HOSPITALS

In the summer of 2005, Charity Hospital, the country’s second largest, provided medical care to the poor and uninsured of New Orleans and had one of the nation’s busiest emergency rooms. Rebuilt for the sixth time in 1939, it had 2680 beds, and was a major teaching hospital for Louisiana State University. That August Hurricane Katrina struck the city and flooded the first floor of the structure. Aside for a few generators for breathing machines there was no power, no lights, and food was scarce.   On more than one occasion the thermometer topped 100 degrees.  Toilets didn’t flush. There was no water for hand washing and the port-a- potty at the end of the hall smelled.  Observing from the forsaken building, a physician painfully watched each day as helicopters evacuated patients from the roof of the nearby Tulane Hospital, a facility that was 80% owned by the for-profit Hospital Corporation of America, “while our 250 patients were evacuated by twos or threes in boats”.  It took nearly a week before the final 200 were rescued.19 

Of the for-profit institutions, HCA, Hospital Corporation of America is the largest.  The chain was started in Nashville in 1968 by a cardiologist named Thomas Frist.  “The hospital he worked in was poorly run and equipped,” and he and a few colleagues decided to build another one.  He met and partnered with Jack Massey, the man who developed the Kentucky Fried Chicken chain.  They built Parkview hospital in Nashville and bought a second one.  When Thomas junior talked to investors he encountered skepticism.  They didn’t believe a doctor could be a good business man.  The secret of his success, he once said, was the idea of bigness itself. 

The company he founded has become quite large and has “164 hospitals and 106 freestanding surgery centers in 20 states and Great Britain”–and a “market cap” of over 9 billion dollars.

Another of the big four, Humana was established after a few Louisville realtors figured they could make money operating nursing homes. They chose the company name from a list of 500 submitted by a corporate identity consultant. After buying one, then a few hospitals they went public in 1968.  By 1972 they were running 45 hospitals.   In 1978 they took over a second hospital chain and more than doubled in size.  Then in 2018 the company paid $4.1 billion for a 40 percent stake in 76 long-term acute care and rehabilitation hospitals operated by Kindred Healthcare.    

Bob Appel founder of American Medical International worked for a medical diagnostics lab that served hospitals.  When his employer had financial problems Appel purchased the lab and later started acquiring hospitals. 

National Medical Enterprises, now Tenet was formed by three lawyers in 1967.  One was quoted as saying “doctors don’t generally know how to run a business.  A hospital is really just like a hotel.  You just have to know the medical side.15

Community health systems of Franklin Tennessee once owned 25 of the 50 hospitals that were the nation’s most expensive.  In 2014 they controlled 200 hospitals and earned $18 billion in profits.  Then they paid $7.5 billion for a for-profit chain “that had a slew of financial and legal problems”, and they started losing money.  When their debt was close to $15 billion they sold 30 hospitals cheap and they are teetering.3

Currently about 1034 of the nation’s hospitals belong to one of several for-profit corporations.  They have stockholders, earn money, and pay taxes.  Their bottom line was boosted (and government revenues fell) in 2018 when the corporate tax rate dropped from 35% to 21%. 

Our nation’s first, Philadelphia’s “Pennsylvania Hospital’, was founded in 1751 “to care for the sick-poor and insane who were wandering the streets.” The facility was the idea of a Quaker who was medically educated in Paris a century before physicians believed bacteria and viruses cause infectious diseases.  He wanted to emulate Paris’ Hotel-Dieu, the continent’s second oldest. The Parisian facility was established by Saint Landry in 651 AD “to treat pilgrims and the poor.” By the early 21st century the facility had become central Paris’ “top casualty and emergency hospital.”  It closed in 2013.12

In 1811 federal legislators established and funded a home and medical clinic for military veterans. Fifty years later, after half a million fighting men died of wounds and illness in our destructive civil war (1860-64),the government created a number of veterans homes.  They “incidentally” also provided medical and hospital treatment.  50 years thereafter our nation entered the First World War (1917-18).  116,000 men lost their lives.  Many more were wounded and disabled–and a number of facilities were built. 

After they were officially launched in 1921, the Veterans Administration started building hospitals.  By 1948 there were 125, and the VA currently says they operate1600 health care facilities.5 They once cared for all service men and women who had been on active duty, even briefly.  After September 1980 the government began limiting the pool by requiring a “minimum length of service.” The VA and Indian health hospitals are directly and indirectly (through Medicare and Medicaid) federally funded.  

Before Medicare was passed in 1965 U.S. hospitals were largely segregated. Black physicians often couldn’t get privileges to practice at hospitals dominated by whites, and in some of our leading hospitals people of color were cared for in the basement wards of white hospitals.

Established In 1927 in the segregated south, the non-profit Houston Negro Hospital provided work for black physicians, and care for African Americans. 

In St. Louis a hospital for the cities black indigents opened its doors in 1937.  It was named for the Homer Phillips, a black lawyer from Sedalia, a small town in the middle of Missouri that was built on the main east west railroad line.  Raised in an orphanage, then by an aunt, Phillips became a lawyer at Howard University, and moved to St. Louis.  “Intensely interested in the Negro doctor”, he felt “more opportunities would be available for these men of medicine if there were a separate hospital.”  In 1922 St. Louis passed an $87 million bond issue and Phillips made sure the legislation designated one million of the dollars as funds for building a black run hospital.  Once the city had the money, it wasn’t easy to get them to turn it over.  For more than a decade Phillips fought “interests that sought to prevent the hospital’s construction.39 It’s doors opened in 1937, and 2 years later Phillips needed to get additional funding.  The facility was inadequate. “Patients were crowded into dark corridors and their lives were often in jeopardy because of fire hazards.”  By 1961 the institution had trained the “largest number of black doctors and nurses in the world, and it was a leader in developing the practice of intravenous feeding and treatments for gunshot wounds, ulcers, and burns. It closed in 1979.1

The hospital that provided a significant part of my medical training, St Louis City Hospital, was integrated and lost much of its clientele to more upscale facilities when Medicare and Medicaid became the law of the land.  The facility existed until 1985; then it closed.  City and county hospitals elsewhere (Cook County in Chicago, Bellevue in New York, San Francisco City Hospital, and Charity in New Orleans (to  name a few) remain very much alive and well.   

Cook County hospital in Chicago, the caregiver for the poor in our second largest city (committed to providing “quality care with respect and dignity regardless of their ability to pay”) gets close to 40 percent of its operating revenue from state and city taxes.  Of the remaining 60 percent, a third of the money comes from Medicaid, and 9 percent from Medicare.  I don’t know how much the institution gets from private insurance companies.  

New York City has 11 publically funded hospitals plus clinics and nursing homes.  With an annual budget exceeding $5 billion they provide emergency services and hospitalize close to a quarter of a million people a year.6

University hospitals, which are presumed to be “the best” by many, are staffed by esteemed professors who are often astute physicians and who write papers and books. These educational institutions provide complex services that require a team approach and interventions like liver, heart, and kidney transplants.  Many of the researchers who teach future physicians survive on research money supplied by the NIH or pharmaceutical companies.

By the 1950s all of our large cities and many small towns had a modern day facility. The government had constructed and ran military, Veterans administration, and public health service institutions.  Multiple hospitals were operated by religious groups or by university medical schools. 

According to one analysis, U.S. hospitals have been merging at a rapid pace for a decade, forming powerful organizations that influence nearly every health care decision consumers make.  The mergers have essentially banished price competition and raised prices for hospital admissions.  In one analysis of 25 metropolitan areas, between 2010 and 2013, prices rose 11 percent and 54 percent.17 

Public and university hospitals derive their funds from private and governmental insurance, from taxpayers, and from donors. The law says that if charitable organizations want to avoid taxes they must be operated exclusively for “exempt purposes”.  None of the earnings can go to shareholders or individuals.  They can’t try to influence legislation as a “substantial part of their activities.” 

(The list of organizations that could potentially acquire tax exempt status is quite long.  It includes groups that are: “charitable, religious, educational, scientific, literary, testing for public safety, fostering national or international amateur sports competition, and preventing cruelty to children or animals.” Etc…) 4

Some universities and charitable hospitals make a lot of money, and their profits are not taxed.  The Affordable Care Act did not challenge their IRS exempt status.  It did, however, add a few hoops. 

The institutions are now required to have a financial assistance policy that’s written in “plain language” on their web site.  The “audience should be able to understand it the first time they read or hear it.”

They (theoretically, at least) can no longer generate inflated bills, claim they spent an unrealistic amount of money caring for a sick person.  Hospitals typically send out exaggerated bills knowing full well that Medicare or insurance companies will only pay a portion of them. They use the amplified numbers as a starting point for negotiations with insurers, and as a means of demonstrating how charitable they are.  As part of the ACA non-profit hospitals should no longer be able to generate inflated tabs—charges that are higher than the amount insurance companies and Medicare really pay for the services.  Additional charges–the portion of a hospital bill that Medicare and insurance companies don’t usually pay—can’t be pumped up. 

Finally, when a recently treated person doesn’t pay their share of the costs, these institutions are supposed to “make reasonable efforts to determine whether the individual is eligible for financial assistance” before they sick their dogs on them– before they take legal action, sell a person’s debt or notify a credit agency.

In 2013, of the ten most profitable U.S. hospitals, seven were non-profit.  They earned over $1.5 billion, and, of course, didn’t pay any taxes.  They included a few big name institutions:  Gundersen of La Crosse Wisconsin earned $300 million.   Stanford’s teaching hospital had a profit of $225 million”, and the University of Pennsylvania’s hospital in Philadelphia made 184.5 million.”  “The hospitals with the highest price markups earned the largest profits.”  These institutions could have returned some of the tax derived revenues to the government.  (Fat chance.)  They could have increased the number of non-paying patients they cared for.  Since the affordable care act went into effect, they’re often caring for fewer people who can’t pay. If we’re going to make health care affordable we should probably revisit the tax exempt status of some of these institutions.5

A few years back Senator Grassley considered “removing tax-exempt status from teaching hospitals and forcing them to do more for local low-income, urban communities.”   The hospitals fought him and won. 

Much of the care our hospitals provide takes place in one of the country’s 983 state and local government hospitals or in one of the 2845 community sponsored nonprofit institutions.

The people who live far from the cities are served by many smaller institutions that are the product of a community or creations of health care workers who had a dream. Some are financially struggling to exist. 7

In May 2020 the New York Times told how, as a result of the Coronavirus bailout, the non-profit Providence Health System received over $500 million in government funds.  The company was sitting on nearly $12 billion in cash and was earning, in a good year, over $1 billion tax free from its investments in venture capital funds. Two other for-profit hospital groups, HCA and Tenet Healthcare, had billions of dollars in reserves and received $1.5 billion from the government. Ascension Health in St. Louis, a chain that had $15.5 billion in cash, was given $211 million.  And the largest rural hospital system in eastern Kentucky got $3 million, enough for 2 weeks of payroll. 

“Even before the coronoavirus, roughly 400 hospitals in rural America were at risk of closing,” and the 2000 rural hospitals that are in the black, on average, only have enough cash to keep their doors open for 30 days.” 36

In the last decade 113, mostly rural, facilities went out of business.  20 were in Texas, 12 in Tennessee and 7 each in Georgia and Oklahoma. Of the 283 rural hospitals that in 2015 were “vulnerable to closure”, those located in states that did NOT opt for Obamacare Medicaid expansion were especially hard hit.  16.5 percent of the hospitals in states that opted OUT were on the brink versus 8.5% in Medicaid and indigent patients than suburban hospitals.” 

Providing quality health care to our urban population is much more than a hospital issue.  60 million Americans—13 million of which are children lived in rural areas.  5.3 million resided in completely rural counties, 24.6 million in the mostly rural counties and 30.1 million in mostly urban counties. Their numbers have been dropping.  A non-profit: A Healthy Rural America is struggling with the problem.23

A third of the Health Care dollar, $1.1 trillion (2017) is spent on hospital care. The Affordable Care Act led to increased hospital revenues and kept a number of smaller hospitals alive.  States that “expanded Medicaid” saw 7.4 percent more Medicaid discharges in 2014 versus 1.4 percent in non-expansion states.

Total Number of All U.S. Hospitals.186,210
Number of U.S. Community Hospitals5,262
Number of Nongovernment Not-for-Profit Community Hospitals2,968
Number of Investor-Owned (For-Profit) Community Hospitals1,322
Number of State and Local Government Community Hospitals972
Number of Federal Government Hospitals208
Number of Nonfederal Psychiatric Hospitals620
Other Hospitals120

In 1981, a deranged 26-year-old man shot the president of the United States. A bullet hit a rib, and Ronald Reagan was in pain. At the time, neither he nor his aides sensed how close he was to death. As the presidential limousine sped to George Washington University Hospital, Reagan coughed up blood. When he tried to walk from the car to the emergency room, his legs collapsed, but his aides kept him from falling and dragged him to a gurney.  A senior surgeon arrived on the scene and realized the man had lost a lot of blood, and was still hemorrhaging. An operating room was empty and, as a gurney occupied by Reagan was wheeled in, O-negative blood was pumped into his veins. The urgent surgery and transfusions were so successful that few realized Reagan had used up one of his nine lives. 

The first U.S. level one trauma center was established in Chicago in 1970. By 2003 most states had at least one facility where surgeons, neurosurgeons, orthopedists, appropriate anesthetists and operating rooms are available 24 hours a day.  Some facilities have helicopter landing pads.34 Others use nearby airports and bring the severely injured to a hospital by ambulance.  50 million Americans are unable reach one of these centers in less than an hour. 

E.R.s in the U.S. hospital clock 136 million visits a year.  Forty million of them are for minor injuries, auto accidents, and gunshot wounds.35 Sixteen million of the people who are seen are admitted to the hospital.  People with myocardial infarctions who arrive by ambulance are sent to the catheterization/stent department.  Women in labor are wheel chaired to the hospital delivery areas.  The people with a new neurologic problem: a leg or arm that won’t move, inability to speak, loss of vision– are briefly assessed and routed to the CAT scan room.  An X-Ray without contrast only takes a few minutes, and doctors need to be sure the acute brain damage was not caused by a cerebral hemorrhage before can attempt to dissolve a clotted blood vessel.

A few years back (according to a colleague) the physician-in-chief of Northern California Kaiser was visiting one of our ERs and was disturbed by waiting rooms full of people. Some had minor injuries that needed a quick fix; others who were quite ill, had to wait a long time before they were triaged. He decided something needed to be done and he had clout. 

He met with the chiefs of our hospitals and an agreement was struck.  After a person entered the waiting room and registered, he or she would be taken to an exam room and evaluated by a doctor, nurse and tech within 15 minutes.  Lacerations had to be sewn shut, minor fractures casted, and a person sent home within an hour.  Sepsis, strokes, and bleeding were treated promptly.  Tests and consultations were ordered for problems of unclear significance and severity.  Efficient competent evaluation might not always be possible but that was the goal.

Then Dr Pearl retired and waiting room wait time worsened.

San Francisco General Hospital is a hybrid. It’s a trauma center and a teaching hospital. The doctors who care for patients come from the University of California Medical center. The facility also operates the city’s “Community Health Network.” 80% of its $600+ million operating budget is paid for by Medicaid, Medicare, and private insurance, and it gets the other 20% from the city’s general fund. As detailed in an earlier chapter, in response to criticism for their crazy high fees they recently lowered and capped the amount people pay when they are ill and injured and need care.  It’s too soon to tell if their billing approach will be viewed as a beacon for the rest of the country or as a hippy, odd ball gesture.    

A few decades back “the general” developed a unique approach to its visitors who slept outside in unsheltered locations. Many suffered and died prematurely from diseases caused by alcohol, smoking, exposure, and poor sanitation. Violence, mental disorders and suicides were common. San Francisco General “identified individuals who had visited their emergency room five times in 12 months. With the help of attorneys and with a staff of case managers, a primary care physician, nurse practitioner(s), and a psychiatrist, they got many of the people permanent shelter, a primary care doctor, and “benefits.” It was quite a legal feat in people who are disabled by mental illness. In time, 70-75% of the homeless were housed, and emergency department use decreased 50-75%.  That was a few years back, the homeless problem in Northern California has gotten worse and the funding has changed.11

In the 1960s intensive care units were created.  By the end of the 70s each nurse in one of the units cares for one or at most two patients.  Machines monitor blood pressure, pulse, and blood oxygen levels.  Respirators filled lungs. When appropriate food is dripped into stomachs through naso-gastric conduits.  Multiple IV tubes infuse bodies with nutrients and a variety of chemicals and blood products. 

Nurses have always been “the glue that held hospitals27 together.  Their numbers increased during the Second World War II.”  At the end of the conflict RNs earned an average of $2,100 a year, somewhat less than most male workers.  Their wages didn’t rise and their numbers started going down.  There increasingly weren’t enough RN’s to do the job right and those who remained had to work longer and harder.  To keep costs down hospitals froze their wages. These women were dedicated, right?  They wouldn’t quit.  By 1966 the average RN earned $5,200 a year.40 

At the city hospital where I was a resident one nurse passed medications and tried to handle the needs of the ill on an entire ward.  The women (and at the time they were all women) were energetic, amazing, and often exhausted.  Their wages were so low that none of their nursing school graduates wanted to work at our hospital.  When our few nurses went on strike in 1965 the papers thought their action was outrageous.

The idea that in America workers could strike if they were underpaid was challenged when the nation’s Air Traffic Controllers struck in 1981.  President Reagan said they were federal employees and were breaking the law. He gave them 48 hours to return to work or be fired.   His anti union stance changed attitudes.  In a decade, major strikes plummeted from an average of 300 each year to fewer than 30.   Despite an average annual inflation rate of 2.9% and a huge surge in productivity, the federal minimal wage, which was $3.35 in 1981, barely doubled in the 3 post-Reagan decades.   

In the San Francisco Bay Area 2 types of union actions have continued to be effective.  The interruption of BART commuter trains by striking workers always leads to jammed freeways and lengthy commutes.  When the police struck a few decades back the chief went on T.V. and warned that criminals, murderers, and rapists would have a field day.

At Kaiser where I worked, nurses felt they were underpaid.  They knew how to take care of sick or needy patients, but they soon learned that dealing with management was something else.  Every 5 to 10 years or so their contract came up for renewal, they asked for a raise, management hung tough and the nurses decided they needed to strike. 

That was fine with Kaiser.  The insurance money kept coming in.  People didn’t like to cross picket lines unless they were quite ill.  

Before the strike started traveling nurses were hired, elective surgery was canceled, and the very ill were sent to other hospitals. I remember driving to work and seeing throngs of young and middle aged nurses carrying picket signs, and standing by the entrance of the parking structure. They were friends, colleagues.  Many hated the thought of abandoning their patients and some believed strikes were unethical. 

After three weeks of pacing in the heat of the day or under an umbrella nurses started coming back to work.  Most had loans, rent, bills, and lived from one pay check to the next.  When a majority of worses had returned to the job management offered a small raise and signed a long term contract. 

Eventually the nurses hired a labor organizer named Rose Ann DeMoro and everything changed.  In 1968 she declared a 2 day strike, and the hospital prepared.  Critical patients were moved out, elective surgery was cancelled, and traveling nurses were hired.  A few days prior to the date, the strike was cancelled, but it was rescheduled for a date 60 days hence. 

Two months passed.  As before, very ill patients were moved out, nurses brought in, and elective surgeries cancelled.  This time the nurses struck for two days and no one lost much money.  As the strike was ending the union announced it would soon strike again. Management understood what was going on and cried “uncle.” The nurses pay rose substantially and they later fought for and won the right to make improvements to the quality of care they provided.   

Nationwide, one in five nurses belong to a collective bargaining unit. On average their wages are 20% higher than the pay of the nurses who are not in unions. In 2020 the average hourly wage of a registered nurse in half the states in our country was $28 to $34.  The other half earned $35 to $48 an hour. In Hawaii and California the average hourly wage was $50 to $54. 

Inside the large multispecialty hospital where I worked there is a large birthing wing. Large rooms accommodated doulas and invited family.  Nurse midwives handled the uncomplicated vaginal deliveries.  An anesthesiologist or nurse anesthetist was always on duty and performed epidurals.  Needles are inserted into the lower back, into the space between the vertebrae and the membrane that surrounds the spinal canal and lidocaine, a numbing agent was infused. The drug blunted much of the pelvic pain of childbirth.  An obstetrician was hanging around and was available for consultation and urgent C sections. 

In the hospital’s basement 2 CAT scanners and 2 MRI machines created detailed body images far into the night.  The pictures of the sliced body sections were immediately visible on every computer screen in the facility. A radiologist sat in a dark room, carefully checked the images, and looked for anything that didn’t belong.  He or she dictated a report that was transcribed by trained worker in the facility, or increasingly by people in the Philippines, India, or some other country.

