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Inpatient Practice Outpatient Practice

Supplemental Oxygen: Sometimes Less Is Better

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:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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

Categories
Outpatient Practice Public Health

A Pulmonologist’s Opinion About Gas Ranges

Recently, there have been health concerns raised about gas ranges. This has led some cities to prohibit their installation in new homes, including Los Angeles, New York and San Francisco. I am interested in these health concerns for two reasons. First, as a pulmonologist, I want to be sure that the people in our community are safe from health risks. Second, I am getting ready to buy a new range for myself. So, what are the health risks of gas ranges and should you be worried about them?

The basics of cooking ranges

First, some definitions. Many people use the terms “range”, “stove”, and “oven” interchangeably. Technically, an oven is the enclosed box that you bake in. A stove is the surface heating area that you heat pots on. A range is when a stove and an oven are combined into a single appliance. Sometimes the term “cooktop” is used when the stove is separate from the oven. For the purpose of this post, I will use the term “range” for the appliance that combines an oven with a stove.

In the United States, there are essentially four types of ranges: electric, gas, duel fuel, and induction. Electric ranges work by passing an electric current through a metal coil that heats up as it creates resistance to that current. These electric coils (“burners”) can be exposed on the top of the stove or covered underneath a flat sheet of glass. Electric ranges also use electric heating elements inside the ovens. Gas ranges work by igniting a jet of natural gas. The resultant flame is used to heat pots and pans on the stove. Gas ranges also use gas flames inside the oven for baking purposes. Duel fuel ranges use gas flames for the stove to heat pots and pans but use electric heating elements in the oven for baking purposes. Induction ranges work by using electricity to create a magnetic field on the stove that then heats up any pot or pan placed on the stove that contains iron or steel. Induction ranges generally use a standard electric heating element in the oven for baking purposes.

For many years, electric ranges dominated the U.S. appliance market. However, gas ranges are preferred by many cooks because of the better control over the amount of heat generated, for example, allowing the cooking surface to instantly increase or decrease in temperature. Duel fuel ranges combine the advantages of the gas stove for surface cooking with the more even heating of an electric oven for baking. Induction ranges offer the advantages of using electricity, thus avoiding an open flame, while also offering the advantage of being able to instantly control the temperature applied to the pot or pan. Consumer Reports found that induction ranges out-performed electric and gas ranges in cooking tests.

As a general rule, when things burn, the resultant products of combustion are bad for our lungs. Whether that be burning cigarettes, military burn pits, house fires, or indoor wood/charcoal cooking. Natural gas is often called “clean-burning” because it does not produce visible smoke, unlike a wood fire or charcoal fire. However, just because we cannot see or smell the products of combustion from natural gas does not mean that those products of combustion cannot hurt us.

What is natural gas?

Natural gas is a type of fossil fuel produced by the decay of long-dead plants. It accumulates in large gas pockets deep underground and then can be removed by drilling gas wells into those pockets. The main component of natural gas is methane which in pure form, creates water and carbon dioxide when it burns. However, natural gas is not pure methane and instead contains small amounts of other gases and chemicals. The typical components of natural gas include:

  • Methane
  • Ethane
  • Butane
  • Propane
  • Hydrogen sulfide
  • Carbon dioxide
  • Oxygen
  • Nitrogen
  • Trace elements: helium, hydrogen, Xenon, and Neon

When natural gas is burned, these components produce new gases, including carbon dioxide, nitrous oxide, methane, carbon monoxide, formaldehyde, nitrogen dioxide, and particulate matter. Many of these gases can cause lung disease.

Carbon dioxide

It is estimated that a typical U.S. family cooking with a gas stove produces slightly less than a pound of carbon dioxide each day from the combustion of natural gas. This is about the same amount of carbon dioxide produced by coal or gas power plants to generate the amount of electricity required to cook using an electric range or an induction range. So, we don’t really produce more carbon dioxide by using a gas range but we do concentrate that carbon dioxide inside our homes. To illustrate this, I measured the concentration of carbon dioxide in my kitchen before and during the use of my gas range. At baseline, the carbon dioxide level in my kitchen was 646 parts per million.

After turning on 4 burners on the gas stove for five minutes, the carbon dioxide level increased to 1609 parts per million.

I then turned on the overhead exhaust fan for five minutes and the carbon dioxide level fell to 821 parts per million.

Carbon dioxide is a by-product of living animals. Our bodies normally produce carbon dioxide that we exhale with every breath. If the levels of carbon dioxide in our bloodstream builds up, it can be toxic to the human body. Similarly, if the level of carbon dioxide in the air increases and then we breath that air, we can suffer ill health. NIOSH considers breathing air containing over 5,000 parts per million over the course of a 10-hour day to be toxic and over 30,000 parts per million for a 15-minute period to be toxic. It would require cooking for a long period of time in a poorly ventilated kitchen to reach these levels using a gas range.

Carbon monoxide

Like carbon dioxide, carbon monoxide is produced when things burn. However, carbon monoxide is much more toxic to humans than carbon dioxide. It is an invisible, odorless gas. When inhaled, it tightly binds to the hemoglobin molecules in our red blood cells thus preventing oxygen from binding to those hemoglobin molecules. Without oxygen, the cells in our bodies suffocate. We all inhale small amounts of carbon monoxide from our environments so there are always low levels of carbon monoxide in our blood stream. Cigarette smokers have higher levels of blood carbon monoxide than non-smokers. Very high levels of carbon monoxide are fatal. This is how most people die in house fires or die by suicide from running their car in a closed garage. Lower levels of carbon monoxide can cause headaches, ringing in the ears, and confusion. Every house with a gas range should have a carbon monoxide detector installed.

Nitrogen dioxide

The air we breathe is mostly made up of nitrogen – it constitutes about 80% of the gases in air. Nitrogen gas is considered inert – it does not cause any direct harm to the body except when nitrogen dissolved in the bloodstream “boils” and creates nitrogen gas bubbles in the tissues when SCUBA divers ascend too rapidly and get the bends. But when gases are burned, pure nitrogen can be converted into nitrogen oxides. One of these is nitrogen dioxide, which can be very toxic and poses the greatest health risks to our lungs from gas ranges.

Nitrogen dioxide can also build up from decay of certain types of plant materials. In pulmonary medicine, an important result of nitrogen dioxide toxicity is in “silo-filler’s disease”. This occurs when nitrogen dioxide builds up inside of poorly ventilated silos storing silage. If a farm worker enters that silo and inhales high concentrations of nitrogen dioxide, the lungs can become injured. In the short-term this can result in ARDS (acute respiratory distress syndrome), where the lungs are damaged and fill up with inflammation and fluid, thus blocking air from getting into the lung’s alveoli (air sacks) where oxygen normally transfers into the bloodstream. In the long-term, small airways in lungs exposed to high concentrations of nitrogen dioxide can fill up with scar tissue, resulting in permanent blockage of air getting to the alveoli. This is called “bronchiolitis obliterans“. A famous event resulting in pulmonary nitrogen dioxide toxicity occurred in Cleveland in 1929. At that time, a fire arose in the Cleveland Clinic in a room where large amount of old x-rays films that were made of nitrocellulose were stored. The resultant nitrogen dioxide gas produced by the burning x-ray films resulted in 129 deaths, including one of the Clinic’s founders, Dr. John Philips.

In lower concentrations, nitrogen dioxide can irritate small airways causing asthma. This can be particularly insidious because nitrogen dioxide does not cause allergic reactions, unlike many allergic triggers of asthma such as cats dander or pollens. For this reason, most people with asthma worsened by nitrogen dioxide do not realize that it is their gas cooking range that is making them sick. A 2013 meta-analysis of 41 studies found that indoor gas stove use increases the incidence of asthma in children. A recent study estimated that 12.7% of childhood asthma is due to nitrogen dioxide and other by gases produced by gas ranges. Adults with asthma may be less affected by gas ranges than children based on a 2003 study of 445 subjects.

Formaldehyde

Every middle school student who accidentally opened the jar of preserved frogs in biology class knows how noxious inhaling formaldehyde is. It is another toxic by-product of natural gas combustion. Formaldehyde is also produced by burning cigarettes and can be released by wood adhesives in newly constructed houses. It is often one of the suspected culprits in patients with “sick building syndrome”. When inhaled, formaldehyde can cause eye irritation, nose irritation, throat irritation, and cough. Meta-analyses in 2010 and 2018 showed that environmental formaldehyde in homes is associated with asthma in children. Formaldehyde is also considered a carcinogen. A 2018 study found that using even 1 gas burner turned on low increased air formaldehyde levels above safe thresholds.

Particulate matter

Natural gas is often called “clean-burning” but that is not exactly true. Tiny particles (< 10 μm) of soot are produced when gas is burned, even if those particles cannot be easily seen with the naked eye. Breathing particulate matter can cause cough and worsened asthma. It is one of the main causes of respiratory symptoms when outdoor air quality is poor, due to air pollution. Some particulate matter is produced from food as it is cooked, however, gas ranges produce particulate matter even if there is no food being cooked.

Fire

Accidental house fires are another harmful consequence of gas ranges. It surprises me that there are not more of these. Spilled cooking oil or a dishtowel accidentally dropped onto an open flame can quickly develop into a kitchen fire. The National Fire Protection Association estimates that there are 179,500 fires due to cooking in the United States, accounting for 49% of all house fires. Ranges account for 61% of cooking-related house fires and 87% of cooking-related fire deaths. Interestingly, electric ranges are more likely to cause house fires than gas ranges. There is very little research in fire risk from induction ranges compared to electric or gas ranges but given that induction cooktops produce no heat if a pan is removed, it would seem that there would be less risk of fire if the induction range was accidentally left on after cooking. Grease fires may also be less frequent given the absence of a flame (gas ranges) or hot electric coil (electric ranges).

Fire is a particular risk for people with lung disease who require supplemental oxygen. As pulmonologists, we caution our patients to never use their oxygen in the kitchen when using a gas range. However, there is no risk of fire when using supplemental oxygen around an induction range.

Thermal injuries

Both electric ranges and gas ranges produce high heat. Small children who don’t know any better can get severe hand and finger burns from reaching up to an electric or gas burner. Even experienced cooks often burn their hands from accidentally touching a hot burner. Induction ranges substantially reduce the risk of burns. Only the bottom of a pot or pan gets hot; the surface of the range does not heat up. So unless a toddler touches the bottom of a pan, there is no danger of thermal injury with an induction range.

So, what are the downsides of induction ranges?

The main problem with induction ranges is that they are expensive. The cheapest electric or gas range is several hundred dollars less than the cheapest induction range. However, a provision of the Inflation Reduction Act to discourage gas ranges provides a tax credit of up to $840 to replace gas ranges with electric or induction ranges. This only applies to Americans with lower incomes. Those with middle incomes can qualify for a reduced amount of the tax credit while those with higher incomes are not eligible for any tax credit. Although induction ranges can be expensive, it is anticipated that prices will come down in the future as the market for induction ranges increases. Consumer Reports recently rated ranges and found that the top rated induction ranges cost about the same as the top rated gas or electric ranges. The least expensive of the top four rated induction ranges costs $1,200.

A second problem with induction ranges is that the bottom of pots and pans must contain iron or steel. Copper, purely ceramic, aluminum, and glass cookware will not work with an induction range. If you have to buy all new steel/iron plated cookware, it can considerably add to the cost of a new induction range. An easy way to determine if a given pot or pan will work is to see if a refrigerator magnet sticks to the bottom.

A final problem with induction ranges is that you cannot generate extremely high heat. This is especially a problem for restaurants using very high heat output gas flames for wok cooking. These high heat levels are generally not achievable with an induction cooktop. However, there are now “induction woks” being marketed that surround the wok bowl with an induction element, thus permitting cooking temperatures similar as can be produced using high-output gas burners.

“I have a gas stove. What can I do to reduce the risk of harm?”

If you have a gas range, the most important step you can take is to ventilate the kitchen. This can mean opening kitchen windows when the weather outside permits. If you have a fan that you can put in that window, even better. If you have an exhaust hood above your range, then turn it on when cooking. An exhaust hood that blows air outside is optimal. If a child in the house has asthma, then try to keep that child out of the kitchen when cooking. If you are unsure of how effective your kitchen ventilation is, you can buy a home CO2 monitor for about $80. If the CO2 level increases significantly when you are cooking, then your ventilation is likely inadequate.

A second way of minimizing harm from a gas range is to use other kitchen appliances for cooking instead of the range whenever possible. For example, an electric kettle can be used to heat water rather than boiling water in a pot on the gas stove. An air fryer can replace the use of a gas oven for many foods. And a slow cooker can be used instead of the range range for chili, stews, and soups.

“Should I switch out my gas range for an induction range?”

