|
REVIEW ARTICLE |
https://doi.org/10.5005/jp-journals-11007-0016
|
Approach to Optimal Oxygen Therapy in the Management of COVID-19 Patients during Pandemic: An Indian Perspective
1Department of Pulmonary Medicine, Shri Lal Bahadur Shastri Medical College and Hospital, Mandi, Himachal Pradesh, India
2Atal Medical and Research University, Mandi, Himachal Pradesh, India
Corresponding Author: Surender Kashyap, Atal Medical and Research University, Nerchowk, Mandi, Himachal Pradesh, India, Phone: +91 9988882615, e-mail: vcmedicaluniv.mandi@gmail.com, surenderkashyap@hotmail.com
How to cite this article: Bhardwaj M, Kashyap S. Approach to Optimal Oxygen Therapy in the Management of COVID-19 Patients during Pandemic: An Indian Perspective. Indian J Chest Dis Allied Sci 2022;64(2):114–123.
Source of support: Nil
Conflict of interest: None
Received on: 15 July 2021; Accepted on: 15 December 2021; Published on: 10 June 2022
ABSTRACT
Background: A sudden spike in positive cases in the second wave of COVID-19 pandemic took Government, Public, and Healthcare system by surprise in India. It was bigger and deadlier than the first wave. Unsupervised oxygen delivery practiced in oxygen buses and pandals by untrained individuals was a matter of concern and should have been discouraged. This resulted in wastage of oxygen which could have led to catastrophic consequences. Awareness about the optimal use of oxygen by identifying errors in prescribing/practicing oxygen therapy will go a long way in saving lives. This article provides a quick review of oxygen therapy with a focus on the rationale use of oxygen and plausible solutions to mitigate wastage in a resource-constrained scenario, such as the COVID-19 pandemic.
Keywords: Awareness, COVID-19, Crisis, Oxygen, Rationale, Solutions.
ABBREVIATIONS USED IN THIS ARTICLE
CXR = Chest radiography; HRCT = High-resolution computed tomography; GGOs = Ground-glass opacities; LFNC = Low-flow nasal cannula; HFNC = High-flow nasal cannula; VM = Venturi-masks; SFM = Simple face mask; PRM = Partial rebreathing mask; NRM = Non-rebreathing mask; NIV = Non-invasive ventilation; NIPPV = Non-invasive positive pressure ventilation; Hb = Hemoglobin; ABG = Arterial blood gas analysis; FiO2 = Fraction of inspired oxygen; PaO2 = Provides accurate estimate of oxygenation; PaCO2 = Partial pressure of arterial carbon dioxide; SpO2 = Arterial oxygen saturation; CO2 = Carbon dioxide; LPM = Liters per minute; B/M = Breaths per minute; LTOT = Long-term oxygen therapy; ARDS = Acute respiratory distress syndrome; COPD = Chronic obstructive pulmonary disease; CPAP = Continuous positive airway pressure; BiPAP = Bi-level positive airway pressure; PEEP = Positive end-expiratory pressure; IPAP = Inspiratory positive airway pressure; COVID-19 = Coronavirus disease 2019; VT = Tidal volume; PBW = Predicted body weight; VV ECMO = Veno-venous extracorporeal membrane oxygenation; MV = Mechanical ventilation; ICU = Intensive care unit; psi = pressure per square inch; CO-RADS = COVID-19 reporting and data system; RAT = Rapid antigen test; RT-PCR = Real-time reverse transcriptase-polymerase chain reaction; ROX index = Respiratory rate-oxygenation index; RR = Respiratory rate; P-ox = Pulse oximetry; STP = Standard treatment protocol; WHO = World Health Organization
INTRODUCTION
The second wave of coronavirus disease 2019 (COVID-19) pandemic hit India in the middle of March 2021, overwhelming the healthcare system of the country. India became the new epicenter of the COVID-19 pandemic with more than 29 million cases recorded by the second week of April 2021, second only to the United States. The majority of patients who landed in hospitals were in a severe or critical stage of illness and required high flow oxygen round the clock resulting in an acute shortage of critical drugs and oxygen.1 Optimum delivery of oxygen is vital to save patients with acute respiratory failure. As per the Annual Report of the Ministry of Health and Family Welfare, Government of India 2020–2021, 15375 dedicated COVID-19 facilities with 151,821 dedicated isolation beds including oxygen supported beds were identified, i.e., 80583 intensive care unit (ICU) beds including 40,545 ventilator beds were allocated for COVID-19 patients.2 In a study, Kapoor et al.3 suggested that the potential requirement of ICU beds in 2020 was 2.8 times the current numbers. The estimated bed: patient ratio in public hospitals is 0.55 per 1000 people in 12 states comprising 70% population of India. State-wise distribution of ICU facilities is skewed and dismally poor at the district level, and so is the availability of oxygen supply.3,4 There is an urgent need to upgrade medical facilities with oxygen support in the country to meet the exuberant demand of oxygen in such an unprecedented pandemic situation.
Steps, like the installation of pressure swing adsorption oxygen plants, diverting industrial oxygen to medical use, and importing oxygen from foreign lands were undertaken in order to improve the availability of oxygen.5 In May 2021, National Task Force was formed by the Supreme Court of India to ensure rational and equitable distribution of oxygen to all States/Union Territories.6 Unsupervised oxygen delivery in oxygen buses and pandals may not only harm patients but would also lead to the wastage of limited resources. Though medical oxygen has been in use since 1950s, the evidence so far suggests that the understanding of usage of the oxygen is poor among healthcare staff too.7 This work brings a quick review of the basics of oxygen therapy, barriers to optimal use, and plausible solutions in the context of the COVID-19 pandemic in resource-limited settings.