A multi bed outpatient recovery area was staffed by nurses.  They prepared and observed patients before and after interventional radiologists performed biopsies or invasive procedures.  The unit also served as the pre and post procedure area for people having an emergency heart catheterization.  A cardiologist was always on call, no more than 15 minutes from the hospital, and available 24 hours a day, to catheterize and stent the coronary arteries of people who are probably having an acute myocardial infarction.

Gastroenterologists, who sometimes worked at bedside in the intensive care unit, had a dedicated in-patient procedure room, with equipment. If needed we would insert a scope and treat people whose upper GI bleeding was ongoing or those who had a bolus of food lodged in their esophagus.

There were medical, surgical, and pediatric intensive care units and a coronary care unit.

Hospital rooms had piped in oxygen and suction, a place where a partner or parent could spend the night and an annoying T.V. on the wall. 

A special inpatient pharmacy provided a large range of medications, including specialized drugs and infusions, 24 hours a day.

Pathologists processed, stained, examined, and interpreted the significance of tissue that was removed from bodies.  Samples were often sent “out” for molecular diagnostics (DNA/RNA analysis).

Phlebotomists drew blood and brought it to the lab where it was extensively tested.  The labs also cultured and assessed stool, urine, blood, spinal fluid, sputum etc.

And there were clerks, social workers, discharge planners, janitors, patient transporters, painters, security people, guards, physical, occupational, and speech therapists, dieticians, telephone operators, IT personnel, people who provide food for the patient and staff, and engineers who regulate and repair the electrical, cooling-heating and other building systems.

In 2017 American hospitals were responsible for $1.1 trillion of the nation’s $3.5 trillion in health care expenditures, and an average day in the hospital was costing nearly $4 thousand.28

I was employed by a pre-paid group, and all the physicians and surgeons were salaried.  The hospital had ten large operating spaces and the OR had a calendar that was controlled by a scheduler.  Each area was manned between 8 AM and 3 PM by a hundred or so nurses, technicians, and others.  In the late afternoon most of the rooms closed.  The few that remained open handled the overflow. One was available around the clock for urgent cases.  During the work day each of the designated areas was managed by a different surgical subspecialty, and had some unique equipment,

Gawande explained the importance of introducing the patient who will undergo surgery to everyone in the O.R., including the person who cleans the floor and the medical student.  He thinks the presentation gives everyone permission to sound an alarm if they notice a problem. Before a case starts, all the people who might play a role gather around the patient and are introduced. Then a “time out” is called.  The nurse or physician in charge would ask the patient their name and what they thought was about to happen, When indicated the involved breast or extremity was inked. (“In 1995 when a nurse told Florida Surgeon Rolando Sanchez he was cutting off the wrong leg, he kept going and she started to shake and cry. He felt he had gone too far.  The leg he had started to remove couldn’t be repaired and there was no turning back.”) 29

A surgeon or team of surgeons usually performed all the cases in a morning or an afternoon block.  If three hips were replaced that half-day, one surgical team usually did them all.  After each operation, the room had to be cleaned and efficiently turned around.  In bloody cases, like a hip replacement, soaked pads were not thrown on the floor.  They were instead bagged, and the containers were tied and slipped into the hall outside the room.  Following invasive surgery, when blood in the abdomen made it hard to be sure no foreign objects remained in the area, the sponges were counted before and after the operation.  Post-operatively, people went to a recovery area where 20 to 30 nurses cared for them for variable periods of time.  If a spinal anesthetic was used, the patient remained in the observational area until the numbness had worn off.  

In fee-for-service facilities surgery accounts for a substantial part of hospital revenue.  Akron General Hospital published what it charges on its website. The bill for using the operating room at their facility, which is part of the Cleveland Clinic, depends on “the complexity” of the procedure.  Their billers created five intervention levels: For those on the lowest rungs the first hour costs $2718.  Each additional half hour adds $1100 to the bill.  For level 5 procedures—the most complex– the room cost is $4935 for the first hour and $2200 for each additional half hour.20  

Free-standing facilities currently perform many of the “interventions” that were once done in hospitals: cataract surgery, colonoscopies, knee arthroscopies, cosmetic surgery, pain management, dental and ENT procedures. In 2019 there were 6100 ambulatory surgical centers in the U.S., and they performed more than half of that year’s 35 million operations and procedures.21

A 6 year old seemed cross eyed and saw an optometrist who realized the child had a 6th nerve palsy. The nerve that controls the lateral movement of his eye wasn’t working and that set off all kinds of alarms.  He was immediately sent to an ophthalmologist. The physician detected evidence of brain swelling and ordered an emergency MRI. That night one of the two hospital pediatric neurosurgeons told the parents their son had a brainstem tumor. The child was admitted and started on high dose steroids to decrease the pressure inside the skull. A few days later two pediatric neurosurgeons at Oakland Kaiser Hospital made a small opening in the rear of the child’s neck and removed the back of a vertebra.  They then sucked out the medulloblastoma cells (it is a friable malignant tumor) and rolled an MRI machine into the OR.  It revealed a tiny trace of tumor had invaded his spinal canal.  The vertebrae was replaced and fastened, and the wound was sewn shut.

Post operatively the child had obstructive hydrocephalus—fluid was not flowing from one chamber of the brain to the next one. It was possible he would need a shunt that transferred fluid from his brain to the space in the abdomen called the peritoneum. As a first step, under anesthesia a small hole was drilled in his skull and a thin sterile videoscope was passed through the brain into the fluid filled chamber in its middle.  The scope was maneuvered through the narrow passages that connected the ventricles, the fluid filled brain chambers. Cobweb like tissue was blocking the flow of fluids and it was pushed aside. Fluid started circulating normally and a shunt wasn’t needed.

After the child recovered from the surgery his insurer paid ¼ to ½ million dollars for proton beam radiation to destroy the small segment of tumor that remained.  It couldn’t be surgically removed without causing major neurologic damage.  Protons give off most of their energy (in a quick burst) to a precisely focused part of the body. This type of therapy decreases the amount of radiation to healthy tissues around the treated area.

The child was sent to the “Seattle Proton Therapy Center a facility where 10-foot-thick, lead-lined concrete walls isolate a particle accelerator that harnesses and fires protons generated from hydrogen gas. It was one in a national wave of costly facilities funded a decade or so back by private investors and lenders. The Seattle facility treats 500 people a year. “In 2018, after a net loss of $81 million over the prior two years, its original backers were handed a $135 million loss as part of a negotiated Chapter 11 bankruptcy.14” But they were still in business. At one time there were 27 proton centers in the U.S. They were expensive to build and maintain and their services are not covered by all insurance providers, so those that are still working are struggling financially.

Elsewhere on the planet, there are remote government funded community hospitals, in low and very low income countries—like Malawi and Bangladesh.  As described by the Harvard M.D. who spent time in Nepal, they are commonly located in far off corners of their nation and are the only options available to the poorest of the poor.  With 50 to 100 beds they serve 100,000 to a million people, and their doctors can usually perform a few orthopedic and general surgical procedures and C sections.  They have some X- ray capability, but commonly lack certain basics:  In Nepal 15% didn’t have piped in water; 20% lacked electricity; 55% didn’t have gloves, and 30% were unable to provide oxygen to those who need it22.

REFERENCES:

Marketplace Medicine—the rise of the for-profit hospital chains by Dave Lindorff a Bantam Book, 1992

Privatization and Public Hospitals by Charles Brecher and Sheila Spezio 20th century fund press, 1995

Black Physicians in the Jim Crow South by Thomas Ward, University of Arkansas Press 2003

Homer Phillips  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642069/pdf/jnma00694-0003.pdf 

https://en.wikipedia.org/wiki/Homer_G._Phillips_Hospital

Unexpected Necessities — Inside Charity Hospital, Ruth Berggren, M.D. N Engl J Med 2005; 353:1550-1553 October 13, 2005 https://www.nejm.org/doi/full/10.1056/NEJMp058239

Anna Deavere Smith, Let me Down Easy. Health Care In New Orleans Before And After Hurricane Katrina, 

https://www.npr.org/sections/health-shots/2015/06/09/412964

https://www.axios.com/the-collapse-of-community-health-systems-1513304786-f5a411e6-e0dd-401b-af65-9dc81be4be80.html

https://www.washingtonpost.com/news/to-your-health/wp/2016/05/02/these-hospitals-make-the-most-money-off-patients-and-theyre-mostly-nonprofits/?utm_term=.a7a2c1145547

https://www.irs.gov/charities-non-profits/charitable-organizations/exempt-purposes-internal-revenue-code-section-501c3

https://www.healthleadersmedia.com/finance/top-5-differences-between-nfps-and-profit-hospitals

https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/NationalHealthExpendData/downloads/highlights.pdf

http://www.miamidade.gov/auditor/library/Cook_County_Health%26Hospitals_System.pdf

https://www.beckershospitalreview.com/finance/the-community-hospital-survival-guide-strategies-to-keep-the-doors-open.html

The community hospital survival guide: Strategies to keep the doors open by Ayla Ellison June 15th, 2015

Anesthesia:  Biographical sketch of Dr. William T. G. Morton. U.S. National Library of Medicine. Concord, N.H. 1896.

https://archive.org/details/101495446.nlm.nih.gov/page/n7/mode/2up

Wier LM, Hao Y, Owens P, Washington R. Overview of Children in the Emergency Department, 2010. HCUP Statistical Brief #157. Agency for Healthcare Research and Quality, Rockville, MD. May 2013.  Kindermann D, Mutter R, Pines JM. Emergency Department Transfers to Acute Care Facilities, 2009.HCUP Statistical Brief #155. Agency for Healthcare Research and Quality. May 2013.

Inspired by the results, two California foundations started similar programs at six California public hospitals. One of them, Highland Hospital, the facility with the busiest emergency room in the county, targeted individuals who visited the ER ten or more times a year. A legal and health care team managed to get virtually all who were certifiably unable to work onto SSI. The $800 a month they received from the federal government was enough for a shared room and some food. Once the indigents had “benefits,” Medicaid, the federal government, paid for their medical care, and the state and county saved $2 million. But the start-up programs have largely ended, the funding has been used up, and in 2014, Obamacare kicked in and funding changed.

http://www.ansamed.info/ansamed/en/news/sections/generalnews/2013/05/15/France-Hotel-Dieu-oldest-Parisian-hospital-closes_8708351.html

https://www.uphs.upenn.edu/paharc/features/creation.html

The Troubled Health Dollar by Steven Fredman. Virtualbookworm publisher. 2013.

Rami Grunbaum, Seattle Times, December 4, 2018. Proton center’s restructuring approved by bankruptcy judge;

http://www.fiercehealthfinance.com/story/several-u-s-hospitals-rake-huge-profits/2010-08-31

https://www.healthcarefinancenews.com/blog/five-reasons-hospitals-become-profitable

Reed Abelson, NY Times, Nov. 14, 2018 When Hospitals Merge to Save Money, Patients Often Pay More

Fast Facts U.S. hospitals 201700  https://www.aha.org/statistics/fast-facts-us-hospitals

Robin Rudowitz  

https://www.healthaffairs.org/doi/full/10.1377/hlthaff.25.w393

Cleveland Clinic Patient Price Information List https://my.clevelandclinic.org/-/scassets/files/org/locations/price-lists/akron-general-patient-price-list.ashx

21. Health Industry Distributors Association. 2018 Ambulatory Surgery Center Market Report. Available online at https://www.hida.org/distribution/research/market-reports/2018-Ambulatory-Surgery-Center-Market-Report.aspx . Accessed July 16, 2019

https://www.cathlabdigest.com/content/freestanding-ambulatory-surgery-centers-new-strategy-cardiovascular-services

The neglected hospital .  Interview:  N Engl J Med 2020; 382:397-400 Dr. Ruma Rajbhandari. https://www.nejm.org/doi/full/10.1056/NEJMp1911298 

In the 2 decades –between 1990 and 2010, the percent of rural dwellers went from:

  • 21 to 15 percent in the north east
  • 28 to 24 percent in the Midwest
  • 14 to 10 percent in the west and
  • 31 to 24 percent in the south. 

Children in rural areas had lower rates of poverty (18.9 percent compared with 22.3 percent)—Healthy Rural America puts the percent of children who live in poverty at 25%.  In 2015 more country dwellers were uninsured (7.3 percent compared with 6.3 percent).  According to Healthy Rural America, the rural population tends to be older, sicker, and poorer, and they are more likely to be uninsured and unemployed.

There’s a need to build a sustainable and diverse health care workforce.  Rural dwellers have less access to health care workers and “critical access hospitals” It’s challenging to get patients and enough care givers to the  right place at the right time.  Transportation can be challenging; there’s a lack of access to high speed internet.  And, as with all of medicine, people argue about how we are going to pay for care.  .  Phil Pollakof plp@sbcglobal.net

https://www.congress.gov/110/plaws/publ23/PLAW-110publ23.pdf

https://www.amtrauma.org/page/LegUpTraumaReauth

file:///C:/Users/User/Documents/joc30383.pdf

https://www.govtrack.us/congress/bills/101/hr1602

Ether Day by Julie Fenster. copyright 2001.  https://archive.org/details/etherdaystranget00fens/page/112/mode/2up

The Youngest Science, by Lewis Thomas.  Viking Press 1983

https://www.vox.com/2019/1/22/18183534/zuckerberg-san-francisco-general-hospital-er-prices

An emergency field hospital, in Central Park –corona virus  New Yorker, Rivka Galchen, April 20, 2020

The Cost Conundrum, by Atul Gawande. New Yorker June 21,2009

Planet Money the economics of hospital beds. podcast

helipads http://stophelipad.org/faqs.shtml

ER STATISTICS https://www.beckershospitalreview.com/hospital-management-administration/25-facts-and-statistics-on-emergency-departments-in-the-us.html

New York Times:  May 26, 2020. How wealthiest hospitals reaped billions in bailout.

https://nurse.org/articles/highest-paying-states-for-registered-nurses/

 Nurses strike   https://www.registerednursing.org/do-unions-benefit-harm-healthcare-nursing/#:~:text=According%20to%20the%20Bureau%20of,nearly%2040%20years%20ago%2C%20a

nurses pay  https://work.chron.com/salaries-changed-nurses-23316.html

One-Third of Hospitals in Developing World Lack Running Water

https://www.jhsph.edu/news/news-releases/2016/study-one-third-of-hospitals-in-developing-world-lack-running-water.html

In low- and middle-income countries 50 % of remote health care facilities lacked piped water, 33 % lacked improved toilets and 39% lacked handwashing soap.

https://www.sciencedirect.com/science/article/pii/S1438463917303760/

CHILDBIRTH

I was in the delivery room for his final performance–the last time an obstetrician named Bill Masters, a doctor who would go on to become a world famous sex specialist, helped a child slide through a woman’s birth canal.  I don’t remember the baby’s sex or weight or its mother’s glee.  But I remember Masters presenting the newborn to its mom with the flourish of a circus maestro, and I recall my fellow med student fainting. His wife was pregnant.

As a junior in medical school I spent three weeks catching babies at Homer G. Phillips, the black public hospital in North St. Louis.  I and my fellow student were the only white guys in the facility.  Napping in a sleeping room on the second floor we were periodically awakened by a nurse yelling “don’t push—don’t push” as the creaky elevator carrying the almost-mother slowly whirred upwards.

Shortly after my grandmother was born her mother died.  In her day death was common when childbirth was complicated by “post partum bleeding, or infections” or when the baby was unable to get through the pelvis.

The U.S. has the unenviable honor of having the “highest rate of maternal mortality in the industrialized world.” —17.8 per 100,000 in 2009.  It’s especially high for African American women.6

The global maternal death rate has decreased by 44% in the last 25 years, but each year in the world’s 24 poorest countries, 400 women die for every 100,000 live births.  In recent decades most western countries have cut their death rates in half; in the U.S. the number of women dying almost doubled.  In California focused healthcare significantly helped reduce the mortality rate. 5

Throughout recorded history women “midwives” have assisted other members of their sex give birth.  In the late 1800s and 1900s physicians, virtually all of whom were men, moved in and took over.  In 1915 40% of all births were attended by midwives and by 1935, 20 years later, close to 90% of births were performed by male physicians.

In the U.S. Thirty three percent of children are delivered by C-section. (9% of the women who give birth this way had prior C-sections.)  The nurse midwife who brought me up to date explained that in her practice about seven percent of women are delivered by C-sections and only one in 400 women require an episiotomy, and incision to widen the birth canal.

Giving birth vaginally is usually painful and half of the deliveries performed by the midwife I consulted had epidurals.  A derivative of Novocaine is infused into the space outside the lower end of the spinal canal.  The drug usually controls the pain of child birth. When a physician delivers the frequency of an epidural nears 95%.

C-sections carry the risk of bleeding, infection, and of nicking the bowel and bladder. 7 When the mother has active vaginal herpes or the infant would have to come out feet or bottom first, vaginal delivery brings with it an extra possibility of harm that usually more than justifies the approach.  But that’s not the reason for the “worldwide explosion.” In Mexico City C -sections are performed for 45% of births.7   In China the C-section rate was 35% in 2014.

At $10-15,000 a try, in vitro fertilization (and other forms of assisted reproductive technology) led to the birth of a million babies between 1987 and 2015.  The Center for Disease Control keeps track of successful births after 37 weeks of single, live, normal weight children.  The number depends on factors such as: was the embryo fresh or frozen?  Did it come from donor or non donor eggs?  How many attempts were made? and how old was the woman?13  Under ideal conditions the process is successful, per attempt, 21% of the time.4

Before Obamacare became law, pregnancy was commonly classified as a pre existing condition.  Medicaid picked up the bill if the woman was sufficiently “low income”.  But some of the uninsured earned a bit too much.   After 2010 expectant women could purchase insurance and they couldn’t be charged more because they were pregnant.  If they wanted marketplace coverage they had to “enroll in a health plan during the open enrollment period, set by either the employer or the feds.”

During the first seven years after the ACA (Affordable Care Act) became law 13 million pregnant women “gained access to maternity services.”  Medicaid expansion played a role. (Medicaid also covered “contraceptive supplies, sexually transmitted infections, and “screening” for sexual violence and breast and cervical cancer.”) 1,2

In 2006 the 4.3 million births in this country rang up a bill of $14.8 billion.  A vaginal birth in 2010 was costing between $5000 and $7000; C sections went for about $10, 000.

The care of low and very low birth weight infants contributed another $18.1 billion to the birthing price tag.  Modern doctors have the incredible ability to keep not-quite-ripe small infants alive, and premature newborns account for half a million of the live births in this country.  Some of these kids spend weeks in neonatal intensive care units at a cost, nationwide, of $26 billion.  That turns out to be “about half of all the money hospitals spend on newborns.” 1.7 percent of newborns weighed less than a thousand grams when born and one half of one percent were under 500 grams.  Eighty five percent of the infants “survived to be discharged from the hospital.”3.

Prenatally doctors and nurse midwives check pregnant women for diseases that can be transmitted to their new born–infections like HIV and hepatitis B.   Obstetricians checking for fetal abnormalities usually perform the first fetal ultrasound when a woman is 18 to 20 weeks pregnant. Screening tests are also performed for genetic and developmental problems.  The second decade of the 21st century saw the emergence of blood tests that analyze fragments of placental DNA floating in the mother’s blood.  Fetal DNA and placental DNA are identical.  By pregnancy week 10 the level of fetal DNA in the blood of the pregnant woman is usually high enough to perform an accurate test. The studies look for chromosomal abnormalities and they aren’t perfect. The alternative, amniocentesis, is “invasive” and can induce a miscarriage one half to one percent of the time.  Near birth ultrasound exams are performed to check the baby’s position and detect problems like placenta previa, a situation where the placenta covers the opening of the cervix and prevents a normal birth.

The fear of malpractice haunts the birthing profession.   Childbirth mishaps, mistakes, and bad outcomes still account for close to 10% of all malpractice suits, and the amount awarded to injured children can easily be a million dollars or more.  It takes an immense amount of money to care for a damaged child for 80 years.  Not surprisingly the malpractice insurance rates for gynecologists are among the highest.  (see malpractice.9)

For a period of time health insurers were overly aggressive in their attempt to get women out of the hospital shortly after they gave birth.  Congress reacted.  The Newborns’ Act was signed into law on September 26, 1996.  It includes important protections for mothers and their newborn children with regard to the length of the hospital stay following childbirth.  (HMOs) that are subject to the Newborns’ Act “may not restrict benefits for a hospital stay in connection with childbirth to less than 48 hours following a vaginal delivery or 96 hours following a delivery by cesarean section.”

There are about 40,000 Ob/Gyn physicians in the U.S. When I graduated medical school (1962) most were men.  In their early years in practice they delivered babies.  As they and their cliental aged the doctors spent an increasing portion of their time tending to the organs of conception.  That’s changed.  By 2001 seventy two percent of the residents in the subspecialty were women.  During the last 35 years our local medical school, the University of California in San Francisco, trained and deployed hundreds of nurse midwives some of whom practice at local hospitals.  The safety of home deliveries on low risk women by nurse midwives has been documented time after time, but this approach still accounts for less than 30,000 of the babies born in the U.S. each year.

