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Chapter 2

We Must Inhale and Exhale. But Why?

Sometime after midnight, one deep January night, I remember walking into my bedroom and staring down at my first child in her crib, born on New Year’s Eve and now barely two weeks old. The silver moonlight poured in through the window, illuminating her outline. Her eyes were closed tight, her arms thrown over her head as if in an eternal stretch, her head tilted slightly to the right. Her intoxicating newborn smell brought rapture and calm.

Like millions of parents before, I considered the serenity of a newborn’s sleep, its restorative depth, but I also instinctively checked on function, to make sure life still blazed within despite the outward calm. This meant checking her belly, to make sure she was breathing. Of course she was: her chest and abdomen moved up and down under her blanket in the rhythmic flow we all recognize as life.

When we observe our loved ones sleeping, old or young, human or pet, we are instinctively drawn to their breath. There is something essential in it we are all attuned to, something we both automatically and unconsciously equate with life. Each time we check on each other, we are validating the words of the Roman philosopher Cicero, dum spiro, spero, “As I breathe, I hope.”26

Physiologically, what we are observing is the miracle of gas exchange, taking from the atmosphere an invisible element and bringing it into our body to be consumed. The process begins with a signal from the brainstem, the primitive part of the brain at the base of the skull, which travels through nerves down to the muscles of inspiration, instructing them to contract. The biggest and most important of these muscles is the diaphragm, a thin, dome-shaped sheet of skeletal muscle that separates the thorax (chest cavity) from the abdomen.

With each signal, the diaphragm contracts downward, pulling the thoracic cavity and the lungs with it. This creates negative pressure in the trachea and lung tissue, and with this negative pressure air rushes in, just as water flows down a river. Entering through the mouth or nose, the air travels down the back of our throat, past the vocal cords, and into the trachea. About halfway down the sternum, the trachea divides into the left and right bronchi, which divide again and again into lesser bronchi, termed bronchioles. The air moves through the bronchioles, which extend deep into the lungs, like tendrils from a star erupting in space, until finally it penetrates into cave-like recesses, deep in the lungs. Known as alveoli, and resembling cells of a honeycomb, these grapelike clusters at the end of the increasingly narrow breathing tubes are where gas exchange occurs.

Continuing its natural flow from an area of high concentration to one of low concentration, oxygen moves effortlessly through the thin surface of alveoli, just a single cell thick, to the adjoining capillaries. Here, thousands of hungry red blood cells grab oxygen, and together they are pumped by the heart to the arteries and then to the tissues of the organs, which are infiltrated with a vast network of capillaries. At the tissue level, oxygen hops off the red blood cell and diffuses through the capillaries into the cells of whatever organ or muscle is nearby.

Within each cell are mitochondria, the specialized organelles in which cellular respiration takes place: oxygen joins with glucose to produce carbon dioxide, water, and adenosine triphosphate (ATP). ATP is our primary source of energy, the molecule that drives many of our bodily reactions, including muscle contraction, enzyme production, and the movement of molecules within our cells. ATP causes these reactions by breaking off one of its phosphate groups, whose electrons are in a high-intensity state, and transferring this energy to drive the necessary processes of the cell. Now adenosine diphosphate, it gets recycled back to the mitochondria to become high-energy triphosphate again through the ongoing process of cellular respiration.

Figure 2:The human respiratory system.

A byproduct of oxygen use and cellular respiration is carbon dioxide (CO2), which diffuses out of the cell, into the blood, and back into the capillaries, which now flow to veins. Not used by our body, CO2 is shunted back to the lungs by our venous system, where it diffuses into the alveoli. From there, the air, with its new mixture of gasses, is pushed out through the network of bronchioles and bronchi as the diaphragm relaxes with exhalation, and ultimately expelled out of the mouth or nose and back into the atmosphere. The CO2 disperses easily into the air, where its levels are very low at 0.04 percent of atmospheric gas. Levels of oxygen in the atmosphere stand at a comparatively robust 21 percent, so on our next breath we are able to fill up again with this molecule of life. (The rest of the atmosphere is almost all nitrogen, harmless to us but also useless.)

Figure 3: Gas exchange at the alveolar level.

We are attuned so closely to this process of inhalation and exhalation in our slumbering loved ones because we have an instinctive understanding of its urgency: while we can skip meals, breathing must be continuous. The system must be finely coordinated as gas levels need to be kept within a very narrow range in our blood. Receptors in our aorta and carotid artery continuously monitor levels of oxygen and carbon dioxide and send feedback to the respiratory center in our brainstem. Even the slightest change in the levels of gas will trigger more signals or fewer to go out to our muscles of inspiration. The activity in the respiratory center of our brainstem also feeds back to our cerebral cortex, or higher brain, making us aware of any impending danger. This creates the alarming sensation we are all familiar with if our brain senses something wrong with our oxygen or carbon dioxide levels, as when we hold our breath.