COVID-19 and the Lungs
COVID-19 is a communicable disease spread mainly by droplets and aerosols through airborne routes. The causative agent is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is an enveloped, positive-sense single-stranded ribonucleic acid virus belonging to the human Betacoronavirus family, Nidovirales order, and Sarbecovirus subgenus. The incubation period of COVID-19 infection ranges from 5 to 15 days (average 4–5 days), and its basic reproduction number (Ro) is 2–2.5. It primarily affects the lungs but can involve any organ. Commonly, patients of COVID-19 present with complaints of dry cough, breathlessness, body aches, and loss of taste and smell. The clinical spectrum of COVID-19 is wide (Table 1). COVID-19 reporting and data system (CO-RADS) score of ≥4 out of 6 on computed tomography (CT) thorax correlates well with COVID-19 illness. Other tests include raised D-dimer levels, increased neutrophil/lymphocyte ratio, and raised inflammatory markers, such as C-reactive protein, lactate dehydrogenase, ferritin, and interleukin-6 (IL-6). The pathogenesis is not fully understood. The SARS-CoV-2 virus has an affinity to angiotensin-converting enzyme-2 (ACE-2) receptors, commonly found in ciliated nasal epithelial cells and alveolar type II cells and other tissues including the heart, endothelium, kidney, and intestine. Alveolar flooding together with uncontrolled complement-mediated vasculitis and microthrombi formation in pulmonary vessels results in a profound ventilation perfusion mismatch. Histopathological assessment of lung specimens reveals diffuse alveolar damage, fibrin-rich hyaline membrane formation, and type II pneumocyte hyperplasia.8–10
| Severity of disease | Asymptomatic/Mild (Stage I: Infective phase) | Moderate (Stage II: Pulmonary phase) | Severe (Stage III: Hyper-inflammatory phase) |
| Clinical presentation | Fever, cough, myalgia, loss of smell, and taste RR: 12–16 B/M* (Adults) SpO2 ≥95% CXR: usually normal |
Dyspnea appears Hypoxemia present RR: ≥24 SpO2 = 90–94% CXR: bilateral opacities Peripheral and sub-pleural mostly Middle and lower lobes involved |
Dyspnea worsens Profound hypoxemia Complications: ARDS, septic shock, encephalopathy, heart failure, AKI, and DIC RR: >30 SpO2 <90% CXR: Diffuse infiltrates HRCT thorax: GGOs, crazy-paving, reverse halo |
| Timeline (Days) | 0–5 | 5–10 | >10 onwards |
| Preferred O2 delivery device | Nil | LFNC with miniature reservoirs SFM | VM/NRM HFNC/NIV Mechanical ventilation |
Surprisingly, many patients of COVID-19 reported little or no discomfort despite incidental findings of low oxygen saturation on pulse oximetry. In a study on 1099 hospitalized COVID-19 patients, Guan et al.11 found that only 18.6% of patients reported dyspnea, although a number of patients had abnormal CT (86%) and low PaO2/FiO2 (partial pressure of arterial oxygen/fraction of inspired oxygen) ratios with a common need for supplemental oxygen therapy (41%). Huang et al.12 reported similar findings.12 This phenomenon has been named as “happy hypoxemia”. Patients often delay hospital appointments and land up later in the critical stage.13,14 Clinicians should remain vigilant and any fall in oxygen saturation should prompt initiating of immediate appropriate care.
Chain of Oxygen Wastage
During the second wave of the COVID-19 pandemic, it was particularly observed that patients reported to a health facility when they were critically sick with their oxygen levels dangerously low. There is a chain of potential oxygen wastage in pre-hospital and hospital settings which needs to be identified and corrected.15,16
Inadequate knowledge of oxygen therapy results in sub-optimum management at dedicated COVID-19 care center (DCCC) and subsequent unnecessary referrals to dedicated COVID-19 health center/dedicated COVID-19 hospital (DCHC/DCH).
The problem continues during transportation as the ambulance healthcare team is often unskilled. The quality of oxygen therapy is usually sub-optimal in ambulances, especially for chronic obstructive pulmonary disease (COPD) patients.
Improper handling of oxygen cylinders (regulators/flow-meters) by untrained hospital staff while shifting patients from ambulance to wards and thereafter can cause significant oxygen leaks.
Besides, doctors pooled in from different specialties for COVID-19 duties would have little or no training/work experience in oxygen therapy in critical care.
Data regarding oxygen delivery practices during the COVID-19 pandemic is scarce. However, a review of the literature, including the notable British Thoracic Society audit 2015,7 revealed that oxygen is often delivered unsupervised and without a clear prescription. In a study in the United Kingdom, 20% of 1000 COPD patients presented with respiratory acidosis to the hospital because of improper pre-hospital oxygenation.17 In another series of 254 patients coming via ambulance with acute exacerbations of COPD, the odds of serious adverse outcomes with hyperoxemia with normoxemia was 9.2% compared to only 2.8 for hypoxemia.18 Improved oxygen prescription practices can result in optimal oxygen delivery to patients.
Preparedness for Future Waves of Pandemic
The multi-component remedial measures to improve oxygen delivery practice are as follows:
At the Level of Institution (Fig. 1)
Education sessions in the form of seminars/posters/simulation workshops should be conducted to give hands-on training about oxygen delivery devices to the healthcare team.19
COPD patients can be allotted “oxygen alert stickers” along with venturi-masks (VM) @ FiO2 of 0.24–0.28 to prevent hypercapnia.16
Separate oxygen order chart which clearly states details of oxygen therapy, like indication, target oxygen saturation, delivery device, total duration, and schedule of intermittent monitoring.20
Daily oxygen audit by hospitals.
Anticipatory storage of oxygen to meet patient demands for at least 72 hours.
Public should be educated about oxygen monitoring via pulse oximetry and safe use of oxygen cylinders/concentrators at homes through posters/videos on social media platforms preferably in the vernacular language or via virtual outpatient departments (OPDs).
Patients, attendants, healthcare workers, and the public should be sensitized about the side effects of uncalibrated oxygen therapy and complications like fire/explosion through counseling/posters.16,19
At the Level of Government
Raising public awareness regarding safe oxygen use, installation of oxygen plants preferably near hospitals/healthcare centers, and judicial measures to stop hoarding/black marketing of oxygen cylinders/concentrators.
Oxygen Therapy
In 1798, Thomas Beddos21 documented the medical use of oxygen for treating conditions, like asthma and congestive heart failure. He was later conferred the title of Father of Respiratory Therapy.21 The common indication of oxygen therapy is respiratory failure leading to hypoxemia, in conditions, such as asthma, COPD, cystic fibrosis, bronchopulmonary dysplasia, heart failure, obstructive sleep apnea, and pneumonia.22
Hypoxemia is an independent risk factor for poor outcomes in COVID-19 patients regardless of the cause.11,12,23 The goal of oxygen therapy is to correct hypoxemia which subsequently relieves dyspnea. As per the latest World Health Organization (WHO) COVID-19 guidelines, updated on 25 January 2021, supplementary oxygen therapy is recommended to any patient with emergency signs (severe respiratory distress, absent breathing, central cyanosis, shock, coma, or convulsions) during resuscitation to reach the target SpO2 of ≥94% and to any otherwise stable hypoxemic patient to reach target arterial oxygen saturation (SpO2) of >90% or ≥92–95% in a pregnant woman. Lower oxygen targets of SpO2 88–94% are reserved for patients with COPD who are at risk of developing hypercapnia in the setting of uncontrolled oxygen therapy.23 Pulse oximetry and arterial blood gas (ABG) analysis are common tools to assess the oxygenation status of the patient.