The short answer is that most people do not need to ditch their gas ranges if they already have one. However, if your kitchen is poorly ventilated or lacks an exhaust fan over the range, then replacing your gas range with an electric or an induction range may make sense. Also, if there are children in the house, the health risks of a gas range increase significantly, especially if one of the children has asthma or another lung disease. If someone in the home uses supplemental oxygen, then getting rid of the gas range can reduce the risk of a house fire, particularly if the oxygen-user does the cooking.

For climate-conscious people, changing gas to electric or induction ranges can appear on the surface to be the more responsible choice. However, if your local electricity producer uses fossil fuel power plants, then there really is not much advantage in electric or induction ranges since the overall CO2 production is similar. Here in Ohio, we can choose our electricity provider and for several years, I have purchased electricity from providers that only produce electricity from wind and solar sources. So for me, an induction range will result in less overall CO2 production than a gas range. People in other parts of the country where the electrical grid sources electricity from hydroelectric power-plants can also reduce their CO2 footprint by switching from gas to electric or induction ranges.

For me, I don’t have any lung disease and no longer have children in the house. I like breathing clean air in the home and I like to minimize my personal CO2 footprint. However, I also like the ability to easily regulate the cooking temperature that in the past was only achievable with a gas stove but is now achievable with induction stoves. We are building a new house and had to decide what kind of appliances to install. So, I just ordered my new induction range.

January 15, 2023

Categories
Outpatient Practice

Does Your Hospital Need A Cancer Survivorship Clinic?

Prior to 1946, cancer was a surgical disease. If a cancer could not be completely removed during an operation, then it was incurable. But in 1946, two Yale University pharmacologists, Dr. Louis Goodman and Dr. Alfred Gilman, published their findings that by treating a patient dying of lymphoma with nitrogen mustard, the patient’s tumors shrank. The impetus for their experiment was the observation during World War I that soldiers who survived mustard gas attacks developed low white blood cell counts and were susceptible to infections. Goodman and Gilman hypothesized that the same chemical used in gas warfare could treat white blood cell malignancies. Thus, the era of cancer chemotherapy was born.

When I was a medical student 40 years ago, chemotherapy rarely cured anyone – it merely postponed dying from cancer by a few months. However, since then, the number of chemotherapy drugs has dramatically increased. Now, we also have immunotherapies, driver-directed therapies, and hormonal therapies to treat cancers. These treatments are much more effective than early chemotherapies and can not only offer the hope of long-term suppression of cancer but can also often cure cancer. And each of these treatments has its own set of short-term and long-term complications. Currently, there are 18.1 million cancer survivors in the United States and that number is expected to grow to 22.5 million over the next ten years. Of those cancer survivors, 16.3 million will live for more than 5 years. The good news is that we now have more people surviving cancer than ever before but the bad news is that we now have more people living with the side effects of cancer treatment than ever before.

Historically, oncologists were in the business of treating cancer. Once cancer was cured, the oncologist discharged the patient to the care of their primary care physician so that the oncologist could focus on their next patient with newly diagnosed cancer. But primary care physicians are largely untrained in managing the medical complications attendant to cancer treatment. As a result, we have an unfilled gap in medical care – patients in a no-man’s land of medical problems that their primary care physician is unfamiliar with and that their oncologist often places a lower priority on. This unfilled gap is cancer survivorship.

There are four major components to cancer survivorship care:

  1. Surveillance. Cancer can recur and early detection of recurrence leads to early treatment of recurrence which in turn leads to the best long-term survival. However, the  surveillance monitoring guidelines frequently change and each type of cancer requires different radiographic or blood test monitoring.
  2. Prevention. Cancer treatments can cause medical conditions by themselves but they can also make patients more susceptible to other medical problems. Preventive care can often avert these problems.
  3. Treatment side effects. Every cancer therapy has its own set of side effects and if untreated, these side effects can often be debilitating.
  4. Coordination of care. The management of cancer survivors can be complicated, often requiring multiple specialists simultaneously.

A cancer survivorship clinic should ideally incorporate all four of these components.

Surveillance

Cancer screening falls squarely in the purview of the primary care physician. Family physicians and general internists are accustomed to being responsible for ordering routine screening mammograms, pap smears, and colonoscopies. But once a patient is treated for a cancer, the guidelines for those tests change and primary care physicians are often uncertain what tests to order and how often to order them. Current guidelines include the following:

  • Breast cancer. Survivors should have an office visit with history and physical examination every 3-6 months for the first three years, every 6-12 months for the next two years, and annually thereafter. A diagnostic mammogram should be performed annually for the first 3-5 years and then a screening mammogram performed annually thereafter. All women with breast cancer should be offered genetic testing and genetic counseling.
  • Prostate cancer. Prostate cancer is unique among cancers because there is a wide spectrum of severity. Some prostate cancers grow so slowly that they do not require any treatment whereas others can rapidly metastasize and be fatal. The PSA (prostate-specific antigen) blood test is the mainstay of prostate cancer surveillance. For patients with localized disease, it should be tested every 6-12 months for the first 5 years and then annually thereafter. For patients with more extensive disease, it should be tested every 3-6 months.
  • Colon cancer. For patients with stage I disease, a colonoscopy should be performed 1 year after surgery and then every 3 years thereafter. Patients with stage II or III disease should also have regular colonoscopy but should additionally have a history and physical examination plus a CEA blood test every 3-6 months as well as a CT scan of the chest/abdomen/pelvis every 6-12 months.
  • Lung cancer. The chest CT is the mainstay of surveillance for lung cancer survivors and, along with a history & physical examination, should be performed every 6 months for the first two years and then annually thereafter. After five years, changing to a low-dose screening annual chest CT can be considered.
  • Other cancers. There are different surveillance recommendations for melanoma, testicular cancer, lymphoma, thyroid cancer, and brain cancer. The surveillance for every cancer is unique and may require interval history and physical examinations, blood testing, and/or radiographic imaging.

Prevention

Preventive medicine recommendations are fairly similar for all cancer survivors. Healthy living strategies for one cancer are generally the same for other cancers. A healthy diet, weight loss if overweight, regular exercise, and appropriate vaccinations are appropriate for cancer survivors as well as for the general population. Because many cancer survivors may have lingering immunity impairment from chemotherapy, vaccinations are especially important.

Smoking cessation is an essential component of cancer survivorship. Approximately 12-15% of cancer survivors are current smokers. The patient cured of their lung cancer by lobectomy will be at increased risk of a second lung cancer if cigarette smoking continues. Smoking cessation can also help prevent laryngeal cancer, bladder cancer, pancreatic cancer, kidney cancer, esophageal cancer, and others,

As more and more cancers are found to have genetic contributions, genetic testing has become routine in oncology. Ideally, genetic testing be done after genetic counseling but with the widespread availability of gene testing, any provider can order these tests. At the least, referral to a genetic counselor should be made for all patients with abnormal cancer-related genes. Not only can this improve early diagnosis and prevention of other cancers in the patient but it can also improve cancer diagnosis and prevention in susceptible family members.

Treatment side effects

Each kind of cancer has its own specific treatment. And each treatment has its own specific side effects. As the number of cancer treatments has increased exponentially in the past decades, so have the number of treatment side effects. The result is that cancer survivorship has almost become a sub-specialty of its own. To a degree, this has been met by other subspecialties. For example, we now have “onco-nephrologists” who are kidney specialists who sub-specialize in managing the renal complications of cancer treatments. We have “onco-pulmonologists who sub-specialize in pulmonary complications of cancer treatments. Similarly with cardiology, infectious disease, and gastroenterology. But these sub-specialists are few in number and only located in large, tertiary care, academic medical centers. Moreover, their expertise is organ-specific and frequently, cancer survivors have complications affecting more than one organ or affect a part of the body that does not fall under the expertise of the nephrologist, pulmonologist, or cardiologist. Here are some of the most common medical conditions seen in cancer survivors:

  • Osteoporosis. Many cancer treatments can increase the risk of osteoporosis including chemotherapy-induced premature menopause, use of aromatase inhibitors for breast cancer, use of corticosteroids, and use of anti-androgen prostate treatments. Baseline bone density tests at treatment onset followed by regular interval bone density tests should be offered to patients receiving these treatments. Early treatment of osteopenia and osteoporosis can prevent subsequent bone fragility fractures.
  • Fatigue. Cancer survivors can have fatigue for many different reasons including side effects of radiation therapy, surgery, or medications. However, other common causes of fatigue should not be overlooked including thyroid dysfunction, sleep disorders, anemia, depression, and heart disease.
  • Peripheral neuropathy. Many chemotherapy drugs can cause damage to the peripheral nerves. Some of the more common drugs include vincristine, cisplatin, oxaliplatin, bortezomib, and paclitaxel. These are usually “stocking-glove” distribution sensory neuropathies. However, drugs such as vincristine can cause intestinal autonomic neuropathy resulting in constipation. In addition, radiation therapy can result in peripheral neuropathy from injury to nerves within the radiation ports. Peripheral neuropathy management in cancer survivors may include physical therapy, medications (such as duloxetine), and injury prevention (such as daily foot inspections).
  • Pain. Cancer-related pain is often managed by palliative medicine specialists but cancer survivors often have chronic pain, even if their cancer is cured. This often results in patients transferring care from the palliative medicine specialist to a pain management specialist. As with other causes of chronic pain, multimodality comprehensive pain management is considerably more effective than relying solely on pain medications such as opioids.
  • Cardiotoxicity. Patients receiving radiation therapy to the chest region are susceptible to developing pericarditis, cardiomyopathy, coronary artery disease, and valvular heart disease. Anthracycline drugs (such as doxorubicin and daunorubicin), fluorouracil, and trastuzumab can cause heart failure and may require serial cardiac ultrasound testing. Many other chemotherapy drugs can also cause heart disease. The management of drug-induced heart failure is similar to the management of other causes of heart failure.
  • Pulmonary toxicity. Chest radiation and many chemotherapy drugs can cause interstitial lung disease. Bleomycin is particularly notable because it can cause interstitial lung disease with respiratory failure years after treatment if a patient is inadvertently exposed to high oxygen concentrations, for example, while undergoing anesthesia. Driver-directed cancer treatments, such as tyrosine kinase inhibitors, can cause lung damage. Checkpoint inhibitors used as immunotherapy for cancer can also cause pneumonitis. In many cases, pulmonary toxicity can be minimized by early diagnosis and treatment with corticosteroids but patients may require bronchoscopy to exclude infection.
  • Gastrointestinal toxicity. Diarrhea is common with chemotherapy. Pelvic radiation can additionally result in diarrhea or incontinence. Checkpoint inhibitors can cause hepatotoxicity and colitis. In some cases, corticosteroids can relieve symptoms but patients require microbiologic testing of the stool to first exclude infection.
  • Renal toxicity. The kidney can suffer many kinds of injury from cancer treatment. Chemotherapies, checkpoint inhibitors, and driver-directed therapies can all directly cause acute kidney injury. Electrolyte disorders of potassium, sodium, phosphorus, and calcium can result from both cancer treatments or from the underlying cancer. In addition, paraneoplastic glomerular disorders, glomerular injury from tumor lysis syndrome, and glomerular injury from monoclonal gammopathies can occur.
  • Sexual health needs. Sexual dysfunction can result from post-surgical changes, chemotherapy, hormonal therapy, radiation therapy, and  premature menopause. Many cancer survivors are hesitant to initiate discussion about sexual dysfunction so it is important that providers create an environment where patients are comfortable discussing sexual health.
  • Fear of recurrence. About half of cancer survivors have mild to moderate fear or worry that their cancer will come back and 7% of survivors have these fears to a severe degree. This carcinophobia can be emotionally consuming. In mild cases, support groups can be helpful. More severe cases benefit by cognitive behavioral therapy. Other psychosocial issues such as depression, anxiety, and post-traumatic stress disorder are also common.
  • Financial insecurity. It is expensive to have cancer. Frequent office visits, costly medications, costly tests, and unexpected surgeries can be financially devastating, even for those patients with health insurance. In addition, reduced income for both patients and caregivers results from necessary time off work. Hospital financial counselors and social service staff can often be helpful.

Coordination of care

With care simultaneously being provided by physicians from many different specialities, cancer survivors often find themselves asking: “Who is in charge of my medical care?”, especially after cancer treatment has finished. Coordination between the patient’s medical oncologist, surgeon, radiation oncologist, internal medicine specialists, social worker, psychologist, genetic counselor, and neurologist can be challenging. Although primary care physicians are adept at coordination of care for patients with chronic disease, the unique multidisciplinary care needs of cancer survivors can often be overwhelming for the primary care office. Coordination of care can be the responsibility of the medical oncologist in some situations, the primary care physician in some situations, or patient navigators in others. The important thing is that every cancer survivor knows who is coordinating their care and that all of the various providers involved in that patient’s care also know who coordinating care. This is particularly essential to ensure that recommended tests and medication changes actually get done.

