonary toxic effect of oxygen is called the production comes from mitochondria. Accidental electron leakage
Smith effect. The partial pressure of oxygen on inspiration is about 160 usually occurs at the energy transition stage of the cytochrome chain
mm Hg above sea level. This value can be increased by inhaling 100% (protein complexes I and III), but the increase is proportional to the
oxygen, thereby increasing the inspiratory air pressure to 760 mm Hg or intensity of the hyperoxia. Additional sources of ROS result from the
increasing the pressure of the breathing mixture to a theoretically no interaction of O2 molecules with mitochondrial accretion enzymes,
limit [1,10]. including cyclooxygenases, peroxidases, lipoxygenases, and cytochrome
Hyperoxia causes alveolar or interstitial macrophages in the lung to P450; (5) endothelium contains a lot of nitric oxides (NO) so that the
release early response cytokines (IL-1 and TNF). These cytokines acti­ interaction with O2 molecules and superoxide anion produces nitrogen
vate pulmonary endothelial cells, epithelial cells, monocytes and lym­ dioxide (NO2), reactive nitrogen species and peroxynitrite anion
phocytes, which produce chemokines such as IL-8, CXCL1, and CXCL2/ (ONOO-). The peroxynitrite anion combines with carbon dioxide to form
3. This chemokine functions by binding to the chemokine receptor additional NO2 [10,17].
CXCR2 and regulating neutrophil recruitment to sites of inflammation, Under hyperoxia conditions, there is a ROS spike and cell death
leading to increased vascular permeability and inflammation in HALI (Fig. 6). This is regulated by several mechanisms, namely: (1) Loss of
and BPD (Fig. 4) [29,30]. plasma membrane integrity from lipid peroxidation by ROS; (2) ROS
ROS spikes are regulated by the primary target cell, the pulmonary damage to mitochondrial membranes and deactivation of enzyme sys­
capillary endothelium (Fig. 5). There are several early mechanisms of tems and cytochrome chains; (3) This results in the release of cyto­
hyperoxia, namely (1) the ROS spike in proportion to the PO2 during chrome C into the cytoplasm; (4) ROS damage in the nuclear membrane
hyperoxia; (2) O2 molecules are reduced to ROS by NADPH (nicotin­ and DNA fragmentation; (5) Cell trauma includes steps 1, 2, and 4 that
amide adenine dinucleotide phosphate hydrogen) and oxidase (NOX) in trigger the production and release of proinflammatory cytokines and
the plasma membrane; (3) damage to the plasma membrane lipid bilayer chemokines into the extracellular space; (6) This activates platelets,

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Fig. 4. Mechanism of hyperoxia causing ALI (Acute Lung Injury) and BPD (Bronchopulmonary Dysplasia) [29].