Pulse Oximetry
Pulse oximeter is a portable, cost-effective, easy-to-use device that measures the percentage of hemoglobin (Hb) saturated with oxygen non-invasively. It works on the Lambert–Beer principle, which utilizes differential absorption patterns of oxyHb and deoxyHb at two wavelengths of 660 nm (red) and 940 nm (infra-red), respectively, in a pulsatile arterial blood flow. SpO2 determined by pulse oximeter is within 2–4% of actual oxygen status of arterial blood PaO2.24 Formula proposed by Madan25 can aid clinicians to gauge PaO2 status by looking at SpO2 values on the monitor, especially in critically ill patients. The latest data suggested that pulse oximetry played a crucial role in the early detection of silent hypoxemia and timely intervention during the COVID-19 pandemic both in ICUs and at home.26,27 Pulse oximeter has its pitfalls too. It can give false readings in the presence of skin pigmentation, polished nails, hypotension, peripheral vasoconstriction, abnormal Hb like carboxyhemoglobin and methemoglobin, anemia, and motion artifacts.24,27
Arterial Blood Gas Analysis
Arterial blood gas analysis provides an accurate estimate of the oxygenation (PaO2), ventilation (PaCO2), and acid–base (pH) status of the patient. It is superior to pulse oximetry in deciding intervention and ventilatory management in critically ill patients.
Hypoxemia (arterial partial pressure of oxygen; PaO2 <60 mm Hg) is a weak stimulus for a respiratory drive unless associated with hypercapnia (PaCO2 >40 mm Hg). Resultant respiratory alkalosis owing to increased minute ventilation causes a leftward shift of Bohr’s hemoglobin-oxygen dissociation curve resulting in increased affinity of Hb for oxygen, accordingly for a given PaO2, SpO2 depicted by pulse oximetry becomes high. Therefore, in COVID-19 patients, ABG analysis for the estimation of PaO2 is more appropriate than non-invasive monitoring of SpO2 by a pulse oximeter. It is advisable to undertake intermittent ABG analysis in ICU patients to determine the exact oxygenation status, especially in resource-constrained countries.24,28
Oxygen Delivery Systems
Oxygen is produced by fractional distillation of air in large volumes for commercial purposes. Another method for small-scale production is via oxygen concentrators for limited use. The third method is through pressure adsorption plants (PSA), where nitrogen is absorbed from ambient air to concentrate oxygen for the hospital supply. It is stored in gaseous form under pressure or liquid form at very low temperatures in cylinders and tanks.
Industrial oxygen was diverted for medical use during the second wave of the COVID-19 pandemic in the face of oxygen crises. Though industrial oxygen contains 99.5% v/v oxygen, it differs in quality, content, and purity when compared to medical oxygen. Therefore, there is a possibility of microbial and gaseous/particulate matter contamination. So, industrial oxygen is not intended for human use unless strict parameters for impurities and moisture control are applied vigilantly.29,30 The International Pharmacopeia and WHO recently issued technical specifications of oxygen purity (v/v oxygen) according to the method of production; air liquefaction process: ≥99.5%, PSA plants: 93% ± 3, and oxygen concentrator: >82% which should be strictly adhered to for medical use.30
Oxygen Cylinder
Commonly used oxygen cylinders are B, C, D, E, and G. B type cylinder is made of stainless steel, stores 1200–1500 liter (L) oxygen at a working pressure of 2133.5 pounds per square inch (psi) with working time of 11–12 hours @ 2 L per minute (LPM). D type cylinder stores 7000 L compressed gas at a working pressure of 1900 psi. B and D type cylinders are used for bedside use and central oxygen supply system, respectively. Atlas equation can provide rough estimate of remaining time once cylinder is put to use; 
.
This simple calculation may provide quick information regarding the availability of oxygen in the store at point of care.31
Liquid Oxygen System
Oxygen is often stored in liquid form because storage is less bulky and less extensive than same capacity high pressure gaseous storage. Liquid oxygen is a cryogenic liquid with boiling point of –238°F (–183°C). Liquid oxygen tanks are available in capacities ranging from 2000 L to 150,000 L and are primarily designed to meet oxygen demands at level of hospital/institution. Small portable liquid oxygen canisters last longer than compressed gas oxygen cylinders but are costlier.
Oxygen Concentrator
Oxygen concentrator draws in the room air which is passed through molecular sieve absorbing nitrogen and leaving oxygen with concentration more than 90%. Oxygen concentrators which are of portable and stationary types and are commonly used by patients with low oxygen demands who are on long-term oxygen therapy (LTOT). Stationary concentrators weigh about 10 kg and are safer and relatively cost-effective as compared to compressed gas oxygen cylinders. However, the equipment requires uninterrupted electric supply of about 300 watts/hour and can provide oxygen supply to the tune of 0.5 to 10–15 LPM. Portable miniature oxygen concentrators are smaller in size, less bulky about 4.5 kg, costlier and well suited for patients living active lives with minimum flow requirement up to 2 LPM. There is flexibility with the power source; alternating current or direct current can be used. Oxygen can be delivered either continuously or when the patient initiates breath. Pulse mode of delivery can prevent wastage of oxygen as compared to continuous mode and therefore should be encouraged.22,30
Oxygen Delivery Devices
Oxygen delivery devices are broadly categorized into low- and high-flow delivery systems. Nasal cannula, nasal catheter, and trans-tracheal catheter are low-flow systems with variable performance as FiO2 delivered is variable. Simple face mask (SFM), partial re-breathing mask (PRM), non-re-breathing mask (NRM), reservoir, and tracheostomy mask are categorized as variable-performance devices with reservoir systems. Venturi-mask (VM) and high-flow nasal cannula (HFNC) are high-flow fixed performance devices.31–35 High-flow delivery device unlike low-flow system ensures that the entire oxygen requirement of the patient is met by the device irrespective of his/her inspiratory effort and is not necessarily defined by flow rates. Any of these devices should be introduced at a particular level depending on the respiratory status of the COVID-19 patient and is usually decelerated from HFNC to SFM/NC in a step-wise manner (Table 2, Flowchart 1).