Carbon dioxide is what causes most of the initial problems when we hold our breath, because as it builds up in our blood during a breath hold, it begins to break down into acid. This acid is toxic to our cells, especially as it begins binding with proteins and other molecules it shouldn’t, impeding the normal function of cells. As the breath hold continues, lack of oxygen also becomes a problem, and as cellular respiration in our mitochondria ceases with the dearth of oxygen, cellular death ensues. The cells of the heart muscles are especially sensitive to this, and cardiac arrhythmias can ensue in extreme cases of too much carbon dioxide or too little oxygen. Breathing is the most important thing we are aware of doing, and the body regulates it tightly.

The foundation of our understanding of these pulmonary processes, and indeed of all Western medicine, was laid in ancient Greece. After the mythical Apollo and his mystical son Asclepius, whose rod is the symbol of medicine today, the first legendary but real figure in the history of medicine was Hippocrates, born in 460 BCE on the Greek island of Kos. He is forever known for creating the oath that all physicians still recite when they receive their diploma, and is deservedly known as the Father of Medicine for his insight that disease was the consequence of natural processes and not the work of magic or the gods.27

In addition to contemplating many other anatomical systems, Hippocrates studied breathing. He recognized that the inhalation of air was fundamental to life. For this reason, Hippocrates and the Greeks viewed air as something vital and transcendent. They called it pneuma, which literally means air or breath but for the ancient Greeks also meant life force. This pneuma was inhaled and then passed through the lungs, into the blood, and on to the heart, where it became the pneuma zoticon, or vital spirit. This vital spirit was then carried to the organs, including the liver and brain, where it was transformed into pneuma psychicon, or animal spirit, which was considered the driving force, created by the body from air. From spirit (air or pneuma) to vital spirit to animal spirit, the Greeks and Hippocrates insightfully saw the essence of our existence as a continuum from the atmosphere.28

Some five hundred years after Hippocrates, Claudius Galenus was the next great figure to change how we think about breathing and circulation. Better known simply as Galen, he was born in September 129 CE, in the Aegean Sea town of Pergamon, part of modern-day Turkey. His father, a wealthy patrician, originally had plans for his son to become a philosopher and statesman. These plans changed when the father dreamed that the mythical physician Asclepius visited him with a decree that his son study medicine. Galen’s father spared no expense, and Galen was educated at the best institutions throughout the Roman Empire.

When he finished his studies, Galen settled into practice in Pergamon. He became the personal physician to the gladiators of the high priest of Asia by performing an act of daring. According to his own report, he eviscerated a monkey and then challenged the other physicians to repair the damage. When none stepped forward, he did the surgery himself, successfully restoring the monkey and winning over the high priest. He later moved to Rome and became the personal physician to several emperors, most notably Commodus, who reigned from 161 to 192 CE.

Galen contributed to many areas of medicine, and added to our understanding of the lungs and circulatory system. He noted that “blood passing through the lungs absorbed from the inhaled air the quality of heat, which it then carried into the left heart.”29 Human dissection was prohibited by Roman law, but Galen dissected both primates and pigs. He was the first to describe the two separate systems of circulation, the arteries and the veins. He believed that the liver, with its dark purplish interior, was where blood originated. From the liver, he postulated, half of the blood went out to the veins and was delivered to the tissues and consumed. The other half went to the lungs via a vein, where it picked up pneuma, then on to the heart, the arteries, and then the tissues.

Although Galen’s theories on blood flow would be proven to be partially wrong, he was important, like Hippocrates, because of his methodology. Galen cemented the notion that medicine and disease were not the products of divine intervention from the gods but could be discerned from empirical evidence and deduction based on observation and cause and effect. Nonetheless, more than a thousand years passed before his ideas on the movement of oxygen within the blood’s circulation were corrected.

In somewhat ironic contrast to his philosophy, Galen’s ideas were accepted as gospel over the centuries, particularly his ideas on the flow of blood into both arteries and veins, and on the liver as the epicenter of blood production. Fortunately, the idea that the breath was important also did not change, as can be seen when the Renaissance scientist Alessandro Benedetti poetically wrote in 1497: “The lung changes the breath, as the liver changes the chyle, into food for the vital spirit.”30

The man who changed our understanding of blood flow was William Harvey, an English physician trained in Padua, Italy. He, like Galen, had a big personality, and he frequently walked around with a dagger on his belt, as was the fashion in rough-and-tumble Renaissance Italy. His opinion of his fellow man was not high, and a biographer who lived at the same time claimed, “He was wont to say that man was but a great mischievous baboon.”31

Upon establishing himself in England after his Italian internship, Harvey published De Motu Cordis et Sanguinis (On the Motion of the Heart and Blood) in 1628, cementing his reputation as a giant in the history of medicine. This work was seminal in our understanding of the basic physiological principles of how blood travels in the body. Harvey had two breakthrough insights. He noted that he had learned from his Italian mentor that the veins all had one-way valves, pointed away from the tissues and organs and toward the heart. Why the venous system, which was postulated by Galen to bring blood to the organs as the arteries did, had back valves to keep blood away from those parts of the body was not easily explained.

