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Chapter 3

An Infant’s Drive to Breathe

The lungs not only facilitated the beginning of terrestrial life on this planet, they also facilitate the beginning of our individual lives. During the final trimester of pregnancy, the lungs are the only organ in the fetus that is not working. The heart is beating away at a fiery 160 beats per minute, the kidneys are making urine, with the baby peeing right into the amniotic fluid (which is then swallowed again by the baby in a repeating cycle). The brain and muscles are awake with kicks and backflips and rolls. But the lungs remain completely silent and nonfunctioning.

This all changes, and abruptly, when the baby emerges from the womb. The lungs must turn on in an instant in order to begin their job of oxygen extraction and carbon dioxide release. To measure the success of this change, all hospitals throughout the world use what is called the APGAR score, named after the distinguished professor of surgery from Columbia University, Virginia Apgar. The first woman to attain full professorial status at Columbia’s medical school, Dr. Apgar devised this beautifully simple and elegant way to assess the health of a newborn in 1953.

At one and five minutes after birth, the Appearance, Pulse, Grimace, Activity, and Respiration are assessed, and a score of 0, 1, or 2 is recorded for each, for a maximum of 10. The majority of babies easily achieve a score of 8 or 9. The purpose of the APGAR score is to identify babies at immediate risk and to take proactive measures to improve whatever deficiency is present. This could mean just agitating the baby until he or she wakes up, or it could mean giving more oxygen or inserting a breathing tube into the lungs. Sometimes in medicine inaction is preferable, along the lines of “First do no harm.” A low APGAR score is not one of these times. A newborn scored at 6 or 7 will usually improve on her or his own. A score under 5 is panic time.

The APGAR score reflects, on the most basic level, the ability of the lungs, heart, brain, and muscles of the chest to appropriately make the lightning jump from living in fluid to living in air. But of these four systems, the lungs have by far the most work to do, because in utero they are like a soaked sponge, filled with the mother’s amniotic fluid. The fetus’s source of oxygen is the placenta, that radiant red jellyfish-like structure that is expelled after birth. The placenta neatly takes oxygen-rich blood from vessels imbedded in the uterus and channels it to the fetus through the umbilical vein.

Once in the umbilical vein, the blood travels through a series of open ducts, one through the liver and another through the right to the left side of the heart, to ensure that the dormant lungs are bypassed. The blood then goes out the left side of the heart to the aorta, where it feeds the organs. The tissues expel the oxygen-depleted blood back into veins, where it ultimately travels back into the mother’s body through the umbilical artery.

The free oxygen ride must come to an end, and it does so dramatically at birth. In an instant, the ducts through the liver and heart close, shunting blood to the lungs to pick up oxygen. The brain must simultaneously start firing signals to the muscles of inspiration. The eyes must open and adjust to the harsh light of the world. Finally, the lungs, still filled with amniotic fluid, must inflate in an instant with the first breath of life. The alveoli pop open for the first time and, with that first deep breath, suck the fluid up and immediately begin extracting oxygen from the atmosphere. The lungs change from being water-filled to being air-filled, from being dormant to extracting oxygen, all in the first few seconds of life.

Unfortunately, for some babies this leap from in utero to living in the atmosphere is not without significant complications. I experienced this firsthand one day. On a brutally hot day in late spring, I drove frantically to the hospital in dense Philadelphia traffic with my very pregnant wife. Adding to the discomfort, my wife was intermittently squeezing the blood out of my arm in retaliation for the contractions in her belly.

We drove right up to the hospital and gave the attendant my key. A man instantly emerged with a wheelchair, and we were whisked up to the preadmission area for pregnant patients. A nurse in bright-green scrubs immediately and unceremoniously put a glove on her hand and inserted it into my wife. “You’re almost completed dilated,” the woman said. “We need to get you into the delivery room. Now!”

Our hearts started racing as we instinctively clutched each other’s hand. The nurse left, but not for long, and when she came back, she was accompanied by a horde of other hospital workers. With mechanical efficiency, one of them jabbed my wife’s arm for an IV line, another thrust a blood pressure cuff around her bicep, and a third strapped a monitor onto her belly to measure the baby’s heart rate. Then she was quickly moved to the delivery room, up onto the bed, and into position.