Cancer survivorship clinics

So, does your hospital need a cancer survivorship clinic? And if so, who should run it? In some hospitals, cancer survivorship is the purview of the medical oncologist. But the medical needs of cancer survivors can last for years or decades after the cancer is cured and many oncologists simply do not have the bandwidth to meed these needs for dozens or hundreds of cancer survivors while still meeting the needs of patients being actively treated for their cancer. Some primary are providers are able to assume the oversight and coordination of care for cancer survivors. But cancer survivorship care has become fairly specialized with the result that many primary care providers lack the training or experience in the unique chronic care of the cancer survivor.

A solution in some communities is the dedicated cancer survivorship clinic. This could be staffed by an oncologist, a general internist with a special interest in cancer survivorship, a physical medicine specialist, or even an advanced practice provider with training in the care of cancer survivors. Although large cancer specialty hospitals have dedicated survivorship clinics, this is an unmet medical need in most community hospitals.

It is time that medical directors and hospital administrators at community hospitals take responsibility for creating cancer survivorship clinics. One out of every 17 Americans is a cancer survivor and these cancer survivors are often hiding in plain sight in every small community in the United States. A community does not need to have a tertiary care oncology practice in order to support a cancer survivorship clinic. Indeed, such a clinic can be overseen by a general internist or a family medicine physician.

As cancer treatments continue to advance, so do the needs of cancer survivors. It is time that we bring survivorship clinics to our community hospitals.

December 27, 2022

Categories
Outpatient Practice

Who Should Treat Hepatitis C?

An August 2022 study in the MMWR found that only 1 out of 3 people with hepatitis C are getting treated… and all of the patients in the study had health insurance. What are the barriers to treatment and how can we overcome them?

Summary Points:

  • Hepatitis C is common: 2 million Americans have chronic active infection.
  • Hepatitis C is under-treated: only 1 out of 3 insured Americans diagnosed with hepatitis get treated.
  • New therapy regimens have simplified the treatment of hepatitis C
  • It is time for primary care physicians and advance practice providers to treat most patients with hepatitis C

 

Hepatitis C is incredibly common. Worldwide, 100 million people have been infected and 71 million have chronic liver disease from the virus… that’s 1% of the world’s population! Here in the United States, hepatitis C has infected 1.5% of Americans and 2 million Americans have chronic active infection. More than 75% of infected people have no symptoms and do not realize that they are infected. Once initially infected, two-thirds of people go on to have chronic active infection. Of those, about one out of five will develop cirrhosis about 20 – 30 years after the initial infection.  It causes 19,000 deaths per year in the U.S. It is the most common cause of chronic liver disease and is the leading reason for liver transplantation.

Because it is so common and because most patients are initially asymptomatic, the Centers for Disease Control and the United States Preventive Services Task Force both recommend that all adults > 18 years of age be tested at least once for hepatitis C. The screening test is a simple and widely available blood antibody test. If the screening test is positive, then the next step is a blood hepatitis C RNA test to determine if the patient has chronic active infection. If the RNA test is negative, then the patient has resolved the infection and does not have chronic hepatitis C. But if the RNA test is positive, then the patient has a chronic infection and and should be considered for treatment.

Prior to 1991, hepatitis C was incurable. For the next 20 years, alpha interferon and ribavirin were the only available treatments. However, these drugs had significant toxicity, required a very long duration of treatment, and only resulted in cure of 6% of treated patients. Over the past 10 years, new anti-viral drugs have been developed that can cure the vast majority of patients and only require 8 to 12 weeks of treatment. So, why aren’t more people being treated and cured?

There are not enough hepatologists

Unlike most infections, the treatment of hepatitis C has been the realm of hepatologists, rather than infectious disease specialists or primary care physicians. However, hepatologists are relatively few in number. Most hepatologists do a 1-year hepatology fellowship following completion of a 3-year gastroenterology fellowship. Hepatology is a relatively new subspecialty. In 2006, the first board examination for hepatology was offered and there are only 59 hepatology fellowship training programs in the United States. Currently, there are 7,296 U.S. healthcare providers whose self-described practice is > 50% hepatology. However, the majority of these are gastroenterologists and advance practice providers with only a minority being board-certified hepatologists. There is little financial incentive for gastroenterology fellows to train for an extra year to become hepatologists. A study published in the January 2021 edition of Hepatology Communications found that the median total compensation for hepatologists in the U.S. is $320,728 which was less than the total compensation for gastroenterology assistant professors at $329,600. In other words, the reward for doing a hepatology fellowship is that you make less money than you would had you not done the extra year of training.

Most hepatologists practice at a relatively few large, referral hospitals. Consequently, most hospitals do not have a hepatologist on their medical staff, thus requiring patients with hepatitis C to travel long distances in order to be evaluated and treated by a hepatologist. This has resulted in a geographic barrier for most patients and is a contribution to the low rate of infected patients getting treated.

What is so complicated about treating hepatitis C?

Treating most infections is relatively simple: you get a culture, you give an inexpensive antibiotic for 5-7 days, and you’re done. But treating hepatitis C is a lot more complicated and requires specialized testing, counseling, expensive medications, and laboratory follow-up. The current recommendations for treatment are published jointly by the American Association for the Study of Liver Disease and the Infectious Disease Society of America. This is a lengthly document that is daunting for most non-hepatologists. A Simplified HCV Treatment Algorithm for Treatment-Naive Adults Without Cirrhosis is available that summarizes the recommendations in just 1 page:

Initial evaluation. Once a patients are diagnosed with hepatitis C, they need to undergo a series of laboratory tests including:

    • FIB-4 calculation. This is based on the patient’s age and three blood tests (AST, ALT, and platelet count). An on-line calculator is available to easily determine the FIB-4 score.
    •  Cirrhosis assessment. Cirrhosis can be identified by a FIB-4 score > 3.25, liver biopsy, transient elastography (“Fibroscan”), imaging (CT or ultrasound), clinical evidence of cirrhosis, or laboratory test (such as the “Fibrosure” blood test).
    • CBC
    • Liver function tests
    • Glomerular filtration rate
    • Hepatitis C viral load (HCV RNA)
    • HIV test
    • Hepatitis B surface antigen
    • Pregnancy test (for women of childbearing potential)

Treatment regimens. There are 12 drugs approved to treat hepatitis C and choosing among them can be formidable for non-hepatologists. Different drug regimens are used for different viral genotypes. In addition, several drugs that were approved in the past 10 years have been recently discontinued as more effective newer medications have been introduced. The result is that physicians who do not keep up with new developments in hepatitis C medications on a regular basis often feel uneasy prescribing treatments. Fortunately, there are two currently recommended medication treatments for hepatitis C in patients without cirrhosis, regardless of which genotype of hepatitis C patients are infected with:

    1. Mavyret – glecaprevir (300 mg) + pibrentasvir (120 mg) for 8 weeks
    2. Epclusa – sofosbuvir (400 mg) + velpatasvir (100 mg) for 12 weeks.

Laboratory monitoring. The newer hepatitis C medications do not require routine lab monitoring. This is a significant improvement over previous drugs that required regular blood tests during treatment. Because of the possibility of drug interactions, patients with diabetes taking hypoglycemic drugs should have their glucose levels checked periodically and patients taking warfarin should have their INR levels checked periodically.

Post-treatment testing. 12 weeks after completing treatment, patients should have liver enzymes checked. They should also have a hepatitis C RNA level checked at that time to confirm that they are cured. Those patients who continue to have detectable HCV RNA may require referral to a specialist.

The two drugs used to treat hepatitis C are expensive. Mavyret costs $34,000 for an 8-week course if purchased out of pocket ($13,000 to $16,000 if purchased using GoodRx). Eclusa costs $31,000 for a 12-week course ($11,000 to $19,000 if purchased using GoodRx). Because of their expense, most commercial insurance companies require prior authorization when these medications are prescribed and this poses another barrier for non-hepatologists who are less familiar with the drugs.

The simplified recommended treatment regimen for patients with compensated cirrhosis is very similar to that used for patients without cirrhosis with the main difference being that Mavyret can be used for any genotype of hepatitis C but Eclusa can only be used for genotypes 1, 2, 4, 5, & 6. To make things utterly simple, if prescribing Mavyret, the same management protocol can be used whether or not a patient has compensated cirrhosis.

The simplified treatment regimens are applicable to most patients with chronic hepatitis C infection. Patients not eligible for one of the two simplified regimens will likely require referral to a specialist. This includes patients with:

  • Prior hepatitis C treatment
  • End-stage renal disease
  • Decompensated cirrhosis 
  • HIV or HBsAg positive
  • Current pregnancy
  • Known or suspected hepatocellular carcinoma
  • Prior liver transplantation

So, who should treat hepatitis C?

It is clear that the shear number of Americans infected with hepatitis C is too great for all patients to be treated by the country’s relatively few hepatologists. But fortunately, the newer regimens are very protocolized, making their use much simpler that previous regimens. Because of this, two groups of providers are now in position to treat most patients with hepatitis C.

  1. Primary care physicians. In the past, primary care physicians referred patients with hepatitis C to hepatologists or gastroenterologists for treatment. The drugs were toxic, expensive, and required complex regular monitoring. Furthermore, busy primary care physicians did not want to deal with insurance prior authorization for drugs that they were not very familiar with. The simplicity of the new treatment regimens now makes it easier for primary care physicians. All that is required is creation of a hepatitis C order set in the electronic medical record and a fairly straight forward prior authorization that the office nurses can usually do on their own.
  2. Advance practice providers. Treatment regimens that are based on protocols are ideal for nurse practitioners and physician assistants. This can be a great option for larger primary care groups or for hospitals that designate an advance practice provider to specialize as the go-to hepatitis C treatment provider.

A time for change…

In summary, the number one cause of chronic liver disease and number one indication for liver transplantation can now be cured relatively easily. In communities that lack easy access to a trained hepatologist, the newer hepatitis C treatment regimens lend themselves to implementation by either primary care physicians or advance practice providers. In order to improve the numbers of Americans who are cured of hepatitis C before it results in cirrhosis, we must overcome historical barriers to treatment. Our hospitals can help by sponsoring CME programs to train primary care physicians in hepatitis C management and by financially supporting advance practice providers to specialize in hepatitis C management.

September 22, 2022

Categories
Epidemiology Inpatient Practice Outpatient Practice

2022-23 Influenza Season Predictions

You would think that August would bring a lull in the work of U.S. influenza epidemiologists. But August is when we get some of the most important information that predicts what our winter flu season will look like. And the projections are a little scary this year.

The best predictors of North American influenza in our winter is Australian influenza during our summer. Normally, influenza season in Australia starts in April and runs through October, corresponding with winter in the Southern Hemisphere. What happens with influenza in Australia usually fairly closely matches what happens later in the year in the United States. Thus, by examining the epidemiological data from the Australian Department of Health’s Influenza Surveillance, we can predict when influenza cases will start to be seen, what age groups will be affected, what serotypes will be predominant, and what severity will occur here in the United States and Canada.

Recent U.S. influenza seasons

Over the past 3 influenza seasons, we have seen an inverse relationship between COVID cases and influenza. One of the primary reasons for fewer influenza cases when COVID cases increase is social distancing and mask-wearing to prevent COVID. It turns out that these measures help prevent COVID but they are even more effective to help prevent influenza. We can see that effect in the 2019-20, 2020-21, and 2021-22 influenza seasons.

The graph above shows seven previous influenza seasons in the United States. The 2019-20 influenza season (green line) started off quite severe with sustained high numbers of cases from December through March. The onset of the COVID pandemic in the United States in March 2020 marked the closure of schools, work from home initiatives, and public masking. This coincided with a precipitous fall in influenza-like infections at the end of March.

The 2020-21 influenza season (pink line) was the mildest in recent history with only a small peak in cases of influenza-like infections in November and December. At this time, social distancing and masking were more ubiquitous and the COVID vaccines were not yet widely available. It was not until the summer of 2021 that influenza-like infections began to rise – this was a time when COVID vaccines were widely available and it was generally believed that the end of the COVID pandemic was in sight. Consequently, mask mandates were discontinued, children returned to schools, and workers returned to their workplaces. This created conditions that allowed influenza to have a summer rebound.

The 2021-22 season is in red with red triangles. It peaked in December, much earlier than usual. This coincides with the rise in case numbers of the Omicron variant of COVID that caused people to resume masking and social distancing in December. Once these measures to prevent the spread of COVID went back into effect in December 2021, the frequency of influenza-like infections fell.