Harvey’s second important observation was made through painstaking dissections of humans and animals. He calculated that the output of the heart was a lot greater than previously thought, about five liters per minute. He correctly reasoned that the tissues could not consume that volume of blood each minute, as proposed by Galen. He needed a more reasonable explanation, a system that was simple yet elegant—and that went against fifteen hundred years of dogma. So he proposed something often found in nature: a system of reuse and recycle, a continuously flowing system, a circuit, or, as we know it now, circulation. Blood is not consumed by the tissues—it is reused over and over.

As Harvey correctly deduced, blood moves in a circle. From the arteries, it goes past the tissues, where oxygen hops off and carbon dioxide hops onto our molecules of hemoglobin, then to the veins and the right side of the heart, through the pulmonary artery to the lungs, where the carbon dioxide produced from tissue respiration is released and oxygen is picked up, then to the left side of the heart, then out again through the vast arterial system and back to the tissues. Blood is continuously cycled in a beautiful loop, with the bone marrow (not the liver) replenishing the red and white cells as needed.

Figure 4: The circulatory system.

The idea was received as scientific heresy at first, thanks to the primacy of Galen’s views. In response to the widespread doubt, Harvey gave a lecture in May 1636, which stands out for being as instructive as it was gruesome. Dressed in a billowy white dissecting gown, he spoke in Latin to the professors, students, and general public at the University of Altdorf, in Bavaria, Germany. First, a live dog was placed on a dissecting table and strapped down. Next, Harvey declared, “It is obviously easier to observe the movement and function of the heart in living animals than in dead men.” With this, he cut open the thorax of the writhing dog with a knife, to expose the beating heart, and then sliced the blood vessel next to the heart to show the audience the vast amount of blood now spurting out. His goal was to drive home his point that the heart was a pump, and that this amount of blood could not be consumed by tissues but must recirculate.32

Despite the theatrics, many of Harvey’s contemporaries remained skeptical. Caspar Hoffman, a scientist present at his University of Altdorf lecture, declared, “video sed non credo,” “I see it, but I don’t believe it.” Other critics pointed out two big leaps of faith Harvey had to make in order for his theory to work. The first was that there had to be some network of vessels between the arteries on one end and the veins on the other. We now know about capillaries, but Harvey had no tools to see or discover those tiny blood vessels. He made an educated assumption, as is so often needed in science. Confirmation would come just a short time later, in 1661, when Marcello Malpighi published his work De Polmonibus observationes anatomicae (Anatomical Observations on the Lung), confirming with the use of the microscope that capillaries did indeed exist.

The second leap of faith related to why and how the blood changes from dark to bright. Again, Harvey had a sense that something essential in the atmosphere, drawn in by the lungs, turned blue blood a bright scarlet. Nobody then had any idea about the role of oxygen, but Harvey intuited it in Lectures on the Whole Anatomy (1653), when he made the profound observation: “Life and respiration are complementary. There is nothing living which does not breathe nor anything breathing which does not live.”

Establishing what was in the atmosphere that the lungs and body needed to capture would take a lot longer. The ancient Greeks had identified the air as one of the four classical elements, along with fire, water, and earth. Throughout the following centuries, air was believed to be a single substance. Not until the eighteenth century did scientists begin experiments to tease out the different chemical elements, including those contained in air. Joseph Priestley is credited as one of oxygen’s first discoverers, his experiments taking place in 1774 and then being published over the next few years in Experiments and Observations on Different Kinds of Air. One of these experiments documented that both a mouse and the flame of a candle would die in a sealed jar of air. Next, Priestley created a new gas by focusing light with a magnifying glass–like apparatus onto a piece of mercuric oxide—and he noticed that this new gas kept both the candle lit and the mouse alive a lot longer than unadulterated air. Priestley shared his observations with French scientist Antoine Lavoisier, who would conduct further experiments on the purification of air—and give us the name oxygen.

Harvey’s basic model of circulation remains intact today. We have improved our understanding of inflammation and genetics and cellular movement, but our ideas about what our circulation is doing and why have not changed. To break with centuries of established dogma was not easy, but an analysis of Harvey’s methods reveals how most scientific breakthroughs are made.

First, Harvey ignored the dominant theory (in this case, one that had reigned for the previous fifteen hundred years). He then made a few astute observations and, based on limited data, posited a unique theory. He tested his hypothesis with more data collection and saw that it seemed to hold. He stuck with it despite two holes in his model (no knowledge of capillaries or oxygen). With this knowledge, we today understand the importance of keeping a patient’s circulation moving with fresh oxygen. We are also painfully aware of just how severe the consequences are when this circuit is disrupted.

The brain recognizes the importance of the breath and guards respiration very closely by monitoring oxygen and carbon dioxide levels. To keep up with demands, the system was set up to tolerate a lot of failure, with five hundred million alveoli present in our lungs. Spread out, these alveoli would cover approximately one hundred square meters, the size of a tennis court. Because of this, it’s possible to lose one lung entirely and still function adequately. Another fail-safe mechanism is the efficiency of gas transfer, with the surface that oxygen must pass through to get out of the alveoli and into the capillaries microscop­ically thin at one-third of a micron. A micron itself is a billionth of a meter, or a thousandth of a millimeter. The distance oxygen needs to traverse to get from the alveoli to the capillaries could double without any noticeable shortness of breath at rest.