“What about my epidural?” my wife asked, squeezing my arm again as another harsh contraction pulsed through her. The doctor came in, young and fresh-faced, in blue scrubs and blue hat. She nodded at us and then studied the baby’s heart rate on the monitor. It had dipped down with the contraction, which was normal enough, but it was going too low, and staying too low for too long. After a long spell of slow, low-pitched, tortuous beeps, the pinging of the heart rate on the monitor resumed its brisk pace.

“Listen, there’s no time for an epidural. You need to get this baby out. He’s ready. Your body is ready. We need to do this.”

“You’re sure?” My wife looked anxiously around, stressed by the prospect of more pain.

“Yes, quite sure,” the doctor responded evenly. “We need to get this little guy out. There’s something irritating him in there. His heart rate is intermittently dropping too low. Way too low. He needs to come out now.”

Wild thoughts entered my head. He was a few days early, and now his heart rate was sporadically bottoming out. Questions about whether this would affect his brain, and whether his lungs would be ready to wake up and answer the call of terrestrial life, entered my head.

For the next fifteen minutes, my wife’s contractions came and went. With each one, the little guy’s heart rate dipped too low and for too long. But it always came back up, granting us some feeling that everything was okay.

Finally, in response to one long, very painful contraction and a lot of pushing, the baby’s head appeared in the canal, his hair all curly and slimy. “Okay, let’s do it on the next one,” the doctor said, now fully suited in blue paper scrubs and elbow-length white gloves, her energy raised to the next level.

The next contraction came, and through the searing pain and exhaustion, my wife screamed and pushed, completely absorbed in that private world of childbirth. But from her pain and monumental effort came a result—my son’s head popped out. The excitement was tempered by the sounds of his heart monitor, which began bleating out the low drone of his heart rate crashing again. It dropped much lower than before, down to forty beats a minute. My wife stopped pushing, the contraction gone. Her face relaxed, and then her pelvis. The baby retreated to where he had come from, and the slow heart rate that should have started to recover by now didn’t. And it was dropping lower and lower, now thirty, now twenty, with no signs of recovery. Then the pinging heartbeat dropped to its lowest and slowest pitch yet, a sickening sign of a life slipping away.

“Don’t stop! Don’t stop!” the doctor pleaded, grabbing my wife’s hand in hers. “You need to get this baby out. Push! Push! Push!” I joined into the entreaties and started screaming, “Push! Push!” Confused, and shielded from the reality of her newborn’s devastatingly low heart rate, my wife started pushing again. Once and nothing; then twice and nothing.

“One more big push!” I yelled. It was my turn now to squeeze her arm, and I squeezed it hard. Finally, with a huge effort and a high-pitched scream, my wife pushed with all of her might, and the little guy came squirting out in rush of liquid and slime. He was beautiful, but he wasn’t moving at all. His head and body were completely flaccid, his eyes shut, and his skin a sickening pale blue.

It was clear now what had caused his heart rate to dip low: around his neck the umbilical cord was wrapped tight in a single, well-defined knot. It all made perfect sense. As he got farther down the birth canal, the umbilical cord, constrained by its tether to the placenta, had wrapped itself tighter and tighter, like a perfectly constructed noose.

The nurse quickly cut the cord, and she and the and doctor brushed past me and put the baby on the newborn bed, a bright warming light shining down.

“Somebody page pediatrics. Stat!” the doctor yelled. “His APGAR is four.”

She then turned the warming lamp up to high and shook our child’s chest. He did nothing, remaining flaccid and blue. The doctor grabbed the oxygen mask and strapped it onto his face, but still nothing happened. Ten seconds passed, then twenty, then thirty, without the faintest hint of a limb stirring.

A nurse hurriedly got an intubation tray ready to insert a tube into my son’s mouth and hook him up to a ventilator. If he couldn’t breathe, the ventilator would have to do it for him. I took a look at the instruments the staff was about to employ. The intubation blade, about six inches long and shiny silver, would be used to pull open his mouth to get a good look at the airway opening. The tracheal tube was a simple piece of plastic with a balloon on the end, ready to be thrust down to deliver the breaths of life. There was no question about him needing the tube. We were just waiting for the pediatricians now.