| Device | FiO2and flow rate (LPM) | Merits | Demerits contraindications | Indications/interventions |
|---|---|---|---|---|
| LFNC | 0.24–0.28 and 2–6 | Cheap Patient can eat, drink, and speak No claustrophobia No risk of rebreathing |
Flow rate >4 LPM can cause nasal drying and irritation | Ideal for LTOT and low flow oxygen requirements Used for patients at home isolation Position nasal prongs properly (facing upwards and curved towards face) Prefer nasal cannula with reservoirs |
| SFM | 0.60–0.80 and 6–8 | Good choice for blocked nasal passages Mouth breathers |
Skin irritation Eye irritation Must remove mask to eat Risk of rebreathing at rates less than 5 LPM |
Used for patients at home isolation and hospital for moderate COVID-19 illness Proper fitting of mask |
| VM Green Red Orange Yellow White Blue |
0.60 and 15 0.40 and 10 0.35 and 8 0.31 and 8 0.28 and 6 0.24 and 4 |
Most reliable and accurate delivery of fixed FiO2 | Skin irritation Eye irritation Must remove mask to eat |
Used for hospitalized patients with high oxygen requirements VMs (0.24–0.28) are suited to patients with CO2 retention like COPD Ensure flow rates as per protocol |
| NRM | 0.80–1.0 and 10–15 | Meets high flow oxygen needs | Skin irritation Eye irritation Must remove mask to eat |
Use proper fitting mask and flow rate as prescribed Reservoir bag should be inflated at all times Frequent assessment and titration needed Avoid removing mask intermittently for toiletry needs |
| NIV | CPAP BiPAP |
Decrease work of breathing CO2 washout |
Skin/eye irritation Aerophagia Clautrophobia Must remove mask to eat Intolerance to high pressures common Poor compliance |
Most useful in hypercapnic respiratory failure Ensure proper fit to avoid air leaks Intermittent use can improve compliance Frequent bedside assessment required |
| HFNC | 0.95–1.0 and 15–60 | Reliable delivery of FiO2 Meets high flow oxygen needs Patient can eat, drink, and speak |
Tolerance issues Compliance issues |
Most useful in hypoxemic respiratory failure Can substitute NIV in case of poor tolerance Frequent assessment and titration neede |
Low-flow nasal cannula is a plastic disposable device containing two tips or prongs roughly 1 cm long and connected to oxygen tubing. It is placed in the vestibule of nose and secured in place with help of a plastic strap. It operates at oxygen flow rates from 1 to 6 LPM and FiO2 range of 0.24–0.44. In a patient with a normal ventilatory pattern, each LPM increase in nasal oxygen supply increase FiO2 by approximately 4%. Nasal cannula with miniature reservoirs in the form of moustache and pendant are available to economize oxygen delivery. The reservoir fills with oxygen during exhalation and delivers it during inhalation. However, it has some disadvantages, such as nasal trauma, mucosal irritation, easy dislodgement, and FiO2 delivered can be inconsistent. The nasal cannula is mostly suited for low oxygen requirements and can be used at home for patients on LTOT. Nasal cannula with miniature reservoirs can be utilized in the current COVID-19 pandemic to minimize oxygen wastage. Also, nasal prongs or cannulas are preferred in young patients for better tolerability.23
Face masks are broadly of two types: simple face masks and face masks with reservoir bags. Simple face mask is a disposable plastic device with oxygen inlet at the base and holes or ports for inhalation and exhalation purposes, respectively. Input flow ranges from 5 to 8 LPM and FiO2 achieved is from 0.40 to 0.60. The volume of reservoir is 20–200 mL and a minimum flow of 5 LPM is required to prevent rebreathing of exhaled air. Simple face mask is easy to apply and good choice for patients with blocked nasal passages and mouth breathers. Furthermore, these face masks have risk of aspiration in unconscious patients and interfere with eating/further airway care. Simple face mask is an ideal oxygen delivery device for patients at home isolation and in hospitals with moderate COVID-19 illness.
Face masks with reservoir bags are high capacity systems which can be used in severe COVID-19 illness with higher oxygen requirements not met by SFM. Non-rebreathing mask can deliver FiO2 of 0.80–0.90 at flow rates of 10–15 LPM. It has a reservoir with 1 L capacity and three unidirectional valves; two expiratory valves on sides of mask and one inspiratory valve between mask and reservoir. The expiratory valves prevent air entrainment and inspiratory valves prevent movement of exhaled gas into the bag. When bag is fully inflated, it can deliver up to 100% pure oxygen.
Venturi masks are air entrainment devices which ensure that a fixed FiO2 is delivered to sick patients. It works on the principal of Bernoulli which states that when gas passes through a narrowed orifice at a rapid velocity, pressure drops to sub-atmospheric levels resulting in entrainment of air from surroundings into the mainstream flow. Venturi mask is supplied by color-coded adapters that change the rate of oxygen flow passing the air entrainment port, thereby influencing the amount of room air (FiO2 21%) entrained to deliver fixed FiO2. Most recent VMs have adjustable air entrainment ports. Oxygen to air entrainment ratio can be
calculated using a formula or magic box tool;
this formula use percent FiO2 instead of decimal, i.e., 21 instead of 0.21.
The FiO2 delivered depends on the velocity of oxygen jet and size of port, so FiO2 is always less than 100%. A 4% increase in FiO2 from 24% onwards with increase in flow ranging from 4 to 15 LPM; max FiO2 = 60%. Venturi masks (FiO2 0.24–0.28) are best suited for COVID-19 patients with carbon dioxide retention among COPD patients, wherein overzealous oxygen therapy can worsen hypercapnia.22,32–34
High-flow nasal cannula
There has been dramatic rise in the use of high-flow nasal cannula during COVID-19 pandemic. Guy et al.35 advocated that HFNC can benefit COVID-19 patients with non-hypercapnic acute hypoxemic respiratory failure outside the ICU setting. Several other studies have suggested that putting patients on HFNC can delay/avoid intubations, thereby not only decreasing poor outcomes associated with invasive ventilation but also helps to divert critical care resources to the needy. Furthermore, patients using HFNC can feed and communicate freely.35,36 Inadequate heating and humidification of air can produce discomfort and poor compliance. Concerns of increased risk of infection to healthcare workers has been largely refuted by the experts on the basis of 2012 analysis on SARS patients.37 Respiratory rate-oxygenation index (ROX index; formula: SpO2/FiO2/respiratory rate), a simple bedside test, has a role in guiding therapy in COVID-19 pneumonia. If ROX values are ≥4.88 at 2, 6, or 12 hours of HFNC initiation, odds of HFNC success are high with 95% confidence interval and P value <0.001 individually.38,39 In an unblinded clinical trial in patients with acute hypoxemic respiratory failure without COVID-19, Ni et al.40 reported that there was a significantly greater reduction in intubation rate and ICU mortality with HFNC as compared to non-invasive ventilation (NIV). Data regarding the role of HFNC as primary therapy in hypercapnic respiratory failure is emerging. It can be used as an alternative therapy where intolerance to NIV is a concern.41
*High-flow nasal cannula is a high flow oxygen blender system that can supply 100% pure humidified oxygen at a flow rate of 8 LPM in infants and up to 60 LPM in adults. It dilates nasopharyngeal airways by pressing from the interior outwards, thereby decreasing airway resistance and improving thoraco-abdominal synchrony. The FiO2 achieved is higher with patient keeping their mouth open. Properly heated and humidified gas at high flow rates washes out CO2, decreases dead space, recruits alveoli to increase end-expiratory lung volume, has a positive end-expiratory pressure effect, and thus, leads to increased tidal volume. The augmentation in lung volume was consistent in both supine and prone positions in COVID-19 patients.41,42 Recently, the Ministry of Health and Family Welfare Government of India in their updated National clinical management protocol for COVID-19 stated that initially flow rate can be set at 20–30 LPM with FiO2@ 40% (can be increased up to 100%) and can be titrated by 5–10 LPM increments to achieve desired SpO2.42
Non-invasive Ventilation
Non-invasive ventilation refers to the delivery of positive pressure ventilation in the absence of an artificial airway, like an endotracheal tube or tracheostomy. Non-invasive ventilation decreases morbidity and mortality in patients with acute hypoxemic respiratory failure. The use of NIV has shown promising results in weaning critically ill adult patients off the mechanical ventilator.43 It has become the standard of treatment in COPD patients with acute respiratory failure leading to acute or acute chronic respiratory acidosis. Non-invasive ventilation guidelines44 have listed other indications, such as cardiogenic pulmonary edema, post-operative respiratory failure, and immunocompromised patients. WHO has recommended to use HFNO/NIV only in selected COVID-19 patients with mild acute respiratory distress syndrome (ARDS) under close monitoring with proper airborne precautions.23 Fu et al.45 have reported that PO2/FiO2 <200 mm Hg 1–2 hours after initiation of NIV is an independent risk factor for intubation in COVID-19 patients with acute hypoxemic respiratory failure.