neutrophils and macrophages, resulting in a secondary ROS spike from Oxygen toxicity to the CNS is influenced by increased PCO2, stress, fa­
inflammatory cells. Direct cell trauma causes necrosis or “unplanned” tigue and cold [10,11].
cell death. In addition, the release of cytochrome C into the cytoplasm
(A-1) and plasma membrane damage (A-2) triggers other cellular pro­ 5. Lung toxicity
cesses, which instruct the cell to "commit suicide" through the process of
apoptosis (programmed cell death) [10,17]. The effects of lung toxicity occur after prolonged oxygen exposure.
Effects of hyperoxia can be seen in neonates and adults. In neonates, Symptoms appear after a latency period whose duration decreases with
there is retrolental hyperplasia after exposure to high oxygen concen­ an increase in PO2. In normal humans, initial toxic effects appear after
trations. A cardiology study found that routine oxygen supplementation 10 h of 1 ATA oxygen exposure. The clinical picture is divided into three
in non-hypoxemic patients with acute myocardial infarction could phases, namely: (a) tracheobronchitis, (b) ARDS, and (c) pulmonary
worsen the patient’s condition. In hospitalized patients who do not interstitial fibrosis [18,20,33]. Oxygen can be tolerated above sea level
require supplemental oxygen, there will be an increase in PaO2 levels for about 24–48 h without severe tissue damage. Prolonged exposure
(generally above 120 mmHg) if given, affecting the deterioration of causes tissue injury [1,32]. Oxygen 2 ATA can cause characteristic
clinical outcomes. There are conflicting data about the dangers of pulmonary signs and symptoms within 3–6 h of exposure, uncontrolled
hyperoxia in patients following cardiac resuscitation or mechanical cough for about 10 h, chest pain and shortness of breath. In most pa­
ventilation. Given hyperoxia’s potential harm and lack of benefit, the tients, symptoms improve about 4 h after not being exposed to oxygen
clinical target should not exceed the physiologic threshold [31]. Oxygen [28]. The fluid formation in the lungs causes shortness of breath and a
toxicity can affect several organ systems, including the central nervous burning feeling in the throat and chest when breathing is very painful.
system, lungs and other tissues such as the eyes [28]. Oxygen is delivered to body tissues at nearly normal partial pressures of
oxygen due to the hemoglobin-oxygen buffer system [1,27,28].
4. Central nervous system (CNS) toxicity
6. Toxic effects on other tissues
CNS toxicity described by Bert includes various initial symptoms and
signs. However, perioral twitching and small muscles of the hands, facial Toxic effects of oxygen on the eye include reversible narrowing of the
pallor and cogwheel breathing are common due to intense peripheral peripheral visual field, progressive and reversible myopia, and cataracts.
vasoconstriction due to hyperoxia and twitching of the diaphragm [28]. Ocular effects are expected when the entire eye is exposed to high-
Vertigo, nausea, behavioral changes, confusion, and seizures may occur pressure oxygen, e.g. oxygen delivery via a facemask [1,27]. Neonates
if exposure continues. Seizures begin with loss of consciousness and and premature infants exposed to high concentrations of oxygen cause
progress in three phases; (1) a tonic phase with generalized hypertonia retinopathy, chronic lung disease and intraventricular hemorrhage.
lasting about 1 min, (2) a clonic phase with seizures lasting about 2–3 Premature babies with a gestational age of fewer than 30 weeks or a
min, (3) a post-critical phase of about 10 min [1,32]. Concomitant birth weight of 1500 g have a greater risk, about 60% [1,27,28].
neurogenic pulmonary oedema with seizures has also been reported. Hyperoxia inhibits macrophage proliferation and increases

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Fig. 5. Initial mechanism of hyperoxia [10].

inflammation. Alveolar epithelium and alveolar capillary endothelial The chest X-ray may show an alveolar interstitial pattern with an
cells are vulnerable targets for injury by hyperoxia [6,7,14]. In Acute irregular distribution with moderate volume loss from atelectasis, but
Lung Injury (ALI) conditions caused by hyperoxia, pulmonary micro­ there is no clinical way to diagnose oxygen toxicity [10]. Biopsy of lung
vascular hyperpermeability causes the alveoli to fill with plasma specimens may show changes in oxygen toxicity, but the biopsy excludes
extravasation, which can cause pulmonary oedema and coagulation other causes of lung injury. Oxygen toxicity can be minimized by
disorders and fibrin deposition to occur in the fibrinolysis pathways. maintaining PaO2 <80 mmHg or FiO2 <0.40–0.5. The severity of HALI is
Type II alveolar epithelial cells are injured by oxygen free radicals, proportional to the PO2 (significantly above 450 mm Hg, or FiO2 0.6)
disrupting surfactant production [11]. and the duration of exposure [8,10].
At high PaO2, the hemoglobin-oxygen buffering mechanism fails and Anatomically, the surface epithelium of the lung is susceptible to a
tissue PaO2 increases by 100–1000 mm Hg. ROS’s endogenous antiox­ destructive inflammatory response. This inflammation damages the
idant enzyme systems are utilized in cell death at high oxygen concen­ alveolar capillaries leading to impaired gas exchange and pulmonary
trations. ROS’s oxygen toxicity caused by ROS proceeds in overlapping oedema [10]. ROS induce the lung to secrete chemoattractant, and cy­
phases based on the injury’s degree of severity and recovery. These tokines stimulate macrophages and monocytes, accumulating into the
stages are initiation, inflammation, proliferation and fibrosis. Initially, lungs and causing ROS. The leukocyte-ROS interaction exacerbates the
there is increased ROS and antioxidant depletion, and the lung fails to injury. Studies have shown that severely reduced cell layers become
clear itself of mucus. The inflammatory or exudative phase is charac­ increasingly oxidized, and antioxidant levels decrease, ROS-induced
terized by the destruction of the lung lining and the migration of leu­ activation of various transduction pathways that regulate cellular re­
kocytes from inflammatory mediators to the injury site. In the subacute sponses, i.e. adaptation, repair or cell death by apoptosis, oncosis, or
proliferative phase, cellular hypertrophy occurs, increased surfactant necrosis [11].
secretion in removing type II alveolar cells and increased monocyte Increased mortality in patients with hyperoxia compared to hypoxia
cells. The terminal phase is the fibrotic phase, where the lung has irre­ and normoxia (guidelines used for hyperoxia PaO2 300 mmHg) in 6326
versible and permanent changes. There are collagen deposits and patients with post-cardiac arrest or myocardial infarction from 120
thickening of the lung interstitial spaces, and the lung becomes fibrotic hospitals [34]. A retrospective cohort study also found an increased
[10,11]. mortality rate in hyperoxia in 2894 stroke patients from 84 ICUs,
Clinically, progressive hypoxemia, or high O2 pressure in the blood, measuring PaO2 in the first 24 h (Hyperoxia: PaO2 300 mmHg; Nor­
requires increased FiO2 and assisted ventilation, which further exacer­ moxia: PaO2 60–300 mmHg) [35]. Another study reported an increased
bates the pathophysiological changes associated with oxygen toxicity. mortality rate in patients with hyperoxia in 83 septic patients in the ED

