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Introduction: The application of hyperbaric oxygen therapy for patients with both acute and chronic traumatic brain injury has been suggested for over five decades. In the past decade, the design and quality of studies were more detailed and thorough leading to an improved unerstanding of the uses of HBOT and the profiles of the patients who can benefit the most.

Objectives: Perform a comprehensive literature review of hyperbaric oxygen therapy application for the treatment of patients with both acute, subacute and chronic traumatic brain injury.

Methods: Extensive literature search from 1969 to April 2023 was performed on April 1st 2023 within the following databases: Cochrane Library, PubMed, Google Scholar, and Web of Science, including humans clinical data, in articles providing information on the type of treatment and clinical outcomes. Articles were first categorized into acute-subacute traumatic brain inury and chronic traumatic brain injury and further classified into low, medium or high level quality.

Results: There was high level evidence including nine randomized controlled trials, one meta-analysis and two prospective study evaluating the clinical effects of hyperbaric oxygen therapy in patients suffering from traumatic brain injuries in the acute and subacute settings. Mortality was significantly reduced in all studies that used it as an endpoint, while favorable functional outcomes in survivors showed mixed results.

In chronic severe traumatic brain injury, there is low to moderate evidence including two uncontrolled prospective studies, two cohort studies and eight case reports suggesting improved outcomes.

In chronic mild traumatic brain injury, there is high level evidence including seven randomized controlled trials, and six prospective studies suggesting significant improvement in cognitive function, symptoms and quality of life.

Conclusions: Hyperbaric oxygen therapy may be recommended in acute moderate-severe traumatic brain injury patients (Type 2a recommendation, level A evidence). However, further studies are needed to both evaluate outcomes and to determine the optimal treatment protocols for the different types of injuries (Type 1 recommendation, level A evidence).

Hyperbaric oxygen threrapy should be recommended in chronic traumatic brain injury for a selected group of patients suffering from prolonged post-concussion syndrome who have clear evidence of metabolic dysfunctional brain regions as determined by neuroimaging (Type 2a recommendation, level B-R evidence). Patients should be properly evaluated by standardized cognitive tests and functional brain imaging (Type 1 recommendation, level B-R evidence).

Article Details

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• Open access
• Published: 05 September 2024

Oxygen therapy in acute hypoxemic respiratory failure: guidelines from the SRLF-SFMU consensus conference

• Julie Helms   ORCID: orcid.org/0000-0003-0895-6800 1 , 2 ,
• Pierre Catoire 3 ,
• Laure Abensur Vuillaume 4 ,
• Héloise Bannelier 5 ,
• Delphine Douillet 6 , 7 ,
• Claire Dupuis 8 , 9 ,
• Laura Federici 10 ,
• Melissa Jezequel 11 ,
• Mathieu Jozwiak 12 , 13 ,
• Khaldoun Kuteifan 14 ,
• Guylaine Labro 14 ,
• Gwendoline Latournerie 15 , 16 ,
• Fabrice Michelet 17 ,
• Xavier Monnet 18 ,
• Romain Persichini 19 ,
• Fabien Polge 20 ,
• Dominique Savary 21 , 22 ,
• Amélie Vromant 23 ,
• Imane Adda 24 , 25 &
• Sami Hraiech 26 , 27  

Annals of Intensive Care volume  14 , Article number:  140 ( 2024 ) Cite this article

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Introduction

Although largely used, the place of oxygen therapy and its devices in patients with acute hypoxemic respiratory failure (ARF) deserves to be clarified. The French Intensive Care Society (Société de Réanimation de Langue Française, SRLF) and the French Emergency Medicine Society (Société Française de Médecine d’Urgence, SFMU) organized a consensus conference on oxygen therapy in ARF (excluding acute cardiogenic pulmonary oedema and hypercapnic exacerbation of chronic obstructive diseases) in December 2023.

A committee without any conflict of interest (CoI) with the subject defined 7 generic questions and drew up a list of sub questions according to the population, intervention, comparison and outcomes (PICO) model. An independent work group reviewed the literature using predefined keywords. The quality of the data was assessed using the GRADE methodology. Fifteen experts in the field from both societies proposed their own answers in a public session and answered questions from the jury (a panel of 16 critical-care and emergency medicine physicians, nurses and physiotherapists without any CoI) and the public. The jury then met alone for 48 h to write its recommendations.

The jury provided 22 statements answering 11 questions: in patients with ARF (1) What are the criteria for initiating oxygen therapy? (2) What are the targets of oxygen saturation? (3) What is the role of blood gas analysis? (4) When should an arterial catheter be inserted? (5) Should standard oxygen therapy, high-flow nasal cannula oxygen therapy (HFNC) or continuous positive airway pressure (CPAP) be preferred? (6) What are the indications for non-invasive ventilation (NIV)? (7) What are the indications for invasive mechanical ventilation? (8) Should awake prone position be used? (9) What is the role of physiotherapy? (10) Which criteria necessarily lead to ICU admission? (11) Which oxygenation device should be preferred for patients for whom a do-not-intubate decision has been made?

These recommendations should optimize the use of oxygen during ARF.

Introduction and background

The consensus conference aims to provide evidence-based guidelines for using oxygen in hypoxemic acute respiratory failure (ARF) in adults, excluding cases related to acute lung edema and hypercapnic ARF (type II). These guidelines are intended for healthcare professionals involved in oxygen therapy in pre-hospital, hospital emergency, critical care, and intensive care settings.

Pathophysiology key points

Hypoxemic ARF occurs when the respiratory system suddenly fails to ensure adequate oxygenation, leading to severe acute hypoxemia without hypercapnia. It is diagnosed in the absence of underlying lung disease or acute cardiogenic pulmonary edema [ 1 ], with pneumonia being the main cause.

The definition of hypoxemic ARF remains unclear, and establishing a new definition is the focus of this consensus conference. The severity of hypoxemia varies across studies, typically defined by a PaO 2 /FiO 2 ratio of ≤ 200 mmHg or ≤ 300 mmHg. Hypoxemia results from reduced oxygen pressure in inspired air, alveolar hypoventilation, impaired alveolar oxygen diffusion, shunt, and poor ventilation-perfusion ratios.

Oxygen therapy aims to treat hypoxemic hypoxia by increasing the fraction of inspired oxygen, thereby raising arterial oxygen content. When oxygen saturation is already normal (above 96–98%), the hemoglobin’s affinity for oxygen is low, making the impact of oxygen therapy on arterial content minimal, primarily increasing PaO 2 .

Oxygen therapy can be combined with positive pressure therapy (applying super-atmospheric pressure in the airways to improve alveolar recruitment and maintain airway patency) or ventilation (applying variable pressure in the airways to assist ventilatory effort).

However, hyperoxia, defined as an excessive PaO 2 level, can cause specific lesions, including pulmonary edema, atelectasis, retinopathy, and direct cerebral toxicity. Due to the lack of evidence defining a threshold for hyperoxia-induced damage, a PaO 2 threshold of 100–120 mmHg has been adopted by the authors.

Definition of oxygen therapy methods and devices

Oxygen therapy can be delivered by several devices, including conventional oxygenation, high-flow nasal cannula oxygen therapy (HFNC), positive pressure therapy and non-invasive ventilation (NIV) [ 2 ].

Conventional oxygenation employs fixed-flow devices such as nasal cannulas, single masks, Venturi masks, and high-concentration (reserve) masks. HFNC saturates the inspiratory flow with humidified, warmed air, offering several benefits: FiO 2 stability (as the high flow rate prevents ambient air inhalation), clearance of dead space in the upper airways, reduced bronchoconstriction, improved pulmonary secretion clearance, and a limited PEEP effect, achievable only when the mouth is closed.

Several devices are designed to increase airway pressure, either continuously (Continuous Positive Airway Pressure, CPAP) or during exhalation (Positive End Expiratory Pressure, PEEP). Non-invasive ventilation (NIV) is administered with inspiratory assistance (IA) and PEEP, using a mask or helmet.

Impact of the COVID-19 outbreak on oxygen therapy management

The COVID-19 pandemic significantly altered the use of non-invasive oxygen support, adapting to available resources and guidelines. While conventional oxygen therapy remained the most common support, the use of HFNC increased substantially, reaching 19% in a cohort of 4,643 patients admitted to intensive care for COVID-19 in France, Belgium, and Switzerland [ 3 ].

However, due to conflicting guidelines, limited evidence on device effectiveness, and concerns about aerosolization risk, the use of devices varied considerably between countries. Several simulation studies later demonstrated that the risk of aerosolization was not higher with HFNC compared to NIV or conventional oxygenation devices [ 4 , 5 ].

The « Société de Réanimation de Langue Française (SRLF)» and the « Société Française de Médecine d'Urgence (SFMU)» mandated the « Commission des Référentiels et de l'Évaluation (CRE)» and the « Commission de Référentiels (CR)» to carry out a consensus conference. The members of the two commissions defined six generic questions, and PICO (Patient, Intervention, Control, Outcome) questions [ 6 ] were then submitted to the experts (Appendix 1). An expert was appointed for each generic question proposed. An independent group of intensivists carried out the literature research. GRADE (Grade of Recommendation Assessment, Development and Evaluation) tables presenting literature data were provided [ 7 ] (Appendix 2). A level of evidence was defined for each bibliographic reference cited, depending on the type of study. This level of evidence could be re-evaluated (discounted/overvaluated) considering the methodological quality of the study. The bibliographical references common to each judgement criterion were then collected. An overall level of evidence was determined for each criterion, considering the level of evidence of each bibliographic reference, the consistency of results between the different studies, the directness of the evidence, and cost analysis. A “high” quality of evidence led to a “strong” recommendation (should, should not… GRADE 1 + or 1−). A moderate, low or very low quality of evidence led to an “optional” recommendation (probably should, probably should not… GRADE 2 + or 2−). In the absence of evidence, the issue was recommended in the form of an expert opinion. Where the literature was non-existent, the question could be the subject of a recommendation in the form of an opinion from the members of the panel. The panel was made up of 14 members, coordinated by two chairmen. All practiced in intensive care or emergency medicine. They were chosen by the organizers on the one hand for their clinical interest in the topic, and on the other because they had no related potential conflicts of interest. At the end of the conference, the role of the panel was to provide a consensus text with the conclusions and recommendations of the conference in the form of a clear answer to each of the questions. The experts wrote a text for the panel members debating the assigned question, including the most recent scientific data, their opinions and arguments. A meeting was held for the experts, the panel members and a large audience of intensive care physicians. The experts presented their analyses and the specific scientific data on the question for which they were responsible, and they answered the questions and comments of the panel and the public. After the public meeting, the panel met privately to draft the text answering the questions. Recommendations were formulated according to the GRADE methodology. The proposed recommendations were presented and discussed individually. The aim was not necessarily to obtain a convergent opinion of the panel members for all the proposals but rather to uncover points of agreement and points of disagreement or indecision. Each recommendation was then assessed by each panel member and scored individually from 1 (totally disagree) to 9 (strongly agree). The panel score was defined using a GRADE grid [ 8 ]. To achieve a strong recommendation, at least 70% of the participants had to agree. If there was no strong agreement, recommendations were reworded and then rescored to achieve consensus. The final text contains the conclusions and recommendations of the conference.

Section 1: definitions, scores, oxygen therapy techniques and devices

1: definitions of acute respiratory failure and respiratory distress.

Acute respiratory failure (ARF) is defined as the sudden inability of the respiratory system to ensure satisfactory hematosis. A distinction is made between type I (hypoxemic without hypercapnia) and type II ARF (hypercapnic acidosis). Mixed ARF is defined as the combination of hypoxemia and hypercapnia.

In this definition, hypoxemia is characterized by PaO 2  < 60 mmHg on ambient air, SpO 2  < 90% on ambient air, or the need to administer oxygen to achieve PaO 2  ≥ 60 mmHg or SpO 2  ≥ 90%. Oxygen therapy should not be discontinued to certify the presence of hypoxemia. Hypercapnic acidosis is characterized by pH ≤ 7.35, with PaCO 2  > 45 mmHg.

Respiratory distress is clinically defined by the combination of symptoms described in Table  1 . Signs of respiratory distress may precede hypoxemic ARF, with blood gas showing an initially normal PaO 2 and hypocapnia due to secondary hyperventilation.

Hyperoxemia corresponds to an increase in PaO 2 greater than that obtained by breathing ambient air. PaO 2  > 100–120 mmHg is usually used, in the absence of a consensus threshold.

2. Oxygenation scores and indices

Several oxygenation indices can be used to assess the severity of the deterioration in the patient's hematosis by associating PaO 2 or SpO 2 to the FiO 2 required to obtain it, and possibly with the patient's work of breathing.

The PaO 2 /FiO 2 ratio is used to define the severity of hypoxemia in acute respiratory distress syndrome (ARDS), characterized by a PaO 2 /FiO 2  < 300 mmHg [ 9 , 10 ]. However, this ratio requires arterial blood gas and precise measurement of Fi O 2 .

The FiO 2 of patients treated with standard mask oxygen therapy can be estimated using the Coudroy formula [ 11 ], where Q{ O2 } is the oxygen flow rate in L/min:

To avoid arterial blood gas sampling, the SpO 2 /FiO 2 ratio can be used as a substitute for the Pa O 2 /FiO 2 ratio. SpO 2 /FiO 2 ratios of 235 and 315 correlate with PaO 2 /FiO 2 ratios of 200 and 300 mmHg respectively [ 12 ]. SpO 2 may also be over or underestimated depending on ethnicity, the patient's clinical condition and the reliability of the measurement system [ 13 , 14 , 15 ]. Interpretation of the SpO 2 /FiO 2 ratio requires titration of FiO 2 as SpO 2 is limited to 100%.

The ROX index is defined as the ratio of SpO 2 /FiO 2 divided by the respiratory rate: $ROX = \frac{S_pO_2/ F_iO_2}{FR}$. In patients treated with high-flow nasal oxygen therapy (HFNC), the ROX index has been shown to be useful in predicting the success of this technique [ 16 ]. ROX index < 2.85 at H2, < 3.5 at H6 or < 4.88 at H12 of high flow nasal oxygen therapy is predictive of failure. However, the ROX index does not appear to be as effective in immunocompromised patients [ 17 ], and has not been sufficiently studied in patients with ARF in pre-hospital or emergency care. As with the Sp O 2 /FiO 2 ratio, interpretation of the ROX is subject to FiO 2 titration.

3. Oxygen therapy techniques and devices

The aim of oxygen therapy is to re-establish sufficient hematosis to ensure tissue oxygenation. Its main indication is hypoxemic ARF. Although simple to use and generally without adverse effects, oxygen is a drug, the quantity and method of administration of which must be prescribed according to the pathology and severity of the patient. Recent experimental and clinical studies have highlighted the deleterious pulmonary, cardiovascular, neurological and metabolic effects of hyperoxemia [ 18 , 19 , 20 , 21 ]. In addition, in certain patients (chronic obstructive pulmonary disease (COPD), other chronic respiratory insufficiencies, morbid obesity), excessive oxygen administration can lead to or worsen hypercapnia [ 22 , 23 ].

Standard oxygen therapy can be administered via different interfaces. The FiO 2 delivered depends on the minute ventilation and the seal if a mask is used (Table  2 ).

High-flow nasal cannula oxygen therapy (HFNC) is used to deliver a humidified and heated gas mixture (air/oxygen) with flow rates ranging from 10 to 70 L/min and FiO 2 of 21–100%.

Whether or not combined with oxygen therapy, it is possible to administer continuous positive airway pressure ( CPAP) or tele-expiratory pressure (spontaneous ventilation with positive expiratory pressure) using several interfaces: Boussignac valve, ventilator with dedicated mode.

Ventilation consists in administration of differential pressure to the airways in order to assist, partially or completely, the work of breathing. It may be invasive or non-invasive, administered by means of an external interface (mainly a face mask). As it is not limited to the administration of oxygen, it is not included in the oxygen therapy modalities stricto sensu in this consensus conference.

Section 2: Indications for oxygen therapy, targets and monitoring methods

Question 1: what are the criteria for initiating oxygen therapy in patients with acute hypoxemic respiratory failure.

Recommendation 1A

The panel suggests initiating oxygen therapy in the event of acute hypoxemic respiratory failure (panel opinion, strong agreement).

Recommendation 1 B

The panel makes no recommendation on the initiation of oxygen therapy in patients with respiratory distress without hypoxemia (insufficient quality of evidence, strong agreement).

The panel underlines the importance of initiating oxygen therapy in hypoxemic ARF. However, there is no formal threshold for hypoxemia, and the administration of oxygen has not been compared with the absence of oxygen administration during hypoxemic ARF in a controlled trial with a high level of evidence [ 24 , 25 ] justifying the absence of a strong recommendation.

There is only indirect evidence of oxygen administration in hypoxemic ARF. The effect of oxygen on the symptoms of hypoxemia has been known since the nineteenth century [ 26 ]. Numerous observational studies have shown that saturation < 91% is associated with an increased risk of mortality [ 27 , 28 ]. More recently, a study showed the deleterious effect of a restrictive strategy (SaO 2 88–92%) in ARDS [ 29 ].