The exceptional influenza season was the H1N1 outbreak in 2009-10 when cases began to increase in August and peaked in September and October. This represented an unusually early influenza season that caught physicians off-guard. Making matters worse, this particular H1N1 strain had not circulated for decades and was not predicted to appear that season with the result that it was not covered by that season’s flu shots. These factors together resulted in an unusually large number of cases and large numbers of deaths, particularly among younger people who had no natural immunity to H1N1.

What we are learning from Australia

When will influenza season start?

In the last several years, the influenza season in the U.S. has mirrored the influenza season in Australia that occurs earlier in the year. So, what is Australia telling us this year? First, we are likely to see influenza cases start to increase earlier than normal this season. The graph below shows the last several seasons of positive influenza testing in Australia.

The current influenza season is in red. It began much earlier than in past years and also peaked much earlier. Cases began to rise in late April which corresponds to late October in the Northern Hemisphere. Cases peaked in late May in Australia which corresponds to late November in the U.S. By late July, the Australian influenza season was pretty much over – this would correspond to late January in the United States and Canada. So based on these data, we should expect to see influenza cases start to increase in October 2022 with peak numbers in November and December 2022.

How severe will influenza be this year?

Hospitalization data from Australia predicts that this will be an average year with respect to influenza severity. The graph below shows the number of influenza hospitalizations in Australia over the past several seasons. The current season is in red with hospitalizations mimicking the case number graph above. Hospitalizations began to increase in April and were back to baseline by late July. 

Based on this data, in the United States, we should expect influenza-related emergency department visits and hospitalizations to peak in November and December 2022.

What ages will be most affected?

A unique finding during the current Australian influenza season has been the propensity to affect children. The graph below shows the number of laboratory-confirmed influenza cases by age.

The largest case rates have been in people under age 20. This would predict that U.S. pediatricians will be seeing more influenza than U.S. internists this season.

Will the influenza vaccine cover it?

The vast majority of cases of influenza in Australia were influenza A with unusually few cases of influenza B as shown in the graph below.

The seasonal influenza vaccines in Australia this year included the following serotypes:

Egg-based quadrivalent influenza vaccines:

  1. A/Victoria/2570/2019 (H1N1)pdm09-like virus;
  2. A/Darwin/9/2021 (H3N2)-like virus;
  3. B/Austria/1359417/2021-like (B/Victoria lineage) virus; and
  4. B/Phuket/3073/2013-like (B/Yamagata lineage) virus.

Cell-based quadrivalent influenza vaccines:

  1. A/Wisconsin/588/2019 (H1N1)pdm09-like virus;
  2. A/Darwin/6/2021 (H3N2)-like virus;
  3. B/Austria/1359417/2021 (B/Victoria lineage)-like virus; and
  4. B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.

Although it is still too early to be confident of Australian vaccine effectiveness, we can look at whether the strains seen during the flu season corresponded to the strains covered by the influenza vaccines. In all, 97.4% of influenza A (H1N1) isolates were antigenically similar to the vaccine components. 93.2% of influenza A (H3N2) isolates were antigenically similar to the corresponding vaccine components. And all of the influenza B isolates were similar to the corresponding vaccine components. The U.S. quadrivalent influenza vaccine for the 2022-23 season has identical components to the egg-based quadrivalent influenza vaccine used in Australia. Therefore, it is likely that this season’s flu shots will cover the strains of influenza that we are likely to see in North America.

What we should do in the U.S.

Based on the Australian experience, there are several steps that we should take to prepare ourselves for the 2022-23 influenza season:

  1. Start vaccinating early. It takes about 2 weeks for immunity to develop after a flu shot. Therefore, we should insure that most Americans get vaccinated in September this year if case numbers begin to rise in October as anticipated. If cases peak in late November, as expected, then people who wait until December or January to get vaccinated will have waited too long.
  2. Target kids for vaccination. With children being disproportionately affected by influenza in Australia, it is likely that we will see the same trend in the U.S., particularly as schools return to in-person classes.
  3. Prepare for a surge of hospitalizations in November and December. Normally, this is a low-census period for medical admissions in American hospitals. It is also a time when many people get elective surgeries over the winter holidays and before the end of the calendar year to take advantage of annual insurance deductibles. If the early influenza peak occurs as expected, we may need to institute routine pre-op influenza testing for elective surgeries much as was done with COVID testing during the worst of the COVID pandemic.
  4. Anticipate the effect of Thanksgiving travel. Thanksgiving and Christmas holidays are times when many Americans travel to be with family. The Australian influenza season predicts that U.S. influenza cases may be peaking around Thanksgiving. This could result in holiday travel accelerating influenza spread this year.

No one can predict the influenza season with 100% accuracy. But if historical trends follow, then the U.S. will likely experience a similar season as Australia. Given that most Americans are starting to relax as the COVID-19 case numbers fall, we could be especially vulnerable to influenza this year, particularly if it comes early and preferentially affects children as expected.

August 10, 2022

Categories
Epidemiology Inpatient Practice Outpatient Practice

Preparing For Monkeypox

Monkeypox is spreading rapidly across the United States. There are steps that every hospital and every medical practice need to take now to protect patients and healthcare workers. As of yesterday, there were 6,326 known cases and undoubtedly considerably more that have gone undiagnosed. Infected patients will be presenting to your hospital, office practice, and emergency department in the next few weeks.

Where did monkeypox come from?

Monkeypox is a type of orthopoxvirus that is related to smallpox. It was first found in monkeys in a Danish research lab in 1958. The virus is not unique to monkeys, however, and has since been found in various mammalian species in Western Africa. Humans have sporadically become infected after contact with infected animals. Although most human cases have been reported in Africa, there have been occasional clusters of cases in other countries over the past 20 years.

One of the most notable clusters occurred in the United States in 2003 when 47 Americans became infected with monkeypox that originated from an infected giant Gambian rat that had been imported from West Africa for sale as an exotic pet. The rat then infected a group of captive prairie dogs that were also sold. Of the 47 cases, all but one person acquired monkeypox directly from an infected animal. In only one case was there human-to-human transmission (from a child to mother).

In July 2021, a traveler from Nigeria was diagnosed with monkeypox in Texas. In November 2021, a second travel-related case was diagnosed in Maryland. The current outbreak began on May 7 2022 when a travel-related case was diagnosed in the United Kingdom. Later that month, cases were diagnosed in Massachusetts and New York. Since that time, the number of cases has been growing exponentially. Because of lack of familiarity with the disease and difficulty in obtaining diagnostic tests, it is likely that most cases initially went undiagnosed and that the true number of U.S. cases is much higher.

How is it spread?

Because the initial cases were reported in gay men, there is a misconception that monkeypox is a sexually-transmitted disease, like syphilis or HIV. It is not. Monkeypox is primarily spread by skin-to-skin contact, similar to MRSA. Thus, the initial cases occurred in gay men not because they had sex with other men but because they had close skin contact with infected men. Although the virus can also be spread by respiratory secretions, it is not as contagious as other respiratory viruses, such as COVID. Therefore, it requires closer and/or more prolonged exposure for airborne transmission. However, because it can be spread by both contact and airborne routes, both contact and airborne isolation is recommended for inpatients. Other points to know about monkeypox transmissibility:

  • It can be transmitted to and from pets
  • Bed linens, clothing, eating utensils, and drinking glasses can be infectious
  • Infected persons remain contagious until scabs have all crusted over and a layer of new skin has developed
  • Usual hospital disinfectants can eliminate the virus
  • The average incubation period is 7 days and persons can be contagious during the incubation period

Signs, symptoms, and diagnosis

As of today, most cases have been in men who have sex with men. However, since monkeypox virus is spread by skin contact (rather than sexual contact), the demographic of infected people is expected to rapidly change in the next few weeks. A person does not have to be gay or to even have sex with another person to become infected. Common signs and symptoms reported in a recent article in the New England Journal of Medicine include:

  • Rash – 95% (with 64% having <10 lesions)
    • Anogenital – 73%
    • Trunk or limbs – 55%
    • Face – 25%
    • Palms or soles – 10%
  • Fever – 62%
  • Lethargy – 41%
  • Myalgia – 31%
  • Headache – 27%
  • Pharyngitis – 21%
  • Lymphadenopathy – 56%

Because 98% of the 528 patients reported in this article were either gay or bisexual men, the incidence of anogenital lesions may be higher than in other patients. The rash is most frequently described as vesiculpustular (53%) but can present as a macular rash (4%), multiple ulcers (19%), or single ulcer (11%). Additional photos of the rash can be found on the CDC website.

Image: UK PHS

The diagnosis is made using swabs of skin lesions – preferably 2 swabs, each from a different lesion. Testing is done by orthopoxviral PCR and results can be available in 2-3 days. Specimen handling procedures can vary from lab to lab so be sure to follow specific instructions from the lab that the sample will be sent to. Until recently, testing was only available through the CDC and results could take 1-2 weeks. Now, testing is available through local health departments as well as several commercial labs making it possible to submit specimens as a regular send-out test from U.S. hospitals. Serology testing is also available through the CDC but the turn around time is 14 days.

Treatment

In cases reported during this outbreak, the mortality rate is low and in most people, the disease is self-limited and of mild-moderate severity. Consequently, to date, only a minority of patients receive anti-viral treatment (5% in the New England Journal of Medicine study). Certain patients are at higher risk of severe disease and these patients should be targeted for treatment:

  1. Those with severe disease (hemorrhagic disease, confluent lesions, sepsis, encephalitis, or other conditions requiring hospitalization)
  2. Immunocompromised persons
  3. Children (particularly those < 8 years old)
  4. Persons with exfoliative skin disorders (atopic dermatitis, psoriasis, etc.)
  5. Pregnant or breast-feeding women
  6. People with monkeypox complications (secondary bacterial skin infection; severe gastroenteritis; bronchopneumonia; etc.)
  7. Involvement of anatomic areas at risk of permanent injury (eyes, mouth, anus, genitalia, etc.)

The treatment of choice is tecovirimat (TPOXX). This drug is currently only available through the Strategic National Stockpile. Physicians have to contact either their state health department or the CDC (770-488-7100 or email at Poxvirus@cdc.gov). The dose is 600 mg PO BID x 14 days given within 30 minutes after a full meal of moderate/high fat. Drug side effects can include headache and nausea. TPOXX may reduce blood levels of midazolam and may increase levels of repaglinide.

Other treatments that may be effective but have less scientific data to support their use include intravenous Vaccinia immune globulin, cidofovir, and brincidofovir.

Vaccination

There are two vaccines available that are effective against monkeypox.Both of these are live virus vaccines (unlike most routine vaccines such as COVID vaccines or flu shots). The JYNNEOS vaccine contains a live non-replicating virus. The ACAM200 vaccine contains a live replicating virus.

JYNNEOS is given as 2 injections with the second dose given 4 weeks after the first dose. Full immune response develops 2 weeks after the second dose. The most common side effects are fatigue, headache, and myalgias. Unlike ACAM200, the JYNNEOS vaccine is not contraindicated in immunocompromised persons, pregnancy, or HIV infection.

The ACAM200 vaccine contains a live replicating Vaccinia virus that is given as a single dose. Because ACAM200 contains a replicating virus, it is contraindicated in immunocompromised persons, HIV infection (regardless of immune status), pregnancy, persons with heart disease, children < 1 year old, persons with eye conditions requiring topical steroids, and persons with a history of exfoliative skin disorders (eczema, atopic dermatitis, etc.). Although most side effects of ACAM200 are mild, 1 out of every 175 persons receiving it develop myocarditis or pericarditis. It takes 4 weeks for maximal immune development after vaccination.

Both vaccines are available from the Strategic National Stockpile. Because of limited supply (particularly of the JYNNEOS vaccine), widespread vaccination of the public and of most healthcare workers is not currently advised. Currently, the CDC only recommends pre-exposure prophylaxis vaccination for people at very high-risk of exposure (primarily laboratory workers performing diagnostic testing for monkeypox). The CDC anticipates expanding the indications for pre-exposure prophylaxis vaccination to broader populations as supplies of the vaccine increase in the future.

Most monkeypox vaccines are currently being given for post-exposure prophylaxis. When given within 4 days of exposure, vaccination can prevent the disease and when given between 4-14 days after exposure, vaccination can reduce the severity of monkeypox infection. Persons who should be prioritized for vaccination include:

  • Known contacts who are identified by public health via case investigation, contact tracing, and risk exposure assessments
  • Persons with a sexual partner in the past 14 days who was diagnosed with monkeypox
  • Persons who have had multiple sexual partners in the past 14 days in a jurisdiction with known monkeypox
  • Healthcare workers with a high risk exposure such as:
    • Unprotected contact with skin, lesions, or bodily fluids of a patient with monkeypox
    • Aerosol-generating procedures without N-95 mask and eye protection

Healthcare workers with an intermediate risk exposure should be offered post-exposure vaccination on a case-by-case basis and after discussion of the risks and benefits with the exposed healthcare worker. Intermediate risk exposures include: (1) being within 6 ft of an infected unmasked patient for more than 3 hours when the healthcare worker was not wearing a mask and (2) contact with patient’s clothing, skin lesions, or soiled linens while wearing gloves but not wearing a gown.

