In Vitro Versus In Vivo Culture Sensitivities: An Unchecked Assumption?

Vinay Prasad, MD*

Nancy Ho, MD^‡

*Medical Oncology Branch

National Cancer Institute

National Institutes of Health

Bethesda, Maryland.

vinayak.prasad@nih.gov

^‡Department of Medicine

University of Maryland 

Case Presentation

A patient presents to urgent care with the symptoms of a urinary tract infection (UTI). The urinalysis is consistent with infection, and the urine culture is sent to lab.  In the interim, a physician prescribes empiric treatment, and sends the patient home. Two days later, the culture is positive for E. coli, resistant to the drug prescribed (Ciprofloxacin, Minimum Inhibitory Concentration (MIC) 64 μg/ml), but attempts to contact the patient (by telephone) are not successful. The patient returns the call two weeks later to say that the infection resolved without sequelae.

Discussion

Many clinicians have the experience of treatment success in the setting of known antibiotic resistance, and, conversely, treatment failure in the setting of known sensitivity. Such anomalies and empiric research described here forces us to revisit assumptions about the relationship between in vivo and in vitro drug responses. 

When it comes to the utility of microbiology cultures, other writers have questioned cost effectiveness and yield (1). Though it is considered a quality measure by some groups in the United States, routine blood cultures seldom change antibiotic choice (3.6%) in patients who present to the emergency room with the clinical and radiographic signs of pneumonia (2)

The objection here is different, but fundamental. Even when culture sensitivities suggest we should change antibiotics, what empirical evidence is there that such changes are warranted? It is by no means a novel doubt. In 1963, at the dawn of in vitro sensitivity techniques, one group questioned their utility to predict clinical outcomes:

“Several objections may be raised…. First, local or host defense mechanisms may act in synergism or antagonism with the antibiotic.  Second, the concentration of antibiotic in tissue fluids, specifically blood, might bear no relation to the concentration at the site of infection…” (3)

And, while substantial pharmacologic progress has been made to ensure proper tissue concentrations, few empirical studies have sought to address the first concern (4). Recent examples suggest the relationship between in vitro and in vivo outcomes may be questionable.

One study of H. pylori tackled this issue (5). Macrolide and metronidazole resistance were determined in lab, and a urea breath test assessed clinical response. Interestingly, treatment with a clarithromycin regiment failed in 77% of persons with clarithromycin-resistant H. pylori compared with 13% of those with clarithromycin-susceptible isolates (relative risk, 6.2 [CI, 1.9 to 37.1]; P < 0.001).  While treatment with metronidazole-based therapy failed in 11% of those with metronidazole-resistant isolates and 38% of those with metronidazole-susceptible isolates (P > 0.25). 

These results suggest that metronidazole susceptibility wholly lacks clinical utility, while clarithromycin sensitivity may be useful. To fully prove the utility of clarithromycin sensitivity testing the authors should show a higher cure rate with a different regiment, and then demonstrate that upfront screening is preferable to empiric treatment and observation.  

Another study suggests that for some organisms and infections— Acanthamoeba keratitis—there exists no relationship at all between in vitro drug sensitivities and the in vivo response (6).

For some conditions, knowing that a causative organism is susceptible in vitro does in fact predict clinical response. For instance, a large study of gram-negative infections treated with cefotaxime found that as the MIC increased, from <4 μg/ml to 64 μg/ml (in vitro), the rate of clinical response fell from 91% to 50% (4). Thus, nearly all patients with susceptible organisms (low MIC) were successfully treated. But, perhaps, what is most interesting about this study is that even resistant organisms were effectively treated in 50% of patients. This finding is supported by work in urinary tract infections, which similarly found a high percentage of clinical response (>80%), even among patients whose causative organisms were resistant to prescribed agents (7).

Basic studies are required for bacteremia, pneumonia, urinary tract infections, endocarditis, and others. To do this work, we should not use our words interchangeably. Treatment failure must refer to an independent clinical outcome and not defined circularly as antibiotic resistance. As of today, faith that in vitro results predict in vivo outcomes remains an unchecked assumption whose treatment implications remain vast and reaching. 

References

1. Glerant JC, Hellmuth D, Schmit JL, Ducroix JP, Jounieaux V. Utility of blood cultures in community-acquired pneumonia requiring hospitalization: influence of antibiotic treatment before admission. Respir Med. 1999;93:208-12.
2. Kennedy M, Bates DW, Wright SB, Ruiz R, Wolfe RE, Shapiro NI. Do emergency department blood cultures change practice in patients with pneumonia? Ann Emerg Med. 2005;46:393-400.
3. Petersdorf RG, Plorde JJ. The usefulness of in vitro sensitivity tests in antibiotic therapy. Annu Rev Med. 1963;14:41-56.
4. Doern GV, Brecher SM. The Clinical Predictive Value (or Lack Thereof) of the Results of In Vitro Antimicrobial Susceptibility Tests. J Clin Microbiol. 2011;49:S11-S4.
5. McMahon BJ, Hennessy TW, Bensler JM, et al. The relationship among previous antimicrobial use, antimicrobial resistance, and treatment outcomes for Helicobacter pylori infections. Ann Intern Med. 2003;139:463-9.
6. Perez-Santonja JJ, Kilvington S, Hughes R, Tufail A, Matheson M, Dart JK. Persistently culture positive acanthamoeba keratitis: in vivo resistance and in vitro sensitivity. Ophthalmology. 2003;110:1593-600.
7. Alizadeh Taheri P, Navabi B, Shariat M. Neonatal urinary tract infection: clinical response to empirical therapy versus in vitro susceptibility at Bahrami Children's Hospital- Neonatal Ward: 2001-2010. Acta Med Iran. 2012;50:348-52.

