2022 Brazilian Thoracic Association recommendations for long-term home oxygen therapy

ABSTRACT

Some chronic respiratory diseases can cause hypoxemia and, in such cases, long-term home oxygen therapy (LTOT) is indicated as a treatment option primarily to improve patient quality of life and life expectancy. Home oxygen has been used for more than 70 years, and support for LTOT is based on two studies from the 1980s that demonstrated that oxygen use improves survival in patients with COPD. There is evidence that LTOT has other beneficial effects such as improved cognitive function, improved exercise capacity, and reduced hospitalizations. LTOT is indicated in other respiratory diseases that cause hypoxemia, on the basis of the same criteria as those used for COPD. There has been an increase in the use of LTOT, probably because of increased life expectancy and a higher prevalence of chronic respiratory diseases, as well as greater availability of LTOT in the health care system. The first Brazilian Thoracic Association consensus statement on LTOT was published in 2000. Twenty-two years later, we present this updated version. This document is a nonsystematic review of the literature, conducted by pulmonologists who evaluated scientific evidence and international guidelines on LTOT in the various diseases that cause hypoxemia and in specific situations (i.e., exercise, sleep, and air travel). These recommendations, produced with a view to clinical practice, contain several charts with information on indications for LTOT, oxygen sources, accessories, strategies for improved efficiency and effectiveness, and recommendations for the safe use of LTOT, as well as a LTOT prescribing model.

Keywords:
Oxygen; Hypoxia; Oxygen inhalation therapy; Delivery of health care

RESUMO

Algumas doenças respiratórias crônicas podem evoluir com hipoxemia e, nessas situações, a oxigenoterapia domiciliar prolongada (ODP) está indicada como opção terapêutica com o objetivo principal de melhorar a qualidade e a expectativa de vida desses pacientes. O oxigênio domiciliar é usado há mais de 70 anos, e a ODP tem como base dois estudos da década de oitenta que demonstraram que o uso de oxigênio melhora a sobrevida de pacientes com DPOC. Existem evidências de que a ODP tem outros efeitos benéficos como melhora da função cognitiva e da capacidade de exercício e redução de hospitalizações. A ODP está indicada para outras doenças respiratórias que cursam com hipoxemia, segundo os mesmos critérios estabelecidos para a DPOC. Tem sido observado aumento no uso da ODP provavelmente pela maior expectativa de vida, maior prevalência de doenças respiratórias crônicas e maior disponibilidade de ODP no sistema de saúde. O primeiro consenso sobre ODP da Sociedade Brasileira de Pneumologia e Tisiologia foi publicado em 2000; após 22 anos, apresentamos esta versão atualizada. Este documento é uma revisão não sistemática da literatura, realizada por pneumologistas que avaliaram evidências científicas e diretrizes internacionais sobre ODP nas diversas doenças que cursam com hipoxemia e em situações específicas (exercício, sono e viagens aéreas). Estas recomendações, tendo em vista a prática clínica, oferecem diversos quadros com informações sobre indicações, fontes de oxigênio, acessórios e estratégias para melhor eficiência, efetividade e uso seguro da ODP, assim como um modelo para sua prescrição.

Descritores:
Oxigênio; Hipóxia; Oxigenoterapia; Atenção à saúde

INTRODUCTION

Chronic respiratory diseases can cause resting or exercise-induced hypoxemia, being among the main causes of decreased quality of life and life expectancy. Because especially of their infectious complications and their related hospitalizations, chronic respiratory diseases result in high costs for public and supplementary health care, as well as for patients and their families. For those who develop hypoxemia, the prescribing of long-term home oxygen therapy (LTOT) may provide benefits, such as a decrease in perceived dyspnea, improved exertional tolerance, and increased life expectancy.

Home oxygen has been used empirically for more than 70 years, and support for LTOT is based on two landmark studies from the 1980s, one by the Nocturnal Oxygen Therapy Trial Group¹ and one by the Medical Research Council Working Party.² Both studies demonstrated that oxygen use improves survival in COPD patients.

Improved survival with LTOT has been demonstrated in patients with stable COPD and severe, chronic hypoxemia.^3-6 In recent decades, accumulated evidence has shown that LTOT has other beneficial effects, such as reduced depression, improved cognitive function, improved quality of life, improved exercise capacity, and reduced hospitalizations.^7-16 In addition, LTOT can stabilize or even reverse pulmonary hypertension (PH) and decrease both cardiac arrhythmias and myocardial ischemia in patients with COPD.^17,18 However, the use of LTOT in other respiratory diseases that cause severe hypoxemia is based on extrapolation of COPD-related data, largely supported by knowledge of respiratory physiology and cellular respiration, which are identical regardless of the disease causing the hypoxemia, as well as its systemic effects.

The first Brazilian Thoracic Association consensus statement on LTOT was published in 2000 and remains a reference for many oxygen therapy protocols in Brazil.¹⁹ In the last 22 years, there has been a large increase in the use of LTOT, partly because of increased life expectancy and an increasing number of patients diagnosed with chronic lung diseases, notably COPD and interstitial lung diseases (ILDs), as well as the fact that the availability of LTOT in the health care system has increased. In addition, in the last 2 years, a proportion of COVID-19 survivors needed to use oxygen during a transition period or became chronic oxygen users.

In Brazil, the protocols for provision of LTOT for free are municipal and state protocols, and this is one of the reasons why we do not have reliable national data on the total number of LTOT users. In the USA, more than 1.5 million patients were receiving LTOT in 2018.²⁰

In Brazil, access to LTOT is guaranteed by the Brazilian Unified Health Care System’s Organic Laws (Federal Laws no. 8080/90 and no. 8142/90) that regulate the conditions for health promotion, protection, and recovery and for guaranteeing this right to every citizen.

We brought together 16 pulmonologists with expertise in oxygen therapy, who conducted a nonsystematic review of the literature and international guidelines for scientific evidence on LTOT in the various diseases that cause hypoxemia and on oxygen use in specific situations (i.e., sleep, exercise, and air travel). With a view to clinical practice, we created several charts to facilitate patient management, with information on main indications for LTOT; different sources of oxygen supply and necessary accessories; strategies for increased adherence, efficiency, and effectiveness; cost reduction; and recommendations for the safe use of LTOT; as well as a LTOT prescribing model (Charts 1-10 and Figure 1). In these recommendations, we chose to use the term LTOT, although we understand that the meaning intended here is broader, that is, it is oxygen supplementation for outpatients, for use during any activity, inside or outside their home.