Healthcare workers with a low risk exposure generally do not require post-exposure vaccination. Low risk exposures include: (1) entering an infected patient’s room without wearing eye protection, (2) being in a room with an infected patient while wearing gown, gloves, eye protection and at least a surgical mask or (3) being within 6 feet of an unmasked patient for less than 3 hours without wearing at minimum, a surgical mask. Additional information about managing exposed healthcare workers can be found on the CDC website.

Isolation recommendations for infected outpatients

The vast majority of people infected with monkeypox can be treated as an outpatient. In order to control the spread of monkeypox in the community, it is essential that infected persons adhere to proper isolation procedures at home for the duration of infectivity. Infected persons remain contagious for 2-4 weeks. Isolation can be discontinued when until all symptoms have resolved, including full healing of the rash with formation of a fresh layer of skin in areas of vesicles and ulcers. Isolation practices include:

  • Remain in the home with no contact with other people
  • Avoid close physical contact, including sexual and/or close intimate contact, with other people.
  • Avoid sharing utensils or cups. Items should be cleaned and disinfected before use by others.
  • Do not share items that will be worn or handled with other people or animals.
  • Wash hands often with soap and water or use an alcohol-based hand sanitizer, especially after direct contact with the rash.
  • Avoid contact with pets
  • Launder and disinfect items that have been worn or handled and that have been touched by a lesion
  • Do not dry dust or sweep as this may spread the virus
  • Do not wear contact lenses (because of risk of spreading the virus to the eyes)
  • Clean and disinfect surfaces with an Environmental Protection Agency-registered disinfectant. If other household members are responsible for cleaning, they should wear a medical mask and disposable gloves, at a minimum
  • If the infected person must leave home for medical care or for an emergency, cover the lesions, wear a well-fitting mask, and avoid public transportation

Infection control in the outpatient office

Although not as contagious as COVID, there is still a risk of an outpatient with monkeypox infecting other patients or healthcare workers. All employees of outpatient medical practices need to be familiar with monkeypox infection control practices to minimize the risk of spreading the infection. Specific measures include:

  • Utilize telemedicine for patients known or suspected to have monkeypox
  • If using pre-registration procedures in advance of patients arrival to the office, include questions about monkeypox signs and symptoms
  • Place patients with known or suspected infection in a private exam room with the door closed. These patients should be escorted from the building entrance directly to the exam room and should not wait in a waiting area
  • Have patients with known or suspected infection wear a surgical face mask with areas of skin rash covered
  • Healthcare workers entering an exam room of a patient with known or suspected infection should wear a disposable gown, gloves, eye protection, and an N-95 mask
  • Use disposable paper exam table drapes and patient gowns. Dispose of these materials using medical waste trash bags and do not shake out gowns or drapes
  • When the patient leaves, sanitize the room surfaces. Most standard hospital disinfectants will suffice. A list of cleaning products can be found on the Environmental Protection Agency website.

Infection control in the hospital

Only a small minority of patients will require admission to the hospital. Some of the indications for admission include pain management (such as severe anorectal pain), soft-tissue superinfection, pharyngitis limiting oral intake, eye lesions, acute kidney injury, myocarditis, and public health infection-control purposes. Infection control measures for hospitalized patients include:

  • Place patients with known or suspected infection in a private room with private bathroom and with the hallway door closed (negative airflow is not required)
  • Transport and movement of the patient outside of the room should be limited to medically essential purposes
  • When patients must be transported outside of their room, they should wear a medical mask and have any exposed skin lesions covered with a sheet or gown
  • Healthcare workers should wear a disposable gown, gloves, eye protection, and an N-95 mask
  • If aerosol-generating procedures are to be performed (e.g., intubation or bronchoscopy), use an airborne isolation room
  • Environmental services such as dry dusting, sweeping, or vacuuming should be avoided in rooms housing infected patients
  • Disposables such as paper towels should be disposed of using medical waste trash bags
  • Use surface cleaning products that are believed to be effective for emerging viral pathogens  (listed on the Environmental Protection Agency website)
  • Do not shake soiled linen, towels, and gowns. Soiled items should be enclosed in a proper laundry bag for transport to the laundry and staff handling laundry from infected patients should wear proper personal protective equipment as recommended by the CDC
  • Visitors should be limited to those essential for the patient’s care and wellbeing

Don’t think of monkeypox as a sexually-transmitted disease

Because the current outbreak has so far primarily affected men who have sex with men, monkeypox has developed a mistaken stigmata of being a sexually transmitted disease. It is important that we educate our patients and our co-workers that it is not necessary to have sex with someone to become infected with monkeypox. Measures that prevent spread of HIV and syphilis will not work with monkeypox. Abstinence will not stop it. Condoms will not stop it.

One of our best weapons against monkeypox is education.

August 3, 2022

Categories
Electronic Medical Records Medical Malpractice Outpatient Practice

The REMS Program And Abortion Laws – What Every Physician Needs To Know

If you or the doctors at your hospital prescribe any of these 11 drugs and live in states that have abortion laws, you need to take action IMMEDIATELY. The medical malpractice implications of teratogenic drugs (those that can cause embryofetal damage) are changing and physicians who prescribe these drugs need to protect their women patients from fetal damage and to protect themselves against future lawsuits.

The FDA created the REMS program (Risk Evaluation and Mitigation Strategy) in 2007 as a way to be sure that physicians take appropriate precautions when prescribing certain high-risk drugs. Typically, the REMS program will recommend physicians to have specific training and certification before being allowed to prescribe these drugs. The problem is that hospitals and pharmacies rarely verify that a physician has been certified for drugs on the REMS list and as a consequence, many physicians prescribe them without having the proper certification. Currently, the FDA lists 60 such drugs on the REMS website. I am most familiar with the REMS drug, mycophenolate mofetil. During my career, I have prescribed mycophenolate… a lot of mycophenolate… typically as an immunosuppressant for various lung diseases.

Mycophenolate, a REMS medication

Mycophenolate mofetil is often sold under the brand names CellCept or Myfortic. It is commonly used in patients who have undergone organ transplant to prevent rejection of those organs. It is also commonly used as an immunosuppressant drug to treat various autoimmune diseases. When used properly, it can be life-saving and is considerably safer than older immunosuppressant drugs, such as cyclophosphamide. In many patients, it is also safer than corticosteroids such as prednisone. The biggest problem with mycophenolate is that it is highly teratogenic. Overall, about half of women who become pregnant while taking mycophenolate will have a miscarriage and 1 out of every 4 live births have serious congenital malformations. Because of the very high risk of embryofetal damage, mycophenolate was added to the FDA’s REMS drug list in 2012.

The mycophenolate REMS requirements are:

  1. Physicians need to apply to the mycophenolate REMS website and undergo an on-line training program before prescribing mycophenolate.
  2. Once certified to prescribe mycophenolate, physicians must educate patients about the risk of miscarriage and fetal harm.
  3. Physicians must insure that women of childbearing potential use adequate contraception – preferably either vasectomy, tubal ligation, or an intrauterine device. In the absence of any of these 3 methods, women must use 2 forms of other approved contraception (for example, birth control pills + condoms).
  4. Women should have a pregnancy test at every office visit.
  5. Woman should be counseled about emergency contraception (Plan B) in the event of intercourse without adequate contraception.
  6. Women must be given the printed REMS information about mycophenolate precautions.
  7. Women should sign an agreement form acknowledging that they understand the risks of mycophenolate and agree to the requirements of the REMS program (note: this requirement was discontinued in January 2021).

All too often, I would see women of child-bearing potential in my office who had been started on mycophenolate by other physicians and who had never been informed about the REMS program. Frequently, these women were not using adequate contraception and were not undergoing regular pregnancy testing. Until last month in Ohio, if a woman became pregnant while taking mycophenolate, we could recommend pregnancy termination. Now, that is no longer an option if it is more than 6 weeks after her last menstrual period and the Ohio legislature has signaled that later this year, it intends to make pregnancy termination illegal in all pregnancies from the time of conception.

The heightened risk of malpractice lawsuits

The implication of anti-abortion laws, such as Ohio’s, is that if a woman becomes pregnant while taking mycophenolate, then there is a 25% chance that her baby will have severe congenital deformities. Children with these deformities can require life-long care and can be very expensive for families. Women taking mycophenolate because they have had an organ transplant or because they have chronic diseases such as lupus are generally not in a good position to provide care for the life of a child with serious birth defects and usually do not have the financial resources necessary for that care. This is especially true for my patients who have undergone lung transplant – the life expectancy after transplant averages about 6 years so these women will not be alive to care for a child with severe deformities.

We live in a litigious society. When faced with the birth of a child who will never grow up to be a normal adult and will incur large healthcare costs, women (or their widower spouses) will seek financial compensation to pay for these costs. Every personal injury attorney in the country knows that the person to name in a lawsuit is the person who has the most money. Hospitals and physicians are the ones with the most money. If a physician prescribed mycophenolate without having REMS certification to prescribe it or if there is no documentation that a woman was educated about pregnancy risks with mycophenolate, then that physician will be highly vulnerable in a malpractice suit.

The best defense for physicians is to get REMS certification before prescribing mycophenolate and adhere to the REMS requirements when prescribing it to any woman with child-bearing potential. The best defense for hospitals is to ensure that every physician prescribing mycophenolate has REMS certification. Electronic medical records make it easy for hospitals to determine which of their physicians are prescribing mycophenolate or other REMS drugs.

What other drugs are on the REMS list?

There are a variety of reasons that the FDA may put a drug on the REMS list. Some are on because of a high risk of anaphylaxis (Palforzia). Some are on because of a high risk of neurological toxicity (Abecma). Some are on the list because of risk of neutropenia (clozapine). Others are on the list because of a risk of over-sedation or addiction (buprenorphine). Of the 60 drugs on the REMS list, 11 are on the list because of the risk of embryofetal toxicity. The following is a list of these 11 drugs and what physician specialties are likely to be prescribing them.

A recent article in the American Journal of Obstetrics & Gynecology lists 141 drugs that are definite teratogens and 65 drugs that are considered to be potentially teratogenic. Of these 206 drugs, only 11 are included on the REMS list. However, the risk of embryofetal toxicity exists with all of these drugs and therefore the risk of medical malpractice lawsuits exists should a woman become pregnant while taking any medication known to be teratogenic and then develops fetal abnormalities.

Currently, 3% of all abortions performed in the United States are because of fetal abnormalities. This works out to about 28,000 per year. In states that ban abortion, these fetuses will go on to be infants with severe birth defects. The implication is that in the future, there will be potentially thousands of new malpractice suits filed each year against physicians who will be blamed for these birth defects because they prescribed a teratogenic drug to a woman who could not legally have her pregnancy terminated.

What physicians need to do right now

In medicine, doctors recognize that prevention is the best cure. The same goes for malpractice lawsuits. The best time to prevent a malpractice suit about a birth defect is before the woman becomes pregnant. To that end, there are measures that all physicians practicing in abortion-ban states should take now:

  • Know which drugs are teratogenic. The recent list from the American Journal of Obstetrics & Gynecology is a good starting point.
  • If you prescribe one of the 11 teratogenic drugs on the FDA’s REMS list, get your REMS certification and follow the REMS requirements.
  • If you prescribe a teratogenic drug that is not on the REMS list, develop a process for educating women of child-bearing potential about the risks of the drug.
  • Document, document, document. Include information in your office notes documenting patient discussions about drug teratogenicity, about contraception advice, and about any printed information that you gave them. 
  • Consider signed acknowledgement forms. In the past, this was a requirement of the mycophenolate REMS program. Even though it is no longer required by REMS, a signed form scanned into the electronic medical record is still a good practice since it can provide very strong malpractice defense.
  • Get comfortable recommending contraception. I have become at ease discussing contraception with my patients and their partners. If the woman is done having children, vasectomy is usually the safest and most effective option. For other women, I am a proponent of IUDs and although I do not place them myself, I know who to refer women to in order to get one. 
  • Educate women about Plan B. The “morning after pill” is available at pharmacies over the counter without a prescription and is effective up to 3 days after unprotected intercourse. Include information about Plan B in the educational materials you give patients when prescribing any teratogenic drug.
  • Understand your state’s abortion laws. In some states, it is (or will be) illegal for a physician to even discuss abortion with a woman or to advise her to travel to another state where abortion is legal. Be very careful what you write in the chart. A note in the electronic medical record stating: “She is 6 weeks pregnant while taking mycophenolate so I recommended she go to the Acme Abortion Clinic across the state line” could be your invitation for a prison sentence and revocation of your medical license. 
  • Do a malpractice insurance check-up. For physicians in Ohio who care for adults, there is a 1-year statute of limitations for filing a malpractice lawsuit. But for cases involving children, that statute of limitation extends to 1-year after the child’s eighteenth birthday. In other words, a physician who prescribed a teratogenic drug to a pregnant woman can be sued by the child 19 years later. Be sure that you either have a comprehensive claims-made policy or a tail coverage policy that will provide coverage long after you retire or leave your practice.
  • For hospital medical directors and administrators, use your electronic medical record’s prescribing database to identify physicians who prescribe REMS drugs and require that those physicians be REMS-certified.
  • For medical schools, education during pharmacology courses about teratogenicity and about the REMS programs has suddenly become considerably more urgent.