There are no published data supporting the use of oxygen to reduce signs of respiratory distress in non-hypoxemic patients. A meta-analysis by Hasegawa et al. included 39 randomized controlled trials, mainly on chronic respiratory failure and palliative care patients [ 30 ] and showed no benefit of oxygen in reducing symptoms of dyspnea. A meta-analysis including COPD patients with dyspnea, mainly with SpO 2  > 90%, showed the same lack of effect [ 31 ]. A randomized controlled trial in end-of-life patients without hypoxemia found no improvement in symptoms of respiratory distress [ 32 ]. Only one small study (28 subjects) showed a positive effect of oxygen therapy on the reduction of dyspnea in patients with moderate hypoxemia [ 33 ].

Question 2: In patients with acute hypoxemic respiratory failure, what are the targets of oxygen saturation?

Recommendation 2 A

Oxygen flow or FiO 2 should probably be adjusted according to pulse oximetry values, to achieve:

SpO 2 ranging from 94 to 98% for patients with no risk of oxygen-induced hypercapnia (GRADE 2 + , moderate quality of evidence, low agreement).

SpO 2 ranging from 88 to 92% for patients at risk of oxygen-induced hypercapnia (GRADE 2 + , moderate quality of evidence, strong agreement).

Recommendation 2 B

The panel makes no recommendation on the “liberal” or “restrictive” strategy of oxygen therapy to be adopted during acute hypoxemic respiratory failure (insufficient quality of evidence, strong agreement).

The deleterious effects of hypoxemia and hyperoxemia have been described previously. Retrospective studies on large databases have confirmed mortality increase for both low and high oxygenation levels, describing a "U" or "J" curve, with lower mortality for target range saturation of 94 and 98%, or for PaO 2 between 100 and 120 mmHg [ 34 , 35 ]. Similar results were found in the specific context of post-cardiac arrest [ 36 ].

Large retrospective cohort studies have shown a correlation between depth of hypoxemia and mortality [ 37 , 38 ]. In these studies, no association was found between hyperoxemia and mortality. Similarly, Madotto et al. showed no relationship between the occurrence of hyperoxemia and prognosis in an ancillary study of the LUNG-SAFE study [ 39 ]. In a large retrospective cohort, however, Palmer et al. showed an association between the occurrence of hyperoxemia episodes and ICU mortality, albeit with no dose–response relationship [ 40 ]. Few studies have compared the effect of different targets of SpO 2 range. In particular, no study has evaluated the effect of low PaO 2 values outside post-cardiac arrest [ 36 ]. The available studies have included different populations, with varying oxygenation targets. In a randomized trial, Girardis et al. showed lower ICU mortality in a "conservative" group defined as PaO 2 between 70 and 100 mmHg or SpO 2 between 94 and 98%, to a "conventional" group defined as PaO 2 above 150 mmHg or SpO 2 between 97 and 100% [ 41 ]. Many subsequent trials were negative for mortality [ 42 , 43 , 44 ] or organ dysfunction [ 45 ], with very heterogeneous targets per group. For several studies, the highest or "liberal" level was in fact relatively low and could be described as "restrictive" in others. Barrot et al. [ 29 ] compared the oxygenation strategy among patients ventilated for ARDS with a restrictive (PaO 2 between 55 and 60 mmHg) and a liberal (90–105 mmHg) group, showing a significant increase in the proportion of mesenteric ischemia in the restrictive group and a low probability of a significant difference on mortality, justifying early termination of the study.

In a prospective randomized pre-hospital trial, Austin et al. showed that a titrated oxygen treatment aimed at obtaining SpO 2 between 88 and 92% reduced mortality, hypercapnia and respiratory acidosis compared with high-flow nasal cannula oxygen therapy in acute exacerbations of chronic obstructive pulmonary disease.

Question 3: In patients with acute hypoxemic respiratory failure, what is the role of blood gas analysis?

Recommendation 3A

Patients with acute hypoxemic respiratory failure should probably not be routinely monitored by blood gas analysis (GRADE 2-, moderate quality of evidence, strong agreement).

There is no strong evidence regarding the superiority of a systematic arterial blood gas analysis strategy concerning mortality and intubation rates. However, several studies [ 46 , 47 ] have shown that no systematic blood gas analysis reduces the number of samples. In one of them, there was a reduction in the duration of mechanical ventilation and length of ICU stay when gas measurements were not carried out systematically, but guided by clinical assessment [ 46 ].

Furthermore, although the incidence of complications from arterial puncture remains low [ 48 ], the severity of some (embolism, thrombosis, aneurysm, arteriovenous fistula), and the invasive and painful aspect of the procedure, particularly when repeated [ 49 ], justify limitation of its systematic prescription.

Recommendation 3B

The panel suggests using venous blood gas analysis to rule out hypercapnia for the evaluation and monitoring of acute hypoxemic respiratory failure (panel opinion, strong agreement).

Recommendation 3 C

The panel suggests that arterial blood gas analysis should be performed when there is a doubt about the reliability of SpO 2 , when it is not measurable, or when PvCO 2 is elevated, so as to confirm and quantify hypercapnia (panel opinion, strong agreement).

Recommendation 3 D

The panel suggests that arterial blood gas analysis should be performed in cases of pathological hemoglobin, suspicion or presence of methemoglobin or CO intoxication, or when there is a non-respiratory indication for arterial blood gas analysis (panel opinion, strong agreement).

The correlation between PaCO 2 and PvCO 2 and between arterial and venous pH seems sufficient to avoid arterial blood gas analysis [ 50 ]. A PvC O 2 threshold below 45 mmHg almost certainly rules out arterial hypercapnia. Furthermore, a multicenter randomized study in four French emergency departments demonstrated reduced patient pain levels when venous blood gas was used instead of arterial blood gas, with no change in the clinical value of the sample [ 51 ].

However, oxygen therapy monitoring should take into consideration the biases and limitations of pulse oximetry. Aside from some studies on patient groups, most technical validation studies of pulse oximeters [ 52 ] and their certification standards have been conducted on healthy volunteers, with some confounding factors, particularly signal noise. SpO 2 accuracy is reduced in peripheral perfusion disorders, pathological hemoglobin (methemoglobin, carboxyhemoglobin, sickle cell disease), and may pose interpretation problems in cases of skin pigmentation [ 53 ].

Moreover, there are differences in the levels obtained from one oximeter to another, with some devices overestimating and others underestimating SpO 2 compared to SaO 2 In a study conducted in ICU patients, the average difference between SaO 2 and SpO 2 approximated 4.4% [ 54 ].

Question 4: In patients with acute hypoxemic respiratory failure, when should an arterial catheter be inserted?

Recommendation 4

The panel suggests invasive blood gas monitoring in patients for whom repeated arterial sampling is indicated (panel opinion, strong agreement).

This position is justified by the painful nature of arterial blood gas sampling, particularly when repeated (see argument in Question 3).

Section 3: Choice of oxygen therapy modality

Question 5: should standard oxygen therapy, high-flow nasal cannula oxygen therapy (hfnc) or continuous positive airway pressure (cpap) be preferred in patients with acute hypoxemic respiratory failure.

Recommendation 5 A

The panel makes no recommendation concerning the use of CPAP rather than standard oxygen therapy in patients with acute hypoxemic respiratory failure (insufficient quality of evidence, strong agreement).

Recommendation 5B

HFNC should probably be used rather than standard oxygen therapy in patients with hypoxemic ARF, with an oxygen flow rate > 6L/min to achieve SpO 2  >  92% or a.

PaO 2 /Fi O 2 ratio < 200 (GRADE 2 + , moderate quality of evidence, strong agreement).

Three studies in non-COVID-19 patients and two studies in COVID-19 patients compared CPAP with conventional oxygen therapy. In non-COVID-19 patients, only one small study in hematology patients found that those treated with CPAP were less likely to be intubated [ 55 ]. The other two studies found no effect on intubation, whereas Delclaux et al. used high-flow CPAP (100 L/min oxygen) [ 56 ] and Brambilla et al. used CPAP with a Helmet interface ( Helmet CPAP ) [ 57 ]. The two trials carried out in COVID-19 patients showed contradictory results on intubation [ 58 , 59 ]. However, in these trials the authors reported frequent discomfort during CPAP, leading to its being discontinued in 15 to 20% of patients. Except in hematology patients [ 55 ] no study has shown a beneficial effect of CPAP on mortality. Of note, no study has compared CPAP with HFNC. A meta-analysis including the three randomized trials comparing HFNC and conventional oxygen therapy in patients with de novo hypoxemic ARF, excluding patients with exacerbation of chronic obstructive pulmonary disease and/or hydrostatic pulmonary edema, showed that patients treated with HFNC were less likely to be intubated (Appendix 3). Nevertheless, none of the three separately analyzed randomized trials showed a significant reduction of intubation [ 60 , 61 , 62 ]. Frat et al. [ 60 ] found that patients treated with HFNC, compared to patients treated with conventional oxygen therapy, had a lower mortality rate, even though this was not confirmed in the two other randomized trials. The meta-analysis showed a trend towards lower mortality in patients treated with HNFC (Appendix 4).

In COVID-19 patients, two multicenter randomized trials showed that patients treated with HFNC were less likely to be intubated than those receiving conventional oxygen therapy [ 63 , 64 ]. However, four other randomized trials did not confirm a beneficial effect of HFNC on intubation [ 58 , 59 , 65 , 66 ]. This discrepancy may be explained by the severity of illness, which differs between trials, lack of power and crossovers in some trials. Nevertheless, a meta-analysis including all these studies found a beneficial effect of HFNC on intubation compared with conventional oxygen therapy (Appendix 3). In contrast, none of these randomized trials found a beneficial effect of HFNC on mortality compared with conventional oxygen therapy, even though the meta-analysis showed a trend towards lower mortality in patients treated with HNFC (Appendix 4).

Given the PaO 2 /FiO 2 ratio at baseline in the different trials in COVID-19 and non-COVID-19 patients and decreased intubation in patients treated with HFNC in a post-hoc analysis of the FLORALI study [ 60 ] in the subgroup of patients with a PaO 2 /FiO 2 ratio < 200, the panel retained a threshold value of PaO 2 /FiO 2 ratio < 200 or an oxygen flow rate > 6 L/min to obtain SpO 2  > 92% as a criterion for initiation of HNFC in patients with de novo hypoxemic ARF.

Section 4: Indications for non-invasive and invasive mechanical ventilation

Question 6: what are the indications for non-invasive ventilation (niv) in patients with acute hypoxemic respiratory failure.

Recommendation 6 A

In the absence of intubation criteria, high-flow nasal cannula oxygen therapy (HFNC) should probably be used rather than NIV in patients with de novo acute hypoxemic respiratory failure (GRADE 2 + , moderate quality of evidence, strong agreement).

Several randomized studies have compared NIV with HFNC [ 60 , 67 , 68 , 69 , 70 ]. None have demonstrated the superiority of any technique concerning intubation, except for Grieco et al., who found that patients treated with NIV using the Helmet device were less likely to be intubated. Frat et al. and Nair et al. found that patients treated with HFNC also tended to be intubated less frequently. A meta-analysis including all these studies showed that patients treated with HFNC tended to be less likely to be intubated (Appendix 5). The FLORALI study [ 60 ] also found a higher mortality rate in patients with de novo hypoxemic ARF treated with NIV than in patients treated with HFNC. The authors suggested that this increased mortality in patients treated with NIV might be related to increased incidence of ventilatory-induced lung injury (VILI) due to high tidal volume in patients treated with NIV. Nair et al. likewise found a trend towards higher mortality in patients treated with NIV. A meta-analysis including all these studies found a trend towards lower mortality in favor of HFNC (Appendix 6). Finally, HFNC appears to be easier to use and better tolerated than NIV.

Recommendation 6 B

The panel makes no recommendation concerning NIV versus standard oxygen therapy in patients with de novo hypoxemic ARF, including immunocompromised patients (insufficient quality of evidence, strong agreement).

Numerous studies have compared NIV with standard oxygen therapy in patients with de novo hypoxemic ARF and have shown conflicting results on intubation. All the older studies showed that patients treated with NIV were less likely to be intubated (Appendix 5). Nevertheless, these studies had small sample size and included heterogeneous patients, 30–75% of whom suffered from acute exacerbation of chronic obstructive pulmonary disease and/or hydrostatic pulmonary edema. The two randomized multicenter trials excluding patients with acute exacerbation of chronic obstructive pulmonary disease and/or hydrostatic pulmonary edema did not find any difference between NIV and conventional oxygen therapy concerning intubation [ 60 , 71 ].

In immunocompromised patients, four randomized trials compared NIV with standard oxygen therapy and/or HFNC [ 69 , 72 , 73 , 74 ]. Only the two oldest studies showed that patients treated with NIV were less likely to be intubated, while the two most recent studies showed no superiority of NIV. This discrepancy may be explained by the fact that in Antonelli et al. and Hilbert et al., patients in the control group were treated with standard oxygen therapy alone, whereas in the control group, 40% of patients in the study by Lemiale et al. and all patients in the study by Coudroy et al. were treated with HFNC. Nevertheless, a meta-analysis including all of these studies found that patients treated with NIV were less likely to be intubated (Appendix 7). Only one study showed decreased mortality in patients treated with NIV [ 73 ]. However, a meta-analysis including all these studies showed a trend towards lower mortality with NIV (Appendix 8).

Question 7: What are the indications for invasive mechanical ventilation in patients with acute hypoxemic respiratory failure?

Recommendation 7 A

The panel suggests that in acute hypoxemic respiratory failure, the presence of any of the following criteria requires intubation (panel opinion, strong agreement):

Cardiac or respiratory arrest due to hypoxemia

Persistent hypoxemia despite maximal oxygenation strategy, with PaO 2 /FiO 2  <  60 mm Hg and/or SpO 2 < 88%.

Recommendation 7 B

The panel suggests that in acute hypoxemic respiratory failure, the presence of one or more of the following criteria should lead to consideration of intubation (panel opinion, strong agreement):

Shock requiring vasopressor

Clinical signs of respiratory distress

Appearance or worsening of vigilance disorders

Worsening hypoxemia despite maximal oxygenation strategy

Persistent hypoxemia despite maximal oxygenation strategy, with Pa O 2 /FiO 2  <  100 mm Hg or SpO 2 < 92%.

Respiratory or mixed acidosis with pH < 7.30

Tachypnea with respiratory rate > 30 or worsening respiratory rate

Bronchial congestion or copious secretions

Recurrent desaturation episodes with SpO 2  <  86%

Intolerance to oxygenation modality

No study has compared presence vs. absence of intubation in acute hypoxemic respiratory failure. The present recommendation was therefore drafted following a vote by the experts consulted, using the DELPHI method.

Numerous studies comparing different oxygen therapy or non-invasive ventilation strategies have proposed need for invasive mechanical ventilation as an endpoint. The risks associated with intubation are manifold, including procedural failure, ventilator-associated pneumonia [ 75 ], induced lung injury, hemodynamic effects and respiratory muscle amyotrophy [ 76 ]. However, delayed intubation has been identified as a risk factor for mortality in several studies [ 77 ] although severity at the time of the intubation decision may be a confounding factor.

Identified failure of an oxygenation strategy and/or failure of non-invasive ventilation and the decision to switch to invasive ventilation consequently aim to avoid exposing the patient to unnecessary intubation.

Hypoxemic cardiac arrest and failure of a maximal oxygenation strategy with persistent deep hypoxemia are the two situations identified by the panel as systematically requiring intubation. Aside from these situations, the decision to intubate must be individualized, taking into account the patient's oxygenation status, progress, tolerance of the strategy initiated, and any other organ failure.

Section 5: The role of adjuvant therapies: awake prone position and physiotherapy.

Question 8: in patients with acute hypoxemic respiratory failure, should awake prone position be used.

Recommendation 8A

The panel makes no recommendation concerning awake prone position in acute hypoxemic respiratory failure not related to COVID-19 (insufficient quality of evidence, strong agreement).

Recommendation 8 B

In acute hypoxemic respiratory failure related to COVID-19, awake prone position should probably be used to reduce the need for intubation in patients requiring high-flow oxygen therapy (GRADE 2 + , moderate quality of evidence, strong agreement).

The clinical data concerning awake prone position (APP) are recent. All relevant studies have been conducted in patients with COVID-19-related type I ARF. Out of the prospective studies, only 9 were multicenter; 8 were randomized [ 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ], and the other was non-randomized [ 86 ].

However, these studies did not show any significant reduction in mortality or length of stay and were discordant concerning intubation. Moreover, while the meta-analytical data available to date suggest no benefit of APP on patient survival or length of stay, they confirm a reduced rate of intubation [ 87 , 88 , 89 , 90 , 91 ].

The largest study was an international meta-trial, i.e. a simultaneous multicenter prospective analysis of individual patient data from six nationwide randomized trials, and found a beneficial effect on the intubation rate [ 80 ]. The patients received high-flow oxygen therapy. Without evidence favoring other oxygenation modalities, it therefore seems legitimate to recommend high-flow oxygen therapy when using APP.