Reference as: Prasad V, Ho N. In vitro versus in vivo culture sensitivities: an unchecked assumption? Southwest J Pulm Crit Care. 2013;6(3):125-7. PDF

Profiles in Medical Courage: Thomas Kummet and the Courage to Fight Bureaucracy

“You can’t fight city hall”-Unknown.

Abstract

Thomas Kummet was an oncologist wrongly accused in his mind of delivering substandard care. His fight for correcting what he believed to be a mistake illustrates the difficulty physicians face when challenging the current peer review system. In an attempt to defend his reputation he filed suit which was eventually dismissed by a Federal Court. His frustration over the futility of his fight is illustrative of the difficulties many physicians have faced in fighting a large bureaucracy and an unsympathetic justice system.

Introduction

Thomas Kummet (Figure 1) was an oncologist at the Phoenix Veterans Administration (VA) Medical Center.

Figure 1. Dr. Thomas Kummet

 He had been chief of oncology/hematology for nearly 20 years and was well-respected by his colleagues, staff and students. He was regarded as an excellent clinician. During his 20 years at the VA he no law suits or adverse actions. While attending on general medicine, the deaths of two patients launched a series of events leading Dr. Kummet to eventually file suit against the VA.

Case Presentations

Case 1

A 72 year old male patient was admitted to the surgical critical care (SICU) unit after being found comatose on the surgical ward.  He had undergone surgery for peripheral vascular disease 3 days earlier, but the resident physician failed to order monitoring of his warfarin therapy. At the time of the transfer, his prothrombin time was markedly elevated and a cat scan showed a large intracranial hemorrhage.  The surgery resident stated to the family that the diagnosis was disseminated intravascular coagulation as a complication of the surgery. Shortly after transfer to the SICU the patient expired.  The attending intensivist, a medical internist informed the family of the true cause of the bleeding which led to the patient’s death. The family sued, and received a settlement before trial.

In accordance with hospital policy, the chart was sent to the surgery service for review. The surgery service selected the intensivist as being responsible, who learned of that action only much later, when the state of Arizona began an investigation and placed the intensivist’s name on its public website as a physician guilty of malpractice.

Case 2

JV was a 67-year-old man who was admitted from dialysis clinic to the Internal Medicine Service in August 1999 with a history of non-insulin dependent diabetes mellitus, end stage renal disease with dialysis, hypertension, anemia of chronic disease, and chronic ulcerations of the feet.  He had developed progressive ascites for several weeks, and had been feeling weak and tired. JV was admitted with a systolic blood pressure of 87 mm Hg, a WBC count of 20,000 cells/mm³, and fever. A medical workup was begun to find the source of a possible sepsis syndrome. The vascular surgery service was consulted with regard to a wound on the patient's left arm which had been the result of an attempted placement for a dialysis access which had failed to mature.  The patient was evaluated and found to have a seroma which was subsequently drained without any complications.  During follow up, it was noted that the patient had a gangrenous left foot with non-reconstructible peripheral vascular disease. Subsequently a below the knee guillotine amputation was performed.

However, JV continued to have intermittent hypotension and fever. In addition to broad spectrum antibiotics he was receiving enoxaparin 30 mg daily as DVT prophylaxis.  On the first postoperative day the consulting intensivist recommended a thoracentesis of a left pleural effusion followed by a paracentesis to exclude these as a source of infection. The thoracentesis and paracentesis were performed without incident. Approximately 2 liters of clear ascitic fluid was removed from the right upper quadrant. About 2 hours after the procedure, the patient experienced the acute onset of abdominal pain, a sudden decrease in blood pressure, a rigid abdomen, apnea and a Code Arrest was called.  He was successfully resuscitated.  His hemoglobin was noted to have decreased from 11 to 7.9 gm/dl.

JV was taken emergently to the operating room where a damage control laparotomy was initiated and a massive hemoperitoneum was noted.  This was evacuated and a vessel on the right upper abdominal wall was identified and ligated. During the exploration it was noted that while the cirrhotic liver was unmarked, but the stomach had a 1 cm perforated ulcer in the anterior wall which was bleeding briskly. This was oversewn and then patched with omentum. During the resuscitation, he received seven units of red blood cells, seven units of fresh frozen plasma, and multiple infusions of crystalloids and colloid solutions in an attempt to maintain blood pressure. A Swan-Ganz pulmonary artery catheter was inserted and fluid resuscitation was guided by pulmonary artery catheter indices.  After adequate fluid resuscitation, he remained hypotensive with a low cardiac index and was supported with a combination of vasopressor agents and inotropes including super maximal doses of dobutamine, dopamine, phenylephrine and norepinephrine.  However, he remained hypotensive, and with the family at his bedside and after a detailed discussion, the family elected to cease support.  The patient died shortly afterwards.

Pertinent Laboratory

His creatinine was 3.2 mg/dL and his blood urea nitrogen was 37 mg/dL. Both his pleural fluid and ascitic fluid were exudative. Blood cultures and peritoneal cultures were all negative. His prothrombin time at the time of his paracentesis was slightly elevated at 13.8 seconds (upper limits of normal 13.3) but partial thromboplastin time and platelet count were within normal limits.

Hospital Course and Surgical Review

When the surgical team was contacted regarding the sudden drop in blood pressure and rigid abdomen, they accused the medicine team of “puncturing” the patient’s liver by the paracentesis with the family present. The family then confronted the resident and intern who performed the paracentesis for this “screw up”. Relevant is that this surgical team is the same that had recently been responsible for the events in case one.  