Abortion prohibitionists have long set their sights on laws to criminalize abortion. There are a myriad of unintended consequences of banning abortion and many of the the socioeconomic consequences will not be fully recognized for several years. For physicians, waiting several years to protect against medical malpractice suits for prescribing a teratogenic drug will be too late. The time for physicians and hospitals to protect their patients and themselves is right now.

July 16, 2022

Categories
Epidemiology Outpatient Practice

Abortion And The Five Whys

If you know four women, then statistically, one of them has had an abortion. The current Supreme Court recently overturned the opinion of a previous Supreme Court and now permits states (or the U.S. Congress) to make abortion illegal. By applying the “5 Whys” approach to abortion, we can learn the root causes of abortion and how to reduce the number of abortions without criminalizing abortion. We can also uncover the hidden costs of abortion bans.

The five Whys

The 5 Whys originated in the early 1900’s in Japan as a method to improve textile production. What does 100-year-old Japanese loom manufacturing have to do with abortion? As it turns out, a lot. Sakichi Toyoda was a Japanese industrialist who invented an automatic power loom that at the time was the most advanced weaving device in the world. He went on to found Toyota Industries, the manufacturer of Toyota automobiles. To address quality issues in manufacturing, he created the “Five Whys” approach. This utilized asking a series of five “Why” questions to determine the cause-and-effect relationship with any manufacturing process. This approach has been incorporated in Kaizen, lean manufacturing, and Six Sigma. It is also a key component of root-cause analysis that we use in hospital quality improvement today.

An example of the Five Whys is as follows: A hospital medical director learns from the infection control department that there have been a cluster of Clostridium difficile infections in certain rooms in the intensive care unit. To understand the root cause, the medical director asks a series of Why questions:

So, the solution to the hospital’s C. difficile problem was not to close ICU rooms or fire the housekeeping employee. The solution was for the purchasing department to buy the correct spray dispensers used with hypochlorite disinfectants. If all 5 of the “Why” questions had not been asked, the root cause would never have been determined and the C. difficile outbreak would not have been eliminated.

Asking 5 Whys can sometimes be overly simplistic. In the C. difficile example, there is one root cause identified at the fifth Why. Sometimes the root cause can be found at the second Why. Sometimes it takes 6 Whys. And sometimes, there are multiple root causes that can be identified at several levels of the Whys. The point is that it is necessary to continue to ask “Why” until the root causes are all identified.

Our country has taken a superficial approach to the issue of abortion. We have let our emotions stop at the first “Why” and have not done an adequate root-cause analysis of abortion. In half of our nation’s states, politicians have determined that many women are getting abortions and asked the first Why. The answer that they found is that there are doctors willing to perform abortions. Their solution has been to criminalize abortion. The problem is that they have not asked the other “Whys”. With abortion, the root causes are complex and can be found at each level of Whys.

The demographics of abortion in the U.S.

Before we can apply the 5 Whys to the issue of abortion, we first must examine the demographics of abortion. The World Health Organization reports that worldwide, about 73 million abortions are performed each year. This equates to 29% of all pregnancies ending in abortion. In the United States, the Centers for Disease Control reports that there were 629,898 abortions performed in 2019 (the latest year data is available). The Guttmacher Institute (which uses a more thorough accounting method) reports that there were 930,160 abortions performed in 2020. This works out to 1 out of 5 pregnancies in the United States ending in an induced abortion. The U.S. accounts for about 1.3% of abortions worldwide. Additional epidemiological facts include:

  • 24% of women under age 45 years old have had an abortion.
  • The most common reason for having an abortion is not being ready to have a child (25%), followed by unable to afford a child (23%), done having children (19%), not wanting to be a single mother (8%), not mature enough to raise a child (7%), interference with education or career (4%), maternal health problems (4%), fetal abnormalities (3%), and rape (< 0.5%).
  • Most women undergoing abortion are in their twenties: 34% of abortions are in women age 20-24 and 27% of abortions are in women age 25-29.
  • 12% of abortions are performed in teenagers with 3.2% under age 18.
  • Black and Hispanic women have disproportionately more abortions than White women. Black women account for 28% of abortions but Blacks make up 13% of the U.S. population. Hispanic women account for 25% of abortions but Hispanics make up 19% of the population. White women account for 39% of abortions but Whites make up 76% of the population.
  • 38% of women undergoing abortion reported no religious affiliation; 24% are Catholic; 17% are mainline Protestant; and 13% are evangelical Protestant.
  • 86% of women undergoing abortion are unmarried and 60% already have at least one child.
  • 75% of women undergoing abortion are low income: 49% live below the Federal poverty level and an additional 26% are at 100% – 199% of the Federal poverty level.
  • 53% of women paid for their abortion out-of-pocket. The average cost of a surgical abortion is $508 and of a medication-induced abortion is $535.
  • 51% of women were using birth control in the month that they became pregnant: 24% were using condoms and 13% were using oral contraceptive pills.
  • 88% of abortions occur in the first 3 months of pregnancy and 67% occur in the first 2 months of pregnancy.
  • 54% of abortions are currently performed by medication (mifepristone and misoprostol).
  • The largest number of abortions were performed in Texas, California, New York and California, however, these are also the states with the highest populations.
  • The states with the highest rates of abortion per 100,000 population are New York, New Jersey, and Maryland.

The demographics of women who undergo abortion is remarkably similar to the demographics of infant mortality. The United States has one of the highest infant mortality rates in the world – we rank 33rd out of 36 OECD countries with only Chile, Turkey, and Mexico having higher infant mortality rates. In states where women no longer have access to abortion, it follows that infant mortality rates will rise. Many of the states poised to criminalize abortion (with either outright bans or 6-week laws) already have very high infant mortality rates:

Applying the 5 Whys to abortion

Once we understand the demographics of abortion in the United States, we can apply the 5 Whys:

  1. Why are there abortions in the U.S.?
    1. Answer: because doctors performed abortions.
  2. Why are doctors performing abortions?
    1. Answer: because a lot of women requested them due to unwanted pregnancies.
  3. Why did women have unwanted pregnancies?
    1. Answer: because effective birth control was not used.
  4. Why wasn’t effective birth control used?
    1. Answer: most commonly because effective birth control methods were too costly and there were cultural barriers to their use.
  5. Why were there cultural barriers to birth control?
    1. Answer: because men and women were not adequately educated about birth control before they had sex.

If we stop after the first why, then the solution to humans having so many abortions is to make abortion illegal and prosecute doctors who perform abortion. But this will ultimately fail. History has showed us that in the past, when abortion was illegal, women still found ways to have abortions, in other words, making it illegal will not make abortions go away. This is especially true today since prior to 10 weeks gestation, a 2-pill form of abortion is safe and effective (mifepristone and misoprostol). Currently, these drugs are approved by the FDA, are readily available, and account for the majority of abortions in the U.S. Even if a future conservative U.S. Congress bans their use, these drugs will continue to be available as street drugs and from international sources – if the war on drugs cannot prevent a marijuana joint from being smuggled into the country for street sale, how can one expect the government to prevent 2 small pills from being smuggled in?

If we stop with the second why, then the solution is to prevent women from having intercourse. There are 3 main instincts that a species must have to keep from becoming extinct: (1) an instinct to eat, (2) an instinct to keep from being eaten, and (3) an instinct to procreate. To stop Homo sapiens from having sex is to somehow overcome one of the most powerful instincts that our species has had for the past 300,000 years and led to us being the dominant species on the planet. It just won’t work. We can pass laws and we can invoke religious decrees but neither is more powerful than instincts embedded in our genes.

At the third why, we find that about half of abortions were in pregnancies where no birth control method was used. In another 37%, inferior birth control methods were used (condoms and birth control pills). Condoms are notoriously unreliable and it is way too difficult for any person to remember to take a birth control pill every single morning for years at a time. IUDs are far more reliable but not all women can tolerate them. Vasectomies are even more effective but that would require men to take more responsibility than many of them want to – I’ve fought an uphill (and usually unsuccessful) battle with many husbands of my patients for who I prescribed teratogenic medications for their advanced lung disease and in who an unwanted pregnancy would likely result in the wife’s death or in severe fetal deformity. However, I suspect that if men had to choose for themselves between the discomfort of a vasectomy versus the discomfort of pregnancy, labor, and delivery, 100% of them would take the vasectomy.

At the fourth why, we find barriers to the use of birth control in the way of cost and cultural discouragement. The cost of contraception is directly proportional to the effectiveness of contraception. Calendar watching is free but is miserably ineffective. Condoms cost about a dollar each but are not much more effective. Nor are diaphragms which are about $25 each. Birth control pills cost about $180 per year and an IUD costs about $800 (but IUDs can last 12 years resulting in a depreciated cost of $65 per year). A hormonal implant costs about $1,000 and lasts for 3 years. A vasectomy costs about $1,000 and a tubal ligation costs about $6,000 with both giving a lifetime of highly effective birth control. The over the counter morning-after pill, Plan B (levonorgestrel), costs $45 and is about 85% effective. Because the majority of women undergoing abortion are low income and a large number have no health insurance, birth control costs are a major contribution to the number of abortions performed in the U.S. The sad reality is that even the most expensive form of birth control is less expensive than the average $8,800 cost to deliver a baby, and that does not even include the indirect cost of maternity leave and raising the child if not put up for adoption.

Even when men and women have health insurance or can afford to buy contraception out of pocket, there are numerous cultural barriers to using contraception. For example, the Catholic Church forbids its members to use any form of contraception and considers contraception to be a sin. The underuse of contraception is perhaps the reason why Catholics have disproportionately more abortions than women of other religions – 24% of women who undergo abortion are Catholic whereas only 21% of the American population is Catholic. Parenthetically, it is notable that 7 of the 9 current Supreme Court Justices are Catholic or were raised Catholic; all 6 of the justices voting to overturn Roe v. Wade are Catholic. Old-Order Amish communities also forbid contraception. Most other religions permit the use of contraception but usually only within the context of marriage.

At the fifth why, we find lack of education. In most states, sex education curricula decisions are left to local school boards. Consequently, there is enormous variation in what is taught in different school districts. Children in many religious-based schools get no education about contraception and children who are home-schooled may get no formal sex education at all. The Centers for Disease Control recommends that children be taught a minimum of 20 sex education topics but fewer than half of American high schools teach all 20 of these. The Guttmacher Institute reports that U.S. adolescents in 2019 received less sex education than in 1995. In short, our educational system, both public and private has failed in sex education and this failure is an important contribution to the number of abortions in the U.S.

So, how do we reduce the number of U.S. abortions?

First, we will never eliminate all abortions nor should abortions be illegal. As a medical student, I assisted in the delivery room with a 12-year-old who was delivering a baby… no 12-year-old should ever have to deliver a baby. Forcing a child, a rape victim, or an incest victim to carry and deliver a baby is truly punishing the victim. In addition to these situations, there will always be unplanned sexual encounters and contraception method failures.

Infrequently entered into the discussion is that in the half century since Roe v. Wade was decided, there have been enormous advances in neonatology that have saved the lives of thousands of children who would have previously died in infancy. However, these same advances have also allowed medical science to keep on life support those with severe fetal deformities and chromosomal abnormalities with no reasonable chance of ever having normal cognitive development or independent function. Fifty years ago, in the pre-Roe era, they would have died within minutes or hours of delivery. These fetal abnormalities can largely be detected by a combination of ultrasound and maternal serum screening tests, neither of which existed in the pre-Roe era. Currently, serious fetal abnormalities account for up to 3% of all abortions. With no access to abortion, these fetuses will now be born and can live for weeks, months, and sometimes even years requiring ventilators, feeding tubes, and 24-hour care. The CDC reported that the annual inpatient hospitalization costs of severe birth defects was $22.9 billion in 2013. That number will be considerably higher when these fetuses can no longer be legally aborted.