Figure 1
Examples of medical certificates requested by airlines to prove that the passenger is fit to fly: the Medical Information Form (MEDIF) and the Frequent Traveller’s Medical Card (FREMEC).

Chart 1
Indications for home oxygen therapy.^a

Chart 2
Sources of high-pressure oxygen.^a

Chart 3
Sources of liquid oxygen (stored at −183°C; 1 L of liquid oxygen = 860 L of gaseous oxygen).^a

Chart 4
Oxygen concentrators (oxygen from room air).^a

Chart 5
Devices and accessories for long-term home oxygen therapy.^a

Chart 6
Strategies to improve the efficacy of long-term home oxygen therapy.

Chart 7
Recommendations for the safe use of oxygen.^a

Chart 8
Protocols for the use of long-term home oxygen therapy: key points.

Chart 9
Oxygen therapy during air travel.^a,b

Chart 10
Long-term home oxygen therapy. International guideline recommendations.^a

PHYSIOLOGY AND PATHOPHYSIOLOGY OF HYPOXEMIA

Oxygen is essential in oxidative phosphorylation, promoting ATP synthesis for energy production. Arterial oxygen content is dependent on the partial pressure of inspired oxygen, which, in turn, is dependent on atmospheric pressure, ventilation, the actual gas exchange, and hemoglobin concentration and affinity for oxygen.²¹

Only a small fraction (less than 2%) of arterial oxygen content is dissolved in plasma and is free from hemoglobin. At sea level, an SpO₂ of 96-98% corresponds to approximately 20 mL of oxygen for every 100 mL of blood.²² The delivery of oxygen to the tissues, in turn, is dependent on arterial oxygen content and cardiac output. The lower the oxygen concentration, the greater the hemoglobin-oxygen affinity, and, consequently, the more decreased the delivery of oxygen to the tissues. An increase in body temperature, acidosis from any cause, or an increase in 2,3-diphosphoglycerate produces a shift in the hemoglobin dissociation curve to the right, decreasing hemoglobin-oxygen affinity and increasing the delivery of oxygen to the tissues.²³

Hypoxemia can be assessed by calculating the alveolar-arterial oxygen tension difference (P[A-a]O₂) or by calculating the oxygenation index (PaO₂/FiO₂). In hypoxemic patients with P(A-a)O₂ within the normal range, the likely pathophysiological mechanism is the presence of hypoventilation. In those with increased P(A-a)O₂ and persistent hypoxemia despite oxygen supplementation or with increased FiO₂, the presence of cardiac or intrapulmonary shunt is suggested. In those who respond to supplemental oxygen, ventilation-perfusion (V/Q) mismatch or altered diffusion should be considered.²⁴

Acute or chronic hypoxemia induces various physiological responses aimed at maintaining adequate delivery of oxygen to the tissues. When PaO₂ is below 60 mmHg, there is an increased ventilatory stimulus, increasing PaO₂ and reducing PaCO₂. The vascular beds irrigating the hypoxic tissue dilate, inducing compensatory tachycardia to increase cardiac output and improve oxygen delivery. The pulmonary vasculature contracts to improve the V/Q ratio in the affected areas. If hypoxemia does not resolve, renal activation will occur to increase erythropoietin production and stimulate erythrocytosis, increasing oxygen transport and delivery capacity. These initial benefits may have harmful long-term effects, since long-term vasoconstriction, erythrocytosis, and increased cardiac output can cause PH and right ventricular failure, decreasing survival. In addition, the energy cost of increased ventilation and increased oxygen demand may contribute to malnutrition in COPD patients.^21-24

DEFINITION OF HYPOXEMIA

At sea level, barometric pressure is 760 mmHg (or 1 atm), FiO₂ is 0.21 (or, as per clinical practice, 21%, a term that is used in scientific papers and will be used in this document), and PaO₂ is 80-100 mmHg in healthy individuals. Therefore, PaO₂ is dependent on altitude, although it should also be adjusted for age (with aging, there is a progressive reduction in PaO₂). Hypoxemia is defined as a PaO₂ below the lower limit of normal; however, this does not necessarily mean that oxygen supplementation will be required.

Classically, the prescribing of LTOT in patients with chronic respiratory diseases other than COPD relies on extrapolation of data from COPD studies. Pulse oximetry is used to screen patients for resting hypoxemia; when SpO₂ is ≤ 92%, a request for arterial blood gas analysis on room air is indicated; in addition, the presence or absence of hypercapnia should be evaluated. :The indications for LTOT are as follows: severe hypoxemia with a PaO₂ ≤ 55 mmHg or an SaO₂ ≤ 88% or a PaO₂ ≤ 59 mmHg or an SaO₂ ≤ 89% in the presence of edema, cor pulmonale (PH), or polycythemia (hematocrit > 55%).^6,20,25 The daily duration of LTOT should be at least 15 h/day, including the sleep period, and the oxygen flow rate should be high enough to raise PaO₂ above 60 mmHg or raise SpO₂ above 90%.^6,20,25

≥Exercise-induced hypoxemia is defined as a reduction ≥ 4 points in exertional SpO₂, even if baseline SpO₂ is within the normal range. LTOT in patients with exercise-induced hypoxemia remains controversial in the literature, it being advisable to consider the magnitude of the decrease in perceived dyspnea after oxygen supplementation or to consider its use in pulmonary rehabilitation.

The mechanisms of action of supplemental oxygen are beyond the correction of hypoxemia and the improvement of oxygen delivery to the cells. In healthy individuals exposed to hypoxic conditions, the accumulation of hypoxia-inducible factors in the cell nucleus upregulates several genes responsible for the physiological responses to hypoxia, including remodeling of the pulmonary vasculature, culminating in PH and increased erythropoiesis.^26,27 Limited evidence from animal models suggests that some of the therapeutic effects of LTOT are mediated by inhibition of hypoxia-inducible factors.²⁸

LTOT IN PATIENTS WITH COPD

Although observational studies have suggested benefits of using supplemental oxygen in COPD, two randomized clinical trials (RCTs) were critical in establishing the basis for the use of LTOT.^1,2 The study by the Medical Research Council Working Party² followed 87 COPD patients for 5 years who had severe hypoxemia, hypercapnia, and cor pulmonale. Patients were randomized into two groups: placebo (no supplemental oxygen) and intervention (LTOT for at least 15 h/day). At the end of follow-up, mortality was 45.2% in the oxygen group and 66.7% in the control group.² The study by the Nocturnal Oxygen Therapy Trial Group¹ randomized 203 hypoxemic COPD patients into two groups: continuous supplemental oxygen and 12-h nocturnal supplemental oxygen. The follow-up period was 12 months, and mortality was higher in the nocturnal oxygen group (hazard ratio = 1.94; p = 0.01).