APP should remain an adjuvant method and should not delay intubation. It should not be considered as a rescue method.

Pending the results of specific studies to come, the data on APP cannot be extrapolated to hypoxemic ARF in non-COVID 19 patients, [ 92 ].

To date, there are no data concerning the time elapsed between symptom onset and APP initiation. In the largest positive APP cohort, it was only performed in ICUs [ 84 ]. Aside from exceptional health conditions, given the high risk of progression to intubation during APP (33% in the study by Ehrmann et al.) and the increased workload for nursing teams, APP should be used only in ICUs.

It seems difficult, due to the substantial heterogeneity of studies, to make precise recommendations concerning APP session duration or minimum daily duration. However, Ehrmann et al. suggested that longer sessions were associated with greater benefit in terms of risk of intubation or death [ 80 ]. Median APP duration was 5.0 h/d [1.6–8.8]. Ibarra-Estrada et al. found a lower rate of intubation or death in patients having received sessions lasting more than 8 h [ 84 ].

The rate of adverse events associated with APP seems low [ 80 ]. On the other hand, patient discomfort and/or inadequate compliance are the main elements of concern with regard to APP tolerance. The pathophysiology of APP effects has only occasionally been explored. Some studies seem to show that inspiratory pressures increased in association with increased airway resistance [ 93 ]. APP should therefore probably be avoided in the most polypneic patients, so as not to increase the risk of self-inflicted lung injury.

Question 9: In patients with acute hypoxemic respiratory failure, what is the role of physiotherapy?

Recommendation 9 A

The panel suggests physiotherapy to promote lung recruitment in clinically stable patients with acute hypoxemic respiratory failure requiring ICU admission (panel opinion, strong agreement).

All physiotherapy treatments must be the result of a team discussion taking into consideration the patient's level of organ failure and the underlying disease [ 94 ]. To date, no randomized controlled trial has evaluated the positive contribution of physiotherapy in patients undergoing oxygen therapy for ARF. Physiotherapy, whether motor or respiratory, cannot be considered as a reference treatment.

Two studies have shown that motor physiotherapy (bed exercises, chair positioning, cycloergometer) improves ventilation distribution in the posterior lung regions [ 95 , 96 ]. In addition, Hickmann et al. found improved hematosis, with an increased PaO 2 /FiO 2 ratio, especially in the most severe patients [ 96 ]. However, these effects were not sustained over time and regressed at the end of the procedure. In addition to respiratory function, motor physiotherapy has other objectives: prevention of bedsores or sarcopenia, maintenance of joint amplitudes, improved comfort…[ 97 ].

There are currently no studies on respiratory physiotherapy in de novo ARF patients. While the recommendations of the American Association for Respiratory Care and the British Thoracic Society address the overall role of respiratory physiotherapy, they do not specifically consider resuscitation or intensive care patients with ARF [ 98 , 99 ]. In these recommendations, respiratory physiotherapy techniques are reserved for ARF patients with additional bronchial congestion. The panel members suggested that the state of congestion of an ARF patient, and the indication for respiratory physiotherapy be assessed by the physiotherapist.

Recommendation 9 B

The panel makes no recommendation concerning systematic respiratory physiotherapy in acute hypoxemic respiratory failure (insufficient quality of evidence, strong agreement).

There are currently no studies on respiratory physiotherapy in ARF patients. While the recommendations of the American Association for Respiratory Care and the British Thoracic Society address the overall role of respiratory physiotherapy, they do not specifically consider ICU patients [ 98 , 99 ]. In these recommendations, respiratory physiotherapy techniques are reserved for ARF patients with additional bronchial congestion. The panel suggests that congestion and the indication for respiratory physiotherapy be assessed by the physiotherapist.

Section 6: organizational measures

Question 10: in patients with acute hypoxemic respiratory failure, which criteria necessarily lead to icu admission.

Recommendation 10 A

The panel suggests that patients receiving conventional oxygen therapy and showing clinical signs of respiratory distress should be managed in an ICU (panel opinion, strong agreement).

Recommendation 10B

The panel suggests that patients receiving HFNC, CPAP or NIV should be managed in an ICU (panel opinion strong agreement).

There has been no randomized trial comparing admission to the ICU vs. hospital ward for patients under oxygen therapy with clinical signs of respiratory distress. However, it seems reasonable for these patients to be admitted to an ICU to ensure appropriate care and monitoring.

When treatment with HFNC, CPAP or NIV is decided, the patient should be directed to an ICU to rapidly identify signs of poor tolerance, respiratory distress and in order to avoid delayed intubation [ 68 ]. In these patients, the rate of secondary intubation appears high, around 30 to 40%, justifying admission to critical care [ 100 ]. While initiation of these techniques can begin in an emergency ward, it should not delay transfer to the ICU.

In the specific context of exceptional health situations, use of HFNC, CPAP or NIV might be considered outside ICUs [ 58 , 101 ].

Section 7: Ethical considerations

Question 11: which oxygenation device should be preferred for patients for whom a do-not-intubate decision has been made.

Recommendation 11

The panel makes no recommendation regarding the preferred oxygenation device for patients for whom a do-not-intubate decision has been made (insufficient quality of evidence, strong agreement).

Patients with ARF for whom a do-not-intubate decision has been made represent about 25% of patients with ARF under HFNC or NIV [ 102 ], and therefore a common situation.

According to the panel, the probability of survival from the acute episode should be considered when deciding on the most suitable oxygenation device. In these patients, HFNC could improve comfort. A randomized controlled trial in oncology showed improved comfort-related outcomes (dyspnea score, dry mouth, sleep quality) in patients treated with HFNC for 72 h versus conventional oxygen [ 103 ].

Another RCT demonstrated an improved dyspnea score on the modified Borg scale when comparing HFNC and conventional oxygen in hypoxemic ARF patients with a “do-not-intubate” decision [ 104 ].

Retrospective studies and single-center cohorts (with small sample sizes and heterogeneous outcome measures) also converge towards positive effects on comfort, maintenance of oral intake, and a low rate of complications or poor tolerance with HFNC versus conventional oxygen therapy [ 105 , 106 , 107 ].

There are no data on the impact of HFNC on mortality in this population. NIV in these patients not only does not improve survival, but also seems to decrease patient comfort (nutrition, communication, tolerance) [ 108 ], 109 ].

Availability of data and materials

Not applicable.

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Helms, J., Catoire, P., Abensur Vuillaume, L. et al. Oxygen therapy in acute hypoxemic respiratory failure: guidelines from the SRLF-SFMU consensus conference. Ann. Intensive Care 14 , 140 (2024). https://doi.org/10.1186/s13613-024-01367-2

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Back to Journals » International Journal of Chronic Obstructive Pulmonary Disease » Volume 11 » Issue 1

Acute oxygen therapy: a review of prescribing and delivery practices

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Authors Cousins J   , Wark P   , McDonald V  

Received 4 January 2016

Accepted for publication 29 February 2016

Published 24 May 2016 Volume 2016:11(1) Pages 1067—1075

DOI https://doi.org/10.2147/COPD.S103607

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Richard Russell

Joyce L Cousins, 1–3 Peter AB Wark, 3–5 Vanessa M McDonald 2–5 1 Faculty of Arts, Nursing and Theology, Avondale College of Higher Education, Sydney, 2 School of Nursing and Midwifery, 3 Priority Research Centre for Healthy Lungs, 4 School of Medicine and Public Health, The University of Newcastle, 5 Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia Abstract: Oxygen is a commonly used drug in the clinical setting and like other drugs its use must be considered carefully. This is particularly true for those patients who are at risk of type II respiratory failure in whom the risk of hypercapnia is well established. In recent times, several international bodies have advocated for the prescription of oxygen therapy in an attempt to reduce this risk in vulnerable patient groups. Despite this guidance, published data have demonstrated that there has been poor uptake of these recommendations. Multiple interventions have been tested to improve concordance, and while some of these interventions show promise, the sustainability of these interventions are less convincing. In this review, we summarize data that have been published on the prevalence of oxygen prescription and the accurate and appropriate administration of this drug therapy. We also identify strategies that have shown promise in facilitating changes to oxygen prescription and delivery practice. There is a clear need to investigate the barriers, facilitators, and attitudes of clinicians in relation to the prescription of oxygen therapy in acute care. Interventions based on these findings then need to be designed and tested to facilitate the application of evidence-based guidelines to support sustained changes in practice, and ultimately improve patient care. Keywords: chronic obstructive pulmonary disease, COPD, type II respiratory failure, oxygen therapy, prescribing, hypoxia, hypercapnia

Introduction

Oxygen is a commonly used drug in the clinical setting 1 – 4 and unquestionably saves lives. However, its use must be carefully considered. Like any drug, it may cause harm when used inappropriately. 4 , 5 In practice, a common misconception that “you can’t give too much oxygen” 1 , 3 or “oxygen won’t hurt” 4 has emerged. This has led to higher levels of oxygen therapy being delivered to patients who are critically unwell or who complain of dyspnea, 3 resulting in increased lengths of stay, 6 higher rates of admission to high dependency units, 6 and an increased risk of death. 7 , 8 Indeed, New 9 states that in the past ambulance crews regarded oxygen as a sort of “medical wet wipe […] not always therapeutic, but never harmful.”

The clinical effect supplemental oxygen can have on patients experiencing acute exacerbations of chronic obstructive pulmonary disease (COPD) is now widely known, 10 yet not completely understood. 11 Uncontrolled oxygen administration, particularly when delivered at high concentrations, can result in a worsening of hypercapnia. 12 , 13 Multiple pathological mechanisms are believed to underlie this phenomenon, 11 , 12 , 14 , 15 with the primary causes being the inhibition of pulmonary vasoconstriction. Resulting in a worse ventilation/perfusion mismatch, and a right-hand shift of the CO 2 dissociation curve (Haldane effect), further increasing P a CO 2 . 13 , 16 Other mechanisms for this phenomenon include further increases in ventilation/perfusion mismatching due to absorption atelectasis and an increased work of breathing due to the higher density of oxygen over air. 17 Initial beliefs that hypercapnia was primarily caused as a result of a “reduced hypoxic drive” have been largely disproved, 18 following the publication of results challenging these earlier hypothesis. In 1980, Aubier et al 18 demonstrated that while minute ventilation initially fell with the administration of high concentrations of oxygen therapy in the COPD patient cohort, this decrease was transient, with minute ventilation returning to levels only marginally lower than when breathing room air initially.

For these reasons, the use of titrated oxygen therapy in this patient group has been advocated for many years. Guidance from the British Thoracic Society (BTS), 17 the Global Initiative for Obstructive Lung Disease 19 and, more recently, the Thoracic Society of Australia and New Zealand 20 advise clinicians to administer oxygen to maintain an SpO 2 between 88% and 92% in an acute hospital setting for patients with COPD and others who are vulnerable. While COPD is the most common chronic disease in clinical practice to cause hypercapnia, 17 other vulnerable patient groups are also at risk. These include those patients with morbid obesity, obstructive sleep apnea, cystic fibrosis, neuromuscular disorders, those with restrictive chest wall deformities, and those using respiratory depressant drugs, such as opioids and benzodiazepines. 17 , 21 In patients who are not at risk of hypercapnic respiratory failure, recommendations vary between professional bodies, with the BTS 17 , 21 advocating for maintenance of an SpO 2 between 94% and 98% and the Thoracic Society of Australia and New Zealand 20 recommending maintenance of an SpO 2 between 92% and 96%. Undoubtedly, the accurate delivery of oxygen therapy is important for all patients; however, the deleterious effects of poor clinical practice in this area are most significant and now well documented in those patients who are vulnerable, particularly those with COPD. 7 , 22 – 27 Austin et al 7 were the first to show clear evidence of the benefits of administering titrated oxygen (delivered via nasal prongs to achieve an SpO 2 between 88% and 92%) to patients with acute exacerbations of COPD. Their results demonstrated that the delivery of titrated oxygen therapy reduced mortality by 58% when compared with those who received high flow oxygen therapy (delivered via a nonrebreather mask at 8–10 L/min). 7 A retrospective review of ambulance practice, conducted by Cameron et al, 28 illustrates this point. This study demonstrated that 80% of the patients with COPD brought in to the emergency department by ambulance had received high concentrations of oxygen during initial response and transfer. They reported an increased risk of serious adverse outcomes in patients who were both hypoxemic and hyperoxemic when compared to those who were normoxemic. However, hypercapnia and acidosis were more pronounced in the hyperoxemic group.

Many authors 3 , 11 , 29 – 33 and professional bodies 17 , 20 argue that oxygen should be treated like other drugs with orders for therapy included on a treatment (drug) chart to improve accurate administration. However, prescription of oxygen therapy has been historically poor, and compliance with or adherence to the written prescription has not been consistently demonstrated. This review examines the literature that has explored prescribing practices internationally with a variety of interventions employed in attempts to improve prescription, administration, and consequently patient outcomes.

Oxygen prescription

The adequacy of oxygen prescription within the acute hospital setting has been studied over many years. 34 – 54 These studies have explored both the presence of a prescription and the adequacy and appropriateness of oxygen prescription in a broad range of patient groups. The literature includes studies specific to vulnerable groups, including those with chronic ventilatory failure, but is not limited to this population with evaluation being undertaken in the general clinical setting. However, since the publication of the BTS Guidelines on acute oxygen administration in 2008, there has been an increasing interest in this topic. Figure 1 depicts a timeline of papers (according to the geographical area that the studies were conducted) that have been published on oxygen therapy prescription and administration practices since 1980. Interestingly, over 27 years, between 1980 and 2007, 17 papers 33 , 35 , 41 – 44 , 46 , 47 , 49 – 51 , 53 – 58 were found that discussed oxygen prescription rates and/or the appropriateness and accuracy of oxygen administration and subsequent monitoring of oxygen therapy. In the 6 years between 2009 and 2015, 12 papers which measured the accurate or appropriate prescription of oxygen therapy have been reported. 34 , 36 – 40 , 45 , 48 , 52 , 59 – 61 Some of these papers also discussed various interventions that have been tested to improve prescription practices.

Overall, the literature suggests that the practice of prescribing oxygen therapy is poor. 34 – 39 , 41 – 44 , 46 , 47 , 49 , 51 , 52

Various reasons have been proposed for this, including:

• insufficient training and education for medical and nursing staff; 33 , 39 , 41 , 42 , 47 , 51 , 54 , 62
• a lack of familiarity with oxygen delivery devices; 51
• a lack of understanding of the effects, role and dangers of oxygen therapy; 35 – 37 , 46 , 61
• staff time constraints; 48
• necessity to maintain SpO 2 >94% due to the “between the flags” track and trigger observations charts; 36
• practical issues related to space and place for prescribing oxygen; 35 , 39 , 61
• difficulties with changing long established behavior; 36 , 60
• patients transferred from other wards/departments with oxygen therapy already in situ; 44
• lack of enthusiasm by senior clinical staff; 44
• communication difficulties between doctors and nurses; 36
• lack of full time staff or staff turnover. 36 , 38 , 48 , 60

In attempts to improve overall prescription rates, different interventions have been tested in various combinations over different periods of time, with varying degrees of success. Interventions that have been employed are presented in Table 1 and the degree of change achieved pre- and postintervention is presented graphically in Figure 2 . These interventions include:

• introduction of oxygen alert stickers; 39 , 59 – 61
• dedicated oxygen order chart; 35
• clearly delineated section on the drug chart or changes to the drug chart to include space for the transcription of oxygen orders; 34 – 36 , 48 , 60
• informational posters; 59 – 61
• email notification/dissemination of information; 60 , 61
• educational session across various clinical specialties and at various key times; 34 , 36 , 39 , 44 , 48 , 56 , 59 – 61
• nurse facilitated reminder system; 38
• development of hospital guidelines/policy to guide practice; 36 , 42 , 59 , 60
• admission bundle with electronic prescribing system; 45
• message alerts on computer login screens. 60

One study 42 demonstrated no or minimal improvement in prescribing practices after implementing an oxygen guideline to inform clinician practice. Despite no change in prescriber behavior, a large improvement was seen in the administration of oxygen according to the prescribed dose (70% vs 95%; P =0.043) and in the clinical assessment of all patients commenced on oxygen therapy, that is, increased measurement of pulse oximetry (69% vs 91%; P =0.001). The assessment of arterial blood gases for those with respiratory disease improved following the introduction of the guideline (from 65% to 87%; statistical significance was not reported) with even greater improvements seen in the reevaluation of arterial blood gases following initiation of oxygen therapy for the cohort with airways disease, increasing to 68% from 34% ( P =0.037). The authors 42 concluded that although little change was seen in the prescribing practices of the doctors, practice improvements were seen. Junior doctors reassessed arterial blood gases more frequently and nurses administered the prescribed dose more frequently and used pulse oximetry more often to assess patients after the introduction of the guidelines. 42 Similar improvements in administration and assessment have been seen in some practice areas in other studies 34 , 38 but not in others 47 in which the presence of an accurate prescription did not improve oxygen administration and assessment practices in these patients.

