Supplemental oxygen is one of the most commonly prescribed treatments in the hospital. Patients with acute or chronic lung disease depend on supplemental oxygen to stay alive. As a natural and necessary substance, oxygen would seem like a safe thing to prescribe for patients that need it. But sometimes too much of a necessary thing can be harmful. So, when is too much oxygen bad for patients? We can take a lesson from vitamins.
The supplemental vitamin industry is based on the tenet that if our bodies need a small amount of a vitamin to live, then it must follow that by supplementing larger and larger amounts of that vitamin, our bodies will function better and better. Americans love this concept and we spend $30 billion every year on supplements. But frequently, too much of a good thing turns out to be a bad thing. Take Vitamin A – it is necessary for normal health and without vitamin A, we can lose night vision and become immunocompromised. A small amount of vitamin A in our diet keeps our bodies functioning normally. But if a person ingests too much vitamin A from supplements or from a dietary source that is high in it (such as polar bear liver), death can result from vitamin A toxicity. The same is true for water: drinking too little and a person dies of dehydration but drink too much and a person dies of hyponatremia. For decades, we thought oxygen was somehow different and that it was always better to err on the side of prescribing too much oxygen than risk prescribing too little. It turns out that we were wrong.
There are a lot of different oxygen delivery options: home concentrators, portable concentrators, compressed oxygen gas tanks, liquid oxygen, etc. In the hospital, oxygen is usually delivered through a medical gas panel that will have outlets for medical grade oxygen, regular air, and wall suction. The oxygen that comes out of these outlets is generally at a maximum pressure of 55 PSI. Conventional oxygen delivery devices (nasal cannulas and simple face masks) in the hospital usually are capped at a maximum flow rate of 15 liters per minute. Heated high flow nasal cannulas can deliver very high oxygen flow rates of up to 60 liters per minute. Mechanical ventilators can blend pure oxygen with room air to achieve anywhere from 21% to 100% inhaled oxygen concentrations (FiO2). As a result, physicians can adjust the amount of supplemental oxygen that a patient receives from a very small amount to a very large amount.
In the past, when EMS personnel would bring a patient with shortness of breath to the emergency department, they would put a mask on that patient and turn the oxygen up to a 15-liter flow rate to achieve close to 100% inhaled oxygen. In the hospitals, doctors would prescribe a high flow of oxygen and then not decrease that flow rate until a patient’s condition was improving and it was time to wean the oxygen down. In our emergency departments, ICUs, operating rooms, and hospital wards, we would give the patient as much oxygen as it took to raise their blood oxygen saturation to 100% and leave the oxygen at that flow rate for hours or days. But it turns out that we were probably harming patients by doing so.
In the past several years, there have been studies showing that prescribing excessively high oxygen flow rates can worsen patient outcomes in adults with lung disease. A study published in this week’s JAMA extended those findings to children. This study looked at 1,567 children, ages 1 – 4 years old, at 14 hospitals in Australia and New Zealand who had respiratory failure. The children were randomly assigned to receive either standard oxygen therapy or high-flow oxygen therapy. The high-flow group received as high as 40 liters per minute, depending on body weight. The standard-flow group received up to 2 liters per minute that was titrated to keep the blood oxygen saturation above 92%. The children receiving high-flow oxygen had a significantly longer length of hospital stay (1.77 vs. 1.50 days), longer duration of time on oxygen (1.07 vs 0.75 days), and higher rate of admission to the ICU (12.5% vs 6.9%).
Other studies have shown that excessive supplemental oxygen can be harmful in adults. A study of 429 patients given supplemental oxygen after resuscitation for cardiac arrest found that 40.7% of those receiving a conservative oxygen flow rate died but 50% of those receiving a liberal (i.e., higher) oxygen flow rate died. A meta-analysis study of 16,037 critically ill patients treated with conservative vs. liberal oxygen therapy found that those treated with liberal oxygen therapy (higher flow rates) had a higher mortality than those treated with conservative oxygen therapy (lower flow rates). A 2022 study of inpatients receiving supplemental oxygen during COPD exacerbations found that those who had arterial oxygen saturations of 88 – 92% had the lowest mortality rate and those patients given greater amounts of supplemental oxygen to maintain arterial oxygen saturation > 92% had significantly higher mortality rates.
For patients having out-of-hospital cardiac arrest, the conservative oxygen approach may be risky, however, A 2022 study from Australia found that cardiac arrest patients treated by EMS personnel with a conservative oxygen strategy (targeting a blood oxygen saturation of 90 – 94%) had a higher mortality rate than those patients treated with a liberal oxygen strategy (targeting a blood oxygen saturation of 98 – 100%). Because there was a tendency to frequently undershoot the oxygen saturation in conservative oxygen therapy group, it is possible that even brief periods of low oxygen saturations can be harmful in patients immediately after a cardiac arrest which may have resulted in the higher mortality rate.