In addition to caring for women during the birthing years, gynecologists have traditionally been the primary care physicians of many otherwise healthy women as they age.  Among other things these physicians pay a lot of attention to the organs of conception.

Cancer of the cervix is “worldwide the third most common malignancy in women.”  It’s much less common in this country (11,000 cases a year) because many women have regular “Pap smears.”  It’s a test that was developed by a New York cytologist named Georgios Papanikolaou.  A Greek who finished medical school in Athens in 1904 then served in the army, Papanikolaou decided early that he wanted to be a researcher.  He was 30 when he and his wife Andromache came to the U.S.  They didn’t speak English and “had little money.”  She got a job as a button sewer for a department store and he tried to sell rugs.  His job only “lasted a day.”  He ended up earning money during his first year in the country playing a violin in restaurants.  Then he got a job in the anatomy department of Cornell Medical College.  His wife was hired as his assistant.12 Using Andromache as a subject he studied the appearance of cells from the lower part of the uterus, the cervix, and he noticed cancer cells looked different.  When he brushed, stained, and evaluated tissue that the end of the uterus was about to shed, he sometimes found “bizarre” changes that indicated a cancer was present.  It took years till his findings were accepted, but he eventually was able to teach doctors to recognize changes that indicated part of the cervix was almost, but not quite malignant.10

Responsible for over 33,000 cervical and vaginal cancers annually in the U.S., human papilloma virus is sexually transmitted and usually causes no symptoms.  Most infections clear within two years, but 14 million Americans are infected annually and 80 million are, at least temporarily, sexually “contagious.”  In 2014 the FDA approved two shot vaccine that effectively prevents the disease.  It works best when it’s given to young women before they are likely to be sexually active, and it covers genotypes 16 and 18 (responsible worldwide for 70% of cervical cancers) and 4 additional genotypes that account for 20%.11

Some parents feel that by immunizing their daughters they are saying we assume you will become sexually active, and that’s a message they’d rather not send

Early on the tools of the GYN trade relied on feel and a speculum.  The uterus and ovaries were felt by trained fingers in the vaginal canal pushing up towards and equally aware fingers on the abdomen pushing down.  When the exam was painful or the woman was large or tense the exam had limited value.

Shadows of the uterus and ovaries are now sometimes visualized using an abdominal ultrasound, a CAT scan, or by placing an ultrasound probe into the vagina and watching a T.V. screen.  The probe charge, in one location (chosen randomly on the Internet), is $200 per exam. I don’t know if insurance companies will pay for the test in the absence of a clear indication. It has not, best I can tell, become “routine”, though actress Fran Dresher and others thinks it should be.  The $6.5 million dollar bill President Bush signed in 2007 “authorized the development of a national gynecologic cancer awareness campaign” but did not mandate screening vaginal ultrasounds.

Gynecologists have long evaluated the inside walls of the uterus with an operation known as a D and C.  They dilate or stretch the cervical area. Then a sharp instrument is placed inside the uterus and the lining cells are scraped off, collected, and examined under a microscope.  The main indication for the operation is unexplained uterine bleeding which could be caused by cancer of the inner lining wall of the uterus. Nowadays there’s a thin narrow scope that can slip into the uterine cavity and allow doctors to look for abnormalities.  In this country hysteroscopy is usually performed in anesthetized patients.  In Australia and elsewhere it’s sometimes performed with light sedation and numbing agents.

Finally the gynecologists were pioneers in the use of a tiny incision and a laparoscope (see surgery) to evaluate ovaries, treat cysts, or tie fallopian tubes so a woman could avoid pregnancy.

Gynecologic surgery is a relatively large ticket item.  In this country 600,000 women have hysterectomies annually.  180,000 (30%) of the operations are done for “fibroids” benign growths that can cause symptoms.8Some hysterectomies are performed in an attempt to reduce or eliminate lower abdominal pain.  The discomfort is sometimes caused by endometriosis, a condition where the kind of tissue that normally lines the inner wall of the uterus is growing elsewhere in the pelvis. Abnormal cells are sensitive to female hormones and can bleed when women are having a menstrual period.  The condition is the alleged cause of the discomfort suffered by millions.

Close to ten million women “have trouble controlling their bladders.” Surgery in addition to medication and pessary (a flexible device that’s placed into the vaginal canal) sometimes helps.  Operations also treat prolapse, a condition where a uterus, stretched by prior child birth, drops into the vagina or bulges into the bladder or rectum.

Finally the fear of ovarian cancer leads to a lot of testing.  This is a real and worrisome condition, but it’s not on the rise.  By age 30 it strikes one in 15,000 and by age 60 afflicts no more than one woman in 1500.   It’s hard to detect at an early stage and benign ovarian cysts found on an ultrasound commonly lead to a number of additional exams and a modicum of anxiety.  Given our current system and abilities, experts tend to discourage routine screening.

Jamila Taylor and Maura Calsyn, “5 Ways the Senate ACA Repeal Bill Hurts Women” (Washington: Center for American Progress, 2017),

https://www.americanprogress.org/issues/healthcare/news/2017/06/30/435357/5-ways-senate-aca-repeal-bill-hurts-women/

N Engl J Med 2008; 358:1700-1711April 17, 2008  Management and outcomes of very low birth weight.

https://www.pennmedicine.org/updates/blogs/fertility-blog/2018/march/ivf-by-the-numbers   

https://www.npr.org/2017/05/12/528098789/u-s-has-the-worst-rate-of-maternal-deaths-in-the-developed-world .

https://www.npr.org/2017/05/12/528098789/u-s-has-the-worst-rate-of-maternal-deaths-in-the-developed-world

https://www.npr.org/2018/05/10/607782992/for-every-woman-who-dies-in-childbirth-in-the-u-s-70-more-come-close

Ellison K, Martin N (December 22, 2017). “Severe Complications for Women During Childbirth Are Skyrocketing — and Could Often Be Prevented”. Lost mothers. ProPublica.

Li HT, et al. Geographic Variations and Temporal Trends in Cesarean Delivery Rates in China, 2008-2014. JAMA. 2017;317:69–76. doi: 10.1001/jama.2016.18663.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593338/

Heavy Menstrual Bleeding in Women with Uterine Fibroids. William D. Schlaff, M.D., et al  NEJM January 23, 2020  https://www.nejm.org/doi/full/10.1056/NEJMoa1904351?query=featured_home   “Half of women with Uterine fibroids (leiomyomas have symptoms:  heavy menstrual bleeding, which can lead to anemia, pelvic pain and pressure, urinary and gastrointestinal symptoms, infertility, and complications of pregnancy.”  They sometimes affect a woman’s physical, psychological, and social well-being.”

https://healthmatters.nyp.org/georgios-nikolaou-papanicolaou/

UpToDate

Papanikolaou   https://www.newscientist.com/article/2202635-georgios-papanikolaou-inventor-of-the-pap-smear-cervical-cancer-test/

https://www.newscientist.com/article/2202635-georgios-papanikolaou-inventor-of-the-pap-smear-cervical-cancer-test/#ixzz6Pk1IW9dU

file:///C:/Users/User/Documents/ART-2013-Clinic-Report-Full.pdf  assisted reproductive technology

HIV

One morning in the 1980s I attended a conference at the medical center, and heard about a tumor, Kaposi’s sarcoma, a cancer of old Italian men. It was affecting members of the gay community.  Pneumocystis, a microbe that had lived harmlessly in most lungs for a millennium, was causing pneumonia in young men. Similar infections had previously attacked the lungs of kidney transplant recipients whose immune system was suppressed.  Some had trouble swallowing and white dots of yeast covered their esophagus.  Previously healthy young men and women developed a bizarre assortment of diseases. Many were quite ill, occupied many of our hospital beds, and were receiving multiple medications.  For almost a decade everyone who contracted HIV eventually died.

In 1983 scientists in France and in the U.S. at almost the same time isolated the responsible virus.   The microbe was colonizing, taking over, and ultimately destroying T lymphocytes, a vital constituent of the system that keeps a lid on many of the organisms that live in the body.  As the virus destroys more and more of our defenders, the immune system loses its ability to control the indigenous microbes. 

We soon learned of cases of the disease in 33 countries.   Actor Rock Hudson died with AIDS and the Hollywood community rallied.  Our blood supply was tainted. Ryan White, a kid with hemophilia had the condition and was not allowed to attend classes.  A journalist who worked for the San Francisco Chronicle published a book called: “And the Band Played On.” The Gay community was particularly afflicted and decimated, and the book told of their struggle and “governmental indifference and political infighting”. Condoms were encouraged and needle exchange programs were initiated.  Gay bath houses were attacked by the police in many cities. Laws were passed that forbade physicians from testing people for HIV without permission.

After the HIV virus wiped out most of a person’s T lymphocytes, their immune system was unable to control the bugs that normally inhabit a body and their disease had morphed into the full blown acquired immunodeficiency syndrome—AIDS.

The HIV virus, we later learned, is not highly contagious.  You could shake hands or hug someone who had the virus growing in their body. Two principles of medicine, however, were turned on their head:  In otherwise healthy people, infectious illnesses were usually caused by a single micro organism.  When it was eradicated the person could stop taking antibiotics.  In people with AIDS antibiotics often suppressed but failed to eliminate the creatures responsible for a disease.  These individuals commonly required lifelong low doses of antibiotics to prevent a recurrence. 

 Also, when we identified the organism causing an infection (like Pneumocystis) we weren’t out of the woods.  The creature had attacked the body because the immune system reached a low point.  Additional problems were brewing.

Within a few years medical detectives in the Cameroon found chimp feces that contained Simian Immune Virus (SIV) with DNA that was identical to the DNA of the most common type of Human Immune Virus (HIV).  The source of the epidemic was a chimpanzee infected with the simian immune virus. 

In the early 20th century chimps were wild game– “bush meat” in parts of Africa.  When wounded, the animals struggled. Presumably on one occasion a human was injured by a chimp he was killing.  Blood containing the Simian Virus entered the hunter’s body and the virus survived and thrived.  Later the pathogen was sexually passed to one person after another.  Sometime in the early decades of the century an infected individual moved to Leopoldville, (now Kinshasa).  In 1920 the town was the capital of the Belgian Congo and was full of migrants. Scientists figure that by the time the colony became an independent country (1960) an estimated 1,000 to 2,000 people were living with HIV.  A physician of the day probably encountered many sick souls who had developed diarrhea, fever and wasting.  There’s no reason to believe that anyone at the time suspected their symptoms were the result of a new virus.

As the Congo, now a new country, was getting started, UN aid workers and volunteers from Haiti were flown in to provide medical care and assistance.  One of them presumably caught HIV, eventually went home, and the virus spread quietly in Haiti for a few years.  Then unknowing carriers visited the U.S. and Europe and passed it on.1 

After they identified the cause of the disease, scientists learned how the RNA virus methodically infects a cell and, uses a special enzyme it brought with it, (reverse transcriptase), to make a DNA version of itself.  The DNA then integrates–becomes part of the host chromosome–becomes a gene.

  • BRIEF GENETIC TUTORIAL (again–sorry)
  • Our alphabet has 26 letters and we use them to make words.
  • The DNA of living organisms uses 4 letter alphabet.   They “letters” are molecules called nucleotides. 
  • Genes are strands of nucleotides.  They tell a cell what to do and make and they occupy up to 3 percent of a body’s DNA. We aren’t sure what the other 97 percent of the DNA is there for.
  • Every cell in a person’s body has 3 billion pairs of DNA nucleotides. 
  • They exist in groups called chromosomes.  Each cell has 23 pairs of chromosomes.
  • The nucleus of every cell in the body contains all 20,000 genes. Some are turned on and some aren’t.
  • To summarize:  The HIV virus knows how to create a DNA version of itself.  That DNA becomes a gene and it commands the cell to make more HIV viruses.

R., a gay 35 year old carpenter, was renting an apartment I owned in the SF Bay area.  I came by one afternoon and heard coughing from the house.  R. let me in and told me he didn’t feel well and was having trouble breathing.  His condition worried me and I suggested he visit a hospital.  He went and the doctors made a diagnosis of Pneumocystis Pneumonia.  He had AIDS.  Treatment was started but he got worse and needed to be intubated.  A tube was inserted through his mouth, passed his vocal cord, and into the main breathing tube. A respirator kept him alive for a week.  It took a few weeks before R. recovered and was able to leave the hospital, but he knew AIDS was a death sentence.  After he came home he moved out of the apartment, bought a house, fixed it up for his family and invited my wife and me over for Sunday afternoon Tea. He told us that he had long wanted have a home of his own before he died.   He looked good, seemed relaxed, and was proud of what he had recently accomplished.  We never saw him again.

The counter attack against HIV started when scientists at Burroughs-Wellcome synthesized compounds that might hinder the activity of the reverse transcriptase enzyme.  In 1985 they sent eleven promising compounds to researchers at the National Cancer Institute, and people at the NCI identified a chemical that worked in the test tube. The drug was given to people with HIV, and their lives were prolonged.

25 months later the FDA approved the drug, and it was marketed by GlaxoSmithKline.  The company sold 225 million dollars worth in 1989.

In the late 1980s and in the 1990s manufacturers started cranking out (and selling) anti HIV drugs.  Some of the agents targeted protease, an enzyme that plays a role in the production of more viruses.  The first Protease inhibitors became available in 1996.

Drugs that work against the enzyme that turns HIV RNA into DNA, (like turning a photograph into a negative) were created by Emory university professors.    They discovered 2 important drugs (emtricitabine and lamivudine.) “Everyone was intrigued but skeptical about our work—no one realized the importance of what we had found,” Schinazi (the physician who developed the drug) said. He “pushed Emory University to file patent applications.”  They did and less than ten years later the University was paid $540 million…a lot of money but considerably less than big Pharma often pays to control a significant medication.     .

Two of the drugs that most effectively prevent and suppress the HIV virus were created in Prague Czechoslovakia by Anotonin Holy.  An intuitive researcher, Holy had been sneaking promising chemical creations through the iron curtain to a colleague in Belgium named Erik De Clercq for 20 years.  At the time a number of rules and regulations restricted trade between the Communist countries and the West.  But Czechs were able to export the hops that Belgians used to make beer and they could import powdered Belgian milk.  Somehow the chemicals got through.  In 1981 De Clercq visited Prague.  Holy took his friend to dinner and stuffed his coat with vials of newly developed compounds. 

In the mid 1980’s the Bristol Myers head of virology was John Martin. A respected researcher, he had developed the herpes fighting drug, guancyclovir when he was in his 20s and was working for Searle.  At the time pharmaceutical leaders were starting to pay attention to HIV and researchers were developing compounds.  At one point Martin heard about a promising new group of antivirals that were discovered by a researcher in Czechoslovakia.  Called “acyclic nucleotide phosphonates” they were just chemicals in a test tube.  No one knew if they were safe or effective.  But for some reason De Clercq in Belgium thought they were special.  So Martin visited Prague and met Holy.  As the two strolled through the city’s narrow streets and cobblestone alleys they got to know and like one another.  Holy wasn’t a complainer.  His lab facilities were limited but he managed to do his work and he had no desire to leave the country of his birth. When Martin returned to the U.S., a CIA officer tried to convince Martin to turn Holy into an “asset” and Martin declined. 

In July 1989 Gorbachev allowed the nation’s of the Soviet Bloc to break away from Russia.  The iron curtain fell, and commerce and travel between the East and the West became relatively easy.  About that time Bristol Myers merged with Squibb and the company’s leadership and goals changed.  The following year Michael Riordan the long suffering, optimistic CEO of Gilead, a failing startup, convinced Martin to jump ship and become one of his company’s new leaders.  Martin (perhaps a little uncertain about his role in the new mega company) agreed and brought two of his best researchers with him.  At the time a number of pharmaceutical manufacturers were trying to fabricate drugs that suppressed the HIV virus, but Gilead was not one of them.  The chemicals Holy had created had been tested in Belgium and they effectively neutralized the HIV virus.  But they needed tweeking before they would be ready for human consumption.  Bristol Myers had planned to license and modify them.  Gilead wasn’t a player.

Then in mid 1991, with the head of Squibb calling the shots, the newly formed mega company decided they weren’t interested in Holy’s chemicals.  They didn’t want to take the risks and make the investment necessary to perhaps develop another HIV medication.  Realizing Squibb’s error, Martin phoned Holy and convinced him to sign a licensing agreement with Gilead.  In July 1991 Holy, Martin, and De Clercq met in a restaurant near the Eiffel Tower and signed a deal on a napkin. Holy’s nucleotide became the basis of several of the most potent medications that are currently used to prevent and treat HIV, and Gilead was finally an important player. 

In 1995, influenced in part by well healed pharmaceutical companies, the World Trade Organization was formed.  It required members “to honor 20 year patents on drugs”.   Poor countries were given until 2005 to comply with the mandate.  (Half the big drug makers are headquartered outside the U.S.).

In 1996 a three drug regimen was shown to successfully suppress the HIV virus. The disease could be controlled in advanced nations. But the companies that owned each drug’s patent charged what they thought they could get away with. The medications were too pricy for most people in the developing world. 

As Nobel Prize winner Joseph Stiglitz explained:  Patents are created for each nation’s needs.  They give the inventor a monopoly for a number of years. When they are appropriately designed they promote innovation and societal well being.  When they are not appropriately designed people die and innovation is suppressed. 

Most nations allow people and companies to patent unique, non obvious inventions.  When it came to medications, India had a different approach.  The country gained its independence from England in 1947.  In 1966 Nehru’s daughter, Indira Gandhi became prime minister. At some point she met with the head of the Indian drug maker—Cipla. He convinced her to allow inventors to patent the process –the way they manufactured a drug.  But the drug itself could NOT be patented in India.  That was the law in India before the country joined the WTO—the World Trade Organization. After India joined they changed their patent law.  Drugs could now be patented.

In  September 2000 Yusuf Hamied, the CEO of Cipla, was invited to the European Commission in Brussels for high level talks with health ministers and heads of large pharmaceutical companies.  The meeting was supposed to discuss access to medicines, especially those that suppressed AIDS, in the developing world.  At the large gathering, after the leaders of various companies made their remarks, Hamied spoke.  Saying he represented the developing world and an opportunity, he offered to provide the three anti retroviral drugs that suppressed HIV at a cost of $800 a year; and/or to set up factories in other nations; and to provide needed medicines to pregnant women so they would not infect their unborn child. Founded in 1935 by Hamied’s father, Cipla is a major pharmaceutical company. His proposal was serious and significant. But his offer was ignored. 

In the early 2000’s, according to Denis Broun M.D. of Unitaid, the powers- -that–be believed “Treatment for AIDS was something for the rich.  It was unthinkable for Africans.” Yusuf Hamied felt the whole of Africa was being taken for a ride.1  

A year after the Brussels meeting James Love, an AIDS activist called Hamied and asked how cheaply he could produce the three drugs that suppressed the virus.  The key to pricing in medicine (according to Hamied) is the cost of the active pharmaceutical ingredients.  If you can get them cheaply, the end product is cheap.  Hamied told Love that Cipla would pay the cost of manufacturing a generic regimen.  He would only charge for the material.  Nevirapine would cost 65 cents a day.  3TC, lamivudine, 35 cents.  And there would be no charge for d4T, Stavudine.  The materials were too cheap.  In other words the three drug regimen would cost $350 a year. 

Donald McNeill of the New York Times felt the offer “was a watershed event.” He put the price of generics on the front page of the NY times, and papers around the world spread the news.

Shortly thereafter Peter Mugyenyi, a Uganda physician and director of the continent’s largest research and treatment center, decided to take matters into his own hands.  “I knew where drugs were, and as a doctor it was my job to save my patients lives.” He contacted Cipla in India, and in defiance of patent laws ordered the drugs. 

When the medications arrived at the airport they were impounded and the doctor was arrested. He refused to leave the airport without his medications.  Eventually the authorities relented. Other nations acted. To many it seemed like the blockade for inexpensive drugs in Africa was broken. 

In 2002 Kofi Annan, the diplomat from Ghana who was the Secretary-General of the United Nations, proposed a Global Fund to buy the drugs. The U.S. insisted that the fund could only buy branded medications or they would pull out. 

Poor countries couldn’t and wouldn’t comply with the WHO directive.  HIV was a killing their people.  143 countries favored relaxation of patent protection. 

“In 2003 South Africa’s competition commission ruled that Glaxo Smith Kline and another company had violated the country’s anti competitive act.  Glaxo was charging excessively high prices and was refusing to license their patents to generic manufacturers in return for reasonable royalties.  The company eventually agreed to allow three generic manufacturers to make and sell three of its AIDS drugs,3  and the company took a 5% fee.

Prior to 2003, the U.S hung tough. Then the Irish singer Bono got together with one of the day’s more influential Republican senators, Jesse Helms, and attitudes changed.  When they met the Senator was 80 and walked with a four-pronged cane.  He was a rightwing evangelical Christian who had exploited racial prejudices in his election campaigns and had called homosexuals “weak, morally sick wretches”.