Rudge et al 61 described a promising quality improvement project that occurred over three cycles which demonstrated dramatic improvements to the accurate prescription of oxygen therapy. Baseline data showed that 55% of patients using oxygen had a valid prescription; this then decreased to 54% following cycle one, but improved to 94% at the end of cycle three. They used four interventions (oxygen prescription chart, oxygen alert stickers, point of care resources, and senior led educational sessions) over a 2-year period on an Acute Medical Unit. 61 While these data are encouraging, there are limitations with the study design; it was a quality improvement audit conducted in one unit of a single hospital and interventions were ongoing both prior to and during the data collection phase.

Similarly, in an earlier audit undertaken by Dodd et al, 35 a large improvement was seen in written prescription practice (before and after implementation of a specific oxygen prescription chart, from 55% to 91%; P =<0.001) with the accuracy of these written prescriptions improving significantly (7% vs 77%; statistical significance was not reported) following the implementation of a dedicated chart on which oxygen therapy could be prescribed. The authors argued that junior doctors have inadequate levels of understanding about the effects and potential dangers of oxygen therapy; however, the improvements seen following the implementation of a dedicated oxygen prescription chart appear to indicate that junior doctors complete required documentation appropriately when it is available and the presence of a chart merely prompted this action. Importantly, this was a single-center study and no data in this study examined the adherence of other clinicians (nurses and other medical staff) to accurately deliver the actual prescription. However, the results from the study by Gunathilake et al 36 suggest that appropriate oxygen delivery improved as prescription rates improved. They demonstrated that the number of patients at risk of type II respiratory failure with saturation levels above 92% decreased from 47% at initial audit to 18% ( P =0.04) following a multicomponent intervention and as prescribing rates increased (2.4% to 34%; P =<0.0001). 36 Despite these encouraging results that demonstrate improvements in practice are possible, the sustainability of this behavior has been questioned by Young and Kostalas. 48 They saw a significant improvement in prescription rates (from 12% to 74%; P =<0.001) 3 months following the introduction of an oxygen prescription section on the drug chart and the delivery of an educational session, but at 12 months this had decreased to 51%.

Also of interest is a study by Medford et al 38 who implemented a nurse facilitated reminder system and found that there were relatively high rates of appropriate oxygen administration prior to the implementation of the reminder system, and that these did not change significantly on reaudit 4 months after implementation (70.6% and 76.5%, respectively; P =0.65). Here, nurses were empowered to remind doctors to prescribe oxygen therapy. This may indicate that in general, nurses are skilled at delivering the appropriate dose of oxygen despite the absence of a prescription as is indicated by the lack of practice change by the nurses and maintenance of a relatively high rate of appropriate administration of oxygen therapy both before and after the intervention.

Knowledge of oxygen therapy and delivery equipment

Knowledge of oxygen therapy and the equipment used to deliver oxygen may also be barriers to optimal oxygen administration. This has been highlighted in a study conducted by Ganeshan et al 62 who reported that commonly used oxygen delivery devices, for example, nasal cannulae, are easily recognized by doctors and nurses with less frequently used devices, such as nonrebreathing masks, being poorly recognized. In addition, when both medical and nursing clinicians were presented with sample case scenarios, a larger proportion (up 97% and 73% of doctors and nurses, respectively) were not able to accurately prescribe the correct dose of oxygen or the appropriate method for administration of oxygen for some of the scenarios described. Interestingly, this study 62 demonstrated that in four out of the seven case scenarios, nurses’ knowledge of the correct delivery devices and oxygen prescription was higher than that of the doctors. Overall, however, knowledge of correct prescriptions was suboptimal.

The authors argue that even if it were compulsory for medical staff to complete written prescriptions of oxygen therapy in wards settings, it is unlikely that staff would be able to prescribe it correctly. These findings are of particular concern in light of the current guideline recommendations. 17 , 20 Disturbingly, these are not stand alone results and are supported by findings from other studies 63 – 65 that show there are large gaps in the knowledge of health care staff on various aspects of respiratory therapy. Considering the frequency with which oxygen is administered in an acute hospital setting and the harm that may be caused, interventions to improve the overall knowledge and practice around oxygen therapy and therefore concordance to evidence-based guidelines are urgently required.

Auditing practice

The BTS has conducted audits of prescribing practices within the National Health Service (NHS) since the implementation of the 2008 guidelines. These audits have demonstrated slow but steady improvements in the rates of oxygen prescription. The most recently available data from the 2013 audit 66 demonstrated that 55% of patients who were using oxygen had some form of written order. This is an improvement from the 2008 audit which showed that only 32% of patients had a written order. 66 These data also demonstrate a steady decline (17.5% down to 13.8%) in the number of patients within the NHS who are using oxygen therapy, 66 which could result in improved patient outcomes and substantial savings for the health service. In contrast, an Australian audit demonstrated that as few as 3% of patients with COPD had an existing oxygen prescription despite 79% of patients with COPD receiving oxygen therapy at the time of audit. 27 This improved level of practice in the UK, where regular audits are performed, may indicate that regular auditing and review of clinical practice and practice gaps can lead to improved clinician behavior.

Current recommendations and future directions

The NHS in their latest oxygen safety report 67 suggests that the main safety concerns for oxygen administration relate to the under- and overuse of oxygen, and that these are caused by the inappropriate prescription, monitoring, and administration of oxygen. Like the BTS, the NHS emphasizes the need for the accurate prescription and monitoring of patients with pulse oximetry. Similarly, the 2015 Thoracic Society of Australia and New Zealand guidelines for acute oxygen use in adults also recommend that oxygen therapy is prescribed with a specific record documented in the patient notes and drug chart, the main requirements being the documentation of a target SpO 2 range.

It is clear that there is a need to improve the prescribing practices for all patients across hospital settings. Although the authors have postulated on the reasons behind why evidence-based guidelines are not adhered to, very little data exist examining why high flow oxygen continues to be given in practice (particularly in the prehospital and emergency department setting) or why the written prescription of oxygen therapy remains low. Medford et al 38 and Hickey 44 suggest that analysis of doctors’ views on the prescription of oxygen therapy is needed and that strategies for optimizing the behavior of permanent nursing staff are necessary; 38 however, to date, few data have been published relating to these points. As such, little is known about the barriers or facilitators that exist to improve the implementation of these strategies in practice, yet, published literature from the past 30 years demonstrates that despite a number of interventional strategies aimed at improving practice, it continues to be a challenging practice to change.

The knowledge practice gap is a common phenomenon in health care 68 with some authors 69 suggesting that the provision of guidelines and evidence from research, while necessary, are not sufficient in bridging the knowledge practice gap. Specifically, this has been demonstrated with the oxygen prescription data. A convincing evidence base now exists, yet the consistent application of the evidence (prescription and delivery of low flow oxygen to maintain SpO 2 88%–92% in vulnerable patient groups) is not applied in daily practice. Funk et al 70 argue that determining the perceptions of clinicians is vital in addressing this knowledge–practice gap. Ultimately, clinicians are responsible for the delivery of care. If we are to reduce or eliminate barriers to implementing research knowledge into practice, clinicians’ opinions are vital. Tailored interventions while effective can be variable; however, a 2015 Cochrane Review concluded that “interventions tailored to address identified barriers are probably more likely to improve professional practice than no intervention or the dissemination of guidelines alone.” 71

Throughout this review, we have presented international data surrounding current practice for the prescription of oxygen therapy. These data demonstrate that the rates of concordance to recommended practice have seen a necessary change in oxygen prescription; however, there remains substantial room for improvement. This is evidenced in the large audit conducted by Roberts et al 26 in 2010–2011 in which 16,018 patients admitted with acute exacerbations of COPD to hospitals in 13 European countries demonstrated a high level of adherence (85%) to the Global Initiative for Obstructive Lung Disease 72 standards for the management of acute exacerbations of COPD, administering titrated oxygen therapy, to achieve PaO 2 >60 mmHg or SpO 2 >90%. 72 Despite this high level of adherence, >1,623 (10.1%) of the patients across the hospitals received either high flow oxygen or no supplemental oxygen (despite being hypoxic). Many practice gaps exist, which lead to poor patient outcomes. Pilcher and Beasley 32 suggest that there is an entrenched culture of routine and indiscriminate administration of high-concentration oxygen to acutely ill patients. This culture must change and there is a clear need to examine the barriers, facilitators, and attitudes toward oxygen and its prescription in acute care if we are to improve practice and minimize harm in vulnerable patient groups. Effective interventions may assist in translating expert guidelines into clinical practice. These may facilitate the adoption of best practice guidelines and ultimately improve clinical outcomes for COPD and other vulnerable patient groups who are most impacted by poor oxygen administration practices.

Acknowledgment

VM McDonald is supported by a National Health and Medical Research Council Translating Research into Practice Fellowship.

The authors report no conflicts of interest in this work.

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Oxygen in arguably one of the most frequently utilized drugs in modern healthcare, but is often administered to patients at caregivers' discretion with scant evidence as to its efficacy or safety. Although oxygen is administered for varied medical conditions in the hospital setting, published literature supports the use of oxygen to reverse hypoxemia, for trauma victims with traumatic brain injury and hemorrhagic shock, for resuscitation during cardiac arrest, and for carbon monoxide poisoning. Oxygen should be titrated to target an S pO 2 of 94–98%, except with carbon monoxide poisoning (100% oxygen), ARDS (88–95%), those at risk for hypercapnia (S pO 2 88–92%), and premature infants (S pO 2 88–94%). Evidence for use with other conditions for which oxygen is administered relies on anecdotal experiences, case reports, or small, underpowered studies. Definitive conclusions for oxygen use in these conditions where efficacy and/or safety are uncertain will require large randomized controlled clinical trials.

• oxygen therapy
• hyperoxemia
• oxygen efficacy
• oxygen safety
• Introduction

In 1772 Swedish pharmacist Carl Scheele discovered that when heating mercuric oxide and potassium nitrate, candles burned brighter. Scheele did not publish his findings until 1777. Meanwhile, chemist Joseph Priestley was conducting his own experiments with mercuric oxide. His experiments describing “dephlogisticated air” were published in 1775, which credited him with the discovery of oxygen. 1 At this time the chemical theory of phlogiston stated that by burning, the combustible components of a substance are released into the atmosphere. Priestley believed that by heating the mercury he was removing phlogiston (impurities) from the atmosphere, pulling it into the mercury, thus purifying the air. Priestley theorized that dephlogisticated air may have medical applications in serious cases of lung disease, but also warned that use in the healthy body may be harmful. His statement “As a candle burns out much faster in dephlogisticated than in common air, so we might, as may be said, live out too fast, and the animal powers be too soon exhausted in this pure kind of air” has applications today, as we seek to determine how much oxygen is too much. For the purpose of this paper, the discussion of oxygen therapy pertains only to adults, unless otherwise stated.

• Early Oxygen Use

Following Priestley's published findings, Antoine Lavoisier repeated his and Scheele's experiments and proved that oxygen was a chemical element, disproving the phlogiston theory. 2 In 1778 he named the gas oxygen “acid former,” due to his belief that it was a component of all acids. Five years later a French physician treated a patient suffering from tuberculosis with daily inhalations of oxygen, which is believed to be the first medical use of the gas. 1 Throughout most of the 19th century, pure oxygen therapy was not available to the public. Mostly diluted nitric oxide, “compound oxygen,” was widely believed to be a panacea for many common ailments. George Holtzapple is credited with publishing the first case report describing the administration of intermittent oxygen therapy, to a 16-year-old male with lobar pneumonia, at York Hospital in 1885. The patient's cyanosis improved with oxygen therapy and he subsequently recovered. 3 It was not until 1890 that Albert Blodgett administered continuous flow oxygen to a patient with pneumonia to relieve shortness of breath. 4 He estimated that around 200 gallons of oxygen per day was needed for continuous administration: approximately 6 L/min.

• Modern Oxygen Therapy

The understanding of therapy and physiology advanced quickly during the early 1900s, due to the gas poisonings during World War I, and advances in basic science. 1 Physiologists Adolph Fick and Paul Bert further advanced oxygen physiology by describing oxygen in units of partial pressure, which led to the understanding of the differences between arterial and venous blood oxygenation and the relationship to cardiac output and oxygen consumption. John Haldane published the first paper on the rational use of oxygen in 1917. 5 Much of what we consider to be the basic physiologic concepts of oxygenation can be attributed to Haldane. In his paper he describes the respiratory drive as regulated by carbon dioxide, the different types or causes of hypoxemia, and tissue hypoxemia in carbon monoxide (CO) poisoning. He further describes the mechanisms of ventilation-perfusion matching and mismatching and the role of supplemental oxygen as a treatment. Haldane was also the first to describe the effects of oxygen on the pulmonary system.

Oxygen use on the battlefield was first reported during World War I, primarily for the treatment of phosgene gas poisoning. 6 When mixed with water in the lungs, phosgene forms hydrochloric acid, damaging alveolar lining, and at high doses leads to pulmonary edema and eventually to what we know today as ARDS. Oxygen was also used in the treatment of trench nephritis, acute bronchitis, and severe hemorrhage. Oxygen treatment on the battlefield was accomplished by the use of equipment developed by Haldane, which consisted of a pressurized cylinder, pressure regulator, a reservoir, and mask, much like what is currently used today. Experiences learned from the war helped develop a basic understanding of rational oxygen use, ways to administer, and what did not work: mainly intermittent usage in a hypoxic patient. Evidence for oxygen use in trauma care was also gained from the war experience. Despite evidence of the benefit of continuous therapy on the battlefield and the publishing of Haldane's book, Respiration , 7 many physicians continued to prescribe intermittent oxygen therapy into the first half of the 20th century.

• Indications for Oxygen Therapy

Supplemental oxygen is an important part of modern medical care. From prehospital to in-hospital care and anesthesia applications, to long-term usage in chronic lung disease, oxygen use has become so common that it is often taken for granted. Although it is considered a drug and should be prescribed as such, oxygen is often given to patients at the caregiver's whim, and frequently without a physician's order. 8 , 9 This occurrence in the hospital setting is common because oxygen is readily available, abundant, and cheap when employing the large liquid systems, as do most hospitals. Even after a century's experience and numerous publications concerning oxygen administration, the question remains: what are the evidence-based indications for oxygen therapy in hospitalized patients?

The American Association for Respiratory Care provides guidance for in-hospital use of oxygen other than with mechanical ventilators and hyperbaric chambers. 10 The recommended indications are documented hypoxemia (P aO 2 < 60 mm Hg or S aO 2 < 90%), suspected hypoxemia, severe trauma, acute myocardial infarction, and short-term therapy such as post-anesthesia recovery or surgical intervention. The British Thoracic Society's 11 , 12 and Western Australian Hospital's indications for supplemental oxygen are to maintain normal or near normal S pO 2 (94–98%) for all patients not at risk for hypercapnic respiratory failure, and S pO 2 of 88–92% for those at risk. This guidance specifically states that patients suffering from myocardial infarction and acute coronary syndrome have the same S pO 2 targets as above. Additionally, the guidance states that non-hypoxic breathless patients (other than CO poisoning) do not benefit from oxygen therapy and does not recommend supplementation. Both of the latter associations recommend the use of an oxygen alert card for those patients at risk for hypercapnic respiratory failure, so that in an emergency the appropriate low F IO 2 will be administered.

The remainder of this paper will detail the diseases/conditions for which oxygen is often prescribed as a treatment, and the available evidence to support or refute its use.

• Oxygen Myths

John Downs presented the 2002 Donald F Egan Scientific Lecture entitled “Has Oxygen Administration Delayed Appropriate Respiratory Care? Fallacies Regarding Oxygen Therapy.” 13 Downs outlined what he believed to be 3 commonly held beliefs and the related evidence regarding oxygen therapy.

F IO 2 ≤ 0.6 is Safe.

This is what we were all taught in respiratory school, or at least that F IO 2 > 0.6 produced more adverse effects and F IO 2 < 0.6 produced less. Downs collaborated on a study that treated 54 subjects with ARDS by using high levels of PEEP and decreasing F IO 2 as soon as possible. 14 The study reported an 80% survival rate. A decade later it was reported that subjects who had the lowest P aO 2 /F IO 2 (80 mm Hg) had the lowest mortality, as compared to those who had the highest P aO 2 /F IO 2 (∼200 mm Hg). 15 The major emphasis was lowering the F IO 2 as soon as possible, by applying high levels of PEEP while tolerating a P aO 2 as low as 50 mm Hg. Most subjects were breathing F IO 2 of 0.3–0.4 within 6 hours of intubation.

Register et al conducted a study with subjects undergoing open heart surgery, all of whom were breathing room air preoperatively. 16 It was found that in subjects administered F IO 2 of 0.5 postoperatively had a greater degree of hypoxemia on room air on postoperative day 2 than those given sufficient oxygen to maintain S pO 2 ≥ 90%. After repeating the study using only room air intra- and post-operatively, and finding that most subjects did not have a decrease in blood oxygen levels, as compared to preoperative values, it was postulated that the hypoxemia experienced in the first study was due to the use of oxygen during and after surgery. 17

Garner et al exposed rats with peritonitis to F IO 2 of 0.8, 0.4, or 0.21. Mortality was lowest in the F IO 2 0.2 group, and highest in the F IO 2 0.8 group. 18 Upon postmortem examination it was found that lung pathology did not differ between the groups but there was substantial liver damage with F IO 2 > 0.21. It was postulated that free radical formation caused the liver damage.