Adverse effects of too much oxygen
So, if oxygen is so necessary for us, how can it harm us? There are several effects of excessive oxygen that can result in harm:
- Oxygen toxicity. High oxygen concentrations can damage lung cells by oxidant injury resulting from the production of substances such as superoxide anion, hydroxyl radical, and hydrogen peroxide. We sometimes see this in the intensive care unit in respiratory failure patients who require 100% oxygen concentrations for long periods of time who get into a vicious cycle of pneumonia requiring supplemental oxygen and then the high oxygen concentrations cause further lung damage resulting in the patients needing even higher oxygen concentrations in order to get enough oxygen into the blood stream to keep the body’s organs alive. These patients can end up with permanent lung scarring and never get off of the mechanical ventilator. Lung damage depends on how long a person is exposed to high concentrations of oxygen – brief periods are less harmful than breathing very high concentrations of oxygen for longer periods of time. This mainly applies to those patients in the ICU left on 60% – 100% inhaled oxygen for several days.
- Drug-induced lung disease. Many drugs can cause damage to the lung resulting in inflammation and scar in the lungs (interstitial lung disease). Certain drugs are particularly likely to do this when combined with high concentrations of inhaled oxygen. The two biggest offenders are bleomycin (used in cancer chemotherapy) and amiodarone (used in heart rhythm disorders). When a patient is breathing room air, these drugs are usually safe but when breathing high concentrations of oxygen, these drugs can become very toxic. Bleomycin is particularly notable because the risk of pulmonary toxicity from breathing high oxygen concentrations can persist for many years after the patient was given bleomycin.
- Radiation-induced lung disease. Excessively high amounts of radiation to the chest can cause interstitial lung disease but moderate amounts can be used safely to treat lung cancer. However, when a patient is using high oxygen concentrations, those moderate amounts of radiation can cause interstitial lung disease. Thus, like amiodarone and bleomycin, oxygen therapy can increase the risk of radiation-induced pulmonary fibrosis.
- Adsorptive atelectasis. Room air contains about 21% oxygen and 78% nitrogen. Oxygen readily passes from the alveoli of the lungs (air sacks) into the blood stream but nitrogen does not cross as easily. Because of this, nitrogen in the air helps keep the alveoli of the lungs propped open, similar to using PEEP (positive end-expiratory pressure) on a mechanical ventilator, thus preventing atelectasis. When a person breathes very high concentrations of oxygen, the nitrogen in the alveoli gets “washed out” and as a result, the lungs are more prone to developing atelectasis that can in turn worsen oxygenation. Once again, the patient can get into a vicious cycle of worsened blood oxygen levels leading to the doctor increasing the supplemental oxygen concentration leading to worsened atelectasis leading back to worsened blood oxygen levels.
- Carbon dioxide retention. Our breathing rate is determined by the blood oxygen level (PO2) and carbon dioxide level (PCO2). Patients with COPD are sometimes less sensitive to rising carbon dioxide levels and more dependent on the blood oxygen level to determine respiratory rates. In this setting, by giving too much supplemental oxygen, the patient can lose their respiratory drive and begin to hypoventilate, resulting in a high blood carbon dioxide level. Although this effect on PCO2 levels is usually small, it can be important when combined with other things that can suppress the respiratory drive centers, such as sedatives and opioids.
- Longer oxygen weaning times. When a patient with acute respiratory failure in the hospital begins to improve, the doctor will generally order the respiratory therapist to wean the oxygen off (or back down to the patient’s normal home supplemental oxygen flow rate). The respiratory therapist will then reduce the oxygen flow rate by 1-2 liters per minute, wait a couple of hours, recheck the blood oxygen saturation, reduce the flow rate by another 1-2 liters, etc. It takes less time to wean oxygen off if a patient is on less oxygen to begin with than if they are receiving higher flow rates of oxygen. The doctors generally wait until the oxygen is completely off (or down to the normal flow rate the patient uses at home) before the patient is allowed to be discharged. As a result, longer oxygen weaning times can sometimes lengthen the patient’s hospital stay.
So, what is the right amount of supplemental oxygen?
Our bodies require oxygen to live. If we don’t get enough oxygen, our tissues become damaged. On the other hand, too much oxygen is also bad for our bodies. Here is what we can do in our hospitals to draw the right balance between not enough and too much:
- In emergencies, it is better to give too much than to give too little. In settings such as cardiac arrest, myocardial infarction, and stroke, brief periods of low blood oxygen levels can worsen clinical outcomes. If too much emphasis is placed on using the least amount of supplemental oxygen, there is a greater risk of undershooting the oxygen flow rate and causing low blood oxygen levels for seconds or minutes. Situations where this applies include during transport of cardiac arrest or stroke patients by emergency squads, during CPR for cardiopulmonary arrest, and during the first hours of a myocardial infarction or stroke.