The latest evidence-based guidelines for use of oxygen delivery devices in the context of the current COVID-19 pandemic are illustrated in Table 3.23,42,46 An approach to estimate daily oxygen requirement in a hospital, citing an example of 100 bedded ICU is illustrated in Table 4.
| COVID-19 treatment guidelines: WHO; published March 2021 | |
| Recommendations | |
| Non-mechanically ventilated patients with mild ARDS | |
| 1. | Immediate use of supplemental oxygen to any patient with emergency signs (severe respiratory distress, absent breathing, central cyanosis, shock, coma, or convulsions) during resuscitation to reach target SpO2 ≥94% and to any stable hypoxemic patient to reach target SpO2 >90% or ≥92–95% in pregnant women* |
| 2. | Deliver oxygen flow rates using appropriate delivery devices.*Nasal prongs or nasal cannula is preferred in younger children for better tolerability reasons* |
| 3. | In severely ill hospitalized patients on HFNC or NIV, prone ventilation is suggested# |
| 4. | Cautious fluid management in absence of shock; aggressive fluid therapy may worsen oxygenation* |
| 5. | Positioning like high supporting sitting may improve oxygenation in adults* |
| 6. | HFNC or NIV (CPAP/BiPAP) may be used only in selected patients with mild ARDS under close monitoring. Do not use HFNC in patients with hypercapnia, hemodynamic instability, abnormal mental status, or multi-organ failure, however, HFNC may be safe in mild-moderate and non-worsening hypercapnia. HFNC, NIV, including CPAP should be used with airborne precautions because of uncertainty around potential for aerosolization.# |
| 7. | NIV guidelines make no recommendation on use in hypoxemic respiratory failure apart from cardiogenic pulmonary edema, post-operative respiratory failure, early NIV for immunocompromised patients or pandemic viral illnesses, like SARS and pandemic influenza# |
| Mechanically ventilated patients with moderate-to-severe ARDS | |
| 1. | Prompt recognition and immediate intubation to be attempted by experienced personnel if the patient deteriorates or fails to improve after 1 hour of HFN trial. Pre-oxygenate with 100% FiO2 for 5 minutes using facemask with reservoir bag preferably. Avoid bag-valve-mask ventilation to reduce exposure to aerosols* |
| 2. | Follow conventional ARDS net protocol using VT (4–8 mL/kg predicted body weight, PBW in adults; 3–7 mL/kg in children) and lower inspiratory pressures (plateau pressure <30 cm H2O in adults; <28 cm H2o in children). Low target pH is permitted (<7.15 in adults; 7.15–7.30 in children)* |
| 3. | In adult patients with severe ARDS, prone positioning is recommended for 12–16 hours per day. *Little evidence on prone positioning in pregnancy; women in the third trimester may benefit in the left lateral decubitus position |
| 4. | In moderate-severe ARDS, higher PEEP and recruitment maneuvers are suggested. #Maximal PEEP in younger children is 15 cm H2O |
| 5. | Consider referral to center with expertise in ECMO if the patient does not respond to lung-protective ventilation; PaO2/FiO2 <50 mm Hg for 3 hours or <80 mm Hg for 6 hours# |
| National Clinical Management Protocol: COVID-19, Government of India, Ministry of Health and Family Welfare; Updated May 2021 | |
| Recommendations | |
| 1. | Target SpO2 92–96%, 88–92% in patients with COPD |
| 2. | The devices used for administering oxygen include nasal prongs, a simple face mask, masks with a breathing or non-breathing reservoir bag. The choice of device depends on the increasing requirement for oxygen therapy |
| 3. | N-95 mask should be applied if nasal prongs or HFNC is used |
| 4. | In refractory hypoxemic respiratory failure short trial (1–2 hours) of HFNC may be considered. In case of worsening of hypoxemia, immediate tracheal intubation is attempted |
| 5. | Mechanical ventilation; in adults: Start with low tidal volumes 6 mL/kg PBW with a maximal limit of 8 mL/kg PBW allowed if no side effects occur (pH <7.15, dysynchrony) and lower inspiratory pressures (plateau pressure <30 cm H2O) |
| 6. | Permissive hypercapnia allowed with pH goal of 7.15–7.30 |
| 7. | Proning may be considered as rescue therapy. In severe ARDS, 16–18 hours per day proning is recommended |
| Surviving Sepsis Campaign Guidelines, National Institutes of Health COVID-19 Research; Updated January 2021 | |
| The Panel Recommends | |
| Target SpO2 not more than 96%; start supplemental oxygen if SpO2 <90%* | |
| Non-mechanically ventilated adults with hypoxemic respiratory failure | |
| 1. | HFNC oxygen over NIPPV if no improvement on conventional oxygen therapy# |
| 2. | Closely monitored trial of NIPPV if HFNC is not available# |
| 3. | Early intubation should be performed by an experienced practitioner in a controlled setting if required* |
| 4. | No recommendation on use of awake proning in view of lack of sufficient evidence |
| 5. | No recommendation on use of helmet NIPPV or mask NIPPV |
| Mechanically ventilated adults with ARDS | |
| 1. | Use low VT ventilation (4–8 mL/kg of PBW) over higher VT ventilation (>8 mL/kg PBW)* |
| 2. | Target plateau pressures of <30 cm H2O* |
| 3. | Conservative fluid strategy over liberal fluid strategy# |
| 4. | No routine use of inhaled nitric oxide# |
| 5. | Use higher PEEP strategy (>10 cm H2O) over lower PEEP strategy and monitor for barotrauma* |
| 6. | Prone ventilation for 12–16 hours per day over no prone ventilation in moderate–severe ARDS# |
| Mechanically ventilated adults with severe ARDS and hypoxemia despite optimized ventilation | |
| 1. | Use recruitment maneuvers. #Avoid incremental PEEP maneuver* |
| 2. | Use inhaled pulmonary vasodilator as a rescue therapy; taper if no rapid improvement in oxygenation# |
| 3. | Use VV ECMO if available or refer to ECMO center# |
| Patient on SFM FiO2 = 28% @ 6 LPM |
|
| Patient on VM: (Suppose FiO2 60% @ 15 LPM for one bed) |
|
| Patient on NRM @ 14 LPM for one bed |
|
| Patient on HFNC |
| Suppose maximum settings: FiO2 100% Flow @ 60 LPM for one bed |
|
| Patient on NIV/MV @ 12 LPM |
|
| Daily oxygen requirement of 100-bedded COVID-19 hospital |
| Example: 50 SFM + 20 VM + 15 NRM + 5 HFNC + 5 NIV + 5 MV = 4,32,000 + 4,32,000 + 3,02,400 + 86,400 + 86,400 = 13,39,200 L |
|
Pediatric Oxygen Therapy