Studies that have demonstrated increased survival with LTOT involved patients with severe hypoxemia (PaO₂ ≤ 55 mmHg or SaO₂ ≤ 88%). In contrast, the use of LTOT in COPD patients with moderate hypoxemia showed no survival benefit.^29-31 Other studies of individuals with COPD also demonstrate that LTOT has other benefits in severely hypoxemic COPD patients, such as improvement in quality of life, exercise capacity, and cognitive function, as well as a reduction in pulmonary vascular resistance, right atrial pressure, cardiovascular morbidity, and hospitalizations.^{13,15-18,32-34}

As previously mentioned, the mechanisms of action of supplemental oxygen are beyond the correction of hypoxemia and the improvement of oxygen delivery to the cells. In healthy individuals exposed to hypoxic conditions, the accumulation of hypoxia-inducible factors in the cell nucleus upregulates several genes responsible for the physiological responses to hypoxia, including remodeling of the pulmonary vasculature, leading to PH and increased erythropoiesis.^26,27 Limited evidence from animal models suggests that some of the therapeutic effects of LTOT are mediated by inhibition of hypoxia-inducible factors.²⁸

LTOT is indicated for COPD patients with persistent severe hypoxemia who are clinically stable and have been on optimal drug therapy for at least one month. Those who are clinically unstable, for example, after a recent exacerbation, should receive temporary oxygen supplementation until clinical reassessment 1-3 months after decompensation, since approximately 50% will not require LTOT at follow-up.^35,36 It is recommended that all patients assess the need to increase the oxygen flow rate during exercise and sleep. Excessive oxygen flows should be avoided in order to minimize the side effects of oxygen, especially a worsening of hypercapnia in patients with carbon dioxide retention, with an increase in the risk of sensorial depression and, in extreme cases, of coma due to carbon dioxide narcosis,³⁷ and it is suggested that SpO₂ be maintained at 90-92%.

Pulse oximetry is used to screen patients for hypoxemia; when SpO₂ is ≤ 92%, arterial blood gas analysis is indicated. Arterial blood gas analysis is necessary for prescribing LTOT and is also useful for detecting hypercapnia. As previously mentioned, the indications for LTOT include a PaO₂ ≤ 55 mmHg or an SaO₂ ≤ 88% or a PaO₂ ≤ 59 mmHg or an SaO₂ ≤ 89% in the presence of edema, PH, cor pulmonale, or polycythemia (hematocrit > 55%).^6,20,25

Hypoxemic patients with suspected obstructive sleep apnea (OSA) syndrome or alveolar hypoventilation should be referred for polysomnography. It should be emphasized that in such cases correction of hypoxemia may be achieved with noninvasive ventilation alone, even without supplemental oxygen.³⁸

Smokers should be referred to smoking cessation programs and instructed not to smoke while using oxygen, not because oxygen is flammable, but because it accelerates combustion and increases the risk of fires and explosions.³⁹ In addition, smoking increases blood levels of carbon monoxide, which has a high affinity for hemoglobin and reduces oxygen transport.^6,25,27

Adherence to treatment is essential for achieving the expected benefits of LTOT. Adherence can range from 45% to 70% and can be improved by identifying barriers, facilitators, and prescriber attitudes.⁴⁰ Many patients use oxygen for less than 15 h/day, use oxygen flows lower than those prescribed by their doctors, or both, because they lack guidance about their illness and about the role of oxygen in the treatment, have little improvement in their symptoms, or are afraid of becoming dependent on LTOT.^{6,20,25,41,42} High-quality support from the health care team improves patient adherence to the correct use of oxygen (Chart 6). The decision to prescribe LTOT should be carefully considered, as should the decision to discontinue it. Oba et al.⁴³ observed that only 35% of patients were reassessed correctly and that the rate of appropriate reassessment was significantly higher among pulmonologists than among general practitioners (65% vs. 17%).

LTOT IN PATIENTS WITH CHRONIC LUNG DISEASES OTHER THAN COPD

Cystic fibrosis

In patients with cystic fibrosis (CF), chronic airway infection causes lung damage that results in chronic hypoxemia, with respiratory failure being the leading cause of death.^44,45 The proportion of CF patients receiving oxygen is unknown, and the impact of LTOT on the survival and quality of life of these patients remains unclear.⁴⁵ A review⁴⁵ of 11 studies on oxygen use in patients with CF, only one of which assessed its long-term benefit, concluded that LTOT had no discernible effect on mortality, hospitalization, or disease progression when compared with no oxygen therapy, although it reduced absenteeism from school and work.

There is little evidence for prescribing LTOT in patients with advanced CF, although in the short term some improvement in PaO₂ during sleep and exercise has been demonstrated.⁴⁶ The Cystic Fibrosis Foundation guidelines⁴⁷ suggest that patients with advanced CF be annually evaluated for exertional hypoxemia, nocturnal hypoxemia, hypercapnia, and PH, as well as recommending oxygen use in patients with an SpO₂ ≤ 88% during sleep or during exercise. The British Thoracic Society guidelines⁶ recommend that the indications for LTOT in CF be the same as those in COPD.