High F IO 2 is Protective.

This stems from the belief that elevating the F IO 2 and subsequently the P aO 2 provides a margin of safety and time to react if a patient's clinical condition deteriorates. While this appears logical and is seen frequently in our ICU, the opposite may be the case. According to Downs, the only true indication for prophylactic hyperoxygenation is prior to tracheal intubation. 19 Downs further states that, hypothetically, a patient on F IO 2 of 1.0 and having a P aO 2 of 650 mm Hg, could drop to 90 mm Hg due to lung function deterioration over a period of 15–20 min, but the S pO 2 would not drop below 98%. 13 This drop would not be enough to indicate a problem. But over the next 5 minutes the S pO 2 would drop to 92%, alerting the caregiver to investigate. In this scenario the elapsed time until a problem is detected would be 20–25 min. If that same patient was on F IO 2 of 0.3 with a P aO 2 of 90 mm Hg and an S pO 2 of 99% and experienced the same problem, the S pO 2 would decrease to 94% within 10 min, alerting caregivers to a problem much earlier. Additionally, if a patient is already receiving F IO 2 of 1.0, there is no room to increase once a problem is detected.

Supplemental Oxygen is Useful.

This stems from the “it may not help, but it won't hurt” mentality. In emergency departments, post-anesthesia care units, and during conscious sedation, oxygen is routinely administered despite the lack of evidence to support the practice. In fact, profound hypoventilation can occur without an S pO 2 decrease if oxygen is supplemented. Patients breathing room air who have a small decrease in ventilation will be alerted much earlier by the S pO 2 reading, so the caregiver can intervene. 20 For this reason Downs suggests that postoperative patients not be administered oxygen unless S pO 2 is < 90% and simulation is ineffective.

Downs listed 6 primary conditions that can cause arterial hypoxemia and the specific treatments for each. 13 In only one condition, low F IO 2 , does he recommend that supplemental oxygen is the treatment of choice. His reasoning for the lack of recommendation for oxygen in the other conditions is the belief that, yes, P aO 2 will be increased, but will delay the diagnosis and treatment with the appropriate therapy.

• Chronic Obstructive Pulmonary Disease

The World Health Organization estimates that there are 210 million people worldwide living with COPD, making it a major health issue in many countries. 21 It is estimated that in the United States alone the cost to manage patients with the disease exceeded $49 billion in 2010. 22 An additional $73 billion was associated with hospital admissions. Although oxygen is among the standard management treatments, it was shown over 50 years ago that high F IO 2 increases blood carbon dioxide concentration in some COPD patients. 23 The British Thoracic Society recommends that until an arterial blood gas is obtained, any patient with known or suspected COPD not be given an F IO 2 > 0.28. 24

Denniston et al conducted a prospective audit of 97 subjects with the diagnosis of COPD admitted to the emergency department, representing 101 episodes of COPD exacerbation. 25 At some point in the pre-hospital or emergency department setting, 56% received an F IO 2 > 0.28. For those subjects who received an F IO 2 > 0.28, in-hospital mortality was 14% (8 of 57) versus 2% (1 of 44) for those who received an F IO 2 ≤ 0.28. Demographics and smoking history were not different between the 2 groups. Interestingly, in the ambulance those subjects who either self-identified or were identified by the crew as having COPD received a mean F IO 2 of 0.47, versus 0.6 if they were not identified. Although the ambulance crew administered a lower F IO 2 to those subjects identified as having the diagnosis of COPD, it was still well above the recommended F IO 2 .

In a prospective study including 972 subjects admitted to the emergency department with the diagnosis of COPD, Plant et al found that 20% had respiratory acidosis. 26 In 47% of the hypercapnic subjects, pH was inversely related to P aO 2 , with most being associated with a P aO 2 > 75 mm Hg. As in the aforementioned study by Denniston, the acidotic subjects had a higher in-hospital morality than the non-acidotic subjects (12.8% vs 6.9%).

A recent study comparing high flow with titrated oxygen administration in the pre-hospital setting in 405 subjects with COPD (214 confirmed) was conducted by Austin and colleagues. 27 Subjects were randomized into 2 groups: oxygen via nasal cannula titrated to S pO 2 of 88–92%, or 8–10 L/min of oxygen via non-rebreathing mask. Both groups received standard of care bronchodilator treatments enroute to the hospital. The study results showed that titrating oxygen to maintain an S pO 2 of 88–92% reduced the risk of death from hypercapnia and respiratory failure by 58% in all subjects, and by 78% in those with confirmed COPD. In the high flow oxygen group the number needed to harm was 14.

The need for titrated oxygen is often ignored in the prehospital and emergency settings, presumably due to the belief that hypoxemia is worse for the patient than hyperoxemia. In the COPD patient population this may not be the case. The current literature provides overwhelming evidence that in patients with documented or suspected COPD, titrating oxygen to an S pO 2 of 88–92% reduces the risk of death due to respiratory failure, especially in those susceptible to hypercapnia. Since most oxygen therapy is initiated prehospital, protocols must be implemented to ensure appropriate oxygen therapy is administered throughout the prehospital and hospital course. An interesting concept of providing patients with cards stating that they have a COPD diagnosis and to titrate oxygen to keep the S pO 2 88–92% has been suggested by the British Thoracic Society, in order to identify these patients quickly. A similar approach of a medical alert bracelet or necklace, much like is done for allergies, would also be effective.

• Infants/Neonates

François Chaussier used oxygen in attempts to revive what he termed “near dead” infants, beginning in 1780, 28 but it was not until the 1930s that physicians began using oxygen routinely with neonates. 29 In 1938, Chapple reported delivering F IO 2 of approximately 0.46 to an incubator to treat preterm infants. 30 A decade later, Terry documented over 100 cases of a new type of blindness present in premature infants, 31 but it was not until 1951 that Campbell 32 linked supplemental oxygen to the cause of what was initially termed retrolental fibroplasia and is currently known as retinopathy of prematurity (ROP). The first randomized controlled trial (RCT) to study the association of supplemental oxygen with ROP was published in 1952 by Patz et al. 33 The infants were randomized to either an F IO 2 of 1.0 or titrated oxygen to treat hypoxemia. In the F IO 2 1.0 group, 61% of the infants developed ROP, versus 16% in the titrated oxygen group.

In a retrospective study of risk factors for developing ROP in 2009, Hua et al 34 found that infants that breathed F IO 2 of > 0.8 for any length of time, and those who received any supplemental oxygen for > 8 days had the highest incidence. Additionally, the lower the birth weight, the higher the incidence of ROP for those infants who received oxygen. This study concurred with a 1977 study by Kinsey et al, finding that birth weight < 1,200 g and length of exposure to oxygen increased ROP risk. 35

Early studies that confirmed the association between oxygen and ROP helped to increase awareness of the problem, but, due to lack of ability to continuously measure arterial oxygenation, many premature infants were left profoundly hypoxic, for fear that administering oxygen would lead to ROP. The resulting hypoxia led to increased incidence of cerebral palsy. An early paper from 1961 36 reported that, in a study of 1,080 premature infants, supplemental oxygen administration for < 2 days showed a 17% increase in cerebral palsy, whereas oxygen exposure for > 10 days resulted in a 22% increase in ROP. This was the first study to show that there can be neither too little nor too much oxygen given to premature infants. In a multicenter RCT involving 358 preterm infants, Askie et al showed no difference in growth and development in those infants with S pO 2 of 91–94% than those with S pO 2 of 95% and above. 37

The use of oxygen in the resuscitation of infants in the delivery room has received considerable attention in the last decade. In a paper reviewing the available literature on this subject, Richmond and Goldsmith 38 found that in both animal and human studies, although the results were mixed, there was a trend toward resuscitation with room air being as effective as using 100% oxygen. Animal studies showed that using air was nearly as effective as F IO 2 of 1.0 in reducing pulmonary vascular resistance and may prevent rebound pulmonary vascular resistance increases post-resuscitation. Most of the human studies only examined short-term outcomes, such as survival, Apgar score, and time to first breath, and most were not randomized.

The most recently published study, from the Benefits of Oxygen Saturation Targeting (BOOST) II Collaborative Group, 39 showed that in 3 RCTs including 2,448 extremely pre-term infants (< 28 weeks gestation), targeting oxygen saturation < 90% resulted in a statistically significant increased risk of death ( P = .002), compared to the comparative group targeting saturation of 91–95%. Although the lower targeted saturation group had a significantly reduced incidence of ROP, the infants also had a significant increase in the rate of developing necrotizing enterocolitis.

Judicious use of oxygen with neonates is warranted, although the safe F IO 2 and duration of use are still questionable. The literature clearly shows that administering oxygen despite an S pO 2 ≥ 90% increases the risk of ROP and bronchopulmonary dysplasia. Conversely, maintaining an S pO 2 < 85% increases the risk of cerebral palsy. During resuscitation of infants in the delivery room, the use of room air or low levels of oxygen may reduce pulmonary vascular resistance and increase survival. Additional randomized human studies examining short- and long-term effects of various levels of oxygen use during resuscitation are needed.

The American Association for Respiratory Care clinical practice guideline recommends using caution when administering oxygen to preterm infants, infants with congenital heart lesions, those suffering from paraquat poisoning, or those receiving certain chemotherapy agents. 40 The guidance also cautions that oxygen flow may stimulate laryngeal nerves and alter respiratory patterns. Additionally, oxygen should be administered to treat hypoxemia and prevent hyperoxemia.

Patients suffering from multiple traumatic injuries are nearly always placed on supplemental oxygen, even if not intubated. Oxygen use in emergency care has been mandated in Advanced Trauma Life Support, 41 Prehospital Trauma Life Support, 42 and Advanced Cardiac Life Support, 43 despite scant evidence regarding efficacy and/or safety in this patient population. Oxygen supplementation begins at the point of injury and continues until presentation to the emergency department, usually via a non-rebreathing mask at 15 L/min, often despite S pO 2 readings of 100%. It has been witnessed on numerous occasions in our facility's emergency department: a patient brought in by the life squad wearing a non-rebreathing mask while talking on a cell phone, with the mouthpiece tucked under the mask. Clearly, oxygen administration was not indicated in this situation. The Prehospital Trauma Life Support guidelines 42 for oxygen administration are based on the patient's spontaneous breathing frequency ( Table 1 ). Other than with a normal breathing frequency, 12 – 20 the recommendation is to administer an F IO 2 of at least 0.85, with no mention of arterial oxygenation parameters.

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Prehospital Trauma Life Support Recommendations for Administering Oxygen Based on Spontaneous Breathing Frequency

Much of what the civilian medical community has learned about treating trauma victims was born from the military experiences in treating the casualties of war. Few studies have been conducted to determine how much oxygen trauma patients require, and most are observational. Stockinger and McSwain 44 retrospectively reviewed data from 5,090 spontaneously breathing trauma patients who presented to a civilian trauma center, in an attempt to determine the oxygen needs of trauma patients, in order to advance knowledge for military needs. Forty-three percent of the patients received oxygen, and they died more often than those who did not receive oxygen (2.3% vs 1.1%). Even after correcting for Injury Severity Score, mechanism of injury, and age, those who did not receive oxygen had no worse outcome than those who received oxygen, suggesting that supplementing oxygen does not improve outcomes in trauma patients who are not in respiratory distress.

Barnes et al conducted a prospective study to determine oxygen requirements and usage during transcontinental flights transporting mechanically ventilated wounded war fighters from Iraq to Germany with the Air Force Critical Care Air Transport Teams. 45 During the 6–8 hour flight an integrated computer recorded the ventilator settings and pulse oximetry readings. Oxygen was titrated according to the standard of care guidelines, keeping S pO 2 ≥ 94%. Twenty-two patients' data were recorded, resulting in 117 hours of continuous data. After calculating oxygen usage (L/min), it was found that the mean usage was 3.24 L/min, with a mean F IO 2 of 0.49 for all patients. Sixty-eight percent of the patients required ≤ 3 L/min, suggesting that oxygen requirements for trauma patients may be much lower than what is currently being administered.

Hemorrhagic shock is the leading cause of death in trauma patients, and poses a different set of problems when trying to determine appropriate oxygen administration. Hemorrhagic shock is a result of blood loss that may lead to decreased oxygen supply and cellular hypoxia despite normal arterial oxygenation indicators. Knight et al performed a literature review to increase understanding of the effects of oxygen administration following hemorrhagic shock. 46 The review found that F IO 2 of 1.0 and resuscitation are the most common treatments following hemorrhagic shock, although there is concern that hyperoxia may increase free radical formation and further cell damage. The literature suggested serum lactate should be monitored to assess cellular hypoxia and possibly guide oxygen administration, although the appropriate level remains unclear.

Despite anecdotal and sparse research data, there is no consensus for determining in which trauma patients to administer oxygen, and how much. The United States Special Operations Command's Tactical Combat Casualty Care guidelines state that oxygen may be beneficial for the following patients 47 :

Low oxygen saturation by pulse oximetry

Injuries associated with impaired oxygenation

Unconscious casualty

Casualty in shock

Casualty at altitude

Casualty with traumatic brain injury (maintain S pO 2 > 90%)

Traumatic brain injury represents challenges when caring for a trauma patient, and is a leading cause of death and disability. 48 Much of the available literature's focus is on prehospital management of traumatic brain injury. It is well known that secondary brain injury can develop as a result of several factors, including inappropriate ventilation, glycemic control, cerebral edema, hypotension, and cerebral hypoxia. 49 – 51 Hypoxia has been identified as an independent risk factor for poor outcome with traumatic brain injury. 50 Providing oxygen to the injured brain is crucial to mitigating secondary brain injury, but the appropriate level of P aO 2 remains unclear, since adequate arterial oxygenation may not always equate to adequate brain oxygenation. Chi et al performed a prospective cohort study in 150 trauma patients with suspected head injury undergoing helicopter transport. 52 The study goal was to determine the incidence of hypoxia and hypotension and to assess mortality and disability. Thirty-seven subjects had hypoxic episodes. The mortality for subjects without any secondary insults was 20%, versus 37% for those who had hypoxic episodes. Surviving subjects who experienced hypoxia also had a greater degree of disability at hospital discharge. In an attempt to determine the relationship between hypoxemia and hyperoxemia and outcome, Davis et al performed a retrospective review of 3,420 subjects treated for traumatic brain injury. 53 The study found that mild hyperoxemia (P aO 2 110–487 mm Hg) was associated with increased survival, while hypoxemia (P aO 2 < 110 mm Hg) and extreme hyperoxemia (P aO 2 > 487 mm Hg) were associated with increased mortality.

Although monitoring and treating intracranial pressure remains the standard of care, devices to measure brain-tissue oxygenation are being utilized. Martini and associates 54 reviewed the available published literature on this practice and found that monitoring brain-tissue oxygenation has shown value in determining poor prognosis following traumatic brain injury, and that interventions to increase cerebral perfusion pressure and P aO 2 can result in increased brain-tissue oxygenation. The authors' review also found that retrospective studies suggest that maintaining a target brain-tissue oxygenation (usually 20 mm Hg) may have potential benefits, but prospective studies showed no outcome benefits.

Many trauma patients need little or no oxygen. Oxygen administration should be titrated to achieve normoxemia for all trauma patients except for traumatic brain injury and hemorrhagic shock with increased lactate. There is some evidence that mild to moderate hyperoxemia may increase survival with traumatic brain injury. Hypoxemia and extreme hyperoxemia with traumatic brain injury are associated with a worse outcome. The evidence is still unclear on whether to monitor and target brain-tissue oxygenation and to manipulate physiologic parameters to maintain that target, especially with mounting evidence that hyperoxemia may have deleterious effects. Adequately powered randomized clinical trials are necessary to evaluate the outcome benefits of this practice.

ARDS was first described by Ashbaugh et al in 1967. Historically, the mortality rate for ARDS was reportedly 40–60% 55 – 58 by most accounts, until the turn of the 21st century, when new therapeutic studies emerged that improved outcome. The ARDS Network clinical trial, published in 2001, was the first evidence that ARDS mortality can be improved by changes in mechanical ventilation practice. 59 This landmark study showed that reducing tidal volumes to as low as 4–6 mL/kg of ideal body weight reduced mortality by 22%. Additionally the study supported oxygenation by the use of a PEEP/F IO 2 table to maximize lung recruitment and minimize oxygen exposure, due to earlier evidence in animal models that high F IO 2 may be toxic. The targeted range for oxygenation was P aO 2 55–88 mm Hg and S pO 2 88–95%. Although the best strategy for using PEEP and F IO 2 has not been identified, mounting evidence suggests the use of the lowest F IO 2 possible and the use of adequate PEEP to increase oxygenation without producing cardiovascular side effects. 60

Kallet and Branson 61 performed a literature review in an effort to determine if the ARDS Network study's PEEP/F IO 2 table is the best method for maintaining oxygenation and minimizing oxygen exposure. The authors found that, since the PEEP required for most patients with ARDS is relatively low, the use of the ARDS Network PEEP/F IO 2 table is supported by high level evidence, although there is a small subset of patients who may require an individualized approach to setting PEEP and F IO 2 .