Since the patient expired on the surgical service, the chart in case 2 was again sent to the surgical service to assess attending responsibility. The medical attending at the time of the patient’s initial admission was selected as the responsible physician, again without any knowledge or input from that medical attending.

JV’s family had hired an attorney who hired a nephrologist in private practice from Tarzana, CA to review the case. The physician opined that the paracentesis should not have been performed because of an excess bleeding risk and the patient died as a result of the paracentesis. The physician did not mention the perforated gastric ulcer which was bleeding “briskly” at the time of the operation. A local peer review was conducted and concluded that bleeding was almost certainly from the perforated gastric ulcer and had nothing to do with the paracentesis.

The US Attorney’s Office obtained additional expert opinions from outside the VA who concluded there was no merit to the case and all applicable standards of care were met. Despite these reviews, the US Attorney’s Office settled the case for $250,000. The reason for the decision to settle the case remains unclear.

Local VA Actions

The attending physicians discussed of both cases with the Risk Manager at the Phoenix VA, who dismissed concerns by saying that the hospital needed to maintain its hard-to-recruit-and-retain surgery staff, but that the medical physicians who had been with the hospital for 20 years were less likely to leave.  In addition, the hospital risk manager assured the medical service physicians that the hospital would not report them to the National Practitioner Data Bank, as no one felt they were responsible for malpractice.

New VA regulations were in effect when Case 2 was settled.  Thomas Kummet was the internal medicine attending who was informed by the hospital of the matter for the first time when he was told he had ten days to respond to VA headquarters about the “malpractice” case, and according to the regulations he was entitled to supervised review of the chart and the settlement documents.  However, while he was allowed to see the chart, there were no documents to explain the lawsuit or the rationale for settlement. When the Risk Manager was asked for those documents, it was acknowledged that they would not be provided, no matter what VA regulations stated, as the US Attorney’s office refused to provide them to the hospital. Again Dr. Kummet was assured that the VA did not report physicians to the National Practitioner Data Bank in circumstances where there was no malpractice.

Three VA reviewers found no evidence of malpractice in the management of this patient. However, Dr. Kummet was informed he was being reported to the National Practitioner Data Bank and the State of Arizona as being responsible for a malpractice settlement.

Actions by the State of Arizona Board of Medical Examiners (BOMEX)

After being notified of the NPDB placement, the state BOMEX began their own investigation of Dr. Kummet, after first placing notification on their public website that he and the intensivist in Case 1 were responsible for malpractice.  This prompted patients to begin to ask for details of his “multiple” errors, to be referred to other physicians, and of why he was still allowed to practice. BOMEX asked Dr. Kummet for the medical records, which the local VA refused to provide, claiming Federal law precluded release.  When the state responded that Dr. Kummet’s (only) medical license was therefore at risk, Dr. Kummet hired legal representation.  With that assistance, the hospital sent a copy of the patient’s chart to the BOMEX. 

The state investigation was subsequently completed, no action was taken except to remove the notation on the website that a case was under investigation, and a request by the doctor for the documents of the state’s investigation was denied by BOMEX.

VA Headquarters Actions

The Veterans Administration had come under criticism in the early 2000’s because only 37% of physicians involved in a malpractice settlement were reported to the National Practioner Data Bank (NPDB). The VA initiated a peer review process and began reporting all practioners whose care was judged as substandard to the NPDB. This included some instances of previously settled claims such as Dr. Kummet’s. This new policy was designed to report all physicians because, as it was explained to the local Risk Manager, “it is good for the VA to show that we are tough on physicians.”

After the case was settled, it was referred to John Grippi MD from the Buffalo VA who was heading the VA’s peer review. He referred the case to a non-VA panel consisting of Edmond Gicewicz MD, a retired general surgeon; Norbert Kuberka MD, a retired oncologist; and Gregory Czajka PA, a surgical assistant. The panel concluded that “technical errors in the performance of abdominal paracentesis resulted in significant intra-abdominal hemorrhage”.

Dr. Kummet’s name was submitted to the National Practioner Data Bank, 10 days after he was first informed of the claim settlement and 4 years after the patient’s death.

Legal Action

Dr. Kummet obtained legal counsel and suit was filed in Federal court since the VA is a Federal agency. The suit failed, however, as there is no statutory or case law that required the local institution to follow its own procedures, or to allow physicians due process claims in these matters.

The legal proceedings were unsuccessful at obtaining any documents to support the decision to report to the NPDB, only to be told what was done was legal and in the VA’s best interest. The US Attorney’s office responded to a Freedom of Information Act request by supplying one nearly totally redacted document and claimed everything else was protected attorney work product (Figure 2).

Figure 2. Redacted letter from US Attorney’s Office.

Conclusion

Subsequently, Dr. Kummet left the VA system and is in private practice in Washington State. There are multiple instances where hospitals have retaliated against physicians for financial gain or for reporting substandard care (1). However, this does appear to be applicable in this case. If you, the reader, concludes from the case presentation that Dr. Kummet delivered substandard care, then he was justifiably punished.

On the other hand, if you agree the American Association for the Study of Liver Diseases that a abdominal paracentesis should be performed in patients with new-onset ascites (2) and that the patient’s intraperitoneal hemorrhage resulted from the perforated gastric ulcer rather than the paracentesis, then you likely agree with Dr. Kummet that he was falsely accused by the VA’s peer review system.