ILDs

COPD and ILDs are the main indications for LTOT.⁴⁸⁾ Recent large RCTs of idiopathic pulmonary fibrosis concluded that 21-28% of study participants received supplemental oxygen therapy.^49,50 However, those rates did not differentiate between resting hypoxemia and exertional hypoxemia. A retrospective study of 400 patients conducted in Australia in specialist ILD clinics reported a prevalence of resting hypoxemia of 3.5%.⁵¹

Definitions of exertional hypoxemia vary widely, but regardless, exertional hypoxemia is common in ILD patients, being more severe in ILD than in COPD when compared with the severity of lung function impairment. In addition, exertional hypoxemia is a marker of poor prognosis for these patients.^52-55) Nocturnal hypoxemia affects approximately 27% of patients, and the association with sleep-disordered breathing may increase this prevalence.⁵⁶

The benefit of LTOT in ILD patients is uncertain. A systematic review⁵⁷ found no consistent effects on exertional dyspnea, although exercise capacity improved. Studies on the use of LTOT in ILD patients have a high risk of bias, and it is therefore not possible to estimate the impact of LTOT on survival.⁵⁷ Current clinical guidelines have consistently recommended LTOT for ILD patients on the basis of the same criteria as those used for COPD patients.^4,6,58-62

PH

Precapillary PH is a hemodynamic diagnosis that includes pulmonary arterial hypertension (PAH, group I), PH due to respiratory diseases (group III), and chronic thromboembolic PH (group IV), and can cause hypoxemia.⁶³ Several pathophysiological mechanisms, such as decreased cardiac output in patients with PH, V/Q mismatch, right-to-left shunt, and decreased oxygen diffusion capacity, are involved in hypoxemia, which may be increased by pulmonary vasoconstriction.^64-66

A study conducted by Ulrich et al.⁶⁴ demonstrated that the use of supplemental oxygen in patients with PAH or chronic thromboembolic PH resulted in benefit in exercise capacity and quality of life. In addition, there was improvement in nocturnal SpO₂ and in sleep disturbances in those with exercise-induced hypoxemia and sleep disorders (sleep apneas and nocturnal hypoxemia). Although the duration of oxygen supplementation was short (up to 5 weeks), it is unknown whether the positive effects of oxygen supplementation during exercise translate to long-term benefits.^67,68 An observational study of PAH concluded that the risk of death was significantly higher among patients with severe DL_CO reduction (< 40% of predicted) who did not use supplemental oxygen than among those who did. However, the latter group had more PAH-specific medication use, which constitutes a selection bias.⁶⁹

The use of LTOT in adult patients with Eisenmenger syndrome remains controversial, and there are limited data in the literature. A prospective controlled study⁷⁰ showed no impact of nocturnal oxygen use on exercise capacity, disease natural history, or survival in the 2-year follow-up period. Therefore, the use of LTOT is optional in these patients, and its prescription should be individualized.⁷⁰

Recommendations in guidelines on the use of supplemental oxygen in PH are controversial, probably because of the absence of long-term studies.⁷⁴ Despite limited evidence, it is suggested that LTOT be prescribed for PH patients with a PaO₂ < 60 mmHg, considering symptomatic benefit and correction of exertional desaturation.^6,25

LTOT IN PATIENTS WITH ADVANCED, CHRONIC DISEASES AND IN PALLIATIVE CARE

Promoting early interventions that not only alleviate the symptoms caused by disease progression, but also reduce emergency department visits and hospitalizations and ensure end-of-life care is essential in palliative care planning. Ideally, this requires the participation of a multidisciplinary team consisting of physicians, physiotherapists, nurses, psychologists, and social workers, with appropriate knowledge and training; however, an attending physician with a clear understanding of the patient’s condition is capable of managing the disease progression, prioritizing symptom control.⁷²

The use of oxygen therapy in palliative care requires the assessment of the causes that can be reversed and of objective criteria such as SpO₂, an overall assessment of the patient’s needs, and an individualized treatment plan. This plan should be jointly developed by the health care team, the patient, and his or her caregivers.⁷³

LTOT can relieve dyspnea if this is associated with hypoxemia, bearing in mind that dyspnea is a subjective sensation and is often independent of hypoxemia.⁴ Symptom control in patients with advanced, chronic diseases is a widely discussed therapeutic resource. Current studies and recommendations demonstrate limited usefulness of oxygen therapy in some situations.⁷⁴ In practice, it is observed that the benefits of oxygen therapy are overestimated, whereas its possible risks and limitations are underestimated. An observational study including 114 patients who were near death revealed no benefit from oxygen use, with no difference between administration of oxygen and of medical air for symptom relief when PaO₂ > 55 mmHg.⁷⁵ The eventual improvement would be due to air flowing on the face, with trigeminal nerve stimulation and a reduction in dyspnea; therefore, there is no benefit from oxygen therapy in this context. The British Thoracic Society guidelines,⁶ for example, recommend that oxygen use be limited to those patients with an SpO₂ < 90% on room air and that there is no role for routine SpO₂ monitoring as long as the patient is comfortable in the last days of life.⁷⁶

The side effects of oxygen therapy include acute hypercapnia with central effects and lung injury due to oxidative stress that generally occurs at high oxygen flows.⁷⁷ The use of the oxygen therapy equipment can also lead to activity restriction, dryness of the mucous membranes, and discomfort caused by nasal cannulas or face masks.⁷⁸ The limitations caused by the use of oxygen therapy should be carefully evaluated by a multidisciplinary health care team, since some of them can have a great impact on the quality of end of life in individuals with advanced disease.⁷⁴

The management of dyspnea in patients with advanced, chronic disease is based on the objective assessment of dyspnea, application of energy conservation techniques, optimization of treatment of the underlying disease and its complications, oxygen therapy when hypoxemia is present, cardiopulmonary rehabilitation, and use of noninvasive ventilation.⁷⁸ The use of oral opioids, notably morphine and dihydrocodeine, in doses not exceeding 30 mg/day of morphine or equivalent, has been considered beneficial in the palliation of dyspnea, with no increased risk of respiratory depression, despite adverse effects such as drowsiness, nausea, vomiting, and constipation.^79,80

LTOT IN POST-COVID-19 PATIENTS

SARS-CoV-2 has infected and caused the death of millions of people worldwide, having a major impact on the health care system in several countries, including the lack of oxygen supply. During the pandemic, some concepts related to oxygen use, such as silent hypoxemia^81-83 and high-flow oxygen therapy,^84,85 were widely cited and discussed. Silent hypoxemia occurred most frequently in the elderly and in people with diabetes; in such patients, the hyperventilatory response to hypoxemia may be dampened. A direct action of the virus in the respiratory center, reducing the response to hyperventilation, is a hypothesis that has yet to be confirmed. A shift of the oxyhemoglobin dissociation curve to the left in infected patients could explain the fact that some patients possess greater tolerance to hypoxemia than others.^81-83