ARDS is a condition that is difficult to manage and that requires a balance between ventilating with low tidal volumes and providing the right level of PEEP to support oxygenation and minimizing the harmful effects of high oxygen exposure. Although the results of the ARDS Network trial provide the best evidence for use of the PEEP/F IO 2 table to adjust these variables, and the evidence in the literature suggests the table may be adequate, there is no consensus as to how to best adjust PEEP and F IO 2 for all patients with ARDS. The most important factor to consider is to balance the risk of pressure injury to the lung, by using excessive PEEP and tidal volume, and the risk of oxygen toxicity.

• Myocardial Infarction

According to Centers for Disease Control statistics, heart disease is the leading cause of death in the United States, accounting for more than 600,000 fatalities annually. 62 Myocardial infarction accounts for more than half of these deaths. For more than 100 years oxygen has been used to treat myocardial infarction and angina, 63 with little evidence as to the efficacy or potential harm of this practice. Oxygen administration can cause vasoconstriction, regardless of arterial saturation, and raise blood pressure and lower cardiac oxygen consumption, heart rate, and cardiac index. 64 – 66 Foster et al found that as P aO 2 increased, so did arterial pressure and systemic vascular resistance. 67 Kenmure et al 68 and Thomas et al 69 found an increase in blood pressure and decrease in cardiac output when patients suffering from a myocardial infarction breathed F IO 2 of 0.4. McNulty et al, using a Doppler flow wire, showed in 18 subjects that coronary vascular resistance increased by 41% and coronary blood flow decreased by 29% when the subjects breathed F IO 2 of 1.0 for 15 min. 70 These works showed the physiologic effects of oxygen administration on the coronary system, but the effect on outcome was not evaluated.

Wijesinghe et al performed a review of the published literature that included RCTs of oxygen therapy in myocardial infarction. 71 Of 51 potential studies, only 2 met the inclusion criteria. One of the studies of 200 subjects randomized to either room air or 6 L/min oxygen for 24 hours after having a myocardial infarction found that deaths and the incidence of ventricular tachycardia were higher in the oxygen group, but the difference was not statistically significant. Opiate use was not different between the groups. The other study randomized 50 subjects to either room air or 4 L/min oxygen for 24 hours. Although more subjects experienced an episode of oxygen desaturation, 80% in the room air group ( P < .01), there was statistically no difference in the incidence of ventricular tachycardia and opiate use between groups. Mortality was not evaluated.

Kones's review of oxygen use for acute myocardial infarction found there are no large randomized studies available for evaluation. 72 He found that the evidence supporting oxygen use in patients having acute myocardial infarction but who had normal oxygen saturation was old and of poor quality. Kones noted that recent physiological evidence that oxygen use in this patient population that are not hypoxemic suggests that there is no evidence of benefit and may be harmful. His conclusion was that, in these patients, oxygen should be administered only if saturation drops below 94%, although there is no evidence to support this recommended saturation level.

A recent Cochrane Collaborative meta-analysis cited 3 RCTs comparing groups given oxygen or air when experiencing a myocardial infarction. 73 The 3 studies included 387 subjects, with 14 of those dying. Of those 14, nearly 3 times as many subjects in the oxygen group died, compared to those given air. Although this suggests that oxygen administration may be harmful, definitive conclusions cannot be drawn because the studies had small numbers of subjects, so the results may have happened by chance. The authors' conclusion was that a large RCT is required to refute or confirm these findings.

There is no conclusive evidence for or against using supplemental oxygen for patients experiencing a myocardial infarction. Standard practice is still as pervasive as it was 100 years ago: apply oxygen to all myocardial infarction patients. What little evidence there is in the current literature suggests giving oxygen to hypoxemic patients experiencing a myocardial infarction to maintain arterial saturation of 94–98%. Large RCTs are required to definitively determine the correct practice.

• Cardiac Arrest

Cardiac arrest often results from a myocardial infarction. Even if return of spontaneous circulation is achieved, nearly 60% of these patients will not survive. 74 The high mortality has been associated with anoxic brain injury, cardiac stunning, and reperfusion injury. 75 High concentration oxygen administration during the post-cardiac-arrest period has been questioned as a potential contributor to the high mortality after return of spontaneous circulation. Kilgannon and associates conducted 2 multicenter cohort studies 76 , 77 using the Project IMPACT critical care database to examine the effect of hyperoxia after cardiac arrest and the effect on mortality. The first study 76 included 6,326 subjects, and the end point was in-hospital mortality. The subjects were divided into 3 groups: hyperoxia (defined as P aO 2 ≥ 300 mm Hg), hypoxia (defined as P aO 2 < 60 mm Hg or P aO 2 /F IO 2 < 300 mm Hg), and normoxia (defined as P aO 2 60–300 mm Hg).

Of the 6,326 subjects, 18% had hyperoxia, 63% had hypoxia, and 19% had normoxia. The hyperoxia group had significantly higher in-hospital mortality (63%) than did the normoxia group (45%) or the hypoxia group (57%). In the second study 77 using the Project IMPACT database, Kilgannon's group evaluated 4,459 subjects post-cardiac-arrest to determine the relationship between P aO 2 and in-hospital mortality. Of the 4,459 subjects, 54% died. The observed P aO 2 values were divided into 5 groups: 60–99, 100–199, 200–299, 300–399, and ≥ 400 mm Hg. The results of the study showed that there was an association between increased P aO 2 and increased mortality, even in those subjects who did not have supranormal P aO 2 . For every 100 mm Hg increase in P aO 2 there was a 24% increase in the relative risk of death. Interestingly, a 25% increase in P aO 2 resulted in a 6% relative risk of death. The results of this study suggest that since a relatively small increase in P aO 2 increases mortality, limiting supplemental oxygen as much as possible after cardiac arrest may be beneficial. It is hypothesized that increased free radical formation caused by high concentration delivery, along with reperfusion injury, may be responsible for the increased mortality.

Retrospective studies show that hyperoxia, and possibly normoxia, when supplementing oxygen to post-cardiac-arrest patients may increase mortality. Subjects with hyperoxemia had significantly higher mortality that those with hypoxemia or normoxemia, suggesting that maintaining normoxemia (S pO 2 94–98%) should be the standard practice until large clinical trials are conducted to provide definitive guidelines.

• Congestive Heart Failure

Patients with congestive heart failure often suffer from dyspnea and hypoxia. High concentration oxygen is often given to these patients, despite previous studies showing that administering F IO 2 of 1.0 to healthy subjects decreases cardiac output and increases systemic vascular resistance. 78 , 79 Little is known about the hemodynamic effects of oxygen administration in these patients. Haque et al conducted a small study in which 22 subjects with class 3 and 4 heart failure were divided into 3 separate experiments. 80 Experiment 1 involved 10 subjects having hemodynamic variables measured while breathing room air and then after breathing an F IO 2 of 1.0 for 20 min. Experiment 2 involved 7 subjects having the same hemodynamic measurements collected after breathing room air and then after 5 min on F IO 2 of 0.24, 0.40, and 1.0. F IO 2 of 1.0 significantly reduced cardiac output and stroke volume, and increased pulmonary capillary wedge pressure and systemic vascular resistance, as compared to breathing room air ( P < .01). Graded oxygen showed a progressive decrease in cardiac output ( P < .001) and stroke volume ( P < .02), and an increase in systemic vascular resistance ( P < .005). Additionally, S aO 2 progressively increased, from 93.6 ± 1.5% on room air to 100.0 ± 0% on F IO 2 of 1.0. Based on the results of this small study, the authors recommend that, in the absence of hypoxemia, oxygen should be used cautiously with patients suffering from severe congestive heart failure.

Evidence for use of oxygen with congestive heart failure is scarce. The few available studies are small and too underpowered to make a determination about oxygen administration in these patients. The available literature suggests that inducing hyperoxemia in patients with congestive heart failure may be harmful. Oxygen use should be limited to those patients who exhibit hypoxemia and should be titrated to achieve normoxia. Large RCTs are needed to confirm these findings.

Oxygen is frequently administered to patients suffering from a stroke in the prehospital setting, and is often continued in the hospital, despite current guidelines that recommend not administering oxygen to non-hypoxic patients. 81 The pervasive idea that oxygen therapy is beneficial stems from the fact that ischemic stroke causes a decrease in oxygen to the brain, resulting in tissue hypoxia and cell death. The prevailing logic is that neuroprotection can be achieved by raising oxygen levels in ischemic tissues. 82 Extending the logic further, it was thought that hyperbaric oxygen therapy, which can produce extreme hyperoxemia, would be beneficial for stroke patients, but clinical trials failed to show any benefit. 83 – 85 It is well established that hyperoxemia increases free radical formation and could induce cerebral vasoconstriction and reduced blood flow. 79 , 86 Animal studies have shown increased mortality when exposed to high oxygen levels following cerebral ischemia. 87 , 88

Pancioli and associates performed a retrospective chart review of 167 non-intubated, ischemic stroke patients totaling 600 in-patient days at a university hospital to determine whether these patients had indications for supplemental oxygen. 89 The criteria used for supplemental oxygen therapy are listed in Table 2 . Sixty-one percent of the subjects received supplemental oxygen at some point during their hospital stay, which accounted for 322 days of receiving oxygen. Of those 322 days, 46% met at least one of the pre-established criteria for oxygen use. Of the 348 days in which criteria for supplemental oxygen were not met, the subjects still received oxygen 46% of the time. The authors estimated that not giving oxygen when it is not indicated could produce up to 45% savings in resources. Ronning and Guldvog 90 conducted an RCT including 500 subjects to determine whether F IO 2 of 1.0 for the first 24 hours after stroke would reduce mortality, neurological impairment, or disability, as compared to receiving no oxygen. The subjects in the room air group had a higher 1 year survival, but the difference was not statistically significant ( P = .30). For subjects with severe stroke there was a statistically nonsignificant tendency toward a higher 1 year survival in the oxygen group ( P = .60). Neurological impairment and disability did not differ between the 2 groups. The authors concluded that oxygen should not routinely be given to patients suffering from acute stroke.

Indications for Supplemental Oxygen Therapy

The American Heart Association Stroke Council recommends against oxygen usage for stroke patients. Animal models suggest that giving high levels of oxygen in those with cerebral ischemia may be harmful. The limited evidence in the literature suggests that giving oxygen to patients suffering from acute stroke does not produce any benefit in outcomes, although there may be a small mortality benefit, which needs to be studied further, for those patients having suffered from a severe stroke. A further benefit for not routinely giving oxygen to stroke patients may be in decreased use of resources.

• Wound Infection

Surgical wound infection is a serious complication that can increase hospital stays and costs, 91 – 93 and increase morbidity and mortality. 94 , 95 Bacterial tissue contamination establishes wound infections within a few hours post-surgery, 96 so interventions during this time have the greatest potential to prevent a severe infection. Prophylactic antibiotic therapy is the most common perioperative intervention to prevent wound infection. Due to laboratory evidence that oxidative bactericidal activity is highly dependent on increasing the oxygen tension in a wound, 97 it has been suggested that providing high levels of perioperative oxygen may attenuate bacterial wound infections.

Greif and associates 98 conducted an RCT including patients undergoing colorectal surgery to receive F IO 2 of either 0.3 or 0.8 intraoperatively, and for 2 hours postoperatively. All subjects received prophylactic antibiotic therapy. Wounds that were culture positive were considered infected. Subjects in the F IO 2 0.8 group had significantly less wound infections, versus those in the F IO 2 0.3 group (5% vs 11%, P = .01). Hospital lengths of stay were similar.

In a smaller study, conducted in Israel, 38 subjects undergoing elective colorectal surgery were also randomized to receive the same oxygen concentrations and length of therapy as in the Greif study. 99 The wound infection rate in the F IO 2 0.8 group was higher than in the F IO 2 0.3 group, but the difference was not statistically significant ( P = .53), although this could have been due to the small sample size. Even though the infection rates were not lower in the high oxygen group, the authors could not make a definitive recommendation for the use or non-use of high oxygen concentration.

The current evidence for use of high concentration oxygen to reduce surgical wound infections is mixed. Larger RCTs are required to clarify the issue. Until such trials are conducted, maintaining normoxemia in these patients should be the standard of care, especially with mounting evidence that prolonged hyperoxemia may have other untoward effects.

• Postoperative Nausea and Vomiting

Postoperative nausea and vomiting (PONV) is common, with an occurrence of 20–70% despite current pharmaceutical interventions. 100 – 102 The unpleasantness for the patient notwithstanding, PONV can increase the risk of aspiration pneumonia and can lead to delayed discharge and unexpected hospital admissions following surgery. 103 Recent research suggests that supplemental oxygen may have a positive effect on PONV following selected surgical procedures.

Greif et al conducted an RCT in 231 subjects undergoing colon resection, to receive F IO 2 of either 0.8 or 0.3 during surgery and 2 hours afterward. 104 The incidence of PONV during the first 24 hours postoperatively was recorded. PONV was observed in 17% of the subjects who received F IO 2 0.8, versus 30% in the F IO 2 0.3 group ( P = .03).

Ghods et al 105 randomized 106 subjects undergoing cesarean birth to receive 8 L/min oxygen for 6 hours postoperatively or 5 L/min in the recovery room and no oxygen thereafter, and evaluated the incidence of PONV during the first 6 postoperative hours. PONV occurred in 28% of subjects in the 8 L/min group, and nearly 25% in the control group. The difference between groups was not statistically significant ( P = .66).

Joris et al 106 conducted an RCT randomizing 150 subjects to receive either F IO 2 of 0.3, F IO 2 of 0.8, or F IO 2 of 0.3 oxygen with droperidol, during thyroidectomy, and evaluated the incidence of PONV for 24 hours post-surgery. There was no difference in the incidence of PONV in the F IO 2 0.3 and 0.8 groups (48% vs 46%), but the group receiving F IO 2 of 0.3 plus droperidol was 22%, which was statistically different from the other 2 groups ( P = .004). Time to first meal was significantly shorter in the droperidol group.

Treschan et al 107 randomly assigned 210 subjects having strabismus surgery to the same study arms as the Joris study, with the difference being the use of ondansetron instead of droperidol. PONV was evaluated postoperatively at 6 and 24 hours. As opposed to the Joris study, there was no statistical difference in the incidence of PONV between any of the 3 groups ( P = .28), although the incidence was lower for the ondansetron group (28%) versus the F IO 2 0.8 group (38%) and the F IO 2 0.3 group (41%). The low number of subjects in each group may account for the lack of statistical significance.

Evidence for the use of supplemental oxygen to treat/prevent PONV is mixed. Despite Akca and Sessler's 108 claim, after reviewing 3 studies, that oxygen use may best prevent PONV following abdominal surgery, this is not always the case, because one study they reviewed showed no difference. Much larger clinical trials must be done to provide more compelling evidence.

• Cluster Headache

The first description of cluster headaches (CH) was given by London neurologist Wilfred Harris in 1926. 109 His treatment for these subjects was alcohol injections around the supraorbital and infraorbital nerve. Horton first described the use of oxygen for the treatment of CH in 1952, 110 and was brought to the forefront by Kudrow in 1981. 111 This first systematic study compared oxygen by mask at 7 L/min for 15 min versus sublingual ergotamine. The study showed that both treatments were effective in aborting CH attacks, but oxygen aborted over 70% of the attacks in 82% of the subjects, whereas ergotamine worked as well in only 70% of the subjects. The average response time with oxygen to abort the CH was 6 min, versus 10–12 min with ergotamine.

In 1985, Fogan conducted a small double-blind crossover study comparing oxygen versus air, both at 6 L/min, for the treatment of CH. 112 Subjects scored their degree of relief with each therapy, with the relief score being significantly higher when inhaling oxygen versus air ( P = .01). The average relief score was 1.93 for oxygen inhalation and 0.77 for air inhalation, out of a possible 3.

More recently, Garza conducted a double-blind RCT of 109 subjects with CH to alternately receive 12 L/min oxygen or air via mask for 15 min at the onset of an attack. 113 The primary end point was complete or adequate pain relief at 15 min. The results showed that the primary end point was reached 78% of the time with oxygen inhalation, versus 20% with air ( P = .001). Oxygen was also superior to air concerning the secondary end points of pain free at 30 min, pain reduction at 60 min, and need for additional medication 15 min after treatment.