Dr. Kummel’s experience illustrates that physicians face a hospital peer review and justice system that fails to grant the basic rights to those accused of professional misconduct that it grants to those accused of criminal behavior. These include the right to a speedy and public trial by an impartial jury; to be informed of the nature and cause of the accusation; to be confronted with the witnesses against him; to have compulsory process for obtaining witnesses in his favor; and to have the assistance of counsel for his defense. Furthermore, the decision to settle the lawsuit that negatively impacted Dr. Kummet were made by attorneys without the background or knowledge to know if substandard care was delivered.

Regardless, Dr. Kummet should be admired for his courage in fighting what he views as unfair accusations by those more concerned with political perceptions than improvement in healthcare and a legal system unconcerned with slandering his reputation.

Richard A. Robbins, MD*

References

1. Kinney ED. Hospital peer review of physicians: does statutory immunity increase risk of unwarranted professional injury? MSU Journal of Medicine and Law 2009;57:57-89.
2. Runyon BL. Management of adult patients with ascites due to cirrhosis: An update. Hepatology 2009;49:2087–107.

*Dr. Thomas Kummet assisted in the preparation of this manuscript.

Reference as: Robbins RA. Profiles in medical courage: Thomas Kummet and the courage to fight burearcracy. Southwest J Pulm Crit Care. 2013;6(1):29-35. PDF

Profiles in Medical Courage: The Courage to Serve and Jamie Garcia

“I've seen and met angels wearing the disguise of ordinary people living ordinary lives.”-Tracy Chapman, American singer-songwriter

Abstract

Some of our Profiles in Medical Courage series have dealt with the famous, and several such as Barry Marshall and Archie Cochrane are household names in medical circles. However, some physicians, just as courageous, are not so renowned. Jamie Lynn Garcia was one of those who died earlier this year at the age of 52.  She was a devoted servant of the poor and founder of the Pomona Community Health Center. Her road to becoming a physician was not straight-forward but her life story was an extraordinary one.

Early Life

Jamie was raised in the Westchester section of Los Angeles, just north of the Los Angeles International Airport. She had a rather ordinary middle class upbringing in a Hispanic family where her father was a gardener and her mother a realtor. Her parents were strict Catholics and she attended the Catholic schools. She was a bright student but also had a beautiful singing voice that she was encouraged to develop. "As a child she had severe asthma," but there was a physician who helped her, "a doctor who was inspiring." (1). However, with adolescence her asthma improved but other issues were hard on Jamie. After reading the Bible at age 12, she rejected religion, and after passing a high school proficiency exam, left high school at 16 to become a professional musician.

Rock and Roll Years

Jamie used her voice and her instrumental talent on guitar, bass and keyboards in many of the bands in the Los Angeles during the1980’s while supplementing her income as a realtor (2). These bands followed her eclectic tastes and included country, jazz and pop but the most successful band was the all girl rock band “On the Air”. They had gigs throughout Los Angeles, aired videos on VH1, and garnered the attention of major record labels. However, the band collapsed when the lead singer decided to pursue an education. Several of Jamie’s friends, encouraged Jamie to do the same. Thinking that they might be right, she decided to go to college with no particular goal in mind.

Education

She enrolled at Santa Monica Community College and later transferred to UCLA where she majored in philosophy. During her later years in college she recalled her childhood doctor who treated her asthma. She thought, “I could do that”, and applied to medical school. She attended the University of Washington. There she meant her partner for the next 15 years, Dr. Sue Verrault, a child psychologist. After graduation, Jamie returned to the Los Angeles area for a family practice residency at Pomona Valley Hospital.

As a resident she was moved by what she saw as an enormous need for healthcare of low-income patients, especially those with chronic conditions such as heart disease, diabetes, and asthma. Dr. Jamie, as her patients came to call her, was a compassionate physician, but her faculty noted she spent too much time with patients, especially psychiatric patients. Fearless and confident, she occasionally liberated hospital supplies and took them to the streets to treat the homeless. During her last year in residency, she heard of a homeless man living under a nearby freeway bridge who was in dire need of medical care (2). She crawled under the bridge to find him, and convinced him to come with her back to the hospital. She enrolled him in a treatment program for alcoholics, after which he remained sober.

Pomona Community Health Center

At the time many of the ER’s and clinics were closing in East Los Angeles and she recognized that the inadequacy of the healthcare system to serve the healthcare needs of the poor. While still a resident Jamie partnered with the LA County Department of Public Health to operate the original Pomona Community Health Center, a two-room free clinic serving the homeless, uninsured, and underinsured in east LA County. After completing residency, she continued the clinic with the help of Federal grants (Figure 1).

Figure 1. Dr. Jamie Lynn Garcia (right) with patient at the Pomona Community Health Center.

The next 8 years were difficult. Money was tight but Jamie dreamed of a larger clinic and began the long process of planning the clinic’s expansion. She had no formal training or experience with such a large project, but assembled a board and staff, sketched out each exam room and calculated the cost of materials, planned budgets for doctors, created partnerships to secure a location, and raised over $1.4 million from Federal and other sources.  In 2010 she secured the crucial seed money to build the new clinic and proudly exclaimed on her Facebook page, "We're buildin' a free clinic! We have liftoff!"

Declining Health

Jamie had the fault of many physicians; she often ignored her own health. She had abdominal pain off and on beginning in 2005. When she finally had time to get an abdominal ultrasound in 2008, an ovarian mass was found but it appeared benign and Jamie was too busy to have it investigated. When she got around to a follow-up ultrasound 2 years later, the mass had doubled in size and she was diagnosed with an aggressive form of ovarian cancer. On May 16, 2011, while undergoing chemotherapy she oversaw the groundbreaking ceremony for the new clinic's building on Holt Avenue, in The Village, a "mall" of social services for low income LA residents. She was determined to beat the cancer and complete the new, expanded clinic and live to see it open. "I can't wait to meet the first patient," she told the Inland Valley Daily Bulletin at the groundbreaking (1).