Bono, by contrast, had publically supported Greenpeace, Amnesty International, and had joined Jubilee 2000, a 40 country movement that advocated cancelling third world debt for the millennium.  At one point the Jubilee campaign asked Bono to get the Baptist Nigerian President to write a letter to Baptist churches across southern US states.  He was supposed to explain the Biblical principles behind debt cancellation.

The Baptist leaders listened, and Bono suddenly had access to a lot of strongly Christian Republicans.  That’s why he was able to meet and speak with Jesse Helms.  Helms had been very tough on the concept of foreign HIV drug assistance.  “He’s a religious man”, Bono said, “so I told him that 2103 verses of scripture pertain to the poor, and Jesus speaks of judgment only once – It’s not about being gay or sexual morality, but about poverty. I quoted that verse of Matthew chapter 25: ‘I was naked and you clothed me.’ He was in tears. And later publicly acknowledged that he was ashamed…”

After the meeting vice president “Dick Cheney walked into the Oval office, and told President Bush that, ‘Jesse Helms wants us to listen to Bono’s idea.”  That led to negotiations and Bush’s 2003 plan.

That January in his State of the Union message President Bush announced his policy towards HIV had changed.  His words:  “Today on the continent of Africa nearly 30 million people have the AIDS virus, and across that continent only 50,000 are receiving the medicine they need.  Many hospitals tell people: “you have AIDS.  Go home and die.”  In an age of miraculous medicines no person should have to hear those words.”– “Anti retroviral drugs can extend life for many years.  And the cost of those drugs has dropped from $12,000 a year to under $300 a year.  Seldom has history offered a greater opportunity to do so much for so many. “

Bush would ask congress to spend $15 billion dollars over 5 years to combat the disease.  Since its creation in 2003, the “President’s Emergency Plan for AIDS Relief (PEPFAR)” received more than $70 billion in congressional funds …$6.56 billion in fiscal 2017.  The Trump budget plans to cut the amount the government contributes in 2019 by a billion dollars.

The under $300 number caught the drug industry by surprise, and they fought back.  Within days the administration changed its approach.  Rather than generic anti retro-virals the U.S. government money would be used to buy high priced branded drugs, and fewer lives would be saved.

As Bill Clinton later put it, “If you ran the numbers there was no way the money was enough to save the number who had to be saved in a hurry… it would never be enough unless they bought generics.” 

Many of the drug manufacturers are headquartered outside the U.S.  One hundred and twenty three nations (probably goaded by large corporations) signed an intellectual property rights agreement.-TRIPS, that “came into effect” in January 1995.  It allows members “to promote access to medicines for all.”   Clinton decided to ignore the politics of the situation and do the right thing.   At the time India was a member of the World Trade Organization but patents issued before 2005 were still valid.9 

In late November 2006 Bill Clinton announced an agreement between his foundation, two Indian drug makers: Cipla and Ranbaxy; Aspen Pharmacare, of South Africa, and Matrix Laboratories of Dubai.   The companies agreed to make pills for children that combined three HIV drugs and cost $60 a year.   2 million children in Africa had been infected by their mother and only 10 percent were receiving drugs.  Without treatment 80% would be dead by age 5.

The companies also apparently agreed that “The cost of anti-retroviral drugs (in general) was going to drop to $140 a year, and pills would cost 36 to 38 cents a day.”  The cost of making the medicines would be paid for by a $35 million grant from an international drug-buying consortium and $15 million from the Clinton Foundation.  The funds guaranteed the volume of drugs purchased would be “high enough to justify the lower prices.”  “The large quantity orders for generics was critical to bringing prices for anti retroviral treatment in Africa below $100 per person per year.” 

“After that the difference between branded and generic anti-retro-virals, and the scale of human tragedy in Africa made it impossible for donor funds to spend vast sums of money on expensive drugs.  The global fund and Pepfar eventually committed themselves to buying generics, and the number of people treated exploded.”1

In 2017, per the U.N., 19.5 million people, more than half those infected, were being treated, but 2 million additional people had acquired the disease. Over 25 million HIV carriers lived in Sub Sahara Africa. That year worldwide 75% of people who carried the virus knew they were infected.4 

The UN thinks they can end the epidemic if 90% of those infected know they are infected.  Then 90% of those infected would need to take anti retroviral drugs that effectively lower the measurable blood level of HIV 90 percent of the time.  Seven countries have achieved the 90/90/90 goal.

In 2019 the U.S. is still pretty far from getting HIV under control.  One in six men who has sex with other men will eventually acquire HIV.  Half are Latino or black.  In 2015 there were about 6500 AIDS-related deaths in the U.S.

The CDC (Center for Disease Control) thinks that 1.1 million people are currently infected and 40,000 inhabitants will acquire HIV each year.  83-88% of those infected have been diagnosed, and 85% of the people regularly take medicine that controls the virus; only half take enough pills in the right dose.

People with “decent” health insurance are commonly required to pay two thirds of the cost.5 The estimated average annual cost of HIV drugs is about $20,000 ($360,000 lifetime.)  In the appropriate age and income situations Medicare and Medicaid supply the meds.  The non-profit Ryan White Foundation helps when people can’t afford the drugs. And there are federal programs for some populations.

Pharmaceutical companies have managed to keep the price of drug combinations relatively high by combining one or two relatively cheap anti-retro-virals with an expensive newer drug that is still patented.  Some contend that people are more likely to take one pill that contains several drugs than they are to take a few capsules. 

Most new infections can be prevented with a daily pill that contains two of the more effective anti-viral drugs, but it is not always covered by insurance.8

Anthony Fauci of the NIH is quoted as saying:  “if we had a vaccine this effective-wow”. He was talking about a drug containing polymer that is implanted in a person’s body and slowly elutes significant quantities of a medication that suppresses HIV. 

But we haven’t learned how to eliminate the HIV virus from a body.  The HIV DNA has become one of the genes of too many T cells. 

  1. Tinderbox. By Craig Timberg and Daniel Halperin. Penguin Press. 2012—.

 Fire in the Blood. Documentary Movie.  Written and directed by Dylan Mohan Gray.  2013.

https://www.nytimes.com/2006/11/30/world/asia/01aidscnd.htm l  http://www.cnn.com/2003/ALLPOLITICS/10/23/clinton / http://news.bbc.co.uk/2/hi/americas/3209741.stm https://www.nejm.org/doi/full/10.1056/NEJMp1710914

Treating and Preventing HIV with Generic Drugs–Barriers in the U.S. Erika G. Martin, Ph.D., M.P.H.,and Bruce R. Schackman, Ph.D.

3. The Truth About Drug Companies by Marcia Angell. Random House. 2005

4. https://www.nejm.org/doi/full/10.1056/NEJMp1804306 .  (CDC website.)

5.http://www.gtp.autm.net/story/view/76

6. https://www.sciencemag.org/news/2019/07/simpler-hiv-treatment-and-prevention-strategies-take-center-stage

7. https://www.sciencedaily.com/releases/2019/07/190702112844.htm

8. A 2010 therapeutic manual for doctors listed drugs that block the virus at several transitional sites.  We had more than 10 reverse transcriptase inhibitors, 9 protease inhibitors, 2 entry inhibitors and an integrase inhibitor.  All drugs had side effects.  People who couldn’t tolerate one reverse transcriptase inhibitor often had no problem taking a different one.   When a combination of medications was used, the viral biochemical assembly line was blocked in more than one location, and viral resistance was uncommon.  Refractory HIV however, commonly developed when a person stopped and started the medications.  That happens when people can’t afford their co-pay, when they live in a remote part of the world and don’t have access, or if they merely decide to take a “drug holiday”.

9.  https://uk.practicallaw.thomsonreuters.com/4-621-1358?transitionType=Default&contextData=(sc.Default)&firstPage=true&bhcp=1

TRANSFUSIONS

Blood the liquid that carries nutrition and oxygen to every corner of our body is a mixture of cells and protein rich fluid.   Most of the cells are “erythrocytes” –red cells.  As they flow through the arteries of the lung the tiny discs discard carbon dioxide and acquire oxygen.  When they are propelled through the rest of the body the cells deliver oxygen and collect carbon dioxide.

We didn’t really start to understand the value and danger of transfusing the red solution until 1900 when a Viennese Physician and researcher, Karl Landsteiner, separated blood into its two components: Cells and serum.  “Many but not all normal sera will agglutinate the red cells of other normal persons.  Human beings can be separated into groups, the bloods of those of the same group being harmless to one another8.”

A physician researcher, Landsteiner was six when his father died.  Raised by his mother Fanny, he was “so devoted to the woman that her death mask hung on his wall until he died.”  An esteemed professor, Karl was living in Vienna, the capital of the vast Austro-Hungarian Empire when the First World War ended.  His country had been on the losing side and the imperial lands were carved into many of the nations of modern day Europe.  That winter there were shortages and Landsteiner’s laboratory wasn’t heated.  One day “the Viennese poor cut down the trees around his house for firewood and tore away his fences.”  Feeling personally threatened, Landsteiner moved with his wife and children, to Holland.  During the next three years he lived and performed experiments in a “little cottage with a rose garden” in the seaside town, Scheveningen.  He was assisted by a man-servant and a nun who was “very devout and frequently quit the lab for prayers or to serve as an organist in the chapel.”  After accepting a position at the Rockefeller Institute, he moved his family to New York where he lived “on the floor above a butcher shop on a street with trolley cars.”  Avoiding social activities, he spent his days in the lab, and read and thought at night “until the late hour.”  “His energy was continuous and compelling, and no moment of idleness in the lab was tolerable to him.8”   He was living in New York in 1930 when he received the Nobel Prize.6

In the early 1900s, while still in Vienna, Landsteiner identified three blood types: A, B, and O. They were based on the antigens on the surface of red blood cells,  We now, of course, know that:                                                             

  • A person with Type B blood has “B” antigens on the surface of his or her red cells. 
  • Their serum contains antibodies to blood type A. 
  • If the person is transfused with Type “A” blood, the infused red cells will agglutinate—stick to one another and form a clump.   
  • A person with Type A blood has “A” antigens on the surface of his or her red cells– and antibodies to B in their serum.  If B cells are transfused the new cells will adhere to one another.
  • People who are transfused with incompatible blood got quite ill and can die.  
  • Individuals whose red cells have both A and B surface antigens don’t have serum antibodies to either B or A.  They can receive–be safely transfused with A, B, AB OR O blood.
  • The serum of Individuals with type O blood contains B and A antibodies. They can’t safely be transfused with A or B cells, but their red cells can be instilled into people with any blood type. 
  • In 1937 Alexander Wiener added another red cell surface antigen, the RH, Rhesus factor to the equation.

During the First World War years (1914-1918) a series of doctors learned that when they added sodium citrate to blood it didn’t clot.  With additional additives it could be stored for 2 weeks. 

The notion that blood circulates and that it can be transfused was “based” on the observations of a Brit named William Harvey. In the 1600s he cut open a few living fish and snakes, and learned (and wrote) that the ancients were wrong.  Blood didn’t come from the liver and slowly ebb through the body.  Its flow was “propelled by the heart” and the red stuff traveled through tubes called arteries.  In the 1800s a few doctors used a syringe to remove blood from one person and directly inject it into the vein of another.1 It helped some and harmed others.

The first blood bank was set up by the Russians in 1932. Doctors at Chicago’s Cook County Hospital are given the credit for opening the first American facility. It started to “save and store” donated blood in 1937.  San Francisco’s Irwin Memorial blood bank was established 3 years later.  

When blood, plus a chemical that prevents clotting is put in a test tube, the cells settle to the bottom and the plasma floats to the top.  For blood loss or significant anemia packed red cells or erythrocytes can be transfused. Each tiny disc lives for 120 days.  In transfused blood half the red cells are new and half old, so the average cell in a unit of blood should last 60 days. 

In the test tube full of blood, immediately above the red cells there’s a thin layer of white cells and a stratum of platelets.  The cells and particles only live a few days.  White cells are an important contributor to our defense against infection.  In transfused blood they can cause adverse reactions.  When chemotherapy suppresses the bone marrow white cell levels can get quite low.

Platelets are particles that plug holes and help stop bleeding. Some chemotherapy drugs can significantly suppress their blood levels for a number of days.  When the risk of bleeding is high enough platelets are collected from others and infused.   Blood banks have machines that separate and collect platelets, then reinfuse the platelet poor blood back into the donor.  

In 1940, a year and a half before the U.S. became combatants in the Second World War, London was being bombarded by Nazi planes.  Many in the U.S. wanted to aid the wounded, and an effort to provide the cell free portion of the blood, the plasma, to the Brits was started in New York.  Called Blood for Britain, the organizers attempted to collect thousands of units of blood, separate the cells from the plasma, and under sterile conditions ship the fluid across the Atlantic.  It was a huge undertaking and the man in charge had previously only organized a group of people once.  As a young man, he coordinated the paper routes of ten childhood friends who were delivering 2,000 newspapers a day. 

When he was still a trainee the doctor who was chosen to coordinate the effort, Charles Drew, studied the preservation of blood products.  He wrote a doctoral thesis titled “banked blood”, and he knew how to produce plasma that had a two month shelf life.  Gathering, transporting and processing thousands of units of blood was a complex undertaking but Drew pulled it off and was able to send close to 15,000 pints of the precious fluid to the Brits.  A black man, Drew was born in Washington D.C. and was an outstanding high school athlete. He was Amherst University’s most valuable football player in 1926, went to medical school at McGill University in Canada, and graduated in 1933. In 1941 he became the director of the first U.S. Red Cross blood bank. It was a big honor but he didn’t stay very long.  He resigned because the organization labeled each unit of blood with the donor’s race and didn’t give the blood from a black donor to a white patient. He’s credited with saying “No official department of the Federal Government should willfully humiliate its citizens; there is no scientific basis for the practice; and people need the blood.”  Drew returned to Howard University and became the chief surgeon at Freedmen’s Hospital.7

By the time I entered med school (1958) blood drives had come to my campus annually, and I had been a donor twice.  The Red Cross proudly boasted that it saved the lives of wounded service men and women.  People who were hemorrhaging or very anemic often needed transfusions.   When I graduated in 1962 there were already 4400 hospital blood banks and 178 Red Cross and community facilities.  I never knew what medicine was like before transferable blood was readily available. 

In 1997 several San Francisco Bay area blood banks merged and called themselves Blood Centers of the Pacific.  The non -profit corporations collected huge amounts of blood (200,000 units a year) from willing voluntary donors.  They then checked it for blood type and for disease, fractionated the fluid into its various components, and sold– supplied it to more than 60 hospitals.  Their annual budget exceeded $40 million.

The blood supply is relatively safe in part because of the outrage of an angry man.  In the 70s a California legislator named Paul Gann capped our property taxes.  That made him famous.   But the legislation that bears his name, the Gann Act, has nothing to do with taxes.  It deals with transfusions.   It seems that around 1982 Gann had heart surgery and was transfused.  5 years later he discovered he had HIV.  The blood he received came from someone who was infected with the AIDS virus.  Either the blood donor had not been adequately screened or the blood Gann received was not tested carefully enough.  Gann was furious and apparently felt:  “there oughta be a law.”  So he wrote one. 

Prior to elective surgery California doctors must tell patients that they can store their own blood and have it available should they require a transfusion.  Stock piling blood prior to planned surgery can be tedious and costly.  But it’s intuitively better to get your own blood back than it is to receive that of another.  It’s also the law, so if the patient wants it we do it.  The act also says people can refuse blood from the “bank” and, instead get it from a donor they designate.  The idea makes sense, but the blood from a friend or loved one is no longer safer than banked fluid. Before a unit of blood is given it must be tested for the usual suspects, and it’s logistically near impossible to collect, check, and process designated blood in an acute or urgent situation. 

Before Gann’s outrage some blood bank executives argued that if they looked at blood too carefully they would have to reject many donors, throw away too many units.  Doctors wouldn’t be able to treat the ill.  People would die.  After the Gann incident blood banks (which were pretty good at questioning people about risk factors) got serious about screening blood for HIV, HTLV, Hepatitis B, Hepatitis C, (and a few other illnesses such as mosquito born West Nile virus, Zika, Cytomegalovirus, Chagas, a parasitic disease whose normal habitat is Central and parts of South America, and Babesia, a parasite found in New England that is transmitted by ticks.)

We’re apparently NOT yet testing the 11 million units of blood Americans use each year for dengue, a disease transmitted by mosquitoes that’s common in South East Asia— or for Chikungunya, a West Africa disease that was responsible (between 2014 and 2016) for the fever and joint pain of 4000 American travelers.  Most of them had recently visited a Caribbean island.5. And we don’t test for Hepaitis E, the most common type of hepatitis in India and parts of Asia.2 

Before 1996 blood banks identified viral diseases by checking for the presence or absence of specific antibodies in the serum.  When a virus invades a body, the immune system reacts and makes detectable antibodies.  It was believed that blood that did not contain certain antibodies should not be infectious.  To prove their blood was safe blood banks participated in studies on people who were transfused with blood whose antibody levels had been tested.  2.3 million transfusions were given during the study period and people were subsequently evaluated to see if they remained disease free.  One in every 493,000 infused units caused HIV; Hepatitis C was seen after one in a hundred thousand transfusions, and Hepatitis B one in 63,000.3 Screening was good but imperfect.  During the early weeks after a person is infected, the virus incubates and its number grow.  It takes a while before measurable antibodies develop.  So blood can be contagious when the antibody tests are negative. 

Over time PCR technology improved and we were able to directly detect and measure miniscule amounts of virus. (PCR is like a Xerox machine for DNA.  It allows technicians to make millions of copies of the original, to turn a tiny amount of stuff into a wad large enough to analyze and learn what we are dealing with.)   In 1999 blood banks started using the technique to screen all 66 million units of blood that were transfused.  Between 2006 and 2008, with PCR testing being used, the recipients of 3.5 million Units of blood were checked to see if they had been infected with any of three common chronic viral diseases.  One in 1.85 million units of blood that were free of “measurable” viral particles caused an HIV infection; one in 246,000 transmitted hepatitis C, and one in 410,000 gave the recipient Hepatitis B. We’re not perfect yet.4 

While blood is donated freely, screening the donor, and acquiring, testing and distributing the red stuff is expensive.  A recent survey put the cost of a unit of transfused blood at $522 to $1,183.  In most hospitals much of the blood is used at the time of surgery.   Hospitals vary in size and in the numbers and the types of operations performed.  So it’s not surprising that, in the same survey, acquired blood cost $1.6 million to $6 million per hospital annually. 

  1. http://www.animalresearch.info/en/medical-advances/timeline/blood-transfusion/
  1. NEJM Sept 28, 2017 
  2. N Engl J Med June 27, 1996 
  3. N Engl J Med January 20, 2011
  4. UPTODATE–Chikungunya
  5. https://www.nobelprize.org/prizes/medicine/1930/landsteiner/biographical/
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651504/
  1. https://en.wikipedia.org/wiki/Charles_R._Drew https://www.fda.gov/vaccines-blood-biologics/complete-list-donor-screening-assays-infectious-agents-and-hiv-diagnostic-assays#Multiplex%20Assays
  2. https://royalsocietypublishing.org/doi/pdf/10.1098/rsbm.1947.0002

ANESTHESIA

The Tombstone in the Boston Cemetery marks the site of the “Inventor and Revealer of Inhalation Anesthesia: Before Whom, in All Time, Surgery was Agony; By Whom Pain in Surgery was Averted and Annulled; Since Whom, Science has Control of Pain.” 

The demonstration of Ether’s effect occurred in a Boston Hospital in October 1846. One of the nation’s most active, Boston’s Mass General Hospital was, at the time, hosting up to two surgeries a week.  They were performed in an operating room that was, in essence, a stage.  It was surrounded by a steep amphitheater.  People filled the seats and watched.  One October day the doctor in charge, Dr. Warren told the onlookers “there is a gentleman who claims his inhalation will make a person insensitive to pain.  I decided to permit him to perform his experiment.”

The dentist who administered the anesthetic, Dr. Morton, was described as being strikingly attractive and alternately optimistic and pessimistic.”  He arrived 25 minutes late, took out his narrow neck flask, and filled its bottom with two liquids:  Sulfuric ether and oil of orange. The second chemical was supposed to mask the ether odor.

The man who was about to undergo surgery inhaled “gas” through a mouth piece, and in 3 to 4 minutes he became “insensible and fell into a deep sleep.” He had a mass in his neck and the doctor quickly cut it out. When the operation ended Dr. Warren, the man’s surgeon, spoke to the rapt onlookers. Gentlemen, this is no humbug.  People cheered, and the public took notice.26

 During the Civil War battle of Fredericksburg, Morton decided to help. When a wounded soldier was about to undergo a limb amputation Warren “prepared the man for the knife, producing perfect anesthesia in an average time of three minutes.9

Once operations could be performed without pain surgeons started performing them and a number of hospitals were built or expanded.  Elective surgery became the cash cow that supported one institution after another.