Although the efficacy of oxygen administration for treatment of CH is well documented, there have been observations of rebound CH post-treatment. The rebound effect is defined as a CH that returns more rapidly than usual following complete relief after oxygen inhalation, or an increased number of attacks in a 24 hour period. Geerlings et al performed a retrospective study and found 8 subjects who experienced rebound CH. 114 In these subjects the mean duration until the next CH was 39 min after using oxygen to treat the previous CH versus 933 min if oxygen was not used. The mean frequency of CH per day was 4.1 when using oxygen, versus 2.5 without using oxygen. It is hypothesized that use of lower flow (7 L/min or less) may lead to rebound CH in susceptible patients. Cohen et al evaluated the effectiveness of using 12–15 L/min oxygen for treatment of CH. 115 While headache relief was comparable to studies using lower flows, no rebound CH were reported.

The literature overwhelmingly shows that oxygen is an effective treatment for CH, without any documented side effects. However, in susceptible patients, rebound CH may occur following a previous oxygen treatment, but the mechanism is unclear. It has been suggested that higher oxygen flow may attenuate the rebound effect, but the evidence is mostly anecdotal. Studies are required to determine if higher oxygen flow minimizes rebound CH and to determine the appropriate flow to use.

• Carbon Monoxide Poisoning

Carbon monoxide (CO) poisoning is the leading cause of poisoning death in the United States. CO poisoning is sometimes overlooked because the clinical signs and symptoms are not the same for all patients. It is well established that hemoglobin's affinity for CO is over 200 times higher than for oxygen and that blood CO levels in excess of 20% can affect the brain and heart, due to their high metabolic rate. 116 Tissue hypoxia is the hallmark of CO poisoning, so oxygen is the standard treatment, although pulse oximetry readings are unreliable due to the device being unable to distinguish between oxygen and CO bound to the hemoglobin. In the late 1800s, Haldane showed that high oxygen tension can counteract the hemoglobin to CO affinity. 117 The half-life of CO while breathing room air is approximately 5 hours. Breathing normobaric F IO 2 of 1.0 reduces the half-life to 1 hour, and hyperbaric oxygen therapy reduces the half-life to 20 min. 118 – 120

All CO poisoned patients should receive an F IO 2 of 1.0 at atmospheric pressure for at least 6 hours or longer, depending on blood CO level. If available, hyperbaric oxygen should be used for patients with severe CO poisoning (ie, CO level > 20%, unconscious, those with neurologic deficit, or pregnant women with or without symptoms). 116

• Breathlessness

One of the most controversial and misunderstood uses of supplemental oxygen is for patients experiencing breathlessness. Breathlessness is a common symptom of advanced lung, cardiac, and neuromuscular disease, and the intensity increases as death approaches. 121 , 122 Even with increased understanding of breathlessness and the pharmacologic and non-pharmacological interventions available, it remains difficult to manage. Breathlessness makes caregivers and healthcare providers feel helpless, further complicating management. Upon conducting a survey, Abernethy and associates found that 70% of clinicians would prescribe oxygen for breathlessness despite normal oxygen saturation, and 35% would prescribe oxygen if the patient asked for it. 123 Hypoxemia does not appear to be the driving force in chronic breathlessness.

Abernethy et al conducted a double-blind RCT in 239 subjects with refractory breathlessness, and evaluated the effectiveness of administering 2 L/min oxygen, as compared to 2 L/min air. 124 The study results showed that morning breathlessness improved more in the oxygen group, but improved more in the evening with the air group. Improvement in quality of life was no different between groups, nor was there a difference in breathlessness over a 24 hour period. Breathlessness scores of subjects with moderate to severe breathlessness improved most, irrespective of the treatment arm. The authors concluded that the study results suggest it is the flow of gas through the nasal passages that improves the feeling of breathlessness, regardless of whether oxygen or air is used.

Johnson et al conducted a meta-analysis of the available literature focusing on oxygen to treat chronic refractory breathlessness. 125 Of the 13 studies reviewed, 2 showed a benefit when supplementing oxygen to breathless subjects. These 2 studies involved COPD patients, and the benefit of oxygen administration was small and limited to breathlessness as a result of exertional desaturation in one study. The remaining studies show no benefit of administering oxygen as opposed to air.

Most studies show that oxygen is no better than air for chronic breathlessness in the absence of hypoxemia. There was a modest improvement in breathlessness in COPD patients with exertional desaturation in one small study. Larger, adequately powered RCTs are needed to confirm the results of the smaller studies.

• What the Literature Says

Oxygen is administered for many diseases and conditions in hospitalized patients. The evidence in the literature suggests that supplemental oxygen is clearly indicated in the following instances: reversal of hypoxemia, traumatic brain injury, hemorrhagic shock, resuscitation during cardiac arrest, and CO poisoning.

Oxygen should be administered to target an S pO 2 of 94–98%, except with CO poisoning, due to the inaccuracy of pulse oximetry. Patients with COPD, neuromuscular disease, and obesity who are at risk for hypercapnia should have a target S pO 2 of 88–92%. Patients with ARDS should have a target S pO 2 of 88–95%, due to evidence from the ARDS Network trial. Infants should have a target S pO 2 of 88–94%, depending on gestational age, to prevent ROP, bronchopulmonary dysplasia, and cerebral palsy.

Oxygen is a popular drug and is often administered indiscriminately. The belief that oxygen is harmless and the attitude of “if a little is good, more is better” is common in today's healthcare environment. Severinghaus and Astrup proclaimed that “If introduced today, this gas might have difficulty getting approved by the Food and Drug Administration.” 126 Priestley's words may be even truer today: “The air which nature has provided for us is as good as we deserve.” 1

• Correspondence: Thomas C Blakeman MSc RRT, Department of Surgery, ML 0558, University of Cincinnati, 231 Albert Sabin Way, Cincinnati OH 45267-0558. E-mail: Thomas.Blakeman{at}uc.edu .

Mr Blakeman presented a version of this paper at the 28th New Horizons in Respiratory Care Symposium, “The Scientific Basis for Respiratory Care,” at the AARC Congress 2012, held November 10–13, 2012, in New Orleans, Louisiana.

The author has disclosed no conflicts of interest.

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Topical Oxygen Therapy for Wound Healing: A Critical Evaluation

Affiliations.

• 1 Hand & Microsurgery Medical Group, San Francisco, California.
• 2 Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
• PMID: 34942675
• DOI: 10.52198/22.STI.40.WH1492

Oxygen is an undisputed key factor in wound healing. Adequate oxygen pressure in tissues allows for cell growth and proliferation, necessary for wound healing. In the case of peripheral arterial disease leading to hypoxemia, oxygen supplementation is beneficial. The roles and validity of topical and systemic oxygen therapy in wound healing is debated. Topical oxygen therapy (TOT) is delivered at 100% oxygen saturation and has been demonstrated to increase the pO2 levels within the wound base center, decrease the size of the wound, and decrease the time to wound healing compared to patients that did not undergo topical oxygen therapy. Alternatives to topical oxygen therapy are systemic oxygen therapy including hyperbaric oxygen therapy and inspired oxygen therapy. Systemic oxygen therapy carries the risk of oxygen organ toxicity as the result of an oxidative stress and genotoxicity state. Topical O2 therapy is a viable option for chronic wounds, with its demonstrated effects on decrease in wound size and time to healing. Adjunctive clinical wound debridement's decrease the necrotic debris and therefore the topical oxygen diffusion distance optimizing the therapy effect.

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Angiotensin ii—real-life use and literature review.

1. Introduction

2. renin–angiotensin–aldosterone system, 3. classical raas, 4. nonclassical raas, 5. angiotensin ii as a vasopressor.

6. Immunomodulatory Effects of Angiotensin II

7. adverse effects associated with angiotensin ii, 9. conclusions, author contributions, conflicts of interest.

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Möller Petrun, A.; Markota, A. Angiotensin II—Real-Life Use and Literature Review. Medicina 2024 , 60 , 1483. https://doi.org/10.3390/medicina60091483

Möller Petrun A, Markota A. Angiotensin II—Real-Life Use and Literature Review. Medicina . 2024; 60(9):1483. https://doi.org/10.3390/medicina60091483

Möller Petrun, Andreja, and Andrej Markota. 2024. "Angiotensin II—Real-Life Use and Literature Review" Medicina 60, no. 9: 1483. https://doi.org/10.3390/medicina60091483

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B-cell Depletion Therapy in Pediatric Neuroinflammatory Disease

• Published: 11 September 2024

Cite this article

• Helen C Wu 1 ,
• Grace Y Gombolay 2 ,
• Jennifer H Yang 3 ,
• Jennifer S Graves 3 ,
• Alison Christy 4 &
• Xinran M Xiang 1 , 5  

Purpose of review

B-cell depletion therapy, including anti-CD20 and anti-CD19 therapies, is increasingly used for a variety of autoimmune and conditions, including those affecting the central nervous system. However, B-cell depletion therapy use can be complicated by adverse effects associated with administration and immunosuppression. This review aims to summarize the application of anti-CD20 and anti-CD19 therapies for the pediatric neurologist and neuroimmunologist.

Recent findings

Most existing literature come from clinical trials with adult patients, although more recent studies are now capturing the effects of these therapies in children. The most common side effects include infusion related reactions and increased infection risk from immunosuppression. Several strategies can mitigate infusion related reactions. Increased infections due to persistent hypogammaglobulinemia can benefit from replacement immunoglobulin.

B-cell depletion therapies can be safe and effective in pediatric patients. Anticipation and mitigation of common adverse effects through primary prevention strategies, close monitoring, and appropriate symptomatic management can improve safety and tolerability.

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Data Availability

No datasets were generated or analysed during the current study.

Abbreviations

Advisory Committee on Immunization Practices

absolute neutrophil count

annualized relapse rate

aquaporin-4

body surface area

Centers for Disease Control and Prevention

central nervous system

cerebrospinal fluid

Common Terminology Criteria for Adverse Events

common variable immunodeficiency

electroencephalogram

early onset neutropenia

FDA Adverse Event Reporting System

US Food and Drug Administration

febrile infection-related epilepsy syndrome

granulocyte colony stimulating factor

immunoglobulin A

immunoglobulin E

immunoglobulin G

immunoglobulin M

infusion related reaction

intravenous immunoglobulins

intravenous methylprednisolone

John Cunningham virus

late onset neutropenia

myelin oligodendrocyte glycoprotein

myelin oligodendrocyte glycoprotein antibody associated disease

multiple sclerosis

anti-NMDA receptor encephalitis

neuromyelitis optica spectrum disorder

opsoclonus myoclonus ataxia syndrome

pediatric onset multiple sclerosis

progressive multifocal leukoencephalopathy

red blood cells

randomized controlled trial

subcutaneous immunoglobulins

white blood cells

Lee DSW, Rojas OL, Gommerman JL. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov. 2021;20:179–99. Overview of B-cell depletion therapy, including therapies currently being tested or approved for various autoimmune conditions.

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Key References

• Lee DSW, Rojas OL, Gommerman JL. B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nat Rev Drug Discov. 2021;20:179–99. Overview of B-cell depletion therapy, including therapies currently being tested or approved for various autoimmune conditions.

• McAtee CL, Lubega J, Underbrink K, et al. Association of rituximab use with adverse events in children, adolescents, and young adults. JAMA Netw Open. 2021;4:e2036321. Large retrospective cohort study of 468 pediatric patients studying the short-term and long-term effects of rituximab on adverse effects, infections, and immune recovery.

• Ghezzi A, Banwell B, Bar-Or A, et al. Rituximab in patients with pediatric multiple sclerosis and other demyelinating disorders of the CNS: practical considerations. Mult Scler. 2021;27:1814–22. Review focusing the use of rituximab in children for pediatric onset multiple sclerosis along with other CNS demyelinating disorders.

• Alvarez E, Longbrake EE, Rammohan KW, Stankiewicz J, Hersh CM. Secondary hypogammaglobulinemia in patients with multiple sclerosis on anti-CD20 therapy: pathogenesis, risk of infection, and disease management. Multiple Sclerosis and Related Disorders. 2023;79:105009. Detailed summary and literature review of hypogammaglobulinemia associated with anti-CD20 therapy along with monitoring and management strategies.

• Gandelman S, Lenzi KA, Markowitz C, Berger JR. A proposed approach to screening and surveillance labs for patients with multiple sclerosis on Anti-CD20 therapy. Neur Clin Pract. 2024;14:e200241. This paper provides a set of useful recommendations and guidelines for initiating and monitoring anti-CD20 therapy in patients with multiple sclerosis.

• Krysko KM, Dobson R, Alroughani R, et al. Family planning considerations in people with multiple sclerosis. The Lancet Neurology. 2023;22:350–66. Informative review and recent updates on safety and tolerability of disease modifying therapies, including B-cell depletion therapy, during and following pregnancy.

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Helen C Wu & Xinran M Xiang

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Grace Y Gombolay

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Jennifer H Yang & Jennifer S Graves

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HW wrote the main manuscript and prepared Fig. 1; Table 1, and 2. All authors reviewed the manuscript and provided substantive edits.

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Dr. Graves reports personal fees from Horizon, outside the submitted work. Dr. Gombolay reports funding from Academic CME/TG Therapeutics, outside the submitted work. Dr. Gombolay is a part time CDC consultant for acute flaccid myelitis case review. She is also Media Editor for Pediatric Neurology and Associate Editor of the Annals of the Child Neurology Society. Dr. Christy reports funding from Biohaven/Pfizer, Abbvie, Novartis, and receives stipend from Journal of Child Neurology, outside the submitted work. Dr. Yang reports personal fees from Sanofi, personal fees from American Academy of Neurology, personal fees from American College of Rheumatology, personal fees from Clearview, outside the submitted work. The remaining authors have no relevant financial or non-financial interests to disclose. No funding was received to assist with the preparation of this manuscript.

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Wu, H.C., Gombolay, G.Y., Yang, J.H. et al. B-cell Depletion Therapy in Pediatric Neuroinflammatory Disease. Curr Neurol Neurosci Rep (2024). https://doi.org/10.1007/s11910-024-01366-7

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• J Clin Sleep Med

Obstructive Sleep Apnea and Oxygen Therapy: A Systematic Review of the Literature and Meta-Analysis

Vanita mehta.

1 Department of Anesthesiology, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Canada

Tajender S. Vasu

2 Division of Pulmonary, Critical Care, and Sleep Medicine, Stony Brook University Medical Center, Stony Brook, NY

Barbara Phillips

3 Division of Pulmonary Critical Care and Sleep Medicine, University of Kentucky College of Medicine, Lexington, KY

Frances Chung

Background:.

Hypoxemia is an immediate consequence of obstructive sleep apnea. Oxygen (O 2 ) administration has been used as an alternative treatment in patients with obstructive sleep apnea (OSA) who do not adhere to continuous positive airway pressure (CPAP) in order to reduce the deleterious effects of intermittent hypoxemia during sleep. This systematic review aims to investigate the effects of O 2 therapy on patients with OSA.

We conducted a systematic search of the databases Medline, Embase, Cochrane Central Register of Controlled Trials (1 st Quarter 2011), Cochrane Database of Systematic Reviews (from 1950 to February 2011). Our search strategy yielded 4,793 citations. Irrelevant papers were excluded by title and abstract review, leaving 105 manuscripts. We reviewed all prospective studies that included: (1) a target population with obstructive sleep apnea, (2) O 2 therapy and/or CPAP as a study intervention, (3) the effects of O 2 on the apnea-hypopnea index (AHI), nocturnal hypoxemia, or apnea duration.

We identified 14 studies including a total of 359 patients. Nine studies were of single cohort design, while 5 studies were randomized control trials with 3 groups (CPAP, oxygen, and placebo/sham CPAP). When CPAP was compared to O 2 therapy, all but one showed a significant improvement in AHI. Ten studies demonstrated that O 2 therapy improved oxygen saturation vs. placebo. However, the average duration of apnea and hypopnea episodes were longer in patients receiving O 2 therapy than those receiving placebo.

Conclusion:

This review shows that O 2 therapy significantly improves oxygen saturation in patients with OSA. However, it may also increase the duration of apnea-hypopnea events.

Mehta V; Vasu TS; Phillips B; Chung F. Obstructive sleep apnea and oxygen therapy: a systematic review of the literature and meta-analysis. J Clin Sleep Med 2013;9(3):271-279.

Obstructive sleep apnea (OSA) is the periodic reduction (hypopnea) or cessation (apnea) of airflow due to narrowing of the upper airway during sleep, often accompanied by hypoxemia and sleep disturbance. 1 The prevalence of OSA is estimated to be between 2% and 25% in the general population. OSA is linked to hypertension, ischemic heart disease, stroke, premature death, and motor vehicle crash. 2 – 7

Oxygen desaturation is an immediate consequence of obstructive sleep apnea. Intermittent hypoxemia increases sympathetic activity and norepinephrine levels and leads to hypertension. 8 , 9 It has also been associated with an increased risk of diabetes. 10 Indeed, most of the sequelae of obstructive sleep apnea are more strongly linked to the degree and duration of oxygen desaturation than to the numbers of apneas and hypopneas or disruptions in sleep architecture. 11 The resolution of nocturnal intermittent hypoxemia associated with sleep apnea is a major goal of the treatment of patients with obstructive sleep apnea.