She continued to run the clinic and oversee the construction of the new clinic despite her ongoing chemotherapy. The new clinic opened its doors on July 9, 2012 but three days earlier, Dr. Jamie was admitted to the hospital where she learned she had a large inoperable tumor.  She was advised to prepare for hospice care. On July 27 she died peacefully in her home but had lived to see the clinic open. She was 52.

Legacy

Dr. Garcia received numerous awards (2). She was named Woman of the Year in 2010 by the California State Assembly, a Hospital Hero in 2010 by the National Health Foundation, and her clinic has been recognized by the California State Assembly, National Project Homeless Connect, and the House of Ruth Domestic Violence Shelter. The evening before she died, several doctors from her clinic gathered at Jamie's home and agreed to hang her numerous recognitions on an otherwise-blank wall in the new clinic. "But I don't know, honestly, if there's room for all of them," noted one doctor.

The new 12-room clinic opened its doors on July 9, 2012, and is expected to serve 24,000 uninsured, homeless, and underinsured residents in the Pomona area this year (2). However, her most enduring legacy may be her example in serving the poor. She should be remembered for her enthusiasm, courage and perseverance in making her dream happen. She is representative of the many physicians and other healthcare providers who forgo larger financial awards to serve the poor in relative obscurity. Her life is testimony that "anything is possible" (2).

References

1. Rodriquez M. Garcia helped those who struggled. Inland Valley Daily Bulletin. August 10, 2012. Available at: http://www.dailybulletin.com/news/ci_21288514/garcia-helped-those-who-struggled (accessed 9-10-12).
2. Marks R. RIP Jamie Garcia, a health hero in Pomona, 2010 California Woman of the Year. Off Ramp. August 10, 2012. Available at: http://www.scpr.org/blogs/offramp/2012/08/10/9379/rip-jamie-garcia-health-hero-pomona-2010-californi/ (accessed 9-10-12).

Donations in Dr. Garcia's memory can be made to the Pomona Community Health Center: 1450 E Holt Avenue, Pomona, CA 91767.

Reference as: Robbins RA. Profiles in medical courage: the courage to serve and Jamie Garcia. Southwest J Pulm Crit Care 2012;5:231-4. PDF

Profiles in Medical Courage: Women’s Rights and Sima Samar

“A state that does not educate and train women is like a man who only trains his right arm.”

― Jostein Gaarder, Sophie's World

Richard A Robbins, MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Abstract

Previous profiles have focused on physicians who placed their careers in jeopardy to follow their beliefs. Sima Samar is different because she has not only risked her career, but her life.  She has shown extraordinary courage in ignoring death threats and defying religious misogynists to ensure that Afghan girls and women had access to health care and education. Following the fall of the Taliban in 2001, Dr. Samar became the first woman appointed to a cabinet position in the interim Afghan government. Ousted by religious conservatives, she serves today as the chair of the Afghan Independent Human Rights Commission.

Early Lessons

Samar was born on February 3, 1957 in Jaghori, a major business center situated in the highlands of central Afghanistan. Her father, Qadam Ali, was a civil servant and her mother, Khurshid, was the first of his two wives. She was one of eleven children and a member of Afghanistan's Hazara ethnic minority. The Hazara are a mountain tribe of Shiite Muslims who have been long oppressed by the Sunni majority.  

During Samar’s childhood, women could receive an education. Samar was sent to school and recalls first noticing ethnic tension in the second grade (1). She was mocked by her Sunni teacher for naming a Muslim holy man in the minority Hazara dialect.

Although Afghan women could vote and often held such prominent positions including judges or governmental ministers, they were still subject to a paternalistic society. Arranged marriages, encumbering restrictions, and husbands with multiple wives were common. "My brothers had more freedom than me in every way," Samar recalled to Alex Spillius of the London Daily Telegraph (2). "They could go where they wanted outside the house." Some of her memories were even more distressing. Her elder sister, Aziza, resisted an arranged marriage to a cousin. “Aziza was only 17 years old," Samar told Sally Armstrong (3). "I remember seeing my mother drag her by her hair to the room where our cousin waited and force her to marry him." Aziza died an unhappy woman at age 21, but before she did, she gave her little sister two words of advice- "Study hard".

Samar took her sister's guidance to heart and threw herself into her studies to avoid a similar fate. She became an avid reader, especially devouring Persian books about improving the lot of women and the poor. Her hard work was eventually recognized. Upon graduation from high school in 1975, she was offered scholarships to attend college in both Australia and Hungary. However, Samar's father forbade her to accept either scholarship to study abroad because unmarried women were not allowed to leave home. Even her acceptance at Kabul University was in jeopardy. To receive her father’s approval, she agreed to an arranged marriage to a man of her father’s choice to continue her education.

Kabul and Political Upheaval

Her father’s selection of a husband proved to be a good one. In 1975, at the age of 18, Samar married physics professor Abdul Chafoor Sultani. Luckily, Sultani was supportive of his wife's academic goals, and she genuinely admired him. The couple set off for Kabul University, and began a quiet existence where Sultani was a physics professor and Samar attended medical school. Together they did the cooking, the housework and raised their newborn son.