Children with hypoxemia may present with nasal flaring, inability to drink and feed, grunting, drowsiness, and lethargy. WHO recommends target oxygen saturation ≥94% for children on oxygen therapy.23 The entrainment devices used at high flow rates for adults can act as blenders and can deliver oxygen accurately and effectively in infants and children. These work well with oxygen hoods and masks but not with a nasal cannula, as it offers high resistive loads. Oxygen hoods are used to meet high oxygen requirements FiO2>40% in infants.47,48
Complications of Oxygen Therapy
Administration of supra-physiologic levels of oxygen can result in a multitude of clinical problems, like cough, hemoptysis, dyspnea, dizziness, diaphoresis, seizures, tingling in limbs, blurring of vision, tachycardia, tinnitus, and hearing disturbances. Hypercapnia, carbon-monoxide poisoning, hypoglycemia, cerebrovascular accident, infection, envenomation, or ingestion of toxins are common mimics and should be carefully ruled out before labeling oxygen toxicity. Hyperoxia leads to the formation of reactive oxygen species (ROS) which react with adjoining biological tissues resulting in damage to proteins, lipids, and nucleic acids. ROS-induced oxidative stress ensues in progressive phases of initiation, inflammation, proliferation, and fibrosis depending on the severity of the injury. Exposure time, FiO2, and atmospheric pressure determine the extent of the damage. The pathologic changes of hypoxic acute lung injury (HALI) include alveolar flooding and surfactant disruption resulting in a fall in vital capacity, ventilation-perfusion mismatch, and loss of lung compliance.22,49 High FiO2 (>0.60) for longer periods (≥24 hours) at normal atmospheric pressure (ATA 1) can cause pulmonary toxicity, also known as low-pressure oxygen toxicity or the Lorrain Smith effect. Hyperbaric oxygen therapy (ATA 1.6–4) often results in central nervous system toxicity (also known as the Paul Bert effect). It is commonly reported in oceanic divers who may present with seizures within 30–60 minutes. The incidence of pulmonary symptoms is 5% and central nervous system symptoms is 2% with a seizure rate of 0.6%.50 Recently, tracking methods for oxygen toxicity in the form of cumulative pulmonary toxic dose and unit pulmonary toxic dose have been developed by the University of Pennsylvania, commonly used in the diving community.51 Absorption atelectasis and retinopathy of prematurity are common complications encountered in premature and low birth infants. Patients who smoke while on oxygen therapy often report facial burns. The risk of fire hazards rises tremendously in high-oxygen zones, like respiratory wards/ICUs. The dictum of safe oxygen usage is lowest FiO2 compatible with adequate oxygenation and rapid taper to avoid complications.22,30,32,52
Non-invasive Strategies Supplementing Oxygen Therapy
Prone Positioning
Prone positioning has a potential role in decreasing oxygen demand in COVID-19 patients. It involves repeated alteration in positions from fully prone to right lateral decubitus, semi-fowler’s to left lateral decubitus position every 30 minutes to 2 hours for a total of 16–20 hours a day. A review of the literature showed that it improves drainage of secretions, promotes alveolar recruitment, and allows a more homogeneous distribution of stress and strain. Most of the notable research work including the PROSEVA trial on prone positioning has been on mechanically ventilated patients on sedatives and neuromuscular blockers.53 The scientific evidence about the utility of awake proning in COVID-19 patients is emerging. Caputo et al.54 reported significant improvement in oxygenation (PaO2/FiO2 181 mm Hg in supine position versus 286 mm Hg in prone position) with early self proning in 56 awake non-intubated COVID-19 patients receiving HFNC or non-invasive positive pressure ventilation. However, it was found that the improvement was not sustained and there was no difference in intubation rates among responders and non-responders. Elharrar et al.55 and Sartini et al.56 showed similar findings. A prospective, multicenter, observational cohort study in Spain showed that proning did not reduce risk of intubation.57 Recent meta-analysis by Sryma et al.58 on role of proning in non-intubated patients concluded that no definitive conclusions/consensus could be drawn about the duration and frequency of awake prone positioning that could result in early recovery or lower intubation rates. The latest WHO COVID-19 treatment guidelines23 strongly recommended 12–16 hours prone positioning in mechanically ventilated patients with severe ARDS. It has also been suggested that prone positioning may be used in severely ill hospitalized COVID-19 patients on HFNC or NIV. Contraindications to awake proning include unstable spinal fracture, hemodynamic instability, and recent abdominal surgery. Pregnant patients can lie in left lateral decubitus position or fully prone position.
New Anti-COVID-19 Drugs
Recently, Drugs Controller General of India (DCGI) gave approval to two drugs; 2-Deoxy-D-glucose and Virafin pegylated interferon-alpha 2b for emergency use in patients suffering with moderate to severe COVID-19 illness as additional therapy under supervision. Both the drugs are repurposed drugs and decrease the oxygen requirement of patients. 2-Deoxy-D-glucose is developed by the Institute of Nuclear Medicine and Allied Sciences, a leading laboratory of Defence Research and Development Organisation (DRDO) in collaboration with Dr. Reddy’s Laboratories in Hyderabad. It is available as a powder sachet which can be dissolved in water to be taken twice a day for 5–7 days. The drug collects in virus-infected cells and stops further viral replication. It is proposed to be effective against coronavirus variants too.59 Virafin is administered as a single dose subcutaneous injection. It helps in coping with interferon-alpha deficiency in old patients which happens to be the first-line defense against viral infections.60
CONCLUSIONS
Accurate and proper usage of oxygen therapy is an art that requires extensive evaluation and meticulous execution. Prescription and supervision of oxygen delivery are non-negotiable and can effectively address oxygen shortage in resource-limited countries.19 Optimal and rational use of oxygen will play a pivotal role in saving the lives of COVID-19 patients.