In July 1868 William Morton was agitated because another doctor was trying to claim credit for his invention.  He was in New York, the city was in the midst of a grueling heat wave, and Morton took his wife on a wild carriage ride through Central Park.  Then he abruptly stopped the buggy, got out, and died. He was 48 years old.5

One hundred years to the month later I was asked to see a sick patient with jaundice.  At the time I was the assistant chief medical resident at the San Francisco VA hospital, a collection of buildings on the edge of the Pacific that were usually blanketed in fog and cooled by a breeze from the ocean. The man I examined had yellow eyes, was weak, had no appetite and was lying in his bed.   He recently had a hair transplant and otherwise had been well.  He’d been put to sleep with halothane, the anesthesia of the day. Plugs of his hair were harvested from the back of his head, and planted up front.

The patient told me this had been his second transplant.  He turned yellow the first time and thought he knew what was happening.  He had witnessed fellow service men that got hepatitis when he was stationed in the South Pacific.  He decided to not tell his doctor because he was afraid the physician wouldn’t perform the second set of hair transfers.

This was a few years before liver transplants were being done, so people with failing livers could not be rescued. The patient’s condition got worse, his abdomen filled with fluid, he sank into a coma, and he died. — And it happened because of a hair transplant.

Most anesthesiologists back then didn’t believe “so called” halothane hepatitis was a real entity and wouldn’t accept that the anesthetic they used could cause the problem.  They had “never seen” a case of liver failure they couldn’t pin on one of their patient’s underlying conditions.  Halothane was a smooth, well tolerated anesthetic.  I was a budding gastroenterologist and I knew they were wrong.  Turns out that halothane causes liver failure and death in one of 35,000 patients.  Anesthesiologists needed proof and they got it in 1969 after an MD anesthesiologist visited the Yale hepatologist, Gerald Klatskin.  The doctor said he turned yellow every time he administered halothane to a patient. Klatskin decided to test his theory.  He biopsied the doctor’s liver.  It was normal.  Then the anesthesiologist inhaled halothane and his eyes and skin turned yellow.  A second biopsy showed an injured liver.  Klatskin published a report of the case, and U.S. anesthesiologists stopped administering halothane.  It is still “widely used in developing countries.3

Fast forward 40 years and I’m interviewing the chief of anesthesia at a local hospital.  He’s telling that nowadays general anesthesia is safer than crossing the street.  During the 50 years when the rest of medicine was inventing new operations and trying to cure more diseases, the top anesthesia thinkers were obsessed with safety.

They’d long since learned how to put a person into a state where the patient heard and saw nothing, was impervious to pain, and had muscles that were totally relaxed.  When aroused some people had painful wounds, sensitive areas, inactive bowels, and bodily parts that didn’t function normally.  Grogginess could last a while.  But the recipients of general anesthesia had no memory of the trauma their body had endured.  Doctors and dentists used diethyl ether and later chloroform as early as the mid and late 1840s.  Over the decades drugs changed, but the overall effect has largely remained the same.  One of the current anesthetics of choice is propofol, the drug that killed Michael Jackson.  It’s administered as an intravenous drip.  It starts and stops working rapidly and has a “low incidence of side effects such as postoperative nausea and vomiting and cognitive impairment.1 ”

Some operations are routinely performed using spinal anesthesia, a nerve block or a local infusion of lidocaine. 

In addition to physicians, 43,000 nurses administer much of the anesthesia in this country.  These nurses are educated, trained, licensed, and competent. In all but 15 states they are required to “work under a physician’s supervision”.

The anesthesiologist whose insights I’m channeling credits the emphasis on safety to the skyrocketing cost of malpractice insurance.  It became the focus of a number of physicians who “passed gas” for a living in the 1980s.  I’m sure doctors in the field thought their care was excellent and wondered why they were being singled out.  But the numbers said it all.  In 1974 three percent of all American doctors who bought malpractice insurance were anesthesiologists, and these were the very doctors who were responsible for 10% of all malpractice pay outs.  Outsiders concluded that the care they provided was “below the standard”.

  Malpractice is not a good way to judge medical quality.  Doctors are sued when something major goes wrong and when the responsible physician is arrogant or seems to be hiding something.  It’s also is easier to sue someone you have never consciously spoken to or interacted with, someone who has never become a real person with feelings and regrets.

Nonetheless rates were rising and something had to be done.  The anesthesia societies embarked on something they called the “closed claim project.”  They reviewed malpractice suits that had run their course, that had been litigated, settled or just dropped by the plaintiff.  Discovering what went wrong did not create a legal or other risk for the involved doctor.

Data for events prior to 1990 revealed that in a third of the cases, the person whose families sued had died or had suffered brain damage.  In 45 percent of these people the harm was caused by a “respiratory event”.  When anesthesiologists induce coma they become responsible for the movement of air into and out of the lungs.  They slide a tube through the mouth and pharynx, between the vocal cords, and into the bronchus.  Then they aerate the lungs and the body.  In 7 percent of the respiratory cases the anesthesiologist mistakenly slipped the breathing tube into the esophagus, the tube that transports food and drink to the intestinal system.  It is located above the vocal chords at the lower end of pharynx.  A sphincter at its top end keeps air from entering the gut and helps prevent regurgitation of esophageal contents.

In 12 percent intubation was difficult, and the body was deprived of air for a period of time.  In another 7 percent the doctor got the tube in the right place but didn’t ventilate the lungs adequately.

25% of the law suits were the result of cardiovascular events, arrhythmias of the heart, a drop in blood pressure, and heart attacks.

Nerve damage due to poor positioning and compression of nerves caused 21 percent of the problems.   

Anesthesiologists sometimes instill Novocain or alcohol into nerves in an attempt to mitigate chronic pain.  If they injected a person who was taking blood thinners they sometimes precipitated bleeding; damage caused by the leaking blood prompted some of the legal action. 

6% of the cases were prompted by burns caused by electrical cautery or by IV bags of fluid that were overly warmed.   

There were people whose drop in blood pressure resulted in a loss of vision, individuals whose airways had been damaged during a difficult intubation, and a few who had back pain, emotional distress, or eye injuries. (Anesthesiologists work close to the eyes.)

79% of the problems were attributed to lack of vigilance.  The specialty’s has an old saying:  putting someone to sleep starts with seconds of panic, (intubation) and is followed by hours of boredom.

 After the anesthesiologists learned what they were doing wrong they disseminated their findings, made recommendations, and general anesthesia became safer.

Anesthesiologists now have tools that make it possible to intubate almost everyone.  Small flexible instruments containing long fiberoptic bundles, allow the anesthesiologist to see into dark corners.  Some scopes have chips on their tips and send images to a TV screen.  Anesthesiologists and anesthetists confirm the endotracheal tube is in the right place with a beside ultrasound examination and by measuring and monitoring the carbon dioxide level of air that exits the lungs.  If the level gets too high ventilation may be inadequate.  Since the blood of anesthetized people is enriched with oxygen, a high carbon dioxide concentration is more sensitive than low level of oxygen as an indicator of air movement problems. Complex machines that ventilate the patient regulate and monitor the movement of the gases.  Sophisticated gear has valves and gauges that are routinely checked.  Bells ring and beeps sound when something is amiss. 

  1. http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1941092
  2. https://www.rand.org/pubs/research_briefs/RB9541.html
  3. https://emedicine.medscape.com/article/166232-overview
  4. http://www.emro.who.int/emhj-volume-18-2012/issue-2/article-8.html
  5. Klatskin, Gerald. N Engl J Med 1969; 280:515-522
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920664/
  7. Morton drops dead  https://books.google.com/books?id=P3Z4qpMtxtIC&pg=RA3-PA489&lpg=RA3-PA489&dq=william+morton+asked+to+stop+the+carriage&source=bl&ots=y7O4Dlk72M&sig=ACfU3U1wYJekvi1wib8cC6aCmfB5fH3NAQ&hl=en&sa=X&ved=2ahUKEwjH6KSijrfpAhVWrZ4KHR9eBpgQ6AEwCXoECAgQAQ#v=onepage&q=william%20morton%20asked%20to%20stop%20the%20carriage&f=falsehttps://www.youtube.com/watch?v=wrN-BRrzZ5E

BLOOD TRANSFUSIONS

 

If you prick me do I not bleed?” —Shakespeare

The notion that blood circulates and that it can be transfused was “based” on the observations of a Brit named William Harvey. In the 1600s he cut open a few living fish and snakes, and learned (and wrote) that the ancients were wrong.  Blood didn’t come from the liver and slowly ebb through the body.  Its flow was “propelled by the heart” and the red stuff traveled through tubes called arteries.  In the 1800s a few doctors used a syringe to remove blood from one person and directly inject it into the vein of another.1 It helped some and harmed others.

Before the 20th century, doctors rarely considered transfusing people who bled profusely. Blood solidifies when it is outside the body, and when fresh blood from one person’s veins was infused into the veins of another, it often caused fever, kidney failure, and death.

In a test tube, blood separates into two components. Red stuff, cells, occupy the bottom half of the tube, and clear fluid, serum, fills the top half. In the early 1900s, a Viennese immunologist named Karl Landsteiner mixed his red cells with the serum of others and noticed that some combinations clumped and others didn’t. He wrote a paper and in a footnote suggested there probably were several “types” of blood antigens. Then he and his students spent eight years working out the details. By 1909, they knew there were two populations of antigens on the surface of red cells and two populations of antibodies in the serum. They labeled them A and B and discovered that:

When red cells have B antigens on their surface, their serum contains antibodies that destroy “A” red cells.

When the cells have A antigens on their surface, their serum contains antibodies that break up B red cells.

When the exterior of red cells are not covered with A or B antigens, their serum has antibodies that break up both A and B red blood cells.

When red cells have both A and B antigens on their surface, their serum does not contain A or B antibodies.

During the next few years Landsteiner, a significant Austrian researcher, “discovered how to infect monkeys with the syphilis bacterium and he helped prove polio was an infectious disease,” but his blood group findings didn’t seem to have a practical application.

Karl was 6 when his father’s life ended and he was 40 when his mother died.  He was so devoted to her that he “had her death mask taken” and hung it on his wall for the rest of his life.  He married 8 years after her demise.    

In 1914, the rulers of the great European empires declared war, and 9 million young soldiers killed one another.

In 1917, the U.S. entered the Great War and Oswald Robertson, a doctor from Fresno, California, was sent to the front. He had learned about Landsteiner’s work on blood types and knew that a series of doctors  had recently discovered that when sodium citrate is added to blood it doesn’t clot.  While caring for wounded troops, he collected blood in glass bottles, added sodium citrate to keep it from solidifying, and stored the liquid in ice. During the war, he transfused hundreds of wounded soldiers. Near the end of the conflict, he was teaching doctors from other units how it was done.

After the war, Robertson became a pneumonia researcher in New York. In 1923, he helped develop a school of medicine in China. While there, he developed a bad case of typhus, and when he recovered he returned to the U.S. He continued to be a researcher for most of his life, but he apparently was never again interested in blood or transfusions. He spent the last years of his life working in a laboratory in California’s Santa Cruz Mountains where he studied the death of Pacific salmon.

During the two decades that followed the Great War, there were no blood banks and probably not many transfusions.

When the war ended Karl Landsteiner was living in Vienna. It had been the capital of the vast Austro-Hungarian Empire and was on the losing side of the First World War. The imperial lands were carved into many of the nations of modern-day Europe and there were shortages. That winter, Landsteiner’s laboratory wasn’t heated and a group of poor people “cut down the trees around his house for firewood and tore away his fences.” Feeling personally threatened, Landsteiner moved to Holland with his wife and children. During the next three years, he performed experiments and was assisted by a manservant and a nun who was “very devout and frequently quit the lab for prayers or to serve as an organist in the chapel.” A year or so later, Landsteiner accepted a position at the Rockefeller Institute and moved his family to New York City. On the ship that crossed the Atlantic, he told another passenger how much he loved living in the “little cottage with a rose garden” in the seaside town of Scheveningen, Holland. When he got to New York, he was surrounded by a new and different environment. He lived “on the floor above a butcher shop on a street with trolley cars.” Avoiding social activities, he spent his days in the lab, and read and thought at night “until the late hour.” In 1930, he received the Nobel Prize.  In 1937 Alexander Wiener added another red cell surface antigen, the RH (Rhesus factor), to his equation.


The first blood bank was set up by in Russia in 1932. Doctors at Chicago’s Cook County Hospital are given the credit for opening the first American facility that, in 1937 started to “save and store” donated blood.  San Francisco’s Irwin Memorial blood bank started 3 years later.  

When blood, plus a chemical that prevents clotting is put in a test tube, the cells settle to the bottom and the plasma floats to the top.  For blood loss and significant anemia we transfuse packed red cells or erythrocytes. Each tiny disc lives for 120 days.  In transfused blood half the red cells are new and half old, so the average cell in a unit of blood should last 60 days. 

Just above the red cells in the test tube there’s a thin layer of white cells and a stratum of platelets.  Each lives but a few days.  Platelets are particles that plug holes and help stop bleeding.  When chemotherapy suppresses the bone marrow their levels can get extremely low. In special situations blood banks have machines that dialyze off platelets, and make them available for use in another’s body. Then the platelet poor blood is infused back into the donor. 

White cells are an important contributor to our defense against infection, but in transfused blood they can cause adverse reactions; as a result they aren’t collected and reused. The plasma contains proteins that, among other things, provide clotting factors. 

Before blood is dripped into a body the receiving patients are screened for antibodies in their plasma/serum that might react with transfused red cells. Some of the recipient’s serum is mixed with cells that are about to be transfused.  We need to make sure the cells won’t agglutinate, stick together.

In 1940, a year and a half before the U.S. became combatants in the Second World War, London was being bombarded by Nazi planes.  Many in the U.S. wanted to aid the wounded, and an effort to provide the cell free portion of the blood, the plasma, to the Brits was started in New York.  Called Blood for Britain, the organizers attempted to collect thousands of units of blood, separate the cells from the plasma, and under sterile conditions ship the fluid across the Atlantic.  It was a huge undertaking and Charles Drew, the man in charge had previously only organized a group of people once.  As a young man, he coordinated the paper routes of ten childhood friends who were delivering 2,000 newspapers a day. 

Drew, was a doctor.  When he was a trainee he studied the preservation of blood product, and he knew how to produce plasma that had a two month shelf life.  His doctoral thesis was titled “banked blood.”  Gathering, transporting and processing thousands of units of blood was a complex undertaking but he pulled it off and was able to send close to 15,000 pints of the precious fluid to the Brits.  An African American, Drew was born in Washington D.C. and was an outstanding high school athlete. He was Amherst universities’ most valuable football player in 1926, went to medical school at McGill University in Canada, and graduated in 1933. In 1941 he became the director of the first U.S. Red Cross blood bank.  He left after learning the organization labeled each unit of blood with the donor’s race and didn’t give the blood from a black donor to a white patient. He’s credited with saying “No official department of the Federal Government should willfully humiliate its citizens; there is no scientific basis for the practice; and people need the blood.”  Drew returned to Howard University and became the chief surgeon at Freedmen’s Hospital.7

By the time I entered med school (1958) blood drives had come to my campus annually, and I had been a donor twice.  The Red Cross proudly boasted that it saved the lives of wounded service men and women.  People who were hemorrhaging or very anemic often needed transfusions.   When I graduated in 1962 there were already 4400 hospital blood banks and 178 Red Cross and community facilities.  I never knew what medicine was like before transferable blood was readily available. 

In 1997 several San Francisco Bay area blood banks merged and called themselves Blood Centers of the Pacific.  The non -profit corporations collected huge amounts of blood (200,000 units a year) from willing voluntary donors.  They then checked it for blood type and for disease, fractionated the fluid into its various components, and sold– supplied it to more than 60 hospitals.  Their annual budget exceeded $40 million.

The blood supply is relatively safe, in part because of the outrage of an angry man.  In the 70s a California legislator named Paul Gann capped our property taxes.  That made him famous.   But the legislation that bears his name, the Gann Act, has nothing to do with property tax.  It deals with transfusions.   It seems that around 1982 Gann had heart surgery and was transfused.  5 years later he discovered he had HIV.  The blood he received came from someone who was infected with the AIDS virus.  Either the blood donor had not been adequately screened or the blood Gann received was not tested carefully enough.  Gann was furious and apparently felt:  “there oughta be a law.”  So he wrote one. 

Prior to elective surgery California doctors must tell patients that they can store their own blood and have it available should they require a transfusion.  Stock piling blood prior to planned surgery can be tedious and costly.  But it’s intuitively better to get your own blood back than it is to receive that of another.  It’s also the law, so if the patient wants it we do it.  The act also says people can refuse blood from the “bank” and, instead get it from a donor they designate.  The idea makes sense, but the blood from a friend or loved one is no longer safer than banked fluid. Before it’s given all blood must be tested for the usual suspects, and it’s logistically near impossible to collect, check, and process designated blood in an acute or urgent situation. 

Before Gann’s outrage some blood bank executives argued that if they looked at blood too carefully they would have to reject many donors, throw away too many units.  Doctors wouldn’t be able to treat the ill.  People would die.  After the Gann incident blood banks (which were pretty good at questioning people about risk factors) got serious about screening blood for HIV, HTLV, Hepatitis B, Hepatitis C, (and a few other illnesses such as mosquito born West Nile virus, Zika, Cytomegalovirus, Chagas, a parasitic disease whose normal habitat is Central and parts of South America, and Babesia, a parasite that is transmitted by ticks and is found in New England.)

We’re apparently NOT yet testing the 11 million units of blood Americans use each year for:  dengue, a viral disease transmitted by mosquitoes that’s common in the tropics, Chikungunya a viral illness found in Asia and Africa,  that is spread by mosquitoes and was the cause, between 2014 and 2016, of  fever and joint pain in 4000 American travelers, most of whom had recently visited a Caribbean island.5;  we’re also not checking the blood we transfuse for Hepaitis E, the most common type of acute hepatitis in India and parts of Asia.2 

Before 1996 blood banks identified viral diseases by checking for the presence or absence of specific antibodies in the serum.  When a virus invades a body, the immune system reacts and makes detectable antibodies.  It was believed that blood that did not contain certain antibodies should not be infectious.  To prove they were right blood banks participated in studies on people who were transfused with blood whose antibody levels had been tested.  2.3 million transfusions were given during the study period and people were subsequently evaluated to see if they remained disease free.  One in every 493,000 infused units caused HIV; Hepatitis C was seen after one in a hundred thousand transfusions; Hepatitis B one in 63,000, and HTLV one in 640,000 units.3 Screening was good but imperfect.  During the early weeks after a person is infected, the virus incubates and its number grow.  It takes a while before measurable antibodies develop.  So blood can be contagious when the antibody tests are negative. 

Over time PCR technology improved and we were able to directly detect and measure miniscule amounts of virus. (PCR is like a Xerox machine for DNA.  It allows technicians to make millions of copies of the original, to turn a tiny amount of material into a wad large enough to analyze and learn what we are dealing with.)   In 1999 blood banks started using the technique to screen all 66 million units of blood that were transfused.  Between 2006 and 2008, with PCR testing being used, the recipients of 3.5 million Units of blood were checked to see if they had been infected with any of three common chronic viral diseases.  One in 1.85 million units of blood that were free of “measurable” viral particles caused an HIV infection; one in 246,000 transmitted hepatitis C, and one in 410,000 gave the recipient Hepatitis B. We’re not perfect yet.4 

While blood is donated freely, screening the donor, and acquiring, testing and distributing the red stuff is expensive.  A recent survey put the cost of a unit of transfused blood at $522 to $1,183.  In most hospitals much of the blood is used at the time of surgery.   Hospitals vary in size and in the numbers and the types of operations performed.  So it’s not surprising that, in the same survey, acquired blood cost $1.6 million to $6 million per hospital annually. 

                                                                          

  1. http://www.animalresearch.info/en/medical-advances/timeline/blood-transfusion/
  2. NEJM Sept 28, 2017 
  3. N Engl J Med June 27, 1996 
  4. N Engl J Med January 20, 2011
  5. UPTODATE–Chikungunya
  6. https://www.nobelprize.org/prizes/medicine/1930/landsteiner/biographical/
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651504/ https://en.wikipedia.org/wiki/Charles_R._Drew https://www.fda.gov/vaccines-blood-biologics/complete-list-donor-screening-assays-infectious-agents-and-hiv-diagnostic-assays#Multiplex%20Assays
  8. https://royalsocietypublishing.org/doi/pdf/10.1098/rsbm.1947.0002

VISION

Blind as a bat– -Better than a poke in the eye—–

During the last one and one half centuries we’ve learned how to treat or correct most of the conditions that inhibit our ability to see.