However, politics disrupted their quiet life. The late 70’s were a tumultuous time in Afghanistan. The People's Democratic Party of Afghanistan came to power through the Saur Revolution in 1978. Their rule proved highly unpopular not only within Afghanistan, but also the neighboring Soviet Union. The Soviet Union invaded and installed a puppet government in their place. Sultani and Samar joined the resistance movement fighting Afghanistan's Soviet rule, but the couple's political activism came at a high price. Late one night in 1979, Sutani and three of his brothers were kidnapped by 10 men. They were never seen again. "I still don't know the full who, what and when," Samar told Spillius (2). “Every Friday, we were in front of the big jail from early morning to late evening, hoping for news,” Samar said. “There was no news.”

Her husband's tragic disappearance left Samar alone with a young son and an unfinished education. Leaving her son in the care of her parents, Samar persevered and in 1982 became one of the first Hazara women to obtain a medical degree. After a 4 month residency at Wazir Akbar Khan Hospital, she fled Kabul, retrieved her son and settled in the rural area of Jorhi.  There were no hospitals, no medical facilities, no exam rooms, but there she provided medical treatment to patients throughout the remote areas of central Afghanistan. With only a stethoscope and a blood pressure cuff, she often traveled to see patients on foot or horseback, but gained a first hand knowledge of the hardships they faced. "Practicing medicine in a rural district demonstrated brutally that the lives of women were nearly unbearable," Samar told Armstrong (3), "and that the lack of education was a direct cause of the turmoil the country was in."

Pakistan

In 1984, Samar was stricken with whooping cough and her weight dropped dramatically (4). Unable to find medical care for herself, she traveled to Quetta, the Hazara region of Pakistan. “I went to Quetta for treatment,” she said “but then I realized I could get an education for my son there, and I would be able to get funds to help my work”. Once there, she began her life’s work in earnest. Only one hospital there accepted female patients. With initial funding from the NGO, Inter-Church Aid, she opened a hospital for women and children in 1987. Two years later, she founded the Shuhada (Afghan for martyr) organization, dedicated to women and children's needs (Figure 1). Rauf Akbeari, who would become Samar's second husband, helped oversee the organization's operations.

Figure 1. Panel A: Dr. Sima Samar seeing patients. Panel B: A Shuhada clinic at Kart-e-Sulh in central Afghanistan which serves a population of 9,000.

The Taliban

The Soviets withdrew from Afghanistan in 1992 and the United States that had backed the resistance withdrew as well.  Violence and guerilla warfare erupted in the power vacuum. The eventual victors were the Talban, a group of Islamic fundamentalists. Under the Talban’s reign, women lost most of their rights and freedoms. They were denied the right to equality, freedom, the vote, and the abilities to work or inherit. Even highly educated women were forced into slave labor or begging to survive.

Under the auspices of Shuhada, Samar started to open clinics and schools on both sides of the Afghanistan-Pakistan border. Always controversial, her pursuits were now beginning to attract the unwanted attention of the Taliban.  Not surprisingly, Samar's ongoing efforts at educating and uplifting the poor, especially females, were not looked upon favorably. Similarly, her adamant refusals to don the burqa (head to foot dress), observe purdah (seclusion of women from the public), or silence her calls for equality were not appreciated. Indeed, Samar was openly threatened with death if she did not close down her hospitals and schools for women and girls. According to journalist Sally Armstrong, she simply replied, "You know where I am, I won't stop what I'm doing."

True to her word, Samar ignored myriad death threats and fearlessly continued her work. She sometimes relied on trickery, such as operating schools in private homes or posting lower grade levels than were actually taught to circumvent the Taliban’s rules. At other times, she was more openly confrontational. One such instance was when she confronted a Taliban officer who had commandeered a truck loaded with supplies intended for one of her clinics. Coincidentally, the officer's mother had come to Samar for medical treatment around the same time. "It was construction materials . . . and about 6 metric tons of high-protein biscuits from Norway," Samar explained to Steve Lipsher in the Denver Post (5). "They took the whole thing. I told [the officer], "If you don't release my supplies, I'm going to take your mother hostage here in the clinic." The construction materials were returned the next day.

In addition to her social activism, she continued to serve as a physician. She was the first to recognize the increased prevalence of osteomalacia in women wearing burgas, probably due to lack of vitamin D produced by sunlight, .

After the Taliban

The September 11, 2001 terrorist attacks on the United States led to the US invasion of Afghanistan and the ousting of the Taliban. An interim government with Harmid Karzai as the interim president was put into place in December. Much to her surprise, Samar was appointed as one of five deputy prime ministers and the minister of women’s affairs in the new government, becoming the first Afghan woman ever to hold such a high position.

She returned to Afghanistan from Pakistan but her role as women's affairs minister soon presented its own set of challenges. "I knew that it would be difficult," she told journalist Steve Lipsher (5). "I didn't know that it would be this much difficult." She operated out of her own home, had no office, no supplies, no staff and no budget. Women lined up at her door, telling their tales of abuse, forced marriages, and lost jobs but Samar could do nothing.

To make matters worse, she was ignored in cabinet meetings.  Each time a male minister addressed the group, he opened with the phrase, “Brothers, brothers”. Even Karzai used the same phrase. “During the 23 years of war, there were no women in any decision-making, in any policy roles,” she said (6). “The political parties had no women. So they were not used to a woman’s face, a woman’s presence. We had to make a space for ourselves.” So Samar pulled Karzai aside and told him “Brothers, brothers” excluded her and she called for more female ministers in the government, schools for married women, and an end to arranged marriages. "After the meetings," she told Spillius (2), "people say I make too much noise, so I say: why did they appoint me? I am not confrontational . . . that doesn't work . . . but I have to say what I want for women."