- Target a blood oxygen saturation of 88 – 92%. After the initial resuscitation, titrate the supplemental oxygen flow rate (or the FiO2 on the mechanical ventilator) to the least amount necessary to keep the oxygen saturation between 88 – 92%. For years, physicians have written orders to “Wean supplemental oxygen to maintain oxygen saturation > 92%”. This is probably too high and our default oxygen weaning orders in our electronic medical records need to be revised.
- In the ICU, use other measures to improve oxygenation when patients need more than 60% FiO2. This could include increasing the PEEP on the ventilator, using prone ventilation, giving sedatives, controlling fever, or using neuromuscular blockade.
- Avoid unnecessary use of 100% FiO2 during surgery. In the past, anesthesiologists would sometimes leave patients on 100% FiO2 throughout surgical operations so that there would be no risk of the patient desaturating during surgery. Not only can this increase the risk of post-operative absorptive atelectasis, but it can be particularly harmful if patients have previously received sensitizing drugs or radiation. One of my colleagues was a physician who had been treated with bleomycin years previously for lymphoma. He underwent an elective gall bladder surgery and was left on 100% FiO2 during the procedure. He developed acute lung injury post-operatively and died from bleomycin-induced acute oxygen toxicity.
- We need pharmacologic 2,3-DPG. 2,3-Disphosphoglycerate (2,3-DPG) is a chemical in red blood cells that helps hemoglobin molecules release oxygen. Physiologically, this can result in a shift in the oxy-hemoglobin dissociation curve to the right. This means that oxygen can pop off of hemoglobin easier, allowing the red blood cells to release more of their oxygen to tissues that need it. In other words, 2,3-DPG allows the tissues to get by when there is less oxygen in the blood. Normally, red blood cells release about 30% of their oxygen when they pass through tissues; 2,3-DPG allows them to release more than 30%. What is important to our bodies is not the amount of oxygen in the blood but rather the amount of oxygen that our tissues get. 2,3-DPG allows our tissues to function normally when the blood oxygen saturation is lower. If we could increase red blood cell 2,3-DPG levels pharmacologically, we could use lower amounts of supplemental oxygen in patients with acute respiratory failure.
- Not everyone with a low oxygen saturation needs supplemental oxygen. Insurance will not pay for supplemental oxygen unless a patient has an oxygen saturation of < 89%, either at rest, during exercise, or during sleep. But that does not mean that every patient with brief oxygen saturations < 89% needs supplemental oxygen. The LOTT study showed that COPD patients with oxygen saturations 89 – 92% at rest that desaturated to 80 – 90% with exercise had no benefit from supplemental oxygen, including death rates, hospitalization rates, COPD exacerbations, and quality of life. In my own clinical practice, I have also been hesitant to prescribe oxygen in hyperemic patients who are at fire risk, including those who smoke, have smokers in the home, or use gas cooking stoves. These patients are often more likely to be injured or die from fire caused by supplemental oxygen than they are to die from hypoxemia without supplemental oxygen.
It’s time for auto-titrating oxygen delivery devices
Auto-titrating oxygen devices adjust the oxygen flow rate based on a patient’s oxygen saturation. A 2019 meta-analysis showed that compared to manual oxygen titration, these devices shortened hospital length of stay by shortening oxygen weaning times. A 2020 study of outpatients found that by using auto-titrating oxygen devices, patients had improved 6-minute walk distances and improved dyspnea. It is not surprising that these devices are effective in the hospital – a respiratory therapist cannot be in a patient’s hospital room 24 hours a day to constantly adjust the supplement oxygen flow rate but the auto-titrating oxygen delivery device can. Not only can these devices reduce excessive supplemental oxygen flow rates in hospitalized patients, but they can also reduce excessive oxygen flow rates in outpatients.
The cost to hospitals to buy and implement auto-titrating oxygen delivery devices would be considerable. However, these costs could potentially be off-set by shortened hospital length of stays and by reduction in utilization of respiratory therapists. These devices would also take some of the guesswork out of ordering oxygen flow rates for hospitalized patients resulting in a more standardized and consistent use of supplemental oxygen by hospitalists and intensivists. In addition, there is a potential for a reduction in hospital mortality rates by avoiding excessively high amounts of supplemental oxygen.
There is both an art of medicine and a science of medicine. It is time to harness science to guide the use of supplemental oxygen.
January 26, 2023