One of them, Trachoma, has been a problem for mankind for thousands of years.  Hippocrates thought it made eyelids, look like cut ripe figs.  During the Napoleonic wars, it “raged” through the armies of Europe; and over the centuries it often occurred in clusters within villages or families.11 Caused by a Chlamydia, a type of bacteria that lives and reproduces inside the cell of the host, it leads to scarring of eyelids, and causes eyelashes to damage the cornea.  Antibiotics kill the bug, but it tends to recur.9    The number of people who currently have “the late blinding stage of the disease dropped to 2.5 million in 2019.” 

The prevention of river blindness remains another work in progress. Found chiefly in parts of Africa, the condition is caused by a tiny parasite and is spread by black flies that “breed in fast flowing streams.” In the 1990s The African Programme for Onchocerciasis Control (APOC) successfully treated more than a million at risk people with the anti parasitic drug Ivermectin, and it made a significant difference. Globally, it is estimated that 18 million people are infected and 270,000 have been blinded by the condition.  It’s called onchocerciasis.6

There’s little available data on infants who survive wars, droughts, suffer from malnutrition and develop a vitamin A deficiency.  The resulting dryness and scarring of the conjunctiva, the mucous membrane that coats the inside of the eyelids, can cause them to lose their ability to see.1

The leading causes of blindness in this country are cataracts, glaucoma, macular degeneration, and diabetes.5

Cataracts:  To create a sharp image the eye like the microscope and the telescope needs two lenses. Cataracts occur when the eye’s inner lens becomes cloudy and opaque.  Most develop slowly as we age, though they are sometimes seen in children for a variety of reasons.  Worldwide they diminished vision in many and are the leading cause of blindness.   

A century ago when a person’s lens got so dense that they couldn’t see, the structure was surgically removed.  Afterwards a person could see light and little more unless they wore thick glasses.  No on liked wearing Mr. Magoo glasses, and everyone hated feeling helpless when they woke and couldn’t locate their spectacles.  I remember the days when people didn’t have cataract surgery until they were literally no longer able to see.  The lens removal operation is, apparently, still done in some countries.

Harold Ridley of England is the father of the implantable lens.  The son of a physician he spent his early doctoring days working on cruise ships.  During the Second World War he spent 18 months in Ghana.  Later in Burma, he provided care for former British prisoners of war who had nutritional amblyopia, lazy eye. At some point he treated members of the RAF whose airplanes were damaged by enemy fire and whose cornea’s, the front lens of the eye, had been penetrated by pieces of the plane’s windshield.  The acrylic plastic did not cause an inflammatory reaction. Years later, he was removing a cataract and he recalls one of his students remarked: “It’s a pity you can’t replace the cataract with a clear lens.” That got Ridley thinking.  He started crafting implants from the material that was used to make airplane cockpits and he implanted them into eyes after he removed an opaque lens.” “Sterilization of the lenses was a major problem and he was afraid to tell anyone.  Powerful colleagues had shown hostility to the idea of putting a foreign body in the eye.10There was a learning curve but Ridley and a pupil perfected the surgical technique and a company in East Sussex (Rayner) manufactured the implant.  In 1981 the FDA approved the use of implantable lenses in the U.S. and American eye surgeons adopted the approach.  It’s now part of the bread and butter of ophthalmology. 

The last 50 plus years have witnessed the development and modification of many replacement lenses.  By 2015, 9000 American ophthalmologists were replacing 3.6 million lenses a year.  Worldwide 20 million cataract surgeries are performed annually.2

In the U.S. most surgeons numb the eye, insert a small ultrasound probe, and phacoemulsify (liquify) the dense lens.  Then they suck out the debris, insert a small plastic or silicone lens, and if necessary, sew the incision shut.  My ophthalmologist at Kaiser Oakland told me she doesn’t specialize in cataract surgery.  The eyes she deals with often have additional problems.  So on her surgical half days she only performs 9 operations.  Each takes 6 to 14 minutes.  The complication rate for Canadian surgeons who performed 50 to 250 operations a year was 8 in a thousand.  It was one in a thousand for surgeons who replace a thousand cataracts a year.  In poorer countries phacoemulsification is less common.  Most Americans who need cataract surgery are of Medicare age and the government pays $2500 per eye.  Special lenses can cost an extra $1500 to $2500.  

In India, a land with over a billion inhabitants, cataract surgery took a giant step forward in 1983 when an American Doctor named David Green met a 58 year old eye surgeon named Govindappa Venkataswamy.  When they reconnected 5 years later the Indian physician had mortgaged his home, built an 11 bed hospital and was performing 5000 eye operations a year, 70 percent of them at no charge.  Given the need he was barely scratching the surface.  In the late 1990s it was estimated that 9.5 million people in India were blind as a result of cataracts and 3.8 million were losing their vision annually. The cost of implantable lenses, $100 to $150 per eye was too high for the average Indian. Green and the doctor established a nonprofit manufacturing plant in India and were able to produce an inexpensive quality lenses.  In 2016 the company they founded, Aurolab, manufactured 2.6 million intra ocular lenses, 10% of all produced in the world.  The majority of the lenses are “distributed to NGOs in India and in developing countries.” The company is profitable.
 In 1999 doctors in India performed 1.6 to 1.9 million surgeries in a single year and plans were made to increase the numbers of operations that would be carried out. By 2006 cataract surgery in India, Nepal, and Bangladesh was costing $20 and the lens sold for less than $5.3

Glaucoma:  Often caused by elevated pressures in the eye, Glaucoma is a number of conditions that damage the nerve that transmits images from the eye to the brain. The dramatic, painful eye of angle closure glaucoma is a medical emergency and can lead to visual loss. It occurs relatively infrequently. Open angle glaucoma, on the other hand is relatively common. Experts have learned a lot about the more usual condition, but we don’t know what causes it, and it’s no longer defined merely as a condition where the pressures inside the eye are too high–though they commonly are.  The middle of the eye produces a watery aqueous fluid.  It flows through the pupil, enters the space in the front of the eye, and exits through the spongy tissue that surrounds the edge of the cornea.  In people with the condition fluid is over produced or doesn’t drain normally. The retinal nerve layer thins. People lose peripheral vision and eventually can substantially lose much of their ability to see.

In the western world some ophthalmologists spend a year or more becoming glaucoma specialists.  They learn how to carry out and interpret tests, and when and how to perform one of many operations.  Sophisticated machines allow experts to photograph and follow the appearance of the layers of the retina, the nerve rich stratum that collects the focused light that our brain turns into images.  Gadgets that detect early loss of peripheral vision and that measure the pressure in the eye have entered the digital era. 

The drugs that control the pressure in the eye include beta blockers and prostaglandin inhibitors. Beta blockers cause the eye to produce less fluid and Prostaglandin inhibitors promote drainage. In 2004 when the FDA gave Pfizer the exclusive right to the prostaglandin inhibitor Xalatan, they sold $1.23 million worth of the drug.  Before a generic competitor entered the U.S. market, a month’s worth was costing $80 a month.  Pfizer manufactures and sells its products worldwide and has 43 manufacturing plants in: Ireland, Puerto Rico, the U.S., UK, Germany, Amboise, France; Ascoli, Italy; Belgium and Perth, Australia. 

According to the World Bank, “almost half the world’s population — 3.4 billion people — live on less than $5.50 a day.  For them eye drops aren’t an option. Laser surgery can increase the outflow of fluid.  If that doesn’t work an older operation called a “trabeculectomy”, removing a bit of the mesh network the fluid pours through, can create “a new drainage path.”  In 20 percent of the people who undergo surgery the openings stop working during the first year and two percent fail each year thereafter.15

Researchers checked the records of 113 Brits with open angle glaucoma who failed their last glaucoma appointment due to death.  They had been followed for 7 to 25 years.  During those years about half had undergone surgery for cataracts and 45% for glaucoma. “At final visit, vision was inadequate for driving in the UK in close to half. In 18%, this was due to glaucoma alone, while in 28.9%, other ocular pathologies contributed to poor vision.13”  

AMD, age related macular degeneration, is a major cause of vision loss as we get older.  Something goes wrong in the layer under the retina, and the macula, the part of the eye that provides sharp, central vision, is damaged or destroyed.  The so called “dry” form of the disease mainly affects white people who are 80 or older and we have no effective treatment.                

The less common “wet” form of the disease is sometimes helped by laser coagulation or photodynamic therapy and is commonly treated with Avastin, an antibody that “blocks” the growth of the new blood vessels.  When an ophthalmologist injects the medication into the eye of someone with wet macular degeneration, the disease process slows or turns off.  “Blindness is prevented in most patients, and the majority of treated patients go on to have some improvement in vision.”

Before using it the doctor evaluates the patient.  He or she discusses the risks of injecting the drug, and explains downsides like bleeding and retinal detachment.  On the appointed day the patient is brought to the procedure room and checked.  The edge of the eye is injected with a numbing agent.  A second needle is then passed into the inner cavity of the eye, a chamber full of a gelatinous material known as the vitreous.  The medication is injected and the pressure in the eye is raised for a brief period of time.  Vision is temporarily blurry.  After a period of observation the patient can go home. 

A law caps the amount a U.S. doctor can charge for an Avastin injection.  It can’t be more than 6% of the drug’s price.  The small amount needed to treat an eye had a cost of $50, so the fee Medicare paid for the injection and observation was capped at $3.

Avastin was FDA approved as a drug that slows the growth of cancer.  When the FDA approves a medication for one indication (cancer), the company that produces and markets it is not allowed to talk about other possible ways the drug can make a difference.  Doctors who read the medical literature and learn a drug helps an additional–different condition, do have the legal right to use it for that condition. The doctor does not have to wait for the drug company or the FDA to act.  In spite of the economics eye doctors were injecting Avastin into the eyes of people with wet macular degeneration.  In 2006 the FDA approved a biosimilar, Lucentis.17 It was an almost identical antibody that blocked the growth of blood vessels, was made by the same company as Avastin, and it worked as well.  In 2014 the company was selling it for over $2000 a month, and doctors who used it in their office were able to charge $180 for the visit and the injection.16

Refractory problem:  At some point in most of our lives we can’t see well because our eyes are unable to focus light on the layer of cells at the back of our eyeballs, the retina.  Some people are born with refractory errors.  Others find it increasingly difficult to read small print after they turn 40.  Wearable eye glasses have been used for many centuries. 

In the 1950s people started correcting their vision by placing a thin lens on the surface of their eye.  Contact lenses were initially small and had to be removed at night.

In 1965 Bausch and Lomb, bought the rights to contact lenses that were soft and were created in the kitchen of a Czech chemist.  Once they owned the product’s license the once American, currently Canadian company started a billion dollar industry.14

The man who developed the lens, Otto Wichterle, was a Czech dissident who was jailed by the Nazis in 1942.  In 1958 he lost his University job because he criticized the country’s Communist government.  Continuing his work on the kitchen table of his Prague apartment, he used an instrument made from a child’s building kit (similar to an erector set) and a phonograph motor, and he produced four hydrogel contact lenses.17  When he put them in his own eyes they were comfortable.  Ever a protester, Otto was expelled from the nation’s chemistry institute in 1970 because he supported Czechoslovakia’s attempt to become independent of Russia—the Prague Spring of 1968.  When the cold war ended Otto resumed his scientific activities.  In 1962 he patented his invention and produced an additional 5500 lenses.  At one point he met and learned to trust an American optometrist named Robert Morrison.  When he was harassed by patent attorneys Otto asked Morrison to come to Prague.  “Wichterle said, “Robert, I have decided that I must give patent rights to the gel to someone who can use them in the Western Hemisphere and, perhaps, in some other areas as well.18”   Ulitmately the US National Patent Development Corporation (NPDC) bought the American rights to the lenses from the Czechoslovak government for $330,000.  Then they sublicensed the patent to the Bausch and Lomb Corporation.  Wichterle was paid less than 1/10 of 1 % of the money, but he was now free to speak and travel and he had no regrets. 

In 1989 Gholam A. Peyman, an ophthalmologist and inventor patented Lasik, a laser and computer assisted device that allowed doctors to peel back a flap of the outer skin of the cornea, the front lens of the eye.  The inner corneal layer could then be altered with the beam of a laser, and eyes could focus better.  At the end of the procedure the flap was replaced.  The inventor, Dr. Peyman, was born in Shiraz Iran and went to medical school in Germany.  He’s a constant innovator and has held more than 100 patents.  In 2010 it was estimated that 8 million Americans have undergone the Lasik procedure at a cost of about $2000 per year.

Finally, no sooner is one problem solved than a new one develops.  In a country where the incidence of obesity is increasing as a result of our high caloric diets and diminished activity, more and more individuals become diabetic.  People with longstanding diabetes develop a number of eye problems and can go blind. 

By 2010 close to 7 billion people lived on earth and about 32 million, one in 200 were blind.  An additional 191 million, one in 40, were visually impaired. 

Blood sugars usually have to be elevated for ten to 15 years before blood vessels on the surface of the retina become permeable and weepy and the amount of oxygen that reaches the cells of the eye decreases.  New vessels, signaled by VEGF, grow and impair eyesight.  “Left untreated, nearly half of eyes that develop proliferative diabetic retinopathy will have profound vision loss.”

Lasers are used to destroy the blood vessels that are overgrowing, and the antibodies that block VEGF, the hormone that encourages new blood vessel growth, are injected into eyes.  In 2020, the Medicare paid $1000 to $1800 a session for the VEGF inhibitors that were FDA approved for use in the eye. 

REFERENCES:

In 2019, according to the NIH, the most common causes of blindness are:  Cataracts (51%); Glaucoma (8%);Age-related macular degeneration (5%);Corneal opacification (4%); Childhood blindness (4%; Refractive errors (3%); Trachoma (3%); Diabetic retinopathy (1%)  https://www.ncbi.nlm.nih.gov/books/NBK448182/ 

https://www.who.int/news-room/fact-sheets/detail/trachoma

Trachoma, is it history by H.R. Taylor  https://www.nature.com/articles/eye2008432https://www.who.int/news-room/detail/27-06-2019-eliminating-trachoma-who-announces-sustained-progress-with-hundreds-of-millions-of-people-no-longer-at-risk-of-infection

 https://www.who.int/apoc/onchocerciasis/en/ http://sped.wikidot.com/malnutrition-a-cause-for-visual-impairment

CATARACTS:  Harold Ridley and the intraocular lens     https://rayner.com/wp-content/uploads/2019/02/Invention_of_the_IOL.pdf  https://www.reviewofophthalmology.com/article/thoughts-on–cataract-surgery-2015

https://www.seva.org/site/SPageServer/;jsessionid=00000000.app272a?NONCE_TOKEN=D331A52171C42E9234E1E43A336A29B0&pagename=25_Years_of_Aurolab       https://www.mitpressjournals.org/doi/pdf/10.1162/itgg.2006.1.3.25 

RIVER BLINDNESS  (PAHO-Pan American Health Organization.)  (see: setting the price–Ivermectin)

MACULAR DEGENERATION  https://www.jci.org/articles/view/77540 A Conversation with Napoleone Ferrara

diabetic retinopathy  NEJM 2011;365:1520-6

https://www.nejm.org/doi/exam/10.1056/NEJMcme1909637?ef=article

phttps://www.cbsnews.com/news/nearly-half-the-planets-population-lives-on-less-than-5-50-a-day-worlf-bank-reports/ (half the planets population lives on $5.50 or less a day)

 Glaucoma  https://www.nature.com/articles/6702284

https://www.hopkinsmedicine.org/wilmer/services/glaucoma/book/ch17s01.html

Soft contact lenses phttps://b-c-ing-u.com/celebrities/hard-life-of-otto-wichterle/ 

Lucentis wet macular degeneration https://www.businessinsider.com/price-difference-lucentis-and-avastin-2014-6

soft lenses https://www.mayoclinicproceedings.org/article/S0025-6196(16)00071-9/fulltext

MALPRACTICE


“Never go to a doctor whose office plants have died.” —Erma Bombeck

At 80 he was grey, trim, and smiled a lot. His heart had been damaged by a prior heart attack, but it still pumped well enough to get him through his daily 9 holes of golf. 

His abdominal aorta, the main blood conduit in his abdomen, was bulging, had an aneurysm that was visible on X ray because a rim of calcium that had formed on the inner wall of the large artery.  When it reached a size where the risk of rupture and sudden death outweighed the hazard of an operation I sent him to a surgeon.  The operation went well and 6 weeks post op he was again golfing; his only complaint was abdominal pain that was tolerable but strange.  I ordered an x ray.  Later that day the radiologist called.  The surgeon had left a sponge in the abdomen.  Surgical sponges are marked with radio opaque threads and are easy to spot on x-ray. 

Replacing an aorta is bloody business.  A portion of the large vessel has to be closed off at both ends before the replacement graft is sewn or stapled in.  When it’s cut blood leaks into the abdomen and the surgical team suctions some from the cavity and blots the rest with cotton diaper like “sponges”.  The outside of the intestines and organs are covered with a red film and it gets hard to tell a rag from normal tissue.  When the sponges are thoroughly soaked, they are removed and stacked in a corner of the room.  Before the operation starts the sponges are counted and before the abdomen is sewn shut they are counted again.  If a sponge is missing the abdomen is scoured until the fabric is found.  In this man’s case someone obviously counted wrong. 

Large foreign materials left in the abdomen don’t always cause problems, but they can get infected and their presence is a clear sign that a mistake was made another operation is indicated.  The Latin term res ipsa loquitur, the thing speaks for itself, indicates a situation where lawyers don’t need a witness to prove malpractice.  The evidence of “wrong doing” is obvious and irrefutable. 

I called the patient and told him about the x ray findings.  When he met with the surgeon my colleague was contrite and offered to perform another operation.

First thing doctors are taught in malpractice lectures.  If there’s a mistake admit it as soon as you know something went wrong.  Accept the blame.  Treat the injured party as you would like to be treated.  Most mistakes don’t lead to a law suit.  Legal action becomes more likely when the harm is great and prolonged or when the patient or family is upset with the care they received and/or the attitude of the medical staff.

My patient wasn’t angry or vengeful, and he didn’t want to risk a second operation.  He filed a law suit and asked for $50,000.  Our insurance people reviewed the file, admitted guilt, and offered $10,000.  They may have been low balling him, but it didn’t work.   

Months passed, neither side was giving in, and an expensive trial seemed imminent.  Then one day my patient had a heart attack on the golf course and died.  His family was not compensated.

During the last 50 years the price of medical care has grown and “medical liability costs (excluding malpractice insurance premiums) are thought to be the source of 2.4 percent of the money we spend.11   Medical providers have grown in their ability to improve the quantity and quality of the average person’s life, and physicians and patients are taking more risks. 

Unfortunately at times doctors and nurses seem to have poor people skills.  We doctors may be good students, technically proficient, and methodical.  But too often we are running late.  Our schedules are too tight; we seem to be impatient; and –in the age of computerization– we spend too much of the visit looking at a screen. .    

Errors happen.  The wrong medicine. The wrong dose.  Bed sores.  A preventable fall that leads to an injury.  A sponge left in an abdomen.  A cancer that should have been discovered early. Harm at the time of birth that has lifelong consequences. 

The majority of physicians in a quoted survey said that when something goes wrong they provide “only a limited or no apology; limited or no explanation; and limited or no information about the cause.”   The article’s author, a physician who specializes in malpractice, thinks that too often the problem is caused by a physician’s  need to protect his or her ego and a system that allows doctors to blame shift.1

Prior to 1970 medical malpractice suits were rare.   That year an estimated 12,000 claims were filed but a third were quickly dropped.  Many who had a legitimate case did not sue; of those who did, four of five cases ended in favor of defendant.  Many of the awards didn’t cover the victim’s litigation cost.13

As the 20th century wore on the legal rules of the road changed in one state after another.  Lawyers were increasingly allowed to file claims based on errors that were so obvious that –res ipsa loquitur – the blunder “spoke for itself.”  Claims could be based on the absence of adequate informed consent.  Charitable and nonprofit hospitals had for decades had been shielded from litigation—in the belief that “paying money to the victims could damage the facility’s ability to treat patients.”  In one state after another, they now became responsible for errors that were their fault. (Massachusetts limited their financial vulnerability to $20,000.7)  Jury awards started fluctuating wildly.  At one point injured parties in “California and Nebraska” on average received awards that were 20 times higher than they were in “low-activity states, such as Maine8..

The majority of the injured don’t sue.  In one analysis “Approximately 70 percent of claims were closed with no payment.  Defendants won the majority of cases that went to trial.”  People who litigate tend to have more severe injuries and there has been an increase in the number of million dollar plus awards.  (In New York in 1984 one percent (20,000) of the people who had been hospitalized suffered an in- hospital “negligent adverse event” and 7000 died, but only 3500 of the injured filed a law suit.11)

During the last half century there were three periods of time when malpractice insurance premiums rose dramatically and insurers left some states.  When the lack of “coverage” for medical care was deemed “critical” some legislatures established patient-compensation funds and joint underwriting associations.”   In 1975 California lawmakers limited medical malpractice non-economic damages—compensation for “pain and suffering to $250,000.  No limit was place on the amount of money that could be awarded for costly medical care, lost income, or inability to earn a living because of the malpractice.10.’