She was no more patient with American politicians. She recounts a meeting with Secretary of State Colin Powell in Washington (7). She told Powell, “…please do not repeat the mistakes that you made before… You created these monsters [the Taliban]. Please don’t support them again.” She also chastised him for not being supportive of the Afghan government, spending money on war rather than rebuilding Afghanistan’s infrastructure and having too few US miliary women in Afghanistan. She was no more polite when Powell and Congressional delegations visited Afghanistan (Figure 2).

Figure 2. US Senator Chuck Hagel (left) meeting with President Hamid Karzai (center) and Dr. Sima Samar (right).

In response to her demands, conservatives waged a war of veiled threats and open menace. Matters came to a head in June of 2002 when she was accused of questioning Islam by saying she did not believe in Sharia law in Maujajed’s Message, a Canadian Persian language newspaper (1). Although she vehemently denied the allegation, conservatives ran a front-page headline in a local newspaper calling Samar "Afghanistan's Salman Rushdie," in reference to the Muslim author branded as a heretic by Iran's Ayatollah Ruhollah Khomeini in the 1980s. The damage was done. With little political support at home or the US, Afghan President Hamad Karzai did not appoint her to his permanent government in June, 2003. Certainly disappointed, but unapologetic, she told Kathy Gannon of the Scotsman (8), "I really don't know what my mistake was. I am a woman, I am outspoken, I am a Hazara. That is enough, I guess."

Although Samar's political career was brief, she seems hardly the kind of woman to remain silent. After leaving her cabinet post, she became chair of the Independent Afghanistan Human Rights Commission, and despite ongoing death threats, she continues to operate the Shuhada hospitals and schools and to speak on behalf of women's and human rights. By 2004, the Shuhada Organization operated four hospitals and 12 clinics in Afghanistan and Pakistan, along with 60 Afghan schools. Internationally recognized for her diligent efforts, she also received many accolades, including the 2003 inaugural Perdita Huston Human Rights Award and the 2004 John F. Kennedy Profile in Courage Award. It may be that Samar herself described best why her talents and determination might be best suited to a non-political arena when she told Gannon (8), "I believe we cannot change the country with only words. We have to change it with our minds, our hearts and our attitude."

However, her career in politics may not be over quite yet. In 2011 she was one of the founders of the Truth and Justice Party, a multi-ethnic party opposed to President Hamid Karzai’s regime.

References

1. Gale Encyclopedia of Biography: Sima Samar. Available at: http://www.answers.com/topic/sima-samar (accessed 8-24-12).
2. Spillus A. People say I make too much noise: Dr Sima Samar,Afghanistan's first minister for women's affairs, talks to Alex Spillius. The Daily Telegraph. February 22, 2002.
3. Armstrong S. Rebel unveiled. Chatelaine, April 1, 2002. Available at: http://business.highbeam.com/436992/article-1G1-83994864/rebel-unveiled (accessed 8-24-12).
4. Samar S. Despite the odds - providing reproductive health care to Afghan women. N Engl J Med 2004;351:1047-9.
5. Lipsher S. Women's advocate defies the odds Afghan official battles poverty, male culture. Denver Post, January 27, 2002. Available at: http://www.denverpost.com/archives (accessed 8-24-12).
6. Frey J. A Healing Force For Afghan Women; From Her Cabinet Post, Sima Samar Sees a Long, Hard Road Still Ahead. Washington Post, April 24,2002. Available at: http://www.highbeam.com/doc/1P2-351850.html (accessed 8-24-12).
7. Cott M, Whelan R. Interview with Dr Sima Samar. International Review of the Red Cross 2010;92:847-57. Available at: http://www.icrc.org/eng/assets/files/review/2010/irrc-880-interview.pdf (accessed 8-24-12).
8. Gannon K. She was the minister who fought for Afghan women. Now she is dumped. The Scotsman, June 25, 2002. Available at: http://www.highbeam.com/doc/1P2-12988802.html (accessed 8-24-12).

Reference as: Robbins RA. Profiles in medical courage: women's rights and Sima Samar. Southwest J Pulm Crit Care 2012;5:197-202. PDF

Profiles in Medical Courage: Causation and Austin Bradford Hill

“The secret language of statistics, so appealing in a fact-minded culture, is employed to sensationalize, inflate, confuse, and oversimplify”

-Darrel Huff in How to Lie with Statistics

Abstract

Austin Bradford Hill was a British epidemiologist and statistician who is best remembered for two landmark pulmonary studies. He was the statistician on the Medical Research Council Streptomycin in Tuberculosis Trial. This is regarded as the first randomized clinical trial. The second was the demonstration of the connection between cigarette smoking and lung cancer. However, Hill’s most lasting contribution may be his establishment of a group of conditions necessary to provide adequate evidence of a causal relationship between an incidence and a consequence, widely known as the Bradford Hill Criteria of Causation. In this profile of medical courage we examine his remarkable background that led to the epidemiological equivalent of Koch’s postulates.

Introduction

Recently, two articles have appeared in the Southwest Journal of Pulmonary and Critical Care which involved Sir Austin (Tony) Bradford Hill. The first was Dr. Raschke’s review of Doll and Bradford Hill’s landmark study on the etiology of lung cancer (1). The second was the prior profile in medical courage article on Archie Cochrane, Bradford Hill’s student (2). These prompted me to conduct a study of Bradford Hill and his remarkable career. Although both of his studies are important, his criteria for causation may be his greatest legacy (3). In a time when the unscrupulous utter half-truths to associate an incident with a consequence, Bradford Hill’s criteria for causation are as relevant today as they were when first published in 1965 (3).