Many patients with post-COVID-19 syndrome who developed sequelae after hospital discharge required LTOT. One study found that 13.2% of the patients who were discharged from the hospital required LTOT, and that that need decreased progressively as patients clinically recovered.⁸⁶ In another study, the risk factors associated with the need for LTOT after hospital discharge of patients with moderate to severe COVID-19 were as follows: being male; being ≥ 50 years of age; and having ≥ 3 comorbidities, especially previous lung disease.⁸⁷

National and international guidelines on LTOT do not have specific guidelines for hospital discharge after SARS-CoV-2 infection. A task force of the European Respiratory Society/American Thoracic Society (ATS)⁸⁸ recommends that hospitalized patients with COVID-19 be evaluated for the need for oxygen supplementation at rest and during exercise, since progressive improvement in gas exchange is expected; however, some patients will require oxygen after hospital discharge. Another possibility is the presence of desaturation only during exercise, and therefore the need or absence of need for oxygen supplementation should be assessed_.⁸⁸ The detection of decreased SpO₂ justifies the investigation of previously unknown pulmonary and cardiovascular comorbidities. Early reassessment after hospital discharge is recommended because the need for LTOT may be short-lived.⁸⁸

LTOT IN PEDIATRIC PATIENTS

The initiation, continuation, and discontinuation of oxygen therapy in children have relevant particularities. Therefore, recommendations for adults do not apply to children. The main differences between LTOT in children and adults are as follows^89-93:

• Physical growth and neurological development should be considered.

• The course of some diseases that cause hypoxemia in children is usually favorable; therefore, many children require LTOT only for a limited period of time.

• Most clinical conditions are peculiar to this age group, although the indications for LTOT in older children and adolescents may be similar to those in adults.

• The prescribing and monitoring of oxygen use are based on pulse oximetry rather than on arterial blood gas analysis.

• Specific equipment is required to allow for low oxygen flows.

• Many children require oxygen therapy overnight only, requiring fewer hours than those normally prescribed in adult LTOT.

• Periods such as physical activity (which includes bathing), sleep, and even feedings can lead to drops in saturation; therefore, provision of higher oxygen flow rates on these occasions should be individualized.

• All children require supervision from an adult.

• Provision of oxygen may be necessary at school for school-age children.

Conditions that most often lead to the need for LTOT in pediatric patients include bronchopulmonary dysplasia (BPD), CF, bronchiolitis obliterans, ILDs, and sickle cell disease. Because BPD is exclusive to pediatric patients and because LTOT has some peculiarities in pediatric CF patients, we chose to address these two conditions in more detail.

BPD

The most current definition of BPD is a diagnosis based on persistent radiographic changes of the lung parenchyma in preterm infants born at ≤ 32 weeks of gestational age or at 36 weeks of corrected gestational age who require ventilatory support for three or more days to maintain arterial saturation at 90-95%.^94,95

BPD is the most common indication for LTOT in children and occurs in approximately 40% of very low birth weight newborns (< 1,000 grams).^93,96-98 Its incidence has not decreased over the years, precisely because of important advances in neonatal care, which has increasingly allowed the survival of extremely preterm infants.^94-97

The benefits of LTOT include improvement in physical growth, neurological development, and sleep pattern, as well as a reduction in airway resistance, pulmonary artery pressure, risk of sudden death, and nocturnal awakenings. In addition, keeping the child at home with the family allows a better emotional bond and reduces the risk of nosocomial infections.^89,93

LTOT is indicated for the patient who is clinically stable, remains oxygen dependent (SpO₂ ≤ 92% on room air), and does not have hypercapnia. Two important studies^99,100 demonstrated that maintaining SpO₂ at > 95% was related to a worse outcome, with the need to continue LTOT for a longer period. Since then, maintaining SpO₂ at > 95% has been avoided.^99,100 In contrast, another study¹⁰¹ compared an SpO₂ target of 85-89% with that of 91-95% for children born before 28 weeks of gestation and demonstrated that an SpO₂ target of < 90% was associated with an increased risk of death before discharge, resulting in the early discontinuation of the study.¹⁰¹ Current recommendations are that SpO₂ should be between 90% and 95%, without frequent fluctuations during sleep or feedings.^102,103

LTOT should be considered for patients with BPD who were born at ≥ 36 weeks of corrected gestational age, are clinically stable, and experience a weight gain of 20 grams per day.

The initial oxygen flow rate is 1-2 L/min, maintaining SpO₂ between 92% and 95%. A decrease in oxygen flow may be considered after 4 weeks if the patient is stable and continue experiencing adequate weight gain. The oxygen flow rate should be reduced by 0.25-0.1 L/min, initially while the child is awake, as long as SpO₂ remains at ≥ 92%.⁹⁷

CF

The prescribing of LTOT in CF patients should be individualized, and, in general, children and adolescents should receive it via a nasal cannula, with pertinent adaptations, as in the case of patients with a tracheostomy.¹⁰⁴ Oxygen therapy will reduce dyspnea and delay the onset of cor pulmonale. School children and adolescents with a PaO₂ ≤ 55 mmHg or an SpO₂ ≤ 88% should receive oxygen at the lowest flow rate possible to maintain SpO₂ at > 90%.^90,104 Recent publications by the ATS recommend considering the prescription of LTOT for pediatric CF patients who maintain saturation at 90-93% but have exertional dyspnea.^89,90 The prescription of LTOT for infants and preschool children is indicated to maintain SpO₂ at ≥ 93%, in a manner similar to that in patients with BPD.⁹²

Weaning from LTOT in pediatric patients

Weaning from LTOT may occur with lung growth and maturation, and possible improvement of the lung disease. The physician should clinically evaluate the patient and make sure, on the basis of SpO₂ measurements, that weaning is feasible.^89,90 Weaning will be adjusted weekly by gradually reducing oxygen flow or by discontinuing LTOT for increasingly longer periods of the day, maintaining weekly to monthly medical visits to ensure safe weaning.⁸⁹ Infants receiving flows of up to 0.1 L/min, preschool children receiving flows of 0.1 to 0.25 L/min, and older children receiving flows of 0.25 to 0.5 L/min may be able to discontinue LTOT. After oxygen is discontinued, it is strongly suggested that nocturnal oximetry with an appropriate pediatric device be performed.^89,90 The LTOT equipment must remain in the patient’s home for as long as necessary to ensure his or her safety⁸⁹; the national recommendation suggests a period of at least 3 months after LTOT discontinuation.⁹² Then, monitoring by oximetry should be performed on two occasions one month apart, and, if oximetry values remain adequate, the LTOT equipment can be removed from the patient’s home.⁹²