REFERENCES
1. Coronavirus Outbreak in India - covid19india.org. [cited 2021 Aug 1]. Available from: https://www.covid19india.org/.
2. Ministry of Health and Family Welfare, Government of India. Annual Report 2020-2021. Available from: mohwf.nic.in.
3. Kapoor G, Hauck S, Sriram A, et al. State-wise estimates of current hospital beds, intensive care unit (ICU) beds and ventilators in India: are we prepared for a surge in COVID-19 hospitalizations? medRxiv 2020. DOI: 10.1101/2020.06.16.20132787.
4. Bikkina S, Manda VK, Rao UVA. Medical oxygen supply during COVID-19: a study with specific reference to State of Andhra Pradesh, India. Mater Today Proc 2021. DOI: 10.1016/j.matpr.2021.01.196.
5. Update on Medical Oxygen Availability, Delhi. 2021 [cited 2021 Oct 2]. Available from: https://pib.gov.in/PressReleasePage.aspx?PRID=1712123.
6. Supreme Court of India. Supply of Oxygen. 2021 [cited 2021 Oct 2]. Available from: https://main.sci.gov.in/supremecourt/2021/11622/11622_2021_35_35_27915_Order_06-May-2021.pdf.
7. O’Driscoll R. British Thoracic Society Emergency Oxygen Audit Report National Audit Period:15 August-1 November 2015; 2015.
8. Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J 2020;55(4):2000607. DOI: 10.1183/13993003.00607-2020.
9. COVID-19 infection prevention and control guidance|WHO Western Pacific. [cited 2021 Aug 1]. Available from: https://www.who.int/westernpacific/emergencies/covid-19/technical-guidance/infection-prevention-control.
10. Clinical management of COVID-19 patients: living guidance. [cited 2021 Oct 1]. Available from: https://app.magicapp.org/#/guideline/j1WBYn/rec/Lw7OXL (Accessed on 25 January 2021).
11. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020;382:1708–1720. DOI: 10.1056/NEJMoa2002032.
12. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. DOI: 10.1016/S0140-6736(20)30183-5.
13. Dhont S, Derom E, Van Braeckel E, et al. The pathophysiology of ‘happy’ hypoxemia in COVID-19. Respir Res 2020;21(1):198. DOI: 10.1186/s12931-020-01462-5.
14. Tobin MJ, Laghi F, Jubran A. Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care Med 2020;202(3):356–360. DOI: 10.1164/rccm.202006-2157CP.
15. Pilcher J, Cameron L, Braithwaite I, et al. Comparative audit of oxygen use in the prehospital setting in acute COPD exacerbation over 5 years. Emerg Med J 2015;32(3):234–238. DOI: 10.1136/emermed-2013-203094.
16. Cousins JL, Wark PAB, McDonald VM. Acute oxygen therapy: a review of prescribing and delivery practices. Int J Chron Obstruct Pulmon Dis 2016;11:1067–1075. DOI: 10.2147/COPD.S103607.
17. Hale KE, Gavin C, O’Driscoll BR. Audit of oxygen use in emergency ambulances and in a hospital emergency department. Emerg Med J 2008;25(11):773–776. DOI: 10.1136/emj.2008.059287.
18. Cameron L, Pilcher J, Weatherall M, et al. The risk of serious adverse outcomes associated with hypoxaemia and hyperoxaemia in acute exacerbations of COPD. Postgrad Med J 2012;88(1046):684–689. DOI: 10.1136/postgradmedj-2012-130809.
19. Gunathilake R, Lowe D, Wills J, et al. Implementation of a multicomponent intervention to optimise patient safety through improved oxygen prescription in a rural hospital. Aust J Rural Health 2014;22(6):328–333. DOI: 10.1111/ajr.12115.
20. Wijesinghe M, Shirtcliffe P, Perrin K, et al. An audit of the effect of oxygen prescription charts on clinical practice. Postgrad Med J 2010;86(1012):89–93. DOI: 10.1136/pgmj.2009.087528.
21. Heffner JE. The story of oxygen. Respir Care 2013;58(1):18–31. DOI: 10.4187/respcare.01831.
22. O’Driscoll BR, Howard LS, Earis J, et al. BTS guidelines for oxygen use in healthcare. Thorax 2017;72(Suppl 1):43–45. DOI: 10.1136/thoraxjnl-2016-209729:
23. World Health Organization. Clinical Management of COVID-19 Patients: Living Guidance. Geneva: World Health Organization 2021;16:1–309.
24. Sarkar M, Niranjan N, Banyal P. Mechanisms of hypoxemia. Lung India 2017;34(1):47–60. DOI: 10.4103/0970-2113.197116.
25. Madan A. Correlation between the levels of SpO2 and PaO2. Lung India 2017;34(3):307–308. DOI: 10.4103/lungindia.lungindia_106_17.
26. Pulse oximetry to detect early deterioration of patients with COVID-19 in primary and community care settings. Updated 29 January 2021. [cited 2021 Oct 2] Available from: https://www.england.nhs.uk/coronavirus/publication/pulse-oximetry-to-detect-early-deterioration-of-patients-with-covid-19-in-primary-and-community-care-settings/.
27. Luks AM, Swenson ER. Pulse oximetry for monitoring patients with COVID-19 at home: potential pitfalls and practical guidance. Ann Am Thorac Soc 2020;17(9):1040–1046. DOI: 10.1513/AnnalsATS.202005-418FR.
28. Sood P, Paul G, Puri S. Interpretation of arterial blood gas. Indian J Crit Care Med 2010;14(2):57–64. DOI: 10.4103/0972-5229.68215.
29. Indian Medical Association Hospital Board of India. Industrial oxygen vs. medical oxygen.
30. Health Product Policy and Standards. [cited 2021 Dec 10]. Available from: https://www.who.int/teams/health-product-and-policy-standards/access-to-assistive-technology-medical-devices/medical-devices/oxygen.
31. Atlas G. A method to quickly estimate remaining time for an oxygen E-cylinder. Anesth Analg 2004;98(4):1190. DOI: 10.1213/01.ANE.0000107601.21502.0F.