Many treatment approaches have been employed for the treatment of moderate to severe OSA, but CPAP is the treatment of choice and has been widely prescribed. 12 , 13 In placebo-controlled and uncontrolled studies, CPAP has been shown to reduce apnea-hypopnea index (AHI) and to improve hypoxemia associated with respiratory events during sleep. 14 , 15 CPAP adherence has been reported to be as low as 50%, at least in part because it is a burdensome treatment. 16

Oxygen administration has been used as an alternative treatment in patients with OSA who are not somnolent or not compliant with CPAP; the purpose of supplemental oxygen in this situation is to reduce the deleterious effects of transient hypoxemia during sleep. 17 Supplemental oxygen has been shown to be effective in improving the AHI, respiratory arousal index, and nocturnal desaturation during apneic episodes. 18 However, oxygen therapy may lengthen apnea duration, thus accelerating CO 2 retention. 19

This systematic review aims to investigate the effects of CPAP and oxygen on patients with OSA. This review addresses the following questions: (1) Does evidence from controlled trials support the preferential use of CPAP over oxygen for improving OSA symptoms? (2) Can oxygen therapy be safely used in patients who are non-adherent with CPAP?

For purposes of this analysis, the target population consisted of adult humans with a diagnosis of obstructive sleep apnea defined as an AHI > 5 events per hour. The diagnosis of OSA was made using polysomnography (PSG). The study intervention included either the CPAP and oxygen therapy or oxygen therapy compared with the placebo. Outcomes of interest included the effects on AHI, nocturnal hypoxemia, apnea duration, and arousal index.

Literature Search

The literature search was performed according to the PRISMA (Preferred Reporting Items for Systematic reviews and meta-analysis) guidelines. 20 The databases Medline, Embase, Cochrane Central Register of Controlled Trials (1 st Quarter 2011), Cochrane Database of Systematic Reviews (from 1950 to Feb 2011) were thoroughly searched to include all available evidence for the systematic review. We developed and executed the search strategy with the help of an expert librarian familiar with the literature search protocol of the Cochrane Collaboration. The following target population keywords were used for the literature search: “obstructive sleep apnea,” “obstructive sleep apnea syndrome,” “obstructive sleep apnea-hypopnea syndrome,” “sleep disordered breathing,” “obesity hypoventilation syndrome” and “apnea-hypopnea,” “sleep apnea syndrome and “apnea.” The target intervention keywords used were “oxygen”, “oxygen therapy,” “oxygen inhalational therapy,” “CPAP,” “positive airway pressure,” and “continuous positive airway pressure.” The results of the target population were combined with the target intervention results (using an “and”). Studies focusing on central sleep apnea were excluded by including “NOT central sleep apnea” in the search strategy. The search strategy was limited to English language abstracts and adult human population. Duplicate records, if any were removed from the final search result. We also reviewed the reference lists of relevant articles to retrieve potentially relevant articles.

• Medline (Ovid SP) (1948 to Feb 2011)
• EMBASE (1980 to Feb 2011)
• Cochrane Database of Systematic Reviews (1 st quarter 2011)
• Cochrane Central Controlled Trials Registry (1 st quarter 2011)

The databases of the Cochrane Library were used to confirm the completeness of the search. The time period searched was 1948 to 2011.

Study Selection

The search results were evaluated by two independent reviewers (VM, TSV). First, irrelevant papers were excluded by reviewing the title of the records. Next, the abstract and/or full text articles of the remaining papers were retrieved and carefully evaluated to determine if they met the eligibility criteria.

All prospective studies, including randomized and non-randomized placebo controlled trials were included if they reported the effects of CPAP treatment or oxygen therapy on AHI, oxygen saturation, apnea duration, and arousal index in patients with OSA. Studies not reporting at least one of these outcomes were excluded. All observational studies were graded for strength of evidence according to the Oxford level of evidence. 21 We used the Cochrane risk of bias tool to assess the risk of bias for 6 randomized controlled trials ( Table 1 ). 22

Cochrane risk of bias in included studies

Data Extraction

Data extraction was completed by two reviewers (VM, TSV) and validated by the senior author (FC). Various data extracted from these studies included the type of study, level of evidence, number of patients receiving the study intervention, type of study intervention, duration and effects of intervention on AHI, SpO 2 , arousal index, and apnea duration. We divided the studies into 2 groups: the first group included studies which used CPAP and O 2 treatment; the second group included studies which used only O 2 therapy as an intervention. The methodological qualities of the included studies were independently evaluated by the first author (VM), if any doubt the senior author was consulted (FC). Individual authors were contacted via emails for the details of the results

Statistical Analysis

We performed the meta-analyses by using fixed-effects model if no heterogeneity was present. In order to assess the heterogeneity between studies, we used χ 2 tests and estimated the I 2 statistic. We considered the heterogeneity to be present if the p value on the χ 2 test was < 0.05. In the presence of heterogeneity, we pooled the results by using random-effects (DarSemonian and Laird method) model. The standardized mean difference was used to pool continuous variables that used different scales. We performed separate random-effects meta-analyses among randomized controlled studies comparing CPAP, placebo CPAP, and oxygen. We did not correct for multiple comparisons.

The Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines were followed for the description of the search strategy. Our search strategy yielded 4,793 citations ( Figure 1 ). In the first session of screening, most studies were eliminated based on the predetermined eligibility criteria, leaving 105 articles. In the second session, 105 articles were evaluated and 14 articles were identified as meeting the inclusion criteria, with subsequent exclusion of 91 articles. Articles were excluded for the following reasons: Non-pertinent papers—excluded by abstract/full-text review (n = 64), O 2 therapy in pediatric OSA (n = 11), reviews papers (n = 10), correspondence (n = 4), and case reports (n = 2).

Study Characteristics

Tables 2 and ​ 3 3 summarize study characteristics included in the systematic review. There were 6 studies 23 – 28 that used a randomized control design with 3 groups, each group being assigned to CPAP, placebo CPAP, or O 2 to evaluate the effects of CPAP and O 2 on AHI, O 2 saturation, and arousal indices. Eight studies 29 – 36 used a single cohort in which the outcome was measured in the same study population before and after the study intervention. All of these observational studies compared the effects of room air with O 2 on mean oxyhemoglobin saturation, sleep disordered breathing (SDB) events, and SDB event duration. These 8 studies were graded according to Oxford level of evidence and had a 2b level of evidence. We could not pool the results from the study by Block et al. 33 because the authors did not provide the standard deviation for the outcome of interests.

Study characteristics and effects of CPAP vs. oxygen therapy in OSA patients

Study characteristics and effects of oxygen therapy in OSA patients

Patient Characteristics

Table 2 represents a group of patients who received CPAP and O 2 intervention versus placebo CPAP. Table 3 represents a group of patients who received O 2 intervention compared with control (air). A total of 359 patients were included in the 14 studies. All the patients had a diagnosis of OSA confirmed by in-laboratory polysomnography. The inclusion criteria of the patients differed among the studies selected for the review. Two studies 23 , 33 used AHI > 5; 5 studies 24 – 28 used AHI > 15; one study 32 used SDB event > 50/h, and one study 35 used RDI > 20 for OSA patient selection. Four studies 30 , 31 , 34 , 36 selected patients with a confirmed diagnosis of OSA following overnight PSG with no description of any specific AHI criteria. Most of the patients were male, accounting for 89% of the study population. All the patients in the reported studies had moderate to severe OSA with AHI ranging from 20.5 ± 5 to 88.2 ± 27. The duration of the study intervention across the different studies was in the range of 1 night to 3 months.

Effects on Oxygenation, Respiratory Events, and Sleepiness

Table 2 summarizes the effects of the different treatment modalities on AHI, SpO 2 and arousal events studied by 6 RCTs. The respiratory disturbances occurring during the nighttime in OSA patients were measured using AHI, respiratory disturbance index (RDI), or SDB events. When CPAP was compared with O 2 , CPAP was significantly more effective in reducing AHI, while O 2 was shown to be more effective in elevating the mean SpO 2 and mean nadir SpO 2 during hypoxemic events. Both CPAP and O 2 improved the oxygenation as compared to placebo (sham) CPAP; this effect was statistically significant (p < 0.05). Four studies showed that CPAP versus O 2 therapy was more effective in improving the arousal events/total arousal index, but we could not pool the arousal events for the meta-analysis because of insufficient data.

The effects of CPAP and oxygen supplementation on the daytime somnolence was evaluated by 2 studies. 23 , 24 In one study, nasal CPAP was more effective in improving objectively measured daytime sleepiness than oxygen. This effect was apparent due to the significant efficacy of CPAP in lengthening the multiple sleep latency test (MSLT) time compared to baseline. 23 Similarly, another study showed the effectiveness of CPAP in reducing Ep-worth Sleepiness Scale score; however, it was not statistically different from placebo-CPAP or supplemental oxygen. 24

Effects on Systemic Blood Pressure

Three studies showed the treatment outcome on systemic blood pressure in patients treated with CPAP, oxygen, and placebo-CPAP. 23 , 25 , 26 Two studies showed that CPAP effectively reduced both the systolic as well as the diastolic blood pressure as compared to oxygen (p < 0.05). 25 , 26 In one study, CPAP and oxygen both had the effects in lowering the systolic blood pressure as compared to diastolic blood pressure; however, the changes were not statistically significant. 23

The effects of O 2 therapy on the oxygen saturation and SDB events are summarized in Table 3 . Seven studies showed that oxygen therapy was effective in improving the oxygenation as compared to air (control) in OSA patients. The SDB events showed a decreasing trend in the number of events when the patients received O 2 therapy after breathing room air. One study demonstrated an improved cardiovascular status in OSA patients following oxygen enrichment night. 34 Similarly, another study showed an improvement in daytime somnolence in patients receiving oxygen therapy. 35

Meta-Analysis of Randomized Controlled Trials

Effects on apnea hypopnea index ( figure 2 ).

A pooled analysis of 5 randomized controlled trials demonstrated that the use of therapeutic CPAP lead to a statistically significant reduction in the AHI versus nocturnal administration of oxygen (SMD -3.37, 95% CI -4.79 to -1.96). There was also a statistically significant reduction in AHI in CPAP group versus placebo (SMD -3.65, 95% CI -5.31 to -1.98). Nocturnal oxygen did not show significant reduction in AHI compared to placebo CPAP (SMD -0.32, 95% CI -0.74 to 0.08).

Effects on Mean Nocturnal Oxyhemoglobin Saturation ( Figure 3 )

A pooled analysis of 4 studies that reported mean oxyhemoglobin saturation showed that both therapeutic CPAP and nocturnal administration of oxygen lead to significant improvement in oxyhemoglobin saturation compared to placebo CPAP. Comparison of CPAP to nocturnal oxygen did not demonstrate a significant difference in the degree of improvement in oxygenation (SMD 0.07, 95% CI -0.27 to 0.41).

Meta-Analysis of Observational Studies

Effects on sdb events ( figure 4 ).

A pooled analysis of 6 observational studies showed significant reduction in SDB events with oxygen compared to air (SMD -0.95, 95% CI -1.69 to -0.21).

Effects on Mean Nocturnal Oxyhemoglobin Saturation ( Figure 5 )

A pooled analysis of 6 observational studies showed signifi-cant improvement in mean oxyhemoglobin saturation with oxygen compared to air (SMD 2.45, 95% CI 1.49 to 3.4).

Effects on Sleep Disordered Breathing (SDB) Event Duration

We identified 5 observational studies reporting the SDB event duration as an outcome. 30 – 33 We could not pool the results of these studies for statistical analysis due to the lack of sufficient data. However, 3 of these studies reported that administration of oxygen lead to the prolongation of SDB event duration. 31 – 33

In this systematic review, we identified and reviewed 14 studies evaluating the effects of oxygen supplementation for the treatment of intermittent nocturnal hypoxemia in patients with OSA. We performed a meta-analysis of the six randomized controlled trials that evaluated the effect of CPAP, placebo CPAP, versus oxygen on AHI and SpO 2 . In this analysis, patients with obstructive sleep apnea who used CPAP had signifi-cant reduction in AHI compared to those who used nocturnal oxygen. However, both nocturnal oxygen and CPAP improved oxyhemoglobin saturation equally.

Obstructive sleep apnea is a prevalent disorder with its serious health related consequences. 37 Many patients with sleep apnea have intermittent episodes of hypoxemia at night secondary to the periods of the upper airway obstruction. These episodes have been shown to be associated with harmful sequelae including insulin resistance, cognitive deficit, and the development of other cardiovascular morbidity. 38 – 40 Both nasal CPAP and nocturnal administration of oxygen improve oxy-hemoglobin saturation, but nocturnal oxygen has little effect on the blood pressure surge following apneas in patients with sleep apnea. 41 – 43 On the other hand, CPAP has been shown to lower the blood pressure variability in patients with sleep apnea. 25 , 26 This suggests that there might be some other factors such as hypercapnia, arousals, respiratory efforts, intrathoracic pressure changes, or fragmented sleep contributing to the increase in the blood pressure seen in sleep apnea. 44 – 47 In a study in human adults, the arousals from NREM sleep was shown to increase the sympathetic discharge with increase in the systolic blood pressure. 48

Patients with OSA frequently have cognitive dysfunction and excessive daytime sleepiness (EDS), possible secondary to the combination of hypoxemia and fragmented sleep. These symptoms worsen with increasing severity of hypoxemia and increasing frequency of arousals. Nasal CPAP improves both the arousals and hypoxemia and thereby has been shown to improve the sleepiness in contrast to the nocturnal administration of oxygen. 23 , 49 – 51 On the other hand, both CPAP and oxygen supplementation have been shown to improve psychological symptoms, including depression. 27

CPAP is clearly the treatment of choice in patients with OSA due to its immediate efficacy. It has been shown to improve AHI, hypoxemia, and arousals, thereby improving sleepiness and hypertension in contrast to the nocturnal administration of oxygen. However, patient adherence to CPAP is less than optimum. 52 In one study, adherence to CPAP was reported to be higher in patients who had consultation with the sleep physician prior to undergoing the sleep study, 53 but adherence to CPAP is between 50% and 70%, even with excellent management. 54

Hypoxemia is a major problem for patients with OSA in the postoperative period and hypoxemic episodes have been reported to occur mostly between the postoperative nights two to five. 55 Up to 40% of patients undergoing abdominal or thoracic surgery may experience postoperative hypoxemia. 56 In particular, surgical patients with OSA are at high risk of having postoperative complications. 57 , 58 A recent cohort study showed that oxygen desaturation with SpO 2 < 90% was the most common postoperative complication in patients with OSA. 59 These hypoxemic episodes have been shown to have serious consequences, including poor wound healing, cardiac arrhythmias, and delirium. 60 , 61 The use of supplemental oxygen in the perioperative period has been shown to reduce nausea and vomiting and hospital length of stay, and to improve wound healing. 62 – 64

Long-term oxygen therapy (LTOT) has been shown to improve survival and quality of life in patients with COPD. 65 – 67 However, its role in obstructive sleep apnea treatment is more controversial. The administration of nocturnal oxygen leads to the improvement of intermittent hypoxemia in patients with OSA. It may be considered in hypoxemic patients with OSA who are intolerant to the other treatment modalities for sleep apnea. However, the long-term consequences of chronic nocturnal administration of oxygen are unknown in patients with OSA. Further nocturnal oxygen has been shown to prolong apnea duration in patients with OSA, perhaps as a result of the suppression of the hypoxic respiratory drive. 31 – 33 In an observational study, the rise in blood pressure following each apneic episode was primarily linked to apnea duration and was not linked to hypoxemia. 42 Prolonged apnea duration may also increase the severity of hypercarbia and acidosis in patients with OSA. 19 , 31 , 32 This potential risk mandates careful monitoring for arrhythmias and other consequences of hypercarbia, especially in those with comorbid lung disease.

In conclusion, the evidence from the controlled trials does support the preferential use of CPAP over oxygen in patients with OSA since CPAP significantly improves the oxyhemoglobin saturation and reduces AHI and systemic blood pressure with improvement in daytime sleepiness. On the other hand, oxygen therapy is a double-edged sword, which not only lengthens the apnea duration but potentially increases the risk of hypercarbia with minimal to no effect on blood pressure and daytime sleepiness. Hence, at present it is difficult to recommend oxygen therapy for patients who are non-adherent with CPAP until the results of a multicenter clinical trial, Heart Biomarker Evaluation in Apnea Treatment, are available.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest.

ACKNOWLEDGMENTS

The authors would like to thank Marina Englesakis, BA (Hons), MLIS, Information Specialist, Health Sciences Library, University Health Network, Toronto, Ontario, Canada for her assistance with the literature search.

Author Roles:

• Vanita Mehta: Conception and study design, data extraction, data analysis, and manuscript preparation
• Tajender Vasu: Data extraction, meta-analysis, and manuscript preparation
• Barabara Phillips: Manuscript preparation
• Frances Chung: Conception and study design, acquisition and interpretion of data, manuscript preparation

This study was funded by the Physicians' Services Incorporated Foundation, University Health Network Foundation and Department of Anesthesia, University Health Network, University of Toronto.