Unfortunately, there are times when the system gets overwhelmed and needs help from technology. One night, when I was an intern at a hospital in Boston, I was tasked, despite my inexperience, with getting a man with greatly reduced lung function through the night. Fortunately, I had a lot of help from people who actually knew what they were doing. The practice of medicine can be as much an art as a science. This was one of those occasions.

Past midnight, I sat with my resident physician at the nurses’ station, anxiously awaiting the arrival of Leonard Joseph, a patient from the deep woods of Maine who had gotten knocked down hard with an infectious pneumonia, which had caused a massive outpouring of inflammatory cells into his lungs, clogging up his alveoli so that gas exchange was greatly impaired. He had been placed on a ventilator, and even with this increased level of support, his lungs were stiff and struggled to expand. Oxygen was not getting into his body as he needed it to, and on the other end of cellular respiration carbon dioxide was not getting out.

When the doors finally swung open and the emergency medical technicians wheeled Mr. Joseph out of that cold January night, I nervously accepted a thick package of notes from the Maine hospital that had first seen him. I followed the resident into the intensive care unit room as the patient was being transferred into his new bed, his home for the next month. I saw he was getting 100 percent oxygen through the tube in his throat, a large amount compared to the 21 percent we normally get from the atmosphere.

We gauge how effective the transfer of oxygen to the blood is by measuring the pressure that oxygen produces within the blood of an artery, which is a reflection of how much oxygen is present in the blood. The radial artery, the easily accessible one that feeds the hand, is usually used to obtain a blood sample, which is then sent to the lab for analysis. Historically, the pressure of oxygen in the blood has been measured using a column of mercury, and gauging how much mercury the gas is able to move. A normal, healthy subject, breathing in a 21 percent oxygen mixture from the atmosphere, will generate a pressure of oxygen in arterial blood of about 95 millimeters of mercury (mmHg). The patient from Maine, however, had an oxygen level of only 60 mmHg, and this was when he was breathing in a 100 percent oxygen.

Once the level of oxygen in the blood drops below 60 mmHg, our tissues do not receive enough oxygen. This is when brain cells begin to die, and the heart becomes irritated. Clearly this was a critical situation, and one without an easy solution. Normally we would just turn up the oxygen level on the ventilator, but it was already at 100 percent. To stabilize this patient, something more creative was needed than simply turning up a dial.

The attending physician appeared a few minutes later, and he and the resident discussed some advanced maneuvers to help keep oxygen going in and carbon dioxide coming out. The last thing the attending suggested was “proning.” Then he disappeared. The first question I asked was, “What’s proning?” The resident, Kevin, looked at me wearily and said, “Proning is when you flip the patient over and have them lie on their stomach on the bed.”

I still didn’t quite get it. A groan followed. (There are many potential sources of humiliation in the hospital for an intern.) “‘Why?’ To help with oxygenation. And ventilation. You need to go learn about lung physiology. And you need to go read your West.” Kevin shook his head and sat down to go through the mound of material in front of him.

The West my resident was referring to was a book by John B. West. John B. West is not known outside the small circle of lung medicine practitioners, but within it he stands tall, and through his research and textbooks he has cemented a reputation as the leading educator within all pulmonary medicine in the last hundred years.

Dr. West was born in Adelaide, Australia, in 1928 and developed an interest in science at an early age. He moved to England for his PhD, and then to the University of California, San Diego, to continue his research in pulmonary physiology. There he discovered some unique things about how the lungs work, specifically about how different areas of the lung can have very different blood flow and air flow. Later in his career, he wrote a textbook on pulmonary physiology that changed how we educate medical students. And even later, at the age of seventy, he changed his focus to the physiology of the bird lung.

Following Kevin’s advice, I picked up an updated edition of West’s 1974 textbook, Pulmonary Physiology: The Essentials. The volume is slim in the hand, and its two hundred pages of easy type and large diagrams belie the power of its contents—it is still the starting point for learning about modern pulmonary physiology for physicians today.

Dr. West begins his book with a review of the structure of the lung, and right away he makes an extremely important and powerful statement: The architecture of the lung follows its function. Everything about the lungs should be considered within the context of that fact: form follows function.

This statement is one that broadly defines an entire field of biology. The disciplines of comparative and evolutionary biology consider the origins and development of life around us in the context of form following function. The African lion, for example, lives in the grasslands and is almost strictly a meat eater. For that, it needs to be a predator. Its body is powerful and fast, but it can travel only in short bursts. It has big retractable claws and huge powerful teeth to take down its prey. Its niche, diet, body, teeth, and feet with claws all coalesce into one well-defined purpose. The wild dog, by contrast, has a more diverse diet, so its teeth include some canines but also some molars. The dog’s legs and body are built for speed but also for distance, and it has no big claws, since they’re not needed. Looking at the world from the form-follows-function perspective can be a powerful tool for analyzing nature’s systems.