Another nurse came over with a breathing bag to deliver rescue breaths until they got the tube in. Before strapping on the mask, she gave my son one final shake, and through a miracle, she connected with what was likely the single neuron in his brain that was still firing. He shook his head, took a huge breath, instantly turned a bright red, and let out a huge scream, affirming his secure place in the world.

* * *

On the spectrum of childbirth complications, my son’s issue was serious, but an umbilical cord around the neck is not uncommon. In the 1950s and ’60s, the problem facing pediatricians in the United States was significantly worse, with ten thousand newborns a year dying of a mysterious lung disease, not to mention the other thousands worldwide. Most who succumbed didn’t live past a week. In the United States, another fifteen thousand who were affected by this strange inflammatory condition were left with suboptimal lungs when they recovered.

Typically, these little ones were born early, sometimes by a few weeks, sometimes by a few months, and never got a chance in life. Their deliveries were generally uncomplicated, but within a few minutes of birth their breathing would become labored and noisy. High-pitched grunting would come out of their lungs with exhalation, and their nostrils would flare out and in as they struggled to get enough air into their lungs. Their chest walls would pump up and down, their breath rapid and shallow. Their skin, initially a healthy pink from their mother’s oxygen supply, would turn a grayish blue, the tips of their fingers forbiddingly dark. Other complications followed—bleeding into the brain, kidneys shutting down, and seizures.

From the delivery room, the babies were attended by pediatricians who desperately tried to keep them alive. But there wasn’t much the staff could do, since not much was known about how to treat them at the time, and no medicines existed to cure whatever was happening. And so these babies, often very small but with normal hearts and brains and kidneys and livers, had their lungs collapse for no apparent reason. Many died.

The most famous of these breathing-challenged babies was Patrick Kennedy. Born five and a half weeks early on August 7, 1963, on Cape Cod, he began having breathing difficulties immediately after birth. Transferred to an intensive care unit (ICU) in Boston, he continued to decline, his organs failing. His body finally gave out and he passed away two days later. If there was nothing very remarkable about the baby’s illness, there was something unique about his parents. His father was John F. Kennedy, thirty-fifth president of the United States, and his mother was Jacqueline Bouvier Kennedy, the First Lady.

The nation mourned with them that August, but that was all anybody could do, because nobody had a clue as to what was causing these tragedies.

Mary Ellen Avery, who eventually helped solve the mystery of neonatal respiratory distress syndrome, came from a simple background—her mother was a school principal, and her father, despite being blind, started a successful cotton products business during the Depression in the 1930s. The lesson he taught his children was obvious: problems were meant to be solved.

Mary Ellen started kindergarten early, and then skipped sixth grade. By seventh grade, she was telling everybody she wanted to be a doctor. This desire was no doubt due to the influence of the seventh grader’s neighbor and mentor, Emily Bacon, a professor of pediatrics at the Woman’s Medical College of Pennsylvania, in Philadelphia. Dr. Bacon would take Mary Ellen with her to the hospital some mornings and show her newborns in the nursery. There, one day, Mary Ellen saw an infant grunting and wheezing and turning blue, her first exposure to premature respiratory distress syndrome. If this disease could be cured, she thought, the additional years of life added would quite simply be a lifetime.39

Mary Ellen attended Wheaton College in rural Norton, Massachusetts, where she continued her upward trajectory, graduating summa cum laude in chemistry in 1948. Determined to get the best medical education possible, she applied only to Harvard and Johns Hopkins. She didn’t know then that Harvard didn’t accept women, and she never heard from them. But Johns Hopkins University School of Medicine had been founded in 1893 with money from several wealthy female benefactors, who had insisted that educating female physicians be an equal part of the institution’s mission. They accepted eighty-six men and four women in Mary Ellen’s year.40

Despite the challenges and resistance from some chauvinist professors, Mary Ellen graduated and stayed on afterward for an internship and residency in pediatrics. A month into the internship, in a screening test, she was diagnosed with tuberculosis and was packed off to a sanatorium in upstate New York, where she was instructed to lie down for most of the day while the antibiotics did their job. Once cured, she returned to finish her training at Hopkins in 1954. The hours were long—shifts of thirty-six hours were the norm then—but it was an exciting time to be in medicine. A year earlier, in 1953, James Watson and Francis Crick had written a paper on the structure of DNA, our genetic material. Also around this time, cardiac catheterization started, and accurate diagnosis of heart disease became a reality. The number of available antibiotics expanded to five, then ten, then twenty. Huge medical breakthroughs seemed to be coming once a month.