LTOT IN PATIENTS WITH SLEEP-DISORDERED BREATHING

Sleep-disordered breathing is characterized by repetitive sleep-related respiratory events, causing intermittent hypoxemia and sleep fragmentation, and includes OSA, central sleep apnea (CSA), and sleep-related hypoventilation; OSA is the most prevalent form of sleep-disordered breathing.¹⁰⁵

The intensity and frequency of intermittent hypoxemia during recurrent episodes of apnea/hypopnea during sleep commonly lead to cardiovascular, metabolic, and neurocognitive consequences, impacting morbidity and mortality.¹⁰⁶

Positive airway pressure (PAP) is the standard therapy for maintaining upper airway patency and correcting intermittent hypoxemia.^105,107 However, although PAP is an extremely effective treatment, PAP adherence is limited.^105,107,108

OSA

A systematic review and meta-analysis of RCTs showed the superiority of CPAP over nocturnal oxygen use in reducing the apnea-hypopnea index (AHI) in individuals with OSA.¹⁰⁹ However, previous studies have documented an increase in the duration of obstructive respiratory events during nocturnal oxygen use.^38,110 In a recent meta-analysis, supplemental oxygen therapy, when compared with CPAP, was less efficient in reducing the AHI, the duration of SpO₂ < 90%, and systemic blood pressure, as well as in improving sleep quality.¹¹¹ Oxygen can be used in conjunction with PAP therapy when SpO₂ remains at ≤ 88% for at least 5 min despite adequate titration and complete control of obstructive events (initiate oxygen at 1 L/min and titrate to maintain SpO₂ at 88-94%).¹¹²

CSA

Previous studies have reported the beneficial effect of oxygen supplementation on CSA associated with Cheyne-Stokes respiration in individuals with congestive heart failure (CHF).^113,114 Two meta-analyses compared the effect of CPAP, adaptive servo-ventilation (ASV), and oxygen supplementation on the AHI and on left ventricular ejection fraction (LVEF) in CHF patients with CSA associated with Cheyne-Stokes respiration.^115,116 The first meta-analysis,¹¹⁵ which included 919 patients, showed that ASV was most likely to reduce the AHI, followed by oxygen supplementation and CPAP. In the second meta-analysis,¹¹⁶ which included 951 patients, CPAP and ASV, in contrast to nocturnal oxygen, were found to be equally efficient in improving LVEF. Although ASV can improve the AHI and LVEF, one study observed increased mortality in CHF patients with CSA and an LVEF ≤ 45%.¹¹⁷ Nocturnal oxygen therapy may not eliminate obstructive events that often coexist with central events in patients with CHF.¹¹⁸ In patients with CSA, nocturnal oxygen effectively reduces the AHI secondary to CSA and improves SpO₂, and may serve as an alternative to PAP therapy.^108,119 However, long-term studies assessing the impact of LTOT on CSA are lacking.

COPD-OSA overlap syndrome

The COPD-OSA overlap syndrome causes more severe nocturnal hypoxemia than either COPD or OSA alone, leading to a poor prognosis.^120,121 Nocturnal oxygen therapy may be indicated in COPD patients when nocturnal hypoxemia persists despite appropriate treatment.^38,108,110 However, because oxygen suppresses the hypoxic respiratory drive, it may contribute to prolonging apnea duration, leading to hypercapnia and acidosis in patients with OSA, especially those with COPD-OSA overlap syndrome or hypoventilation.^38,108,110 Current treatment of patients with COPD-OSA overlap syndrome includes regular CPAP therapy, noting that CPAP is indicated in severe or moderate OSA when there are associated symptoms or significant nocturnal hypoxemia. There is no indication for CPAP in mild OSA.¹²⁰

In observational studies, patients with COPD-OSA overlap syndrome who were treated with CPAP had survival rates comparable to those of patients with COPD alone, whereas those with this overlap syndrome who were not treated with CPAP had higher mortality.¹²¹

Obesity hypoventilation syndrome

The obesity hypoventilation syndrome (OHS) comprises the triad of obesity, gas exchange abnormalities (hypercapnia), and absence of alternative explanations for hypoventilation. The most recent publications by the ATS and the European Respiratory Society recommend that CPAP, rather that BiPAP, be used as first-line treatment for outpatients with OHS and severe OSA, an association that is present in more than 70% of patients with OHS.^122,123 However, noninvasive ventilation is preferred in a minority of the patients with OHS who do not have OSA or have milder forms of OSA (approximately < 30%). Oxygen therapy alone in OHS should be avoided because of its detrimental effect on ventilation and the risk of it precipitating hypercapnic respiratory failure.¹²³

OXYGEN THERAPY DURING EXERCISE AND PULMONARY REHABILITATION

Tissue oxygenation depends on factors including the transfer of oxygen from the atmosphere to the lungs; adequate oxygen delivery to peripheral tissues through hemoglobin transport and adequate blood flow; oxygen delivery to the mitochondria for aerobic ATP synthesis; and muscle oxygen utilization.¹²⁴

The main effects that oxygen therapy during exercise has on COPD and ILD are as follows: a central effect, preventing reduced cerebral oxygenation; a ventilatory effect, with decreased respiratory drive resulting from reduced carotid chemoreceptor stimulation and reduced dynamic hyperinflation; a cardiovascular effect, achieved through pulmonary vasodilation, increased cardiac output, and decreased pulmonary artery pressure; and a muscle effect, with reduced muscle dysfunction, reduced lactic acid production, and reduced activity of muscle metaboreceptors, reducing respiratory drive.^125-127 Modulation of these mechanisms can improve symptoms such as dyspnea and fatigue, as well as improving quality of life and exercise capacity, particularly during rehabilitation. However, controversy remains in the literature regarding oxygen therapy, especially for normoxemic patients with or without exercise-induced hypoxemia.