Dr. West states that the main function of the lungs is to facilitate gas exchange. First, oxygen needs to come into the blood and be carried to the cells of the body to keep metabolic processes going. Ventilation—the process of carbon dioxide being released from the bloodstream—needs to follow. Since form follows function, the body must have the ability to augment the work of the lungs to get appropriate amounts of oxygen into the blood and carbon dioxide out even when there are changes in our metabolic demands. Exercise, for example, is a state in which our tissues demand more oxygen and produce more carbon dioxide than usual. Illness from bacteria or viruses is another state that can increase our metabolic demands tremendously as a result of inflammation.

The lungs, for the most part, handle these demands with ease and flexibility. From a starting volume of five liters of air per minute at rest, we can increase our breathing to exchange ten, twenty, and even thirty liters of air per minute, an astonishing amount of gas. Our respiratory rate naturally increases in this situation, but the volume of air with each inhalation also increases, as muscles in our neck and our abdomen not usually used for breathing spring into action, helping to stretch our lungs to accept and release more air. These adjustments are important, since we must exist within a tight physiological space and maintain levels of oxygen and carbon dioxide within a narrow range. Our lungs, with help from the muscles in our chest wall, have the ability to keep us within that range under a wide variety of conditions. The trouble comes when something interferes with this powerful, but at times delicate, system.

Keeping his blood supplied with fresh oxygen, and his ventilation appropriate to expel enough carbon dioxide, was the problem Mr. Joseph was facing that dark January night in Boston. Well past midnight, I could feel the temperature in my body dropping as we prepped our patient for a procedure to put a large-bore intravenous line into his neck. He was on a lot of antibiotics, and unstable on a ventilator, so we deemed that he needed larger intravenous (IV) access to get medicines in more rapidly. For this, we needed to access the internal jugular vein in his neck, and as we carefully scrubbed his neck with cleaning solution, Kevin kept a running commentary.

Kevin spoke about how the patient was in ARDS [acute respiratory distress syndrome], so we would need to keep the pressures in his lung low and try to minimize the work of breathing. He discussed how we would have to keep a close eye on the patient’s oxygenation, and to consider advanced oxygenation and ventilation methods—such as inhaled prostacyclin or maybe even ECMO [extracorporeal membrane oxygenation]—if we couldn’t make some progress in the next few hours. Or perhaps proning.

I did know some of what he was referring to—that oxygen levels needed to be kept at least 60 mmHg in the blood. I also knew that ventilation is measured as the product of the number of breaths in a minute multiplied by how much air is moved with each breath (or tidal volume) and that we care about ventilation because it is the primary determinant of how much carbon dioxide is in the blood. When carbon dioxide builds up in the blood, it dissociates into free hydrogen molecules, which are essentially acid, the amount of which is measured on the pH scale.

The pH stands for potential of Hydrogen, and it is a direct measure of how many hydrogen molecules are present in a solution. The scale typically spans from 0 to 14, with 7 marking the exact middle of the scale. Water at 25 degrees Celsius has a pH of 7 and is considered completely neutral. If there are a lot of hydrogen molecules (H+), we call the solution acidic. On this side of the scale are drinks like black coffee, with a pH of around 5, and tomato juice, with a pH of around 4 (the pH scale is inverse, and a lower pH indicates more acid). On the other side of 7, we call solutions basic, and examples include baking soda–containing liquids, with a pH of 9, or ammonia, with a pH of 11. These solutions have far fewer hydrogen ions than acidic solutions do.

The pH of our blood is 7.40, and it must be kept in the very narrow range between 7.35 and 7.45, with 7.40 being optimal. Living within this pH range is extremely important, because the proteins of our cells—and subsequently metabolism itself—begin to break down when our pH goes too low or too high. The kidneys help to expel or hold onto acid as needed to adjust our pH, but the lungs are a far more powerful system for regulating pH through carbon dioxide, which, as mentioned, breaks down to acid in our blood. We regulate carbon dioxide and acid by simply increasing our breathing and ventilatory rate when too many hydrogen ions are present and the pH is too low, or by slowing it down and letting acid build up when the pH goes too high.

A classic example of when CO2 rises is during exercise, and breathing increases concomitantly to expel the CO2 so our pH doesn’t drop too low. An opposite example is when we hyperventilate at rest without an increase in CO2 production, as can happen during a panic attack. Here one is blowing off too much CO2 and acid, and our pH climbs to dangerous levels, which is why one may be told to breath into a paper bag to inhale the expelled CO2, restoring needed acid to the blood.

As for our patient from Maine, what I didn’t know, but would soon learn, was what we were going to do if ventilation wasn’t adequate and his pH was off, or if we couldn’t maintain the appropriate level of oxygen in his blood. Meanwhile, I stood beside him with a large-bore needle, about to drive it deep into his neck to look for the internal jugular vein, when Kevin somewhat offhandedly mentioned, “Oh, and by the way, if you go in too deep and puncture his lung with that needle, he’s probably going to have a cardiac arrest and die. So be careful, please.” The top of the lung comes up very high in the chest cavity and lies just below the neck. I inserted the needle carefully.