At the end of her three years of clinical training, Mary Ellen was still deeply bothered by babies dying of lung failure, and held to the dictum of the Italian Renaissance scientist and philosopher Galileo Galilei: “I would rather discover a single fact, even a small one, than debate the great issues at length without discovering anything at all.”41 The single issue she wanted to investigate was why these premature babies’ lungs didn’t work at birth, and what was different between a thirty-two-week-old newborn’s lungs and a forty-week-old newborn’s lungs. She decided to work with Jere Mead, who was doing seminal work in pulmonary physiology at the Harvard School of Public Health in Boston.

The disease that we now call respiratory distress syndrome of the newborn had many different names in the 1950s, including congenital aspiration pneumonia, asphyxial membrane disease, desquamative anaerosis, congenital alveolar dysplasia, vernix membrane disease, hyaline membrane disease, and hyaline atelectasis. Most doctors today can’t tell you what most of those words even mean. But the esoteric names sprang from the many theories of the syndrome’s cause, masking the unknown in obscure language. Some believed the infants were breathing fluid into the lungs as they passed through the birth canal. Others hypothesized a heart defect, which was causing fluid to back up into the lungs. Another theory proposed that pulmonary circulation was the source of the problem. Unsurprisingly, clinical trials for potential medicines in human subjects all came back negative.

Despite how far the entire field was from solving this problem, a few things were known. Autopsies noted that the alveoli, those small grapelike clusters where gas exchange takes place, were plugged up with dead inflammatory cells and protein waste, which were named hyaline membranes. This material had a slightly transparent, glassy look. The term hyaline membrane came from the Greek word hyalos, meaning “glass or transparent stone such as crystal.” Most scientists focused their research on this phenomenon.

Mary Ellen, now Dr. Avery, deliberately did not focus on hyaline membranes, or any other existing theory, freeing herself from all preconceptions and throwing herself into understanding the basic physiology of the lung. Her approach, like that of most of successful scientists, was to explore the mechanisms underlying a given process and not just to observe the output. She focused on the basic questions of what allowed the lung to expand and contract, over and over and over again, without being ripped apart or collapsing in on itself, on what gave this wonderful organ its resiliency and strength to breathe 20,160 times per day, moving some ten thousand liters of air, while an additional five liters of blood makes its way through the blood vessels of the lungs every minute. The heart is made of compact, strong muscle. The liver is a dense structure of channels and filters. The lung, by contrast, is mostly air. Under a microscope, it has a thin, lacy structure, delicate in appearance. Where its resiliency and strength came from was a mystery.

Dr. Avery studied the respiratory physiology of different animals from birth to a few weeks old, mapping their lung development and characteristics as they emerged into life. Away from the lab, she continued her clinical work at the Boston Lying-In Hospital, overseeing the care of the newborns. Obstetricians would hand the newborn babies to her, and she would start a stopwatch and write down the data as the baby inhaled for the first time, calculating an APGAR score and then taking blood samples. She ran from room to room, her mind on high alert for any clues about these babies’ lungs.

When babies died from mysterious lung illness, Dr. Avery was at their autopsies, going over their pathology, holding on to the slides for the day when she could make more of a connection between them. One thing that caught her attention during these autopsies was how dense with tissue these little baby lungs were, completely airless, resembling the liver more than the lung. They had failed to inflate.

Dr. Avery visited the library at the Massachusetts Institute of Technology (MIT) on weekends, seeking literature from fields outside of medicine, hunting for new ideas from the minds of chemists and mathematicians. On one of these visits she discovered a book by C. V. Boys entitled Soap Bubbles: Their Colours and Forces Which Mould Them.