In all of these situations, an unwanted pregnancy puts unwanted health and financial demands on the woman. It also places her at a competitive disadvantage in the workplace that can result in gender income disparities and barriers to professional advancement. Adoption is often offered as the solution to unwanted pregnancies but the reality is that most women do not put the child of an unintended pregnancy up for adoption. There are approximately 2.8 million unintended pregnancies in the U.S. every year. The National Council for Adoption reports that in 2020, there were 55,659 public adoptions in the U.S. The USDA estimates that the cost to raise a child to age 18 is $284,000 and this does not include the indirect cost of career development impediment faced by the (often single) mother raising that child.  It may take 2 people to create a pregnancy but it is the woman who pays most of these costs, not the man. Simply making abortions illegal does nothing to address this and in fact, makes it considerably worse.

We can (and should) reduce the number of abortions in the United States. If she didn’t have to have an abortion, no woman would want to have an abortion – it’s not like it is a fun experience. No woman says “What should I do to have fun this weekend? Maybe go to a concert, or go see a movie, or maybe get an abortion?” America’s abortion problem is an unwanted pregnancy problem. The most effective way to reduce the number of abortions is to reduce the number of unwanted pregnancies and for that, we need to turn back to the five Whys and the following conclusions:

  1. We cannot rely on the fantasy of abstinence and chastity. $3.2 billion in child sex lawsuit settlements says that this didn’t work for a lot of Catholic priests so why should it work for everyone else?
  2. We need to improve and standardize sex education and contraception education in our private schools, public schools, and home schools.
  3. Birth control (including vasectomy) should be free for all Americans – 135 women could have an IUD for a year for the same taxpayer cost of one woman on Medicaid delivering an unwanted pregnancy.
  4. We cannot base laws and social expectations founded on unrealistic religious doctrines that defy the most basic elements of human nature.

What do the 5 Whys tell us about the hidden costs of abortion bans?

On the day that the current Supreme Court overturned Roe v. Wade, abortion became completely illegal or illegal after 6-weeks gestation in many states and undoubtedly will become illegal in more states in the months to come. There are hidden costs to everything and by looking at the 5 Whys of abortion, we must be prepared to pay for the hidden costs of abortion bans:

  1. Localities with laws making abortion illegal must also have counterbalancing laws mandating paid maternity leave, government-paid maternal healthcare, and government-paid childcare. Anything less is state-sponsored victimization of women.
  2. Localities with laws making abortion illegal must also have laws providing for the post-delivery healthcare costs of fetuses that have severe fetal deformities and chromosomal abnormalities.
  3. Localities with laws making abortion illegal after 6 weeks of gestation must also have laws providing unlimited free pregnancy testing so that pregnancy can realistically be identified before 6 weeks.
  4. Localities with laws making abortion illegal must be prepared for an increase in infant mortality and should begin investment in programs to reduce infant mortality.

I’m like most Americans

Being retired gives me a freedom that I never had when I was a practicing physician. I no longer have to withhold my opinions about controversial issues for fear of offending my patients who hold different viewpoints or fear of incurring the wrath of deans, department chairs, and hospital CEOs. I can now freely say what I believe.

Abortion is subject to basic economic supply and demand principles like most everything else in life. Making abortion illegal only addresses the supply side and does nothing for the demand side. Focusing only on supply was ineffective with Prohibition in the 1920’s and has been ineffective with marijuana laws today. Economics tells us that reducing supply of a product or service without reducing demand will only increase the price of that product or service – reducing supply alone does not eliminate demand.

When it comes to abortion, I believe it should be legal. But I also believe that we do too many abortions. In short, I’m like most Americans.

The way to reduce demand for abortions is to reduce unwanted pregnancies. By doing a root cause analysis of abortion in the United States using the 5 Whys, we can identify how to reduce the number of abortions by reducing unwanted pregnancies. The 5 Whys also uncover the unintended consequences and hidden costs of abortion bans. Our societal goal should be to make abortions fewer and not to make abortions felonies.

July 2, 2022

Categories
Emergency Department Outpatient Practice

Is The Albuterol Inhaler Obsolete?

For decades, the mainstay of asthma treatment has been a daily maintenance steroid inhaler coupled with an as-needed albuterol rescue inhaler. New evidence suggests that there are better options than albuterol and that it may be time to retire the albuterol inhaler for asthma.

Summary Points:

  • The 2022 Global Initiative for Asthma (GINA) guideline recommends using an asthma rescue inhaler containing formoterol + budesonide instead of a rescue inhaler containing albuterol
  • American physicians have been slow to adopt the GINA guidelines because of the black box warning previously required by the FDA on any inhaler containing long-acting β-agonists including formoterol
  • A new study showed that a rescue inhaler containing albuterol + budesonide was significantly better than a rescue inhaler containing albuterol alone
  • This new rescue inhaler will replace the albuterol inhaler for many patients with asthma

 

The metered-dose inhaler was invented in 1955, when 13-year-old Susie Maison asked her father why she had to take her asthma medication in a squeeze bottle and why it could not be put into a can, like hairspray. Her father was the president of Riker Laboratories (now 3M) and thought that his daughter was onto something. Within a year, Riker released the Medihaler-epi and Medihaler-iso, containing the β-agonists, epinephrine and isoprenaline, respectively. These gave way to the β-agonist inhalers that I prescribed in the 1980’s: Alupent (metaproterenol), Maxair (pirbuterol), Brethaire (terbutaline), Tornalate (bitolterol), Proventil (albuterol), and Ventolin (albuterol). With the international agreement to eliminate inhalers containing chlorofluorocarbons, all of these except albuterol were taken off the market by 2010.  And so, for the past 12 years, albuterol (also known as salbutamol outside of the United Stateshas been the sole short-acting β-agonist available in the United States.

Why use albuterol in asthma, anyway?

Asthma is an obstructive lung disease where the airways of the lungs become narrowed. This narrowing is caused by a combination of bronchospasm and inflammation. Bronchospasm is caused by contraction of the smooth muscles that line the airways and can be relieved by β-agonists, such as albuterol. Inflammation is caused by a group of biochemicals that cause white blood cells such as neutrophils, eosinophils, and lymphocytes in the airways to become activated resulting in swelling of the airway walls and secretion of mucus into the airways. Inflammation can be relieved by corticosteroids.

β-agonists can relieve the bronchospasm component of airway narrowing almost immediately but steroids take hours or days to relieve airway inflammation. Albuterol and other β-agonists only relieve bronchoconstriction and have no effect on inflammation. Albuterol’s duration of action is 3 – 6 hours. Therefore, in an asthma flare, β-agonists alone can provide partial short-term improvement in airway narrowing but will not relieve the underlying inflammation. For decades, asthma treatment has required albuterol and steroids to be given separately. Albuterol and other β-agonists are most commonly given by inhalation, either via a metered-dose inhaler or by a nebulizer. Steroids can be given via metered-dose inhalers on a scheduled basis for prevention of asthma flares. Steroids can also be given by pills (such as prednisone) or by intravenous infusions (such as methylprednisolone) once a patient’s asthma flares up.

The argument against inhalers containing only albuterol

This month, the MANDALA study was published in the New England Journal of Medicine that indicates that a combination of albuterol plus the corticosteroid budesonide in a single inhaler is better for relieving asthma symptoms than an albuterol-only inhaler. In this randomized double-blind study, 3,132 subjects with moderate to severe asthma at 295 different centers worldwide (including the U.S.) were given a rescue inhaler containing only albuterol or were given a rescue inhaler containing both albuterol and budesonide. Those subjects who received the albuterol + budesonide inhaler had 26% fewer severe asthma flares than those who received albuterol alone. The implication of the study is that when a person’s asthma flares up, treating both inflammation and bronchospasm is more effective than treating bronchospasm alone.

This reinforces the asthma treatment guidelines recommended by GINA (the Global Initiative for Asthma). GINA began as a collaborative effort of the U.S. National Institutes of Health and the World Health Organization and over the past 29 years, it has become the gold standard for asthma treatment recommendations. The 2022 GINA Report recommends that the first line asthma reliever treatment should initially be a combined formoterol (a long-acting β-agonist) + steroid inhaler and if this is not available, then the second line is to use two inhalers: an albuterol (a short-acting β-agonist) inhaler plus a separate steroid inhaler simultaneously. The formoterol + steroid inhaler is thus preferred over the albuterol only inhaler as a reliever medication.

The U.S. National Institutes of Health’s National Asthma Education and Prevention Program (NAEPP) updated their asthma treatment guidelines in 2020 and made similar recommendation for the use of a formoterol + inhaled corticosteroid combination inhaler for use as both a maintenance and a reliever inhaler in patients with moderate or severe asthma.

Formoterol is a long-acting β-agonist and is the ingredient in the inhaler, Foradil. It is also an ingredient in the combination inhalers Symbicort (formoterol + budesonide) and Dulera (formoterol + mometasone). Budesonide and mometasone are both inhaled corticosteroids. In 2003, the FDA required that all inhalers containing both long-acting β-agonists + inhaled corticosteroids (such as Symbicort and Dulera) include black box warnings in their package inserts. These warnings stated that long-acting beta agonists have been linked to increased death and that Symbicort, Dulera, and all other combined long-acting β-agonist + corticosteroid inhalers should only be used in patients with severe asthma not controlled by an inhaled corticosteroid alone. The black box warnings further specified that these combination inhalers should be discontinued as soon as possible once asthma is controlled. The black box warnings originated because of the SMART trial (Salmeterol Multicenter Asthma Research Trial) published in 2006. In this study, asthmatics were treated with salmeterol (a long-acting β-agonist) or placebo as a sole maintenance inhaler for asthma and the results indicated increased death in patients receiving salmeterol. An important criticism of this study is that patients were not treated with an inhaled steroid, just the inhaled salmeterol. The implication is that subjects in the SMART trial were only treated for bronchospasm and their airway inflammation was left untreated. Nevertheless, due to the SMART trial, the FDA required the black box warning of risk of death for any inhaler containing a long-acting beta agonist, including those in which the long-acting β-agonist is combined with an inhaled corticosteroid. In 2017, the FDA removed the black box warning on these combination inhalers after further studies showed that the combination inhalers were not associated with increased death (unlike the single agent long-acting β-agonist inhalers).

However, the previously required black box warnings have left an indelible imprint on American physician prescribing practices. Despite the removal of these warnings 5 years ago, many physicians remain hesitant to adopt the GINA guidelines recommending that combination long=acting β-agonist + inhaled corticosteroid inhalers be used as rescue inhalers. Furthermore, the use of inhalers such as Symbicort and Dulera as rescue inhalers is still considered off-label in the United States.

To make matters worse, the asthma management strategy of using a formoterol + inhaled corticosteroid combination inhaler as both a maintenance and a reliever inhaler has been referred to by the National Asthma Education and Prevention Program and others as “SMART” (Single Maintenance And Reliever Therapy). This unfortunate use of the term “SMART” to promote the use of a combination inhaler containing a long-acting β-agonist in asthma has been confused by many clinicians with the SMART study published in 2006 that condemned the use of long-acting β-agonists in asthma and resulted in the previous black box warnings. As a consequence, when many physicians hear about “SMART” asthma therapy, they think that this means “…don’t use long-acting β-agonists for asthma”.

The net result is that American physicians are considerably behind the rest of the world when it comes to using formoterol + corticosteroid inhalers as asthma reliever inhalers and instead continue to rely on albuterol-only inhalers. The graph below from the U.S. FDA shows that formoterol (diamonds) has a similar onset of action as albuterol (triangles) but has a longer effect than albuterol.

The pharmaceutical company, AstraZeneca, is now developing the combination albuterol + budesonide inhaler used in the MANDALA study that is currently only known as PT027. A new drug application was filed with the FDA last month for PT027 so we will likely see it commercially available in the United States in the near future. There is reason to hope that the albuterol + corticosteroid inhaler will be better accepted by American physicians as a rescue inhaler than the formoterol + corticosteroid inhalers.

Is this the end of albuterol?

I think the answer to that question is a pretty solid “No”. Albuterol will continue to be used in COPD and the probable high cost of the combination albuterol + budesonide inhaler will be a barrier to widespread replacement of albuterol-only inhalers in patients with asthma.

What about COPD? Albuterol-only inhalers will continue to be used in another obstructive lung disease, COPD. There is a general reluctance to use inhaled steroids in patients with COPD where, unlike asthma, inhaled steroids increase the risk of pneumonia in most COPD patients. Therefore, albuterol-only inhalers will likely continue to be used as reliever inhalers in patients with COPD.

What about mild asthma? The MANDALA study only looked at patients with moderate to severe asthma. There is a very large population of patients with asthma for whom albuterol-only inhalers seem to work well. This includes patients with exercise-induced asthma and asthma that is only triggered when a person inhales something that they are allergic to (such as cat antigens). These asthma patients were not included in the MANDALA study and so we do not know if the combination albuterol + budesonide inhaler works better than an albuterol-only inhaler for them. As a consequence, it is likely that AstraZeneca will only seek FDA approval for PT027 in those patients with moderate or severe asthma and not in those with mild asthma.