The issue with our patient from Maine was definitely one of impaired gas exchange—that I understood—but my resident’s term ARDS did not mean much to me at the time. The first known mentions of this mysterious lung disease in the medical literature were made in 1821 by the French physician René Laennec, who also invented the stethoscope. In his book A Treatise on the Diseases of the Chest, he described the death of a patient with lungs filled with water but without evidence of heart failure. Fluid in the lungs was certainly familiar to doctors at this time, but it was almost always preceded by the left side of the heart failing. The circulation in the chest begins as our veins empty blood into the right side of our heart, which pumps it to our lungs, where it travels to the left side of the heart to be pumped through the rest of the body. If the left chamber of the heart fails, as often happens with cardiac disease, the blood backs up into the lungs and fluid spills out into the alveoli. But Laennec noticed that in a certain subset of people, fluid was spilling into the lungs without heart failure, without high pressure. The capillaries of the lung were simply leaky, and patients were essentially drowning.

Later in the twentieth century, more of these cases started being reported, often when a soldier was being resuscitated after sustaining an injury in battle. Soldiers would get revived with blood and recover from their wounds, but strangely, afterward, their lungs failed, filling with fluid and later hardening up like a stone. Names like “DaNang lung” and “post-traumatic lung” sprang up in the literature. The disease itself was largely a mystery. It was also a devastating illness, with the mortality rate approaching 80 percent.

Part of the mystery was solved in 1967 in a paper by Dr. David Ashbaugh, of Ohio State University, and colleagues at universities in Denver and Michigan. Together they gathered information on a series of similar cases and coined the new term: acute respiratory distress syndrome, or ARDS. Their paper, published in the journal Lancet, describes the injuries and lung pathology of twelve patients who had a pattern of respiratory failure caused by too much fluid in the lungs.33 The injuries the patients sustained before respiratory failure were disparate—some had trauma, others pneumonia, still others an inflamed pancreas. But their respiratory failure was similar—the extra fluid in their lungs, from leaking capillaries, would lead to dysfunctional inflammation and scarring, eventually turning their lungs rock-hard. As a result, all of these ARDS-afflicted lungs had trouble getting oxygen in and carbon dioxide out.

Dr. Ashbaugh’s paper was a landmark study in that it put a name and a face to a mysterious condition, the first and often the most important step in successfully treating a disease. (One can’t study a disease that has not been properly and accurately described.) And, quite extraordinarily, much of what is described in the paper is still relevant today. Unfortunately, the continued significance of this paper is also a sign of failure. According to the paper, ARDS is a disease in which some dramatic insult to the body occurs, which then causes lung inflammation and capillary leakage with no evidence of heart disease. The findings have not changed because the syndrome is stuck at the stage of description. There was no cure in 1967, and there is still no cure today.

So far, the efforts of physicians to slow or reverse the inflammation and leaky capillaries characteristic of ARDS have been futile. The journals are littered with descriptions of attempts involving different medicines—from steroids to inhaled nitric oxide to inhaled prostacyclin­—­that have come up short. Frequently, these treatments offered hope in mouse models, but every human drug trial has failed.

Even if no single medicine has been shown to improve outcomes, the mortality rate has dropped significantly, from the 80 percent in the 1960s to 40 percent today.34 This improvement reflects a persistent focus on appropriate ventilator settings, nutrition, and physical therapy. There is much one can do in medicine without using drugs, and the dramatic decline in ARDS mortality speaks to this. People like John B. West, investigating how the lung moves air and blood, have been a big part of this progress. Still, with 10 percent of all medical intensive care unit admissions resulting from ARDS, it remains a formidable problem.

After we successfully put the central IV line into Mr. Joseph’s neck, Kevin and I took a closer look at his ventilator. It had initially been quiet, but now its high-pressure alarms were starting to trigger loud pinging noises, indicating a failure to push air into the patient’s very stiff lungs.

We called the respiratory therapist, and he and my resident came up with a plan to lower the driving pressure of air from the ventilator while giving the air a longer time to get in, easing the flow into Mr. Joseph’s rigid lungs. We also had the nurse give him a paralyzing level of sedation, calming any involuntary fighting he was doing with his own respiratory muscles.

The modifications seemed to work, and the ventilator alarms went quiet. But this only told us that the machine was happy. The resident instructed me to check the level of gases (oxygen and carbon dioxide) in the patient’s blood to see if his body was happy. A few minutes later the results were relayed from the lab. Our patient’s oxygen level was just above 60 mmHg, and his carbon dioxide was around 48, corresponding to a pH of 7.30. These numbers were not great, but good enough to get him through what remained of the night.

For the rest of that month, I saw Mr. Joseph every morning at six o’clock, my first patient of the day. I would analyze how he was doing with oxygenation and ventilation, looking for any improvements. In the evening, at home, I would thumb through John B. West’s book. By the end of the month, I began to understand some of the nuances of how gas exchange works, how different parts of the lung receive very different amounts of oxygen and blood flow. Specifically, the lower lobes generally get both a lot more inhaled air and more blood flow. Some of this is likely due to the effect of gravity.