First published in 1912 for English schoolboys, this slim volume was a primer on the physical properties that govern soap bubbles, filled with simple experiments that document the physical properties of liquids and their interaction with air, explaining how soap bubbles are able to stay intact, miraculously floating through the air. Dr. Avery saw a connection between soap bubbles and the alveoli in our lungs. Circular in shape, and needing to stay open to continue gas exchange, alveoli are governed by the same physical laws as those governing soap bubbles.

The key to soap bubbles staying spherical and not collapsing in on themselves lies in their surface tension. Any spherical structure, like a soap bubble or an alveolus in the lung, is bound by a simple law of physics. Formulated by French scientist Pierre-Simon Laplace and English mathematician Thomas Young in 1805, the law states that the pressure exerted on a circular structure is directly proportional to the surface tension in the sphere, and inversely proportional to the radius of the sphere. Extrapolated out, this means that larger bubbles are more stable and have less pressure on them than smaller bubbles, and they are more likely to stay intact. Similarly, a sphere with lower surface tension is more stable and is under less pressure than one with higher surface tension.

The radius of a sphere is simply the distance from the center of the sphere to any edge. Surface tension, however, is more complicated. At the interface between a liquid and a gas, the molecules in the liquid are more tightly bound together than in other areas of the liquid. For example, in a glass of water the water molecules at the surface are much more crowded together than the molecules in the middle of the glass, because there are no water molecules above them to exert a dispersing force. These tightly bunched water molecules at the surface cause tension, which produces the slight dip one can see at the top of a glass of water.

Different liquids have different tendencies to bunch together at the surface. Water has a relatively high surface tension, so molecules are bunched relatively tightly together at its surface. Consequently, water does not make a good bubble, and exists more easily in drops, like rain drops and drops of water in a sink. But if soap is added to water, the surface tension is dramatically lowered. The ends of soap molecules have different properties: one end attracts water (hydrophilic), and the other one repels water (hydrophobic). When placed in water, the hydrophobic ends of soap molecules push their way to the top, which causes the water molecules to separate from one another, lowering the tension and energy between them. This allows a spherical structure like a soap bubble to stay intact, until it dries out and bursts.

At the same time Dr. Avery was learning about bubbles and surface tension, a number of committed scientists, employed by the federal government at the height of the Cold War, were investigating properties of the lung in reaction to chemical warfare. The lungs are a typical entry point for poisonous gases, and understanding the effects of toxins on the lung and how to combat them was a priority. One of these researchers, Dr. John Clements, at the Army base in Bethesda, Maryland, undertook a series of experiments in the mid 1950s to quantitatively measure surface tension in the lung, which demonstrated that lung tissue had very low surface tension compared to other tissues. He then did something simple, which nobody had ever done: he measured pressure across extracted lung tissue with expansion and contraction. As mentioned, the pressure on a sphere like a soap bubble or a lung alveolus is proportional to its surface tension divided by its radius, and lower pressures will mean the bubble will have a greater chance of not collapsing in on itself. Remarkably, the pressure decreased significantly with lung contraction (as the alveoli in the lung were getting small with contraction, pressure should have increased as the radius decreased), and increased significantly with expansion (as the alveoli got bigger, pressure should have decreased as the radius increased). To explain this, Dr. Clements correctly postulated that something must be overcoming the effect of size on pressure, and the only variable left in Laplace’s equation was surface tension.42

Taking his hypothesis further, Dr. Clements imagined that something within the lung must be lowering surface tension so dramatically as to overcome the effect of size on pressure. He correctly postulated it was a soap-like foam, which exerted a dispersal effect as its molecules became more concentrated and the area became smaller, and lost this effect when the lung expanded and pulled the soap like foam molecules apart. The effect of this soap-like foam lowering surface tension would be more important than lung size in calculating pressure if it was a powerful substance (which it was, and is). John Clements later named this substance surfactant, from its effects on the surface tension.

Figure 7: The lungs in cross section, with a conducting airway surrounded by many alveoli.

The definitive discovery and demonstration of the existence of surfactant was a major breakthrough in the understanding of lung physiology, finally explaining the mechanism by which the lung seamlessly expands and contracts, thousands of times a day, without breaking apart with inspiration or collapsing with exhalation. While the heart has dense striated muscle, and the brain its conglomerated networks of communicating neurons, the lung is a thin, graceful structure of interconnecting fibrous tissue that is beautifully held together with a foamy substance that lubricates its functions in a quiet and effortless manner. It is an organ of elegance, not brute strength.