Insurance policies have gotten pricey, and they contribute to the cost of medical care.  Between 2008-2017 for example, the annual cost of insurance for obstetricians and gynecologists in Connecticut, Illinois, and Pennsylvania was in the $170,000 to $200,000 range.  In California similar premiums had price tags of $50,000 to $60,000 a year.12 

I was a salaried doctor in a large physician owned group (Kaiser). During my 40 years I was sued a few times, and it was emotionally painful.  I’d prefer to not judge myself.

I don’t really know what happens to physicians who practice fee for service medicine.  Some share small offices with one or several colleagues.  When sued I assume they are forced to deal directly with representatives of an insurance company. 

I never had to pay a malpractice premium.  Kaiser, my employer, was big enough to be self insured.  In the event of a multi-million dollar settlement—a severe injury that led to expensive lifelong care—an umbrella insurance policy kicked in.

I wasn’t forced to deal with a representative of an insurance business or company lawyers whose chief tactic was delay and endless expensive depositions. 

Suits that alleged malpractice initially went to a fellow physician who was not always that sympathetic, but who usually was one of the groups brightest and best.  Our malpractice doctor typically spent half of his or her time deal with legal allegations and the other half dealing with patients.  After a lawsuit arrived on his or her desk, our colleague read the chart, evaluated the case, and reached a preliminary conclusion. 

All doctors who participated in the care of the injured person were always named, and everyone who was being sued was informed. In serious cases the group hired one or several outside experts and asked them to assess the case.  When necessary they got opinions from additional experts. Physicians who were paid for advising us could not become a witness or consultant for the plaintiff.  If the outside experts thought we were negligent, our people tried to settle.

A large medical-legal department handled the paper work, the release of information and the technical matters associated with lawsuits.  Skilled, knowledgeable company lawyers gave advice and guided physicians through depositions.  When indicated, outside lawyers were hired to handle each case.      .

In my later years working for Kaiser everyone insured by the plan signed an arbitration contract. Cases could not go to a jury.  The Judges chosen were acceptable to the lawyers from each side.  I’m told the approach does not affect overall malpractice costs, but it was easier on the psyche.

 When a plaintiff is awarded compensation in excess of $30,000 the state of California gets involved.  If the case was settled our group has to name the physician most responsible, and that name is posted on a state web site.   If there was a trial and the money was awarded by a judge, the board of medical examiners gets to decide who to blame.    

Doctors responsible for larger settlements often have to appear before a really tough California medical board.  Most walk away with a reprimand, but about one in 10 medical licenses are revoked or suspended.  .

Our tort system is based on blame and fault.   To prevail a plaintiff has to prove that the defendant owed a duty of care, that the defendant breached the duty, and that the breach caused an injury.”

In California people must file suit within a year after they learn they were negligently harmed. (As mentioned previously) the state capped the amount that’s paid for pain and suffering at $250,000 per person.  There is no dollar limit on actual injuries. 

Plaintiffs’ attorneys usually work on a contingency-fee basis, and take a percentage of the award when they win and nothing when they lose. 

Numerous surveys have concluded that in most cases of negligence the doctor was not sued, and when doctors are sued the harm was usually NOT the result of negligence.

In one recent study (12,000 to 17,000 insurance policies a year), 7.4% of the doctors were sued at least once annually.  Most of the allegations were dropped or dismissed, but 1.6% of those suing were paid some money.  The most targeted subspecialties were neurosurgeons, chest surgeons, and general surgeons.  On average 15 to 19 percent of them were sued each year.  That turns out to be an average of a suit every 5 to 6.5 years. The least targeted physicians were generalists, pediatricians and psychiatrists.  Physicians in these specialties generally got legal notice every 20 to 40 years, or one to two times during their medical careers.2

The number of “paid medical malpractice claims” decreased significantly between 2001 and 2016.  They went from 16,000 to 8500 a year, and the average payout “dropped about 23%”.  During that 15 year period the number of suits where people are paid more than half a million dollars didn’t change much.  They led to annual payouts of about $2.5 billion.  Between 2012 and 2016 as many as 60 in a million people filed malpractice claims in our two most litigious states New York and New Jersey.3

Some doctors claim that the fear of malpractice leads to unnecessary testing and plays a major role in health care costs.

“Many countries- like Sweden, Finland, New Zealand, Quebec Canada, and Australia, have a no-fault system”.  Compensation is based on proof of “causal” connection between treatment and injury. Their structure awards damages to patients without proof of provider’s fault or negligence, and it encourages physicians to collaborate in their search for the cause of the injuries.  Although the application of no-fault system differs slightly in each country, the basic idea is to eliminate fault or blame and make the claim process simple so patients with meritorious cases can access the system easily.” It also makes it easier to identify and fix problems.4

It’s possible to get some sense of what would happen if American physicians could no longer be sued for medical malpractice.  Doctors in the military aren’t immune from patient complaints or administrative action, but the government can’t be sued.

In the 1940s a serviceman died after a surgeon “left a towel in his abdomen”.  The family sued. In 1950 the U.S. Supreme court, by creating a “doctrine” called the Feres rule, decided the government was not liable.  The decision was later extended to include anyone receiving medical care from “the government.”  The court rationalized the approach by discussing the special relationship that exists between service members and the U.S. and by pointing out that the laws of malpractice vary from state to state.  That makes litigation complex.  They noted that injured service members who were disabled were paid accordingly.  Some judges apparently feared law suits might affect military discipline.  The decision of the court has been challenged.  Additional suits have been filed, but the court did not choose to re-hear the matter. 

In a recent article a few lawyers felt “repeal (of Feres) may not serve the best interests of service members.”  Most people who are harmed, they pointed out, don’t sue.  Without the threat of legal action, mistakes could be openly discussed, problems could be identified and the system could be improved.   We don’t know, they argued, that giving lawyers standing would make the care people received any better or safer.  “There is little empirical evidence,” they wrote, that civilian malpractice litigation provides incentives to improve the safety of care.5

Sometimes doctors can’t fix or help some sick people because we don’t know how.  Metastatic cancer and dementia top the lack of knowledge list.  But too often the knowledge exists but we don’t deliver.  Gawande.15 (paraphrase)

Delays in retrieving a person’s records, time pressures, and illegible physician notes are common impediments.  Robert Pearl, the former head of Kaiser thinks a computerized health record that pops up every time a physician is visited, one where a person’s medical information is presented to each treating doctor, should make a big difference.16

  1. Medical MalpracticeDavid M. Studdert, LL.B., et al.   January 15, 2004 N Engl J Med 2004; 350:283-292 https://www.healthaffairs.org/doi/full/10.1377/hlthaff.W4.20
  2. https://www.statnews.com/2017/01/13/medical-errors-doctors/
  3. https://www.mdedge.com/clinicalneurologynews/article/48642/health-policy/most-doctors-face-malpractice-claim-age-65
  4.   http://truecostofhealthcare.org/malpractice_statistics/
  5. http://siteresources.worldbank.org/INTRUSSIANFEDERATION/Resources/Malpractice_Systems_eng.pdf
  6. https://digitalcommons.wcl.american.edu/cgi/viewcontent.cgi?referer=&httpsredir=1&article=1608&context=aulr In Defense of Feres: An Unfairly Maligned Opinion. 
  7. Twenty Years of Evidence on the Outcomes of Malpractice Claims Philip G. Peters, JD
  8. 7. https://www.clf-law.com/Medical-Malpractice-Newsroom/Charitable-Immunity-for-Nonprofit-Hospitals.shtml

8.  https://www.nejm.org/doi/full/10.1056/NEJMhpr035470

9.  Robinson GO. The medical malpractice crisis of the 1970’s: a retrospective. Law Contemp Probl 1986;49:5-35

10.  https://www.nolo.com/legal-encyclopedia/how-does-the-micra-damage-cap-affect-california-medical-malpractice-case.html 

11.  Brennan TA, Leape LL, Laird NM, et al. Incidence of adverse events and negligence in hospitalized patients: results of the Harvard Medical Practice Study I. N Engl J Med 1991;324:370-376

12.  file:///C:/Users/User/Documents/policy-research-perspective-liability-insurance-premiums.pdf Medical Professional Liability Insurance Premiums for $1M/$3M Policies, Selected Insurers,

United States. Department of Health, Education, and Welfare. Secretary’s Commission on Medical Malpractice-1973-Medical Malpractice Report.   https://books.google.com/books?id=2PqUFmmYtVIC&pg=PA6&lpg=PA6&dq=in+1970+12,000+malpractice+claims+were+filed&source=bl&ots=_AeitZqpvz&sig=ACfU3U1lIEO0ET8N2IBLcMwBgPmdfJ_F7Q&hl=en&sa=X&ved=2ahUKEwil3M_std7nAhWSKH0KHVksC1QQ6AEwB3oECA8QAQ#v=onepage&q=in%201970%2012%2C000%20malpractice%20claims%20were%20filed&f=false

14.  National Costs of the Medical Liability System Michelle M. Mello, et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048809/#!po=0.892857

15. Atul Gawande: VoxSep 16, 2016, by Jeff  Stein for the first time in human history ineptitude is a bigger problem than ignorance.

16. Mistreated by Robert Pearl M.D., Public Affairs press, 2017. https://www.hcinnovationgroup.com/policy-value-based-care/article/13028465/oneonone-with-dr-robert-pearl-the-permanente-medical-group-ceo-at-world-health-care-congress

INNOVATION,BUSINESS, HIGH PRICES, AND ARTEMISININ

INNOVATION, BUSINESS, AND HIGH PRICES.

This segment of the book tells the stories of :

Innovative medications that were created in the labs of big Pharma, privately funded startups, research hospitals, Universities, or the National Institute of Health.

Funding for research and development that was raised by selling stock at the time of an IPO –initial public offering, or paid for by entrepreneurs, government grants or with donated dollars

New medicines that large pharmaceutical companies tweeked, developed, manufactured, distributed, promoted, and aggressively priced.

And mergers and acquisitions in which company “A” paid billions of dollars to buy company “B” because they wanted to own one or several medications. Then “A’, now saddled with billions of dollars in new debt, needed to sell a lot of their new medicine and they had to charge a lot for the product..

  • A.  Setting the Price
  • B. 2019 Senate hearings
  • C.  Tax and Donated dollars
  • D.  Swiss take control
  • E. Dominating the market
  • F. Artemisinin a drug that the Western World didn’t accept for 30 years, but that has already saved millions of lives

The new drug was developed in China in the 1960 and 1970s the person who led the team that developed the medication, Youyou Tu received the Nobel Prize for her efforts in 2015.  This is the story she told when she received the award:

“I was born on December 30, 1930 in Ningbo, a city on the east coast of China with a rich culture and over seven thousand years of history.

My father worked in a bank while my mother looked after my four brothers and me, the only girl in our family. Our family’s long history of highly valuing children’s education and always considering this as the family’s top priority allowed me to have good opportunities for attending the best schools in the region –I unfortunately contracted tuberculosis at the age of sixteen and had to take a two-year break and receive treatment at home.  Then I resumed my study at the private Ningbo High School (1948–1950) This experience, being ill and cured, led me to make a decision to choose medical research for my advanced education and career After graduation from high school, I attended the university entrance examination and fortunately I was accepted by the Department of Pharmacy and became a student at the Medical School of Peking University.

Most pharmacy courses were designed and taught by returnees such as Professors Lin Qishou (林启寿) and Lou Zhicen (楼之岑) who had received educations and advanced degrees in Western countries. Professor. Lin Qishou gave a comprehensive introduction and hands-on training on how to extract active ingredients from the plants, how to select proper extraction solvents, how to carry out chemistry studies and determine the structures of the chemicals isolated from the plants etc. These courses provided scientific insights into the herbs and plants and more importantly.  They explained how these herbal medicines work, in a way different from traditional Chinese medicine.

China lacked medical resources in the early 1950s. There were only around twenty thousand physicians and several tens of thousands of traditional Chinese medical practitioners in the country   The Ministry of Health of China organized a number of full-time training courses in the late 1950s . In my two and a half year training program, I learned traditional Chinese medical theory and gained experience from clinical practice. Another training program I attended was on the processing (炮制) of Chinese Materia Medica.. Knowledge of such processing, in combination with the scientific explanation, benefited my work enormously.

Malaria is a life-threatening epidemic disease. It was, however, effectively treated and controlled by chloroquine and quinolines for a long period of time. Then most of the plasmodium parasites became drug resistant. 

n the late 1960s following the catastrophic failure of a global attempt to eradicate malaria. Resurgence rapidly increased mortality posed a significant global challenge, especially in the South East Asian countries.

 In the 1960s, the Division of Experimental Therapeutics at the Walter Reed Army Institute of Research (WRAIR) in Washington, DC launched programs to search for novel therapies to support the US military presence in South East Asia. US military force involved in the Vietnam War suffered massive casualties due to disability caused by malaria infection. Up to 1972, over 214,000 compounds were screened with no positive outcomes.”

China was in the middle of the great cultural revolution. “According to Wikipedia the cultural revolution wasa violent movement launched by Mao Zedong that lasted  from 1966 until 1976.  Its stated goal was to preserve Chinese Communism by purging remnants of capitalist and traditional elements.  Mao called on the young people to rebel and insisted that revisionists who formed red guards to grab power.

The Cultural Revolution damaged China’s economy and traditional culture, with an estimated death toll ranging from hundreds of thousands to 20 million. There were a number of massacres.  Red Guards destroyed historical relics and artifacts and ransacked cultural and religious sites. Tens of millions of people were persecuted, purged, exiled and imprisoned. Notable scholars and scientists were killed or committed suicide. Schools and universities were closed and over 10 million urban youths were sent to the countryside.

According to Wikipedia the cultural revolution wasa violent movement launched by Mao Zedong that lasted  from 1966 until 1976.  Its stated goal was to preserve Chinese Communism by purging remnants of capitalist and traditional elements.  Mao called on the young people to rebel and insisted that revisionists who formed red guards to grab power.

The Cultural Revolution damaged China’s economy and traditional culture, with an estimated death toll ranging from hundreds of thousands to 20 million. There were a number of massacres.  Red Guards destroyed historical relics and artifacts and ransacked cultural and religious sites. Tens of millions of people were persecuted, purged, exiled and imprisoned. Notable scholars and scientists were killed or committed suicide. Schools and universities were closed and over 10 million urban youths were sent to the countryside.”

 Youyou:  “Almost every institute was impacted and all research projects were stalled. A lot of experienced experts were sidelined. After thoughtful consideration, the academy’s leadership team appointed Youyou Tu to head and build a Project 523 research group at the Institute of Chinese Materia Medica. My task was to search for antimalarial drugs among traditional Chinese medicines.

As a young scientist, I was so overwhelmed and motivated by this trust and responsibility. I also felt huge pressure from the high visibility, priority, challenges as well as the tight schedule of the task. The other challenge was the impact on my family life. By the time I accepted the task, my elder daughter was four years old and my younger daughter was only one. My husband had to be away from home attending a training campus. To focus on research, I left my younger daughter with my parents in Ningbo and sent my elder daughter to a full-time nursery where she had to live with her teacher’s family while I was away from home for the project. This continued for several years. My younger daughter couldn’t recognize me when I visited my parents three years later, and my elder daughter hid behind her teacher when I picked her up upon returning to Beijing after a clinical investigation.

Our long journey searching for antimalarial drugs began with collection of relevant information and recipes from traditional Chinese medicine.

Malaria was one of the epidemic diseases with the most comprehensive records in traditional Chinese medical literature, such as Zhou Li (周礼), a classical book in ancient China published in the Zhou Dynasty (1046–256 B.C.).

After thoroughly reviewing the traditional Chinese medical literature and folk recipes and interviewing experienced Chinese medical practitioners, I collected over two thousand herbal, animal and mineral prescriptions within three months after initiation of the project. From these two thousand recipes, I summarized 640 prescriptions

After multiple experiments and failures, I re-focused on reviewing the traditional Chinese medical literature. One of the herbs, Qinghao (青蒿) (the Chinese name for the herbs in the Artemisia family), showed some effects in inhibiting malaria parasites during initial screening, but the result was inconsistent and not reproducible. I repeatedly read relevant paragraphs in the literature where the use of Qinghao was recorded as relieving malaria symptoms.

In Ge Hong’s A Handbook of Prescriptions for Emergencies (肘后备急方), I noticed one sentence “A handful of Qinghao immersed in two liters of water, wring out the juice and drink it all” (青蒿一握, 以水二升渍, 绞取汁, 尽服之) when Qinghao was mentioned for alleviating malaria fevers. Most herbs were typically boiled in water and made into a decoction before taken by the patients.

This unique way of using Qinghao gave me the idea that heating during extraction might have destroyed the active components and the high temperature might need to be avoided in order to preserve the herb’s activity. Ge Hong’s handbook also mentioned “wring out the juice.” This reminded me that the leaf of Qinghao might be one of the main components prescribed. I redesigned experiments in which the stems and leaves of Qinghao were extracted separately at a reduced temperature using water, ethanol and ethyl ether.

Sample no. 191 was a symbolic breakthrough in artemisinin discovery.  We produced extracts from different herbs including Qinghao using the modified process and subsequently tested those ethyl ether, ethanol and aqueous extracts on rodent malaria. On October 4, 1971, we observed that sample number 191 of the Qinghao ethyl ether extract showed 100% effectiveness in inhibiting malaria parasites in rodent malaria. In subsequent experiments, we separated the extracts into a neutral portion and a toxic acidic portion. The neutral portion showed the same effect when tested in malaria-infected monkeys between December 1971 and January 1972.

Starting in March 1972, the team started to produce large quantities of Qinghao extract in preparation for clinical studies. Most pharmaceutical workshops were shut down during the great cultural revolution. Without manufacturing support, we had to extract herbs ourselves using household vats etc. The team worked very long hours every day including the weekends. Due to lack of proper equipment and ventilation, and long-term exposure to the organic solvents, some of my team members included myself started to show unhealthy symptoms. This, however, did not stop our efforts.

Some conflicting information was seen from the animal toxicological studies. It was already in the middle of the summer and very limited time was available to us before the malaria epidemic season would end. We would have to delay the study for at least a year if we continued our debate on toxicity. To expedite the safety evaluation, I got permission to take the extracts voluntarily. In July 1972, two other team members and myself took the extracts under close monitoring in the hospital. No side effect was observed in the one-week test window. Following the trial, another five members volunteered in the dose escalation study. This safety evaluation won us precious time and allowed us to start and complete the clinical trial in time.

Traditional Chinese medicine started with a story: “Shen Nong tasted a hundred herbs.” Shen Nong was an ancient Chinese medical practitioner. To understand the efficacy and toxicity of the herbs, he tasted over a hundred herbs himself and recorded all the details, which left us with a lot of precious information. Although Qinghao was prescribed as an herbal medicine for thousands of years, the dose of the active ingredients in these prescriptions was much lower than that in the Qinghao extract we tested. Our desire to get the clinical trial completed and have the medicine for our patients as soon as possible was the real driving force behind our action.

The first clinical trial on the Qinghao extract was carried out in Hainan province between August and October 1972. We treated a total of twenty-one local and migrant malaria patients, nine infected by Plasmodium falciparum, eleven infected by Plasmodium vivax and one with mixed malaria infections. The trial was successful: all patients recovered from the fevers and no malaria parasites were detected

We started isolation and purification of neutral Qinghao ethyl ether extract parallel with the clinical trial in 1972. We carried out a clinical trial of artemisinin between August and October 1973 using artemisinin tablets, which however did not yield the desired results. We examined the tablets returned from the clinical center and found that the tablets were too hard to disintegrate. We resumed the study using artemisinin capsules at the end of September 1973. Dihydroartemisinin was found in September 1973 in an experiment where I tried to derivatize artemisinin for a structural activity relationship evaluation. In a subsequent test in rodent malaria, we noticed that a significantly reduced dose was sufficient to achieve the same efficacy as artemisinin when dihydroartemisinin was administered.

. Dihydroartemisinin is ten times more potent than artemisinin clinically, again demonstrating the “high efficacy, rapid action and low toxicity” of the drugs in the artemisinin category.  “Bench to bedside” – collaboration expedited translation from a discovery to a medicine. 

The herb Qinghao was frequently mentioned in the traditional Chinese medical literature for various clinical applications besides alleviating malaria symptoms. These applications include relieving itches caused by scabies and scabs, treating malignant sores, killing lice, retaining warmth in joints, improving visual acuity, etc. However, little explanation was given on either the species or effective parts of the plant in the traditional Chinese medical literature.

We carried out a thorough investigation and confirmed that only Artemisia annua L. (sweet wormwood) contains artemisinin. In addition to identification of the right species, we also verified the best regions for growing Qinghao, the best collection season and the officinal part of the plant.”