With this knowledge of variable blood flow and air flow within the lungs, researchers eventually came up with the idea to minimize airflow in stiff lungs like Mr. Joseph’s. The reasoning behind this idea is that, since blood flow and circulation are almost certainly compromised given the level of inflammation in the lungs, there is no need for a normal amount of air in each breath. Before this protocol was established, physicians had been blowing too much air into diseased lungs, creating too much stretch, and that extra stress was creating more inflammation. John B. West helped us appreciate that air flow and blood flow can be variable, and attempts should be made to match them. The breakthrough 2000 New England Journal of Medicine study showed that deaths were significantly fewer in ARDS patients who received less air when on the ventilator.35 Practice in medical intensive care units all over the world changed overnight. No study before this, and no study since, has had such a dramatic impact on what we do in the medical intensive care unit.

Mr. Joseph was admitted to the hospital in January 2002, so this article was fresh in everybody’s mind, and throughout the month we kept the air flow in Mr. Joseph’s lungs to the absolute minimum possible while still maintaining ventilation. To compensate for a very low amount of air with each intake, we turned up his respiratory rate from the normal twelve breaths per minute to thirty, even thirty-four at times. Normally, a respiratory rate of thirty-four breaths per minute is not sustainable, but with a machine it is. We considered proning, or flipping Mr. Joseph onto his stomach, while he was on the ventilator, to further decrease stress on his lungs by reducing the effect of gravity, thus giving them a rest and a chance to heal. The front of the lungs is where alveoli are often less affected in diseases like ARDS. (Most recently, proning is commonly being used for patients with COVID-19 as the inflammation from pneumonia almost always begins in the lower part of the lungs.)

Throughout the month, Dr. West taught me about theory, while Mr. Joseph taught me about the real world. Slowly but surely he made progress, his stiff ARDS lungs loosening up enough that he could breathe on his own during the day, while using the ventilator at night. He eventually went to a rehabilitation facility, and from there, presumably, home to the wilds of Maine. As happens so often in the practice of medicine, all we did was keep him alive until he was able to heal himself.

Today, even though specific drug treatments for ARDS are nonexistent, other therapies have shown progress. Foremost among these is extracorporeal membrane oxygenation (ECMO), where blood is taken out of the body, run through a machine that removes carbon dioxide and adds oxygen, and then returned. It functions, in essence, like an artificial lung. It is not a long-term solution and only serves to buy time for the lungs to heal themselves. Studies of this treatment in adults with ARDS have had conflicting results, but it is an option for those who fail on the traditional ventilator.

Looking further into the future, the promise of stem cells is not just a dot on the horizon, but a viable therapy that is now making its way through clinical trials. Stem cells have the ability not only to transform into different cell types but also to mitigate inflammation. A phase 2 study, which analyzes mostly safety, was recently completed in patients with ARDS and showed positive findings.36 Further studies are underway, and the entire pulmonary community is holding its breath to see whether the first treatment to improve outcomes for ARDS patients is on its way.

John B. West thought a lot about the issues of oxygenation and ventilation throughout his long career, from the quiet of his laboratory to the windy heights of cold Mount Everest. For the first five decades of his career, Dr. West studied the same class of animal—mammals. But then he turned his attention to a completely different species—birds—and brought awareness to important aspects of breathing.

Today, some ten thousand species of birds exist on Earth, about twice the number of mammal species. They colonize many different habitats and are able to maintain incredibly high workloads, or metabolic rates. One species that stands out is the hummingbird, which, with a wing beat frequency of up to 70 beats per second and a heart that can go to over 1,200 beats per minute, has a metabolic rate thirty times higher than that of humans. Another remarkable bird is the bar-headed goose, which is able to fly up to thirty thousand feet. These are feats of physiology that humans could not think of matching, and Dr. West believes it is their bird lungs, radically different from human lungs, that allow them to sustain these very high workloads.37

Dr. West’s interest in birds was piqued in 1960, when he spent six months with a team of researchers on Mount Everest. The project was dubbed the Silver Hut Expedition for the tin house in which they lived, on the Mingbo Glacier, at nineteen thousand feet (the nearby peak of Mount Everest is at twenty-nine thousand feet). From this perch, West and the other scientists investigated the effects of high altitude on the human body. After some time in this environment, West had become frightfully tired and thin from the stress of altitude. One morning, as he struggled to get going, he looked out of the window of the Silver Hut, drawn by a quacking noise. Way above his head, at about twenty-one thousand feet, was a gaggle of twelve rather ordinary-looking tan geese flying effortlessly in skies normally reserved for jet airplanes. How could West explain the difference between his own extreme fatigue and the bird’s easy flight?

The answer to his question lay in the design of their lungs. Despite all the obvious differences between birds and humans, one of the most important distinctions is not immediately apparent, though it is the likely key to birds’ success colonizing so many habitats: their lungs have separated out the jobs of oxygenation and ventilation. Our lungs are simple in that they have combined these jobs into a single unit. They expand and contract to provide movement of air, or ventilation, much like a fireplace bellows. The same areas that expand and contract to provide ventilation also house the gas exchange areas that allow oxygen to move into the blood and carbon dioxide to be released.