COPD

Exercise-induced hypoxemia is common in patients with COPD, being found in almost half of patients referred for pulmonary rehabilitation (PR). In general, these patients do not tolerate high-intensity exercise, and a reduction in training intensity is required in many cases; this, however, could limit the efficacy of PR.¹²⁸ In a study evaluating acute oxygen therapy, 124 patients with moderate to severe COPD were divided into three groups: normoxemic patients, patients with resting hypoxemia, and patients with exercise-induced hypoxemia; they underwent a six-minute walk test (6MWT) while receiving oxygen or compressed air.¹²⁹ The two groups of patients with hypoxemia benefited from oxygen therapy delivered by nasal cannula (NC), with increased exercise capacity, although the difference was not clinically significant (> 30 m).¹²⁹ In a study comparing the effects of oxygen and compressed air delivered during exercise training in normoxemic patients without exercise-induced hypoxemia (n = 29), oxygen therapy resulted in increased training intensity and exercise capacity (cycle ergometer endurance: 14.5 min vs. 10.5 min; p < 0.05) during a PR program.¹³⁰ It is of note that oxygen responders present with higher oxygen desaturation¹³¹ and lower exercise capacity¹³² at baseline or a > 10% increase in the distance covered at baseline.¹³²

In a multicenter study involving 111 patients with moderate to severe COPD and exercise-induced hypoxemia (an SpO₂ of < 90% during the 6MWT), oxygen therapy did not result in an increase in exercise capacity or quality of life when compared with supplemental compressed air. It is of note that both groups benefitted from exercise training, with significant increases in exercise capacity and quality of life.¹³³ However, the question remains whether the proposed level of training intensity was actually achieved.¹³⁴ In another study, patients with severe to very severe COPD and resting hypoxemia (n = 50) received oxygen therapy (constant oxygen flow rates vs. automated oxygen titration).¹³⁵ Automated oxygen titration resulted in improvements in oxygenation, walking endurance time, SpO₂, PaO₂, and dyspnea, with no impact on PaCO₂. In comparison with nonresponders, those who responded to automated oxygen titration tended to have lower lactate values, less leg fatigue at the end of the endurance test, and less dyspnea.¹³⁵ In a study comparing oxygen therapy delivered via a Venturi mask and high-flow nasal cannula (HFNC) oxygen therapy during exercise training, both groups of patients benefitted from the exercise training program, with significant improvements in exercise capacity, symptoms, and quality of life.¹³⁶

In a recent systematic review and meta-analysis of 7 studies evaluating oxygen therapy and PR, it was shown that oxygen therapy delivered during PR did not improve exercise capacity, dyspnea scores, or quality of life, although the level of evidence was weak, primarily because of the heterogeneous interventions across studies.¹³⁷

Despite the conflicting results across studies, international guidelines state that patients receiving LTOT should receive oxygen therapy during exercise training and increase the flow as the demand for oxygen increases during exercise.^6,20,25 In some cases, there might be a need for a formal assessment demonstrating improvement in exercise tolerance with the addition of acute oxygen therapy.^6,20,25

ILD

Patients with ILD have reduced exercise tolerance (as assessed by the 6MWT), maximal oxygen uptake, and endurance time. Reduced exercise capacity is associated with poor survival. In a study comparing acute oxygen therapy and supplemental compressed air in patients with mild to moderate ILD (n = 72) and exercise-induced hypoxemia, oxygen was found to increase endurance time, reduce desaturation, and reduce the number of symptoms.¹³⁸ Respondents were those who achieved a lower nadir SpO₂ on the 6MWT performed when receiving compressed air at baseline¹³⁸; a similar result was found when an FiO₂ = 50% was compared with supplemental compressed air.¹³⁹

It is known that patients with ILD can have significant desaturation (e.g., an SpO₂ of < 80% on exertion), and it is not always possible to maintain an SpO₂ > 90% with the use of oxygen therapy delivered by NC. In a study comparing oxygen therapy delivered by a conventional NC and oxygen therapy delivered by a pendant NC with an incorporated reservoir (Oxymizer; Drive DeVilbiss Healthcare, Port Washington, NY, USA) in patients receiving ambulatory oxygen therapy (n = 21), there was improvement in exercise tolerance, but no impact on dyspnea.¹⁴⁰ Although oxygenation improved, the improvement was not sustained during exercise, even with the use of the Oxymizer.¹⁴⁰ In a study of patients with severe ILD (n = 25) tested on room air, receiving oxygen therapy via NC at 4 L/min, or receiving HFNC oxygen therapy with an FiO₂ of 50% at 30-50 L/min (heated to 34°C and humidified), those who received HFNC oxygen therapy showed higher endurance time than did those in the other two groups, with HFNC oxygen therapy being associated with delayed oxygen desaturation kinetics, impaired chronotropic response, reduced perception of dyspnea, and reduced ratings of perceived leg fatigue.¹⁴¹ In comparison with an FiO₂ of 21%, hyperoxia (an FiO₂ of 30-60%) resulted in increased endurance time, decreased ventilation, reduced perception of dyspnea,¹⁴² and significantly improved muscle oxygenation as assessed by fatigability, with reduced leg discomfort during exercise.¹²⁷

Although oxygen therapy has been found to increase exercise capacity, a systematic review showed that oxygen therapy has no impact on dyspnea during exercise in patients with ILD.⁵⁷ Because patients with ILD require high oxygen flow rates in many cases, it is important to select the most appropriate oxygen delivery interface (an NC or a simple face mask, for example), and when a higher oxygen concentration is required, other devices should be evaluated, including nonrebreather masks and HFNC, the latter being selected and used in accordance with institutional protocols.

PH

The benefits and safety of PR in patients with PH have been reported, particularly in the last 15 years. In the guidelines for PR in patients with PH,¹⁴³ based on published protocols, oxygen was delivered as needed, and desaturation was considered an adverse event in 16 (2.4%) of the 674 patients included in the study. In an evaluation of 519 patients included in different studies, exercise training was generally based on ~60% of the maximum HR (which should not exceed 120 bpm) and an SpO₂ > 85-90%. An oxygen desaturation of < 85-90% or an HR > 120 bpm were used as criteria to adjust training intensity, resulting in early exercise termination or a reduction in training intensity.^144,145

OXYGEN DURING AIR TRAVEL

Commercial aircraft flights can reach altitudes of up to 45,000 feet (13,716 m), resulting in major reductions in barometric pressure and PaO₂.¹⁴⁶ Aircraft cabins are pressurized to an altitude of 8,000 feet (2,438 m), and, at this altitude, FiO₂ inside the aircraft is 15.1%; in a healthy individual, depending on his/her age and minute ventilation, PaO₂ and SaO₂ decrease to 60-75 mmHg and 89-94%, respectively.^146-148

In situations of hypobaric hypoxia, an adequate PaO₂ is maintained through an increase in minute ventilation, HR, and cardiac output, as well as pulmonary vasoconstriction with redistribution of blood flow to apical regions, affecting V/Q. Although most individuals tolerate these changes well, some can experience dyspnea, sleepiness, cognitive changes, fainting, and chest pain.