What about cost to patients? Once PT027 is approved by the FDA, it will likely be expensive. A generic albuterol inhaler costs about $30 whereas brand name albuterol is about $75 per inhaler. PT027 will probably be priced closer to brand name combination long-acting β-agonists + corticosteroid inhalers. These typically cost about $300 – $400 per inhaler (a generic formoterol + budesonide inhaler costs about $200 per inhaler). Price alone will make albuterol preferred by those asthmatics without prescription medication insurance. Even for those with insurance, high co-pays and high deductibles may preclude widespread adoption of PT027 as the asthma reliever inhaler of choice.

What about employers? Most employers leave the decision about which drugs will be covered by employee health insurance up to the commercial insurance companies. However, employers may want to pressure insurance companies to include PT027 on their health insurance formularies if the 26% reduction in severe asthma flares using PT027 is confirmed. Currently, asthma exacerbations result in a loss of 8.7 million work days and 5.3 million school days every year in the United States. The total cost of these missed work and school days is $3 billion per year. If the 26% reduction in severe asthma flares translates to a 26% reduction in missed work days and missed school days from asthma, then it may be cheaper overall for employers to include PT027 on their insurance formulary, even if they have to pay higher insurance premiums.

What about hospitals? Hospital formularies typically carry albuterol inhalers and for medical-legal reasons, there will continue to be hesitancy for hospitals to adopt the GINA recommendations of a combination formoterol + inhaled corticosteroid reliever inhaler for hospitalized asthma patients as long as this use is considered off-label by the FDA. Presumably, since it contains a short-acting β-agonist, PT027 will get an FDA approved indication as a reliever inhaler, making it more palatable for hospital pharmacies to replace albuterol on their formularies. However, the cost of PT027 (compared to albuterol-only inhalers) may be a barrier for widespread hospital use.

The bottom line is that for those people with moderate to severe asthma who are either wealthy or have superb prescription medication insurance, albuterol inhalers will likely become obsolete. For everyone else with asthma and for those with COPD, albuterol inhalers will be preferred.

June 28, 2022

Categories
Electronic Medical Records Outpatient Practice

We Need National Telemedicine Tumor Boards

Tumor boards have been shown to improve cancer outcomes by incorporating the expertise of many specialists in order to formulate a personalized treatment plan for each patient. These interdisciplinary management plans can give patients the best chance of cancer control or cure. Tumor boards typically consist of a surgeon, a medical oncologist, and a radiation oncologist but may also include a pathologist and a radiologist. Organ-specific tumor boards may consist of other specialists. For example, a thoracic tumor board may include a pulmonologist or a GI tumor board may include a gastroenterologist. Tumor boards allow specialists to bring their own expertise to an individual patient’s cancer treatment plan in order to determine the timing of surgery, the use of adjuvant or neoadjuvant chemotherapy, and the use of radiation therapy.

Summary Points:

  • Recent advances in cancer care have led to the evolution of different cancer-specific tumor boards
  • There is an unmet need to bring these cancer-specific tumor boards to rural and underserved areas of the country
  • Telemedicine tumor boards offer an opportunity to improve cancer treatment to all Americans
  • There are a number of obstacles that need to be addressed before national telemedicine tumor board implementation

 

Tumor boards have become even more important as advances in cancer genetics have resulted in many new treatments based on the molecular make-up of individual cancers. The advisability and timing of these newer treatments such as immunotherapy and driver-directed therapy can also be incorporated into the patient’s cancer treatment plan during tumor board discussions. Also, patients eligible for clinical trials of promising experimental treatments can be identified during tumor board discussions and enrolled in research studies.

In large medical centers, tumor boards typically meet once every week or two weeks. In smaller hospitals, tumor boards meet less frequently, often monthly. Each patient’s history, physical exam, radiologic staging study results, and tumor pathology results are reviewed. Specialists then develop a personalized cancer treatment plan tailored for that patient. A tumor board is far more efficient than having the patient see multiple physician specialists in their office for separate consultations and then having the physicians forward their individual recommendations to the primary care physician for coordination of care.

Survival of most cancers has improved significantly over the past several decades, largely due to development of new medications to treat cancers and to advances in cancer screening. But cancer is not one disease and cancer treatment has also become highly specialized. Oncologists used to be cancer generalists who were expert in the treatment of all forms of malignancy but now, medical and surgical oncologists specialize. The result is that there are different medical oncologists who treat lung cancer, gastrointestinal cancers, skin cancers, breast cancer, etc. As a consequence, tumor boards have also become specialized with different tumor boards for lung cancers, gynecologic cancers, and breast cancers. Large academic medical centers will often have 8-10 different tumor boards, each for a different type of cancer.

This specialization of oncologists and of tumor boards has posed a challenge for smaller hospitals and rural hospitals that do not have the luxury of multiple medical oncology specialists, surgical oncologists, or gynecologic oncologists. These hospitals either have to rely on general surgeons, general medical oncologists and general tumor boards or have to refer their newly diagnosed cancer patients to large medical centers for subspecialty evaluation that can sometimes be hundreds of miles away.

In the past, tumor boards were held in hospital conference rooms with physicians attending in-person. The COVID-19 pandemic showed us that multidisciplinary conferences could be just as effective when performed remotely. For more than 15 years, I led our medical center’s multidisciplinary interstitial lung disease conference which is the equivalent of a tumor board for non-cancer diseases such as pulmonary fibrosis. We found that our interdisciplinary discussions were just as easily done by a Zoom or Teams meeting as they were by in-person conferences. In fact, we had better attendance when the conferences went remote because physicians who practiced at off-site clinics could more easily attend.

A 2014 proof of concept study involving two Veterans Administration hospitals showed that virtual telemedicine tumor boards were both feasible and well-accepted by participants. The COVID-19 pandemic forced most hospital tumor boards to convert to virtual meetings. A study from the University of Pittsburgh demonstrated that virtual tumor boards during the COVID pandemic were very effective. But can we develop virtual tumor boards utilizing telemedicine technology to bring multidisciplinary expertise to smaller hospitals in order to improve cancer outcomes in rural and underserved areas of the country?

Lessons from institutional review boards

Institutional review boards (IRBs) are sometimes referred to as “human subjects committees” and are multidisciplinary groups that review clinical trials in medicine to ensure that medical experimentation involving humans is performed ethically and with appropriate study design. In the past, each hospital had its own IRB composed of volunteer reviewers. The volume of study proposals and the burden of IRB meetings by physicians, university faculty, and lay public members often resulted in long delays in getting clinical trial proposals approved.

In 1968, the Western Institutional Review Board was founded as an independent ethical review organization that allowed hospitals to outsource their clinical trial reviews for a fee. Hospitals no longer needed to rely on internal human subjects committees and Western was able to turn proposals over more quickly than the hospital IRBs. Our university outsources most of our clinical trial reviews to Western and this has greatly expedited research. Over time, more independent IRBs arose and consolidated. Now, most clinical trials undergo their ethics review by independent IRBs such as Western (now known as WCG IRB). These independent IRBs can match ethics and research specialists with specific clinical trials in order to provide superior reviews in a shorter period of time.

Our nation’s tumor boards can learn a lot from the independent IRBs. By assembling a large group of specialists in the treatment of each type of cancer, state-of-the-art recommendations individualized to each patient’s cancer can be made anywhere in the country, or for that matter, anywhere in the world. And those recommendations can be made faster, thus allowing patients to get started on optimal treatment as quickly as possible. A criticism of American cancer research is that racial and ethnic minorities are often underrepresented as subjects in clinical trials. By better reaching these minorities through telemedicine tumor boards and identifying clinical trial candidates, such disparities could be reduced.

Barriers that need to be overcome

There are several obstacles that need to be addressed before national telemedicine tumor boards can be implemented:

  1. Medical licensure. In telemedicine, the medical encounter is legally considered to occur at the patient’s physical location and not the doctor’s location. As a consequence, physicians providing telemedicine must be licensed to practice medicine in the state that the patient is in at the time of the telemedicine encounter. A physician in Ohio cannot legally provide telemedicine care to a patient located in Florida unless that physician has a Florida medical license. For this reason, state-specific telemedicine tumor boards would be easy to implement from a medical licensure standpoint but a national telemedicine tumor board would require physician participants to have dozens of individual state medical licenses. The development of the Interstate Medical Licensure Compact may simplify the process of obtaining medical licenses in many states but not all states participate in the Compact. A national telemedicine tumor board could perhaps most easily be implemented in the Veterans Administration system since VA-employed physicians can practice in any state as long as they are licensed to practice in any one state.
  2. Cost. Physicians participating in hospital tumor boards are generally not compensated for their time – they participate pro bono as part of their professional duties to the hospital. A 2021 study from a single academic medical center found that the total cost in physician time to participate in the hospital’s 9 separate tumor boards was $648,183 per year. Currently, there is not a mechanism to pay for national telemedicine tumor boards and this would need to be addressed by Medicare and commercial insurance policy changes. Alternatively, this could be financed by subscription fees charged to participating hospitals.
  3. Radiographic and pathologic review. Like medical oncology and surgical oncology, radiologists have become subspecialized. Chest CT scans of patients with lung cancer are reviewed by a thoracic radiologist whereas brain MRIs of patients with brain tumors are reviewed by a neuroradiologist. Pathologists have become similarly subspecialized. Tumor boards at large academic medical centers are usually attended by the subspecialty radiologists and subspecialty pathologists who originally reviewed the patient’s materials. Smaller hospitals will typically only have general radiologists and general pathologists. A mechanism would need to be in place so that subspecialty radiologists could review original radiographic images and subspecialty pathologists could review full slides of tumor biopsy specimens. There are existing telemedicine solutions to both of these challenges but this could require smaller hospitals to purchase equipment and software to transmit radiographic and histologic images.
  4. Malpractice insurance. When a physician’s name appears on a treatment recommendation, that physician can be named in event of a medical malpractice lawsuit. Several years ago, I was a defense expert witness in a malpractice case involving a patient with a rare eosinophilic lung disease. The pathologist reviewing the lung biopsy slides called a pathologist in a different city who was a national expert in pulmonary pathology and asked that pathologist over the phone about the diagnostic significance of all of the eosinophils that were present on the biopsy slides. The second pathologist was named in the suit, even though he had only spoken by phone with the initial pathologist and had not, himself, seen the actual biopsy slides or provided a formal pathology report. Malpractice insurance coverage would need to be worked out before implementing a national telemedicine tumor board. Board participants would either need to have immunity against civil litigation or would have to be provided telemedicine malpractice insurance.
  5. Medical record access. Tumor board participants must have access to patients’ medical records. Many factors need to be considered when formulating a cancer treatment plan including laboratory test results, radiologic images, medication lists, drug allergies, past medical history, family history, social history, and the physical exam. All of these data must be available to tumor board specialists for them to provide the best recommendations for any given patient. Electronic medical records have improved physicians’ ability to access medical information at other hospitals, such as the ‘CareEverywhere’ app on Epic’s electronic medical record. Nevertheless, not all electronic medical record software are equally good at permitting cross-hospital patient information transfer. The success of a national telemedicine tumor board would be contingent on development of robust integrated electronic medical record networks.
  6. Patient selection. Not every cancer patient needs to be presented at a tumor board. For example, the management of a patient with stage 1A non-small cell lung cancer is pretty straight-forward – they get a lung lobectomy. But cancer treatment guidelines change rapidly and it can be difficult for the general oncologist or the general surgeon in a small, rural hospital to keep up with these guidelines. Not too many years ago, the standard of care for stage 1B lung cancer was surgery alone but several years ago, adjuvant chemotherapy was added, followed more recently by neoadjuvant chemotherapy. Last month, a study showed that neoadjuvant chemotherapy plus immunotherapy was better still. There would need to be some process in place to identify those patients who would benefit most from a national telemedicine tumor board. One option could be to refer only those patients that general tumor boards identify as needing discussion at a subspecialty telemedicine tumor board.

Somebody is going to make a fortune

Successful entrepreneurs identify unmet consumer needs and then figure out a way to meet those needs. Those who are successful in a large consumer market become wealthy. Providing specialized cancer treatment recommendations is currently an unmet healthcare need in much of the United States and throughout most of the world. A national telemedicine tumor board has the potential to be an enormous commercial success and has the promise of making whoever can pull it off rich.

However, most physicians did not go into medicine just to be wealthy, we go into medicine so that we can improve people’s lives. I can think of few better ways of improving large numbers of people’s lives than by ensuring that every cancer patient in the U.S. has access to prompt treatment recommendations from specialists up to date on the latest in evidence-based oncology. It is time for national telemedicine tumor boards.

June 22, 2022