Figure 5: Anatomy of a bird’s lung with air sacs for ventilation and air capillaries for gas exchange.

But as West’s observations led him to point out, if an engineer was designing a breathing machine, the functions of gas exchange and air movement would be separated. Birds have such a system. With each breath they take, air moves into air sacs, which are large, easily distensible organs in which no gas exchange takes place. This air then gets shunted to a separate area for gas exchange, termed air capillaries. There, because there is no need for the gas exchange units to bend when a breath occurs, the distance between the air and the blood vessels is incredibly thin, much less than the one third of a micron in mammals, making the exchange even easier. A final difference is that air movement in the bird lung goes around in a circle, much as blood does, so birds get fresh air with both inspiration and expiration. We, in contrast, are limited to getting fresh air only with inspiration.

With all of these differences, Dr. West argued that a bird’s breathing system is more efficient than a human’s. At the same time, our form follows our function. For most of our needs, the lungs we have do an excellent job. It’s only when we follow the bar-headed goose up Mount Everest with no supplemental oxygen, as some have attempted, that a set of bird lungs would come in handy. Biology has set limits, which some people try to ignore, at times to their own detriment.

The design structure of our lungs ties into our method of locomotion and basic needs of survival, which are much different from those of birds. But for all the variance between our classes, the standard blood levels of oxygen attained in a mammal and a bird are, surprisingly, exactly the same—about 95 mmHg in both species. Both bird and mammal systems seem to be tied into this optimal level of oxygen, not too low but not too high.

We know the problem at low levels of oxygen, but at higher levels, above 100 mmHg, oxygen may become toxic by grabbing electrons we don’t want it to grab, in a process similar to the oxidation that produces rust on a car. The laws and limits of chemistry are at work in all of our biological systems, including the gross anatomical structure of the lung.

It’s not just the laws of chemistry that govern our physiology. Other forces of nature are at work as well. As described in the prologue, our lungs resemble a tree branching up into leaves or down into roots. The lungs could also be compared to the tributaries of a riverbed merging to a main waterway. The neurons of the brain, spreading out into tendrils from the main axon, follow a similar configuration. The human body itself is another example, dividing from a main trunk into limbs, which then divide into fingers and toes.

This branching configuration is so familiar because it appears to follow a law of physics first described in 1996 by Duke University physicist Adrian Bejan. Termed the constructal law, it states that, “for a finite-size system to persist in time, it must evolve in such a way that it provides easier access to the imposed currents that flow through it.”38 The best structure for this happens to be how our lungs are designed, with many small branches connected to one big branch. The lungs are tied into the universe of physics like no other organ, perfectly using the space allotted to maximize flow. And optimizing flow, and movement, is clearly one of the purposes of life from a biological perspective.

Figure 6: The airways of the lung, designed to maximize flow.

26. Merriam-Webster Online, s.v. “dum spiro, spero.”

27. Roy Porter, The Cambridge History of Medicine (New York: Cambridge University Press, 2006), 78.

28. Daniel L. Gilbert, Oxygen and Living Processes: An Interdisciplinary Approach (New York: Springer-Verlag, 1981), 3.

29. Paula Findlen and Rebecca Bence, “A History of the Lungs,” Stanford University website, Early Science Lab, https://web.stanford.edu/class/history13/earlysciencelab/body/lungspages/lung.html.

30. Andrew Cunningham, The Anatomical Renaissance (Abingdon, UK: Routledge, 2016), 61.

31. Saul Jarcho, “William Harvey Described by an Eyewitness (John Aubrey),” American Journal of Cardiology 2, no. 3 (September 1958): 381–384.

32. Thomas Wright, William Harvey: A Life in Circulation (Oxford, UK: Oxford University Press, 2013), xvii–xxi.

33. David G. Ashbaugh, D. Boyd Bigelow, Thomas L. Petty, et al., “Acute Respiratory Distress in Adults,” Lancet 290, no. 7511 (August 12, 1967): 319–323.

34. Giacomo Bellani, John G. Laffey, Tai Pham, et al., “Epidemiology, Patterns of Care, and Mortality for Patients with Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries,” JAMA 315, no. 8 (2016): 788–800.

35. Roy G. Brower, Michael A. Matthay, Alan Morris, et al., “Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome,” New England Journal of Medicine 342 (May 4, 2000): 1301–1308.

36. Michael A. Mathay, Carolyn S. Calfee, Hanjing Zhuo, et al., “Treatment with Allogeneic Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome (START Study): A Randomised Phase 2a Safety Trial,” Lancet Respiratory Medicine 7, no. 2 (February 2019): 154–162.

37. John B. West, “How Well Designed Is the Human Lung?” American Journal of Respiratory and Critical Care Medicine 173, no. 6 (2006): 583–584.

38. Adrian Bejan and Eden Mamut, Thermodynamic Optimization of Complex Energy Systems (Dordrecht, NL: Springer, 1999), 71.