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Fig. 6. Mechanisms of ROS regulation and cell death pathways due to hyperoxia [10].

who were given oxygen at 10 L/min [36]. In addition, an increased without an increase in carbon dioxide when the patient breathes room
mortality rate was also found in conditions of severe hyperoxia air. Respiratory failure is divided into acute (sudden) respiratory failure
compared to mild hyperoxia and normoxia (mild hyperoxia: PaO2 and chronic (slow) respiratory failure. The basis for managing respira­
120–200 mmHg, severe hyperoxia: PaO2 >200 mmHg) in 14441 pa­ tory failure consists of supportive/non-specific and causative/specific
tients with mechanical ventilation in the ICU [37]. management. Oxygen should be provided wisely so as not to cause
In patients with severe hypoxemic respiratory failure, it is advisable injury to organs such as the heart, lungs, eyes, nervous system, and
to reassess oxygenation goals to provide the safest support. Oxygen others. Hyperoxia often occurs in managing respiratory failure, so it
supplementation targets the cardiorespiratory system, including arterial requires supervision, especially in administering oxygen. Oxygen should
PO2, arterial O2 content and cardiac output. The generally recom­ be given as needed to avoid hyperoxia. In oxygen therapy, it is necessary
mended targets are an arterial PO2 of 55 mmHg, a hemoglobin level of at to pay attention to the patient’s condition because each condition re­
least 7 g/dL (but may also be 9–10 g/dL), and a cardiac index above 2 L/ quires different oxygen concentrations, so dose adjustments are neces­
min/m2. This target will keep O2 delivery close to normal [31]. sary. These conditions can be divided into critical, severe, and
Future study is expected to find guidelines and updates for oxygen observation conditions. The target oxygen saturation in all these con­
therapy to avoid hyperoxia. Administration of oxygen therapy must be ditions is 94–98%.
based on the patient’s condition because it can have a toxicity effect if
have given in excess. Ethical approval

7. Summary Not applicable.

Management of respiratory failure is closely related to the provision

Sources of funding
of oxygen supplementation, so special attention is needed in its
administration, according to indications and does not have a toxic effect.
None.
Oxygen supplementation in conditions of respiratory failure aims to
overcome hypoxemia. Overexposure to oxygen can cause oxygen
toxicity and lead to hyperoxia. Hyperoxia is a condition in which there is Author contribution
an excess supply of oxygen in the tissues and organs. Clinically, respi­
ratory failure is diagnosed if the PaO2 is less than 60 mmHg with or All authors contributed toward data analysis, drafting and revising
the paper, gave final approval of the version to be published and agree to

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E.E. Lius and I. Syafaah Annals of Medicine and Surgery 81 (2022) 104393

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