John Clements’s paper did not get accepted into the high-powered journal Nature, but appeared instead in a low-level publication, where it was not widely recognized as the landmark study it would become.43 It did, however, reach Dr. Avery, and in 1956 she drove to Bethesda to meet Dr. Clements in person. He knew nothing about neonatal respiratory distress, and she knew nothing about how to properly measure surface tension. He taught her everything he knew about lung physiology, as well as how to build an instrument so she could take her own pressure and surface tension measurements. Dr. Avery quickly came to believe that the afflicted newborns weren’t diseased because of the presence of something, that something being hyaline membranes, but because of the absence of something.44 That something, she believed, was surfactant.

She went back to her lab and built her own balance to measure surface tension, and then she discerned that the lungs of babies who had died from respiratory distress syndrome had very high surface tension. By comparison, the lungs of normal infants had a much lower surface tension. This was the breakthrough she had been looking for since her time as a child visiting the hospital with Dr. Bacon, and the breakthrough humanity had been waiting for since the first premature baby had been born and died a perplexing death.

Dr. Avery published her findings in 1959 in the American Journal of Diseases of Children. Entitled “Surface Properties in Relation to Atelectasis and Hyaline Membrane Disease,” the paper broke the field of neonatal respiratory distress syndrome wide open.45 The key to the disease had been pinpointed. The immature lungs were not making surfactant, the surface tension in the alveoli was way too high, and the alveoli were crashing closed. Hyaline membranes were formed as a byproduct of the inflammation and destruction. Some babies lived long enough for surfactant production to kick in and open up their alveoli, but many did not.

Funding poured in from the National Institutes of Health, and over the ensuing decades, researchers at several different institutions made significant progress toward a cure. Doctors used ventilators to stent the lungs and alveoli open, and steroids were shown to speed up surfactant production in premature babies. Later, an artificial surfactant was manufactured to serve as a replacement. Today the mortality from respiratory distress syndrome is 5 percent of what it was before Dr. Avery’s brilliant insight.

Mary Ellen Avery went on to accomplish other great things in her life. She helped found the field of specialized care for the newborn, known as neonatology, and her textbook, Avery’s Diseases of the Newborn, has been the standard in its field for decades. She became a full professor of pediatrics, and the first female chief of a clinical department at Harvard Medical School. Her guidance produced tens, if not hundreds, of leaders in pediatrics across the country.

As for my son, all has gone well since his delayed first breath of life. He made the difficult transition from living in water to living in air. That day, my son taught me that breathing can be difficult. We take it for granted, but it is a complex process involving the coordination of multiple organs, with the lungs in the center. And a lung is not just a simple pump, pushing gas around. As Dr. Avery began to teach us, it is an organ alive with immunology and chemistry, one that does an extraordinary amount of work under extreme stress from the moment we enter this world.

39. Mary Ellen Avery, MD, interview by Lawrence M. Gartner, American Academy of Pediatrics, Oral History Project, 2009. https://www.aap.org/en-us/about-the-aap/Gartner-Pediatric-History-Center/DocLib/Avery.pdf.

40. Amalie M. Kass and Eleanor G. Shore, “Mary Ellen Avery,” Harvard Magazine, March-April 2018. https://harvardmagazine.com/2018/02/dr-mary-allen-avery.

41. John A. Clements and Mary Ellen Avery, “Lung Surfactant and Neonatal Respiratory Distress Syndrome,” American Journal of Respiratory and Critical Care Medicine 157, no. 4 (1998): S59–S66.

42. John A. Clements, “Lung Surfactant: A Personal Perspective,” Annual Review of Physiology 59 (1997): 1–21.

43. Clements, “Surface Tension of Lung Extracts,” Experimental Biology and Medicine 95 (1957): 170–172.

44. Julius H. Comroe Jr., Retrospectroscope: Insights into Medical Discovery (Menlo Park CA: Von Gehr Press, 1977), 149–150.

45. Mary Ellen Avery and Jere Mead, “Surface Properties in Relation to Atelectasis and Hyaline Membrane Disease,” American Journal of Diseases of Children 97 (May 1959): 517–523.