Patients with chronic lung disease, especially those on LTOT or with borderline SpO₂ levels, as well as patients with other diseases that are accompanied by hypoxemia, will experience worsening hypoxemia and can present with clinical manifestations during flights.^147-150 Therefore, patients at risk of hypoxemia during air travel should be evaluated for the need for oxygen therapy. The use of LTOT, the presence of comorbidities, and reports of respiratory symptoms such as dyspnea, cough, and chest pain during previous flights should be investigated. Patients should only travel when they are in a stable phase of their disease.¹⁴⁸ In addition, during flights, passengers remain immobile for long periods of time and are exposed to low temperatures and dry air, all of which are factors that increase the risk of exacerbations and other complications, such as venous thromboembolism, thus reinforcing the importance of maintaining an adequate SpO₂ during air travel.¹⁵¹

Patients with an SpO₂ > 95% on room air can fly without supplemental oxygen; however, those with an SpO₂ of ≤ 92% should receive supplemental oxygen during air travel. Patients with an SpO₂ between 92% and 95% should undergo a 6MWT or a hypoxia altitude simulation test, the latter being rarely available in Brazil. Patients in whom SpO₂ remains ≤ 84% during either of the aforementioned tests will also require supplemental oxygen during air travel.^149,150 A hypoxia altitude simulation test simulates an aircraft cabin with decreased barometric pressure and FiO₂. Ideally, the test should be performed in a hypobaric chamber; however, hypobaric chambers are scarcely available, and test results are unreliable when the test is performed in a normobaric chamber.^149,150

Patients who require an oxygen flow rate > 4 L/min in order to correct hypoxemia should be discouraged from flying, and, if they do fly, they should use aeromedical transport.¹⁵¹ It is of note that these recommendations are primarily based on studies of patients with COPD and are extrapolated to other respiratory diseases.^152,153

After performing an evaluation, the attending physician must fill out a Medical Information Form, which is provided by airlines and which, in addition to including other relevant information, states that the patient is fit to fly provided that he/she receives the required oxygen flow rate. The form should be filled out at least 72 h before the flight so that there is enough time to submit it to the airline. Patients should plan their trips in advance because time for approval varies across companies.^151-153

On the aircraft, oxygen therapy can be delivered via oxygen supplied by the airline (an oxygen cylinder or concentrator) or via the patient’s own portable oxygen concentrator, provided that it has been approved for in-flight use. While staying at airports, patients must use their own portable oxygen concentrators. The Brazilian Agência Nacional de Aviação Civil (National Civil Aviation Agency) has recently published supplementary guidelines on the use of portable oxygen concentrators on commercial aircraft.¹⁵⁴ The most important points are as follows: only brands approved for in-flight use are allowed; neither concentrators nor batteries can be checked at the airline counter; and batteries must be enough to power a concentrator for at least 150% of the duration of the flight. Unfortunately, commercial airlines do not have homogeneous rules regarding how the aforementioned form should be or the supply of oxygen. Attending physicians must seek information on company policies and procedures in order to provide appropriate patient guidance (Chart 9 and Figure 1).

PRECAUTIONS WHEN PRESCRIBING LTOT

Some precautions should be taken when prescribing LTOT. Patients should receive continuing education and training in oxygen device use, safety, and self-management. Physicians prescribing LTOT should be prepared to do the following: a) determine the objective of and need for LTOT by means of arterial blood gas analysis; b) fill out reports correctly and adhere to municipal or state protocols; c) select a qualified supplier of durable medical equipment; d) titrate oxygen on different occasions (e.g., at rest, during activities of daily living, during sleep, on exertion/during exercise, during trips, and during exacerbations) in order to determine the oxygen flow rate required to maintain an SpO₂ > 90%; e) test the flowmeter, because the oxygen flow rate being displayed might be different from that which is actually being supplied; f) prescribe the most appropriate oxygen flow rate for each specific situation, the minimum duration of use, a variety of sources of oxygen supply, and necessary accessories; g) reassess periodically the need for LTOT for prescription renewal/change; and h) educate patients and their families on the correct use of LTOT, focusing on the importance of treatment adherence. The recommendations are summarized in Charts 1-7 (on practical aspects of prescribing oxygen) and Chart 8 (on the protocol for prescribing oxygen), as well as in Chart 9 and Figure 1 (on air travel).

FINAL CONSIDERATIONS

The use of LTOT became widespread beginning in the 1980s. Despite the scarcity of studies and the number of unanswered questions, the benefits of LTOT were quickly disseminated, and several pulmonology societies around the world began to recommend the use of LTOT. The recommendations herein reflect an integration of current and previously established evidence-with LTOT being prescribed for patients with severe resting hypoxemia in order to improve survival and quality of life-supported by studies of patients with COPD. Existing evidence suggests that LTOT should not be prescribed for COPD patients with moderate resting hypoxemia. Oxygen prescription for ILD patients with severe resting hypoxemia is strongly recommended. Evidence is still lacking on the role of LTOT in other lung diseases, such as PH, and on the use of LTOT during sleep and during physical activity. Future studies should evaluate the safety of the shared decision between patients and their physicians regarding LTOT and the best approach to discontinuing LTOT in patients without severe resting hypoxemia.

It should be noted that LTOT programs have high costs and that it is important to prescribe LTOT correctly so that patients can really benefit from it, achieving the expected results in the medical, social, work, and family realms.^6,19,20,25 We analyzed in detail the recommendations in the three most recent international guidelines on LTOT,^6,20,25 and they are summarized in Chart 10. Although we agree with the recommendations, we emphasize the need for further studies, particularly those focusing on chronic diseases other than COPD.

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• Financial support:

  None.

Publication Dates

• Publication in this collection
  04 Nov 2022
• Date of issue
  2022

History

• Received
  20 May 2022
• Accepted
  31 Aug 2022