32. Bateman N, Leach R. ABC of oxygen: acute oxygen therapy. BMJ 1998;317(7161):798–801. DOI: 10.1136/bmj.317.7161.798.
33. Hardavella G, Karampinis I, Frille A, et al. Oxygen devices and delivery systems. Breathe 2019;15(3):e108–e116. DOI: 10.1183/20734735.0204-2019.
34. Batool S, Garg R. Appropriate use of oxygen delivery devices. Open Anesthesiol J 2017;11:35–38. DOI: 10.2174/1874321801711010035.
35. Guy T, Créac’hcadec A, Ricordel C, et al. High-flow nasal oxygen: a safe, efficient treatment for COVID-19 patients not in an ICU. Eur Respir J 2020;56(5):2001154. DOI: 10.1183/13993003.01154-2020.
36. Frat J-P, Thille AW, Mercat A. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med 2015;372:2185–2196. DOI: 10.1056/NEJMoa1503326.
37. Tran K, Cimon K, Severn M. Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One 2012;7(4):e35797. DOI: 10.1371/journal.pone.0035797.
38. Fink DL, Goldman NR, Cai J, et al. Ratio of oxygen saturation index to guide management of COVID-19 pneumonia. Ann Am Thorac Soc 2021;18(8):1426–1428. DOI: 10.1513/AnnalsATS.202008-934RL.
39. Roca O, Caralt B, Messika J, et al. An index combining respiratory rate and oxygenation to predict outcome of nasal high-flow therapy. Am J Respir Crit Care Med 2019;199(11):1368–1376. DOI: 10.1164/rccm201803-0589OC.
40. Ni Y-N, Luo J, Yu H, et al. The effect of high-flow nasal cannula in reducing the mortality and the rate of endotracheal intubation when used before mechanical ventilation compared with conventional oxygen therapy and noninvasive positive pressure ventilation: a systematic review and meta-analysis. Am J Emerg Med 2018;36(2):226–233. DOI: 10.1016/j.ajem.2017.07.083.
41. Tan D, Walline JH, Ling B, et al. High-flow nasal cannula oxygen therapy versus non-invasive ventilation for chronic obstructive pulmonary disease patients after extubation: a multicenter, randomized controlled trial. Crit Care 2020;24(1):489. DOI: 10.1186/s13054-020-03214-9.
42. Ministry of Health and Family Welfare, Government of India. Clinical management protocol for COVID-19 (in adults) version 6. Updated 24.05.2021.
43. Burns KEA, Adhikari NKJ, Keenan SP, et al. Use of non-invasive ventilation to wean critically ill adults off invasive ventilation: meta-analysis and systematic review. BMJ 2009;338:b1574. DOI: 10.1136/bmj.b1574.
44. Rochwerg B, Brochard L, Elliott MW, et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J 2017;50:1602426. DOI: 10.1183/13993003.02426-2016.
45. Fu Y, Guan L, Wu W, et al. Noninvasive ventilation in patients with COVID-19-related acute hypoxemic respiratory failure: a retrospective cohort study. Front Med 2021;8:638201. DOI: 10.3389/fmed.2021.638201.
46. Surviving sepsis campaign guidelines on the management of adults with coronavirus disease 2019 (COVID-19) in the ICU recommendation chart: include first updates.
47. Frey B, Shann F. Oxygen administration in infants. Arch Dis Child Fetal Neonatal Ed. 2003;88(2):F84–F88. DOI: 10.1136/fn.88.2.f84.
48. Coghill M, Ambalavanan N, Chatburn RL, et al. Accuracy of a novel system for oxygen delivery to small children. Pediatrics 2011;128(2):e382–e387. DOI: 10.1542/peds.2010-3745.
49. Mach WJ, Thimmesch AR, Pierce JT, et al. Consequences of hyperoxia and the toxicity of oxygen in the lung. Nurs Res Pract 2011;2011:260482. DOI: 10.1155/2011/260482.
50. Cooper JS, Phuyal P, Shah N. Oxygen toxicity. Encycl Respir Med 2021;pp. 282–289.
51. Wingelaar TT, van Ooij PJAM, van Hulst RA. Oxygen toxicity and special operations forces diving: hidden and dangerous. Front Psychol 2017;8:1263. DOI: 10.3389/fpsyg.2017.01263.
52. Budinger GRS, Mutlu GM. Balancing the risks and benefits of oxygen therapy in critically III adults. Chest 2013;143(4):1151–1162. DOI: 10.1378/chest.12-1215.
53. Guérin C, Reignier J, Richard J, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368(23):2159–2168. DOI: 10.1056/NEJMoa1214103.
54. Caputo N, Strayer R, Levitan R. Early self-proning in awake, non-intubated patients in the emergency department: a single ED’s experience during the COVID-19 pandemic. Acad Emerg Med 2020;27(5):375–378. DOI: 10.1111/acem.13994.
55. Elharrar X, Trigui Y, Dols A-M, et al. Use of prone positioning in non-intubated patients with COVID-19 and hypoxemic acute respiratory failure. JAMA 2020;323(22):2336–2338. DOI: 10.1001/jama.2020.8255.
56. Sartini C, Tresoldi M, Scarpellini P, et al. Respiratory parameters in patients with COVID-19 after using noninvasive ventilation in the prone position outside the intensive care unit. JAMA 2020;323(22):2338–2340. DOI: 10.1001/jama.2020.7861.
57. Ferrando C, Mellado-Artigas R, Gea A, et al. Awake prone positioning does not reduce the risk of intubation in COVID-19 treated with high-flow nasal oxygen therapy: a multicenter, adjusted cohort study. Crit Care 2020;24(1):597. DOI: 10.1186/s13054-020-03314-6.
58. Sryma P, Mittal S, Mohan A, et al. Effect of proning in patients with COVID-19 acute hypoxemic respiratory failure receiving noninvasive oxygen therapy. Lung India 2021;38(Suppl 1):S6–S10. DOI: 10.4103/lungindia.lungindia_794_20.
59. Ministry of Defence. DCGI approves anti-COVID drug developed by DRDO for emergency use, Delhi. 2021 [cited 2021 Oct 2]. Available from: https://pib.gov.in/PressReleasePage.aspx?PRID=1717007. (Accessed on May 9, 2021).
60. DBT-BIRAC Supported ‘Virafin’ from Zydus Gets Emergency Nod For Treating Moderate COVID-19 Infections In Adults, Delhi. 2021 [cited 2021 Oct 2]. Available from: https://pib.gov.in/PressReleasePage.aspx?PRID=1713722.
61. Gupta D, Agarwal R, Aggarwal A, et al. Guidelines for diagnosis and management of chronic obstructive pulmonary disease: Joint ICS/NCCP (I) recommendations. Lung India 2013;30:228–267. DOI: 10.4103/0970-2113.116248.
________________________
© The Author(s). 2022 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.