China and Vietnam provide 70% and East Africa 20% of the raw plant material.[58] Seedlings are grown in nurseries and then transplanted into fields. It takes about 8 months for them to reach full size. The plants are harvested, the leaves are dried and sent to facilities where the artemisinin is extracted using a solvent, typically hexane a straight-chain alkaline with six 6 atoms that is a colorless liquid, odorless and is widely used as a cheap, relatively safe, largely unreactive, and easily evaporated solvent.  Alternative extraction methods have been proposed.[59] The market price for artemisinin has fluctuated widely, between US$120 and $1,200 per kilogram from 2005 to 2008.[60] it also works on Shistosomiasis

By the beginning of the 1980’s, China started to open up to the rest of the world and the Chinese scientists, including Li Guoqiao contacted professors David Warrel and Nicholas White from the Wellcome Trust and gave them access to data related to the use of artemisinin in the treatment of malaria. These data were first mentioned in a Wellcome Trust publication entitled A present from Chairman Mao (Gardner, 2002), which made these compounds known internationally. After this first encounter Nicholas White became a great advocate of artemisinin and through intense lobbying managed to convince the scientific community to take an active interest in these drugs This is also how a first Western company, Rhône- Poulenc Rorer (RPR, now Sanofi-Aventis), decided to study the potential of these drugs and license one of them, injectable artemether, from Kunming Pharmaceuticals. It took four years from the time of the first meeting in September 1989 to the launch in 1993. Negotiations were difficult as the manufacturer could not conduct direct discussions with a foreign company and had to go via a state organisation (Citic Group), which did not necessarily follow the same goals. Moreover, the Chinese government suddenly decided to promote its relationship with other emerging countries and all the negotiators found themselves having to pursue their talks in Brazil! Nevertheless, a contract was finally signed in July 1990 in the presence of Deng Zhifang, Deng Xiaoping’s youngest son (Fig. 1). But work only started: the technical dossier was not receivable and had to be totally re-written. New studies were requested, including animal toxicity studies though the product had already been widely used in man! Two major clinical trials were conducted, one in Vietnam (Hien et al., 1996) and one multi-centre in different African countries (Bougnoux & Ancelle, 1993Danis et al., 1996). Finally an approval for a limited use in French hospitals was granted, which allowed RPR to market this product in endemic areas.

These data were first mentioned in a Wellcome Trust publication  intense lobbying convinced the scientific community to take an active interest in these drugs (White et al., 1999). This is also how a first Western company, Rhône- Poulenc Rorer (RPR, now Sanofi-Aventis), decided to study the potential of these drugs and license one of them.  . It took four years from the time of the first meeting in September 1989 to the launch in 1993. Negotiations were difficult as the manufacturer could not conduct direct discussions with a foreign company and had to go via a state organisation (Citic Group), which did not necessarily follow the same goals. Moreover, the Chinese government suddenly decided to promote its relationship with other emerging countries and all the negotiators found themselves having to pursue their talks in Brazil! Nevertheless, a contract was finally signed in July 1990 in the presence of Deng Zhifang, Deng Xiaoping’s youngest son (Fig. 1). But work only started: the technical dossier was not receivable and had to be totally re-written. New studies were requested, including animal toxicity studies though the product had already been widely used in man! Two major clinical trials were conducted, one in Vietnam (Hien et al., 1996) and one multi-centre in different African countries (Bougnoux & Ancelle, 1993Danis et al., 1996). Finally an approval for a limited use in French hospitals was granted, which allowed RPR to market this product in endemic areas.  Not in 2010 washington u. manual

it was found that the artemisinin do not only affect the malaria parasites, but are also active against juvenile schistosomes, which was first shown by Chen et al. [25] at the end of the golden decade of antiparasitic drug discovery in the 1970s. In fact, this discovery predates that of scholarly articles on qinghaosu’s use against malaria, which remains its main application.

From the New England Medicine.  “Artemisinin derivatives, used in carefully developed combinations, have recently served as the first-line drugs against most uncomplicated malaria infections. Artemisinins are combined with other drugs so that the fast-acting artemisinin can immediately reduce parasitemia, allowing remaining parasites to be removed by a long-acting partner drug. Monotherapy with the artemisinin compound artesunate is used for initial management of severe disease.

A slowdown in the clearance of parasites in patients treated with artesunate sounded alarms when it was first reported from Cambodia. Subsequently, similar delays in parasite clearance were noted in countries in Asian territories, including Myanmar, Thailand, Laos, and China, collectively referred to as the Greater Mekong Subregion.1 It was determined that parasites that were cleared more slowly after artemisinin treatment carried mutations in the propeller domain of the malarial kelch13 (K13) gene. Although K13 mutations are not reliably associated with increased risk of treatment failure, parasites bearing these mutations are now called “artemisinin-resistant.” Phenotypically, “artemisinin resistance” is defined as a delay in parasite clearance. These parasites recrudesce more frequently than artemisinin-sensitive parasites after standard 3-day therapeutic courses with artemisinin combination treatments (ACTs).

However, 3-day courses do not contain the full treatment doses of artemisinins needed to cure infections, which last 7 to 10 days, according clinical studies conducted in China. When a 7-day treatment course of artesunate is used, it is effective even when early parasite clearance is delayed.2 The same is not true of resistance to other classes of antimalarials, which results in a failure to cure the infection after a full treatment course.

Should a delay in parasite clearance with artemisinin treatments be defined as drug “resistance” or “tolerance”? Either way, 3-day therapeutic courses are losing their efficacy against malarial parasites in the Greater Mekong Subregion. So what matters most to patients and populations at risk is how we handle this emerging threat.

Treatment failures with artemisinin combination therapy can be directly attributed to the partner drug, despite delayed-parasite-clearance phenotypes.2 For example, if piperaquine–dihydroartemisinin treatment is failing in a given region, another combination, such as mefloquine plus artesunate, may prove very effective. May 30, 2019 NEJM. “

https://www.nejm.org/doi/full/10.1056/NEJMp1901233

cultural revolution https://en.wikipedia.org/wiki/Cultural_Revolution#:~:text=The%20Cultural%20Revolution%2C%20formally%20the,China%20from%201966%20until%201976.

https://www.nobelprize.org/prizes/medicine/2015/tu/biographical/ Tu Youyou
The Nobel Prize in Physiology or Medicine 2015

2019 SENATE HEARINGS

On Feb 26, 2019 the heads of 7 pharmaceutical manufacturers appeared before a congressional committee.  The CEO’s of Roche and Novartis—the Swiss—were notably absent.   Senators were trying to learn why the cost of medicine was much higher in America than it was in any other advanced country.   At the end of her 5 minute interrogation Debbie Stabenow of Michigan seemed frustrated by the evasive non-answers she was evoking, and she concluded that companies raise prices because they can. 

She was right and wrong.  I believe CEO’s believe they have no choice.  They are accountable to stock holders. If the company is not profitable their jobs are in jeopardy.  The marketplace they face is not one where their “competitors” are trying to grow market share by cutting their prices.  Quite the contrary.  Industry leaders are charging more each year.  As long as price increases stay below 10% and are some odd number, they don’t seem arbitrary.  Most importantly, when pharmaceutical prices rise no one who matters seems to care.

Not that the spokespeople that defend Pharma are wrong.  Some of the drugs that company researchers spend years developing fail.  When tested, they aren’t effective or are they are toxic, or they don’t have a market niche that makes them profitable. When company money makers lose their exclusivity, generics move in.   

Most advanced nations keep prices down by using a system called “reference pricing”.  They cluster medications that “have identical or similar therapeutic effects”.  Then some insuring nations (like Italy) pay the cost of the cheapest drug in each grouping, and in other countries (like Germany) shell out the price of the average medicine in the collection.  In America the government hasn’t instituted a pharmaceutical price control system. Insurers, phamaceutical benefit managers and the VA negotiate drug prices; Medicare, by law, can’t. 1 

 Many of the CEOs that were in Washington that day seemed less than proud of their contribution to the price problem.  Some seemed anxious to lower prices and/or tie increases to inflation.  In return they wanted to stop giving discounts and rebates to middle men and women–pharmaceutical managers– or give rebates directly to the person that needs them. And if they were going to lower prices they wanted the other companies to follow suit.

Kenneth Frazier, the son of a janitor, and grandson of a South Carolina share cropper was the CEO of Merck. A graduate of Harvard, he was the first black man to head a fortune 500 corporation.  Initially a member of the defense team when Merck was sued because its arthritis medication, Vioxx, increased the risk of heart attacks and strokes, he had also practiced criminal law. He was part of a legal team that won a new trial and eventual acquittal for an Alabama man who had been convicted of murder.5  He told the senators that he felt his company had a duty to be responsible in pricing practices and to contribute to solutions that address patient affordability.  He said that the previous year Merck had decided to not annually increase the net price of their portfolio by more than inflation.  And he pointed out that his company had deployed 70k doses of experimental Ebola vaccine in the Congo. 

The French company Sanofi’s head, Olivier Brandicourt, had, as young doctor “spent two years in the Republic of the Congo. He had then studied malaria during his eight years at the institute of infectious and tropical diseases in Paris.”  He said that two years earlier his company had pledged to keep price increases at or below the U.S. national health expenditure projected growth rate.  He talked about the gap between net and list prices.  Lantus, the company’s long acting insulin had seen a 30% decrease in net at a time when U.S. patients out of pocket costs had increased 60%.  He felt dealing with list price alone would not solve the problem of patient out of pocket costs.6  

Pascal Soriot head of Astra-Zeneca agreed:  “The government has to step up and change the rules.”  Born in France, Soriot currently calls Australia his home. An avid bicyclist he keeps a road bike in the Alps, another in the US, and a third one in Cambridge England.7 He grew up in the north of Paris and when young was a member of a “team”. His story suggests it might have been a bit like a gang. There were “many fist fights.” He was trained in veterinary medicine before he started working for Pharma.   

The new CEO of Pfizer apparently believed the group was not brought to Washington to provide certain senators with an opportunity to publically chastise big shots and show their voters they cared.  He thought the senators wanted suggestions.  Named Albert Bourla, he was a Greek veterinarian who was a former director of Pfizer’s animal health group.  When his turn came he stated he was “particularly humble to take part in such an important policy discussion within the U.S. Senate.  When he immigrated 18 years earlier he could never have imagined such an honor.”  And he told the senators–at the end of the session–that he had made it clear to investors: Pricing will not be a growth driver for the company now or in years to come.  (I wonder how long he will last.)

  Unlike the other CEOs he didn’t point out how many billions of dollars his company was spending on research, how they desperately wanted to discover and develop a new super drug for mankind—not for their bottom line.  And he didn’t talk about his company’s risks and failures.  The suggestions he made provided a decent summary of what everyone (aside from AbbVie) was saying.

Medical breakthroughs, he said, “won’t do anyone any good if patients can’t afford them, and unfortunately the horribly misaligned incentives within our health care system often makes medicines unaffordable for American patients.  We need to fix this.”  

In part restating the thoughts of the other CEOs, Bourla presented four ideas:

All rebates should go to patients. He believes too much money is being swallowed up in the supply chain. His company paid $12 billion this year in rebates.  He didn’t think any of the money found its way to patients.  If discounts were provided to the people who take medications, seniors could save hundreds of dollars a year.  

Medicaid covers the costs of the prescription drugs used by the people it cares for.  “To help ensure that the taxpayer sponsored program receives the lowest price available for all prescription drugs” Congress passed the Medicaid best price rule in 1990.  Pharmaceutical manufacturers, who sell products to people covered by Medicaid can’t charge the U.S. more than they charge a tough bargaining private insurer. 

And as part of the Affordable Care Act, to “offset the overall cost of Medicaid prescription drugs,” 600 brand-name drug manufacturers (under duress) agreed to pay a rebate to the states and Federal government. The amount of rebate is based on a statutory formula: it is a percent of the  Average Manufacturer Price (AMP)—the average price that manufacturers receive from the wholesalers who distribute medicines to retail pharmacies. 

  • For recently approved –“innovator” drugs—the first to contain a “specific active ingredient” –manufacturers pay at least 23.1 percent of the AMP.
  • For blood clotting factors and pediatric medications at least 17.1 %,
  • and for generic drugs at least 13%9
  • In 2016, Medicaid drug rebates totaled $31.2 billion.” 

Bourla repeated the longstanding dream of many in the health care field.  If a drug has less value it should cost less.  If a pill prevents heart attacks its price should be tied to the number of lives it saves.  Or—as Dr Peter Bach of Sloan Kettering pointed out — when Tarceva is used to treat lung cancer people live, on average, an extra year.  If it’s given to someone with pancreatic cancer their life is extended, on average, a week and a half.  The drug’s effectiveness varies but its cost doesn’t.   (So how would Bach and Bourla price penicillin, transfusions, or emergency heart stents?)

Bourla suggested capping seniors out of pocket medicines cost. Americans are increasingly paying a greater percentage of the cost of their medicines (14%) than they do for their time in the hospital (3%).  If someone doesn’t take a needed medication and as a result lands in the hospital, it’s more costly to the health care system.  (Lids on drug costs will also get some of the noisy voters off the backs of the companies and the legislators).

Finally Bourla touched on the problem that congress created and that only congress could fix.  Our laws are keeping Biosimilars off the American market.

Biosimilars are antibodies that bind to the same antigen as an approved monoclonal antibody. They are the generics of the day.  Half are mouse antibodies.  They come from special mice, creatures that were genetically altered.  When they were mere embryos some of their DNA was replaced with human DNA.  As a result when a protein—an antigen—is injected into one of the rodents, the creature makes antibodies that the homo sapiens immune system believes is human in origin.  When one of these “human-ish” antibodies is injected into a person our lymphocytes don’t destroy it.

Monoclonal antibody tutorial

  • There are Billions of B cells in a body. 
  • Each can only recognize one of the billions of different antigens it encounters.  (Antigens: viruses, toxins, pollen.) 
  • When a B cell identifies its fated antigen it creates a unique antibody. 
  • The B cell also clones itself; it makes billions of identical copies of itself. 
  • Each cell in the clone makes the same unique antibody. 
  • The antibodies are thus identical and monoclonal.

In the lab a chosen antigen is injected into a mouse. The animal is given time to recognize the antigen and clone itself–grow billions of B cells that each make the same special antibody. Because large numbers of B cells are present in the spleen, a large bore needle is inserted into an animal’s organ and blood rich in B cells is sucked out. 

  • B cells don’t live long. 
  • Myeloma cells don’t die. 
  • When B and Myeloma cells are fused chemically or electrically, a hybrid cell is created. 
  • It makes and keeps making the antibody; and it doesn’t die. 
  • The mixture of B and fused cells (hybridomas) are put in a special medium. 
  • It allows and encourages un-fused B cells to die off; and it allows hybridomas to multiply, thrive, and make lots of monoclonal antibody. 
  • The basic technology for making monoclonal antibodies is not new or obscure.  It was developed in 1975, and its inventors won the Nobel Prize. 

Humira is a mouse antibody –it blocks—inactivates—some of the body’s important immune modulators— molecules that play a role in the inflammatory process. The cytokine group it obstructs is called TNF, tumor necrosis factor.  When TNF is blocked it’s like a jack knifed truck on the freeway.  The immune/inflammatory reaction is shut down.  To make a biosimilar to TNF, trained researchers must inject the molecule into a humanized mouse, harvest the lymphocytes that produce the desired antibody, fuse the lymphocytes with myeloma cells, and create cells that should live “forever.” They test the antibodies that the cells produce and learn if they are safe and effective.  No two antibodies are, chemically speaking, exactly the same (they are not technically generics.) But like Shakespeare’s rose, good biosimilars “would smell as sweet.”  The\ biosimilars need to be and are as good as the original drug.  To date four pharmaceutical manufacturers have developed and tested effective Humira biosimilars.

In 2009 congress was sold a bill of goods.  They were told something like: we want to make it easier for biosimilars to enter the market.  We want to speed up the process.  So let’s make sure they work, that they are safe and effective.  But let’s not force them to go through extensive controlled trials.  Let’s speed up the process. 

The Biosimilars Act of March 23, 2010, gave biosimilars 12 years of marketplace exclusivity.  Standard medications were getting a 5 year monopoly.  At the end of those years (in the absence of legal gamesmanship) the first standard generic (biosimilar) would theoretically be allowed to compete —unless a valid patent stood in the way. And that’s the rub. All new pharmaceuticals are “protected” by significant and insignificant patents. Pharmaceutical companies have long used insignificant patents –that their lawyers could allege were important–to keep generics off the market for a few years. They have long used a provision in the 1984 Hatch-Waxman act to delay the entry of competitors. Then in 2010, in the guise of speeding biosimilars to the market, industry lobbyists did it again. They shaped a new rule as an amendment to the Public Health Service act.  They titled it an innovation, and they slipped it into the Affordable Care Act—Obama care.  And Ron Wyden, the senator who was most troubled when AbbVie used the loophole, voted for the bill.
AbbVie used loopholes in the law to keep four Humira biosimilars, off the American market for 5 years. Presumably they would have driven down the price of Humira. The company’s lawyers probably had one or several patents that were allegedly being infringed. Abbvie owns 126 Humira patents.  Most (I assume) have little nothing to do with the core drug. Under the new law when there was a patent dispute–in the place of litigation “negotiation was encouraged”.  The bargaining rules (called a dance) are complex, Byzantine.3

In Humira’s case the manufacturers reached an agreement. 4 companies were allowed to market their biosimilars in all countries of the world outside the U.S.  AbbVie kept exclusive control of the American market.  That’s over $9 billion a year for 5 years.  Thanks to our legislators, the U.S. will have to wait for biosimilars until September 2023.4 Bourla explained our law created “reverse incentives that favor higher cost biologics and are keeping biosimilars from reaching patients.  In many cases insurance companies decline to include lower price biosimilars in their formularies because they would risk losing rebates from higher cost medicines.”

Parenthetically Bourla suggested that the administration should obtain trade agreements that prevent foreigners from freely using American innovations.  He didn’t think Americans should pay less for drugs. He thought people in the other western countries should pay more.  “The price control mechanisms of many nations are giving others a free ride on American innovations.”

Richard Gonzalez, the CEO of AbbVie was the target of Senator Wyden’s wrath; One of Pharma’s few CEO’s without a college degree, Gonzalez worked for Abbott for 30 years and retired when he developed throat cancer.  Declared cured, he returned in 2009 as head of a spinoff called Abbvie.8 Gonzalez stated there’s no one solution; and he did his best to avoid discussing the biosimilar elephant in the room.  He pointed out that since its inception in 2013 his company had spent 50 billion dollars in research and had a hepatitis C drug that financially failed. He felt price was only a part of the problem.  Stating a willlingness to work with the committee, he pointed out that his company is charitable. 81,000 patients got free drugs (for an unspecified period of time.)

AbbVie, he explained, has 30,000 employees (and they need to eat). Senator Wyden, in turn, pointed out that Gonzalez’s salary was $22.6 million.  And he got a bonus of $4.3 million dollars.  Was, Wyden asked, the bonus tied to the financial performance of Humira.

In September 2018 congress passed John Sarbanes’ Biosimilars Competition Act.  It is supposed to “shine a light” on backroom, “so-called “pay-for-delay” deals – often made in secret.  They must now be reported to the federal trade commission who, with the justice department, will review agreements, look for anti- trust and anti-competitive behavior and “punish bad actors.”  In other words if a company has a drug with an annual revenue of $10 billion and they keep other drugs off the market for 5 more years (and make an additional $50 billion in U.S. sales) they may be sued, and their lawyers may be forced to settle with the government, admit no wrong, and pay a fine of a few million dollars.  Great law.   

“By 2014” (according to a Harvard Public Health school intellectual-property consultant) “biologics were expected to account for half of all pharmaceutical sales.”  Their prices are often quite high. If congress doesn’t modify the rules we can expect high priced biologics for a long time.

  1.  https://www.nytimes.com/2015/10/20/upshot/to-reduce-the-cost-of-drugs-look-to-europe.html)
  2. https://www.americanactionforum.org/research/primer-the-medicaid-drug-rebate-program/  https://www.americanactionforum.org/research/primer-the-medicaid-drug-rebate-program/ Tara O’Neill Hayes –Feb 7 2019).
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008392/
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008392/
  5. https://www.inquirer.com/philly/business/20101201_New_Merck_CEO_Kenneth_C__Frazier_has_Philadelphia_roots.html
  6. https://web.archive.org/web/20150407084544/http://en.sanofi.com/investors/corporate_governance/corporate_management/bio-brandicourt.aspx?
  7. https://www.affarsvarlden.se/bors-ekonominyheter/soriot-my-son-never-had-a-single-fist-fight-in-his-whole-life-and-i-had-so-many-6810336
  8. https://www.chicagotribune.com/business/ct-xpm-2011-10-20-ct-biz-1020-abbott-white-gonzalez-20111020-story.html
  9. https://www.medicaid.gov/medicaid/prescription-drugs/medicaid-drug-rebate-program/index.html

CSPAN:  PRESCRIPTION DRUG PRICING. https://www.c-span.org/video/?458198-1/lawmakers-press-pharma-ceos-rising-drug-prices