Early Life

Austin Bradford Hill was born into an eminent British family in 1897. His great-great uncle, Sir Rowland Hill, invented the rotary press and introduced the first mail stamp 1840.  His father, Sir Leonard Hill, was professor of physiology at the University of London and did seminal work on the cerebral circulation and decompression sickness of divers.

From childhood, Tony, as he came to be called, wanted to be a doctor but the First World War intervened.  He volunteered as an aviator for the Royal Navy and was sent to the Greek islands to support the attack on the Dardanelles.  His plans were cut short when in November 1917 he was diagnosed with severe pulmonary tuberculosis and was sent home to die. The progress of the disease changed after a therapeutic pneumothorax and he slowly improved. While recovering he contemplated his career. Medicine seemed to be out of the question and he opted to study economics by correspondence courses from the University of London as he convalesced.  Three years later he obtained a Bachelor of Science degree– having attended the university only twice to take examinations.

Early Career

Tony had no desire to make a career in economics. His father’s friend, the prominent epidemiologist, Major Greenwood, helped him obtain a grant from the Medical Research Council (MRC) to investigate the reason for the high mortality of young adults in rural Essex. His investigations concluded that the excess was most likely due to selective migration of the fittest to work in urban areas. The success of his research enabled him to obtain further appointments with the MRC and extend his knowledge of statistics by attending courses at the University of London led by Karl Pearson. In 1927 he followed Major Greenwood to the newly-formed London School of Hygiene and Tropical Medicine and taught statistics to at the Postgraduate Medical School at Hammersmith in London (Figure 1).

Figure 1. Austin Bradford Hill lecturing.

His lectures were published as a series of 17 popular articles in the Lancet during 1937 and later in book form, Principles of Medical Statistics (4). The book became very popular and went through multiple editions making him the best known medical statistician in the world, which is remarkable for someone who held no degree in medicine or statistics. In this book he discussed epidemiological methods for investigating the causes of non-infectious diseases, and introduced randomization. He emphasized the need to compare like with like, to avoid potential sources of bias and to allow for the play of chance. However, he avoided the use of mathematical formulas and set out procedures that needed to be adopted in plain English. By so doing he secured the attention of a medical profession that largely had no basic knowledge of mathematics or statistics. The book was important in persuading physicians to present their research results both logically and quantitatively.

He wrote of his lectures, "I deliberately left out the words ‘randomisation’ and ‘random sampling numbers’ at that time, because I was trying to persuade doctors to come into controlled trials in the very simplest form and I might have scared them off. I think the concepts of ‘randomisation’ and ‘random sampling numbers’ are slightly odd to the layman, or for that matter, to the lay doctor, when it comes to statistics. I thought it would be better to get the doctors to walk first, before I tried to get them to run. So I had been thinking about controlled trials for all of those 10 years and hoping for an opportunity that might arise” (5).

Landmark Investigations

After the War, Bradford Hill succeeded Greenwood as Professor of Medical Statistics and directed the Statistical Research Unit of the Medical Research Council (MRC). He was particularly influenced by one of Pearson’s students, Ronald Aylmer Fisher, who had pioneered the use of randomization in agricultural experiments. Up until this time medical investigations were usually a before-and-after design, i.e., patients were treated and the results compared to historical controls. He realized that confounding variables so inherent in before-and-after studies could change results. Although Bradford Hill had advocated randomization in his book, he had not been specific about the methods.

In 1946 Bradford Hill was presented with the opportunity to put his theories into practice. He persuaded the MRC to launch randomized controlled trials, one in preventive medicine to test a pertussis (whooping cough) vaccine, the other in clinical medicine to assess the effect of streptomycin in the treatment of pulmonary tuberculosis (6). The latter is generally regarded as the first randomized medical trial with patients randomized to a treatment group and a control group by a process using random sampling numbers and sealed envelopes.  These trials were followed by a remarkable stream of articles on the principles of clinical trials including practical and ethical problems.

Meanwhile he launched, with Richard Doll, a case-control study comparing lung cancer patients with matched controls. This study showed conclusively that smoking was the predominant risk factor in developing lung cancer (7). This was followed by other case-control studies, and a long-term prospective study of smoking and health which demonstrated that lung cancer was not the only disease to be caused by smoking. This cohort study was conducted on British doctors, an ideal population whose cooperation was testimony to the respect with which Bradford Hill's work was regarded by his medical colleagues. He was by nature a cautious man, and he had been careful initially to claim that a causal effect of smoking on lung cancer was only one of a number of possible explanations for the association. As the evidence mounted he accepted the causal link as being overwhelmingly the most likely explanation. The reception was lukewarm and in particular he was disturbed by skeptical remarks from Ronald Fisher.  Interestingly, it was Fisher who had nominated Hill as a Fellow of the Royal Society in 1954.

In response to criticism, he formulated 9 principles of causation which were published in 1965 and are listed below (3). Although originally presented as a way of determining the causal link between cigarette smoking and lung cancer, Bradford Hill's Criteria forms the basis of modern epidemiological research. Furthermore these principles are equally applicable to other sciences which study causal relationships between phenomena. 

Bradford Hill’s Criteria for Causation

1. Strength. This is defined by the size of the association as measured by appropriate statistical tests. The stronger the association, the more likely it is that the relation of "A" to "B" is causal. For example, lung cancer death rates are 10-30 times higher in smokers than in nonsmokers.
2. Consistency. The association is consistent when results are replicated in studies in different settings using different methods. As an example, Bradford Hill points out that an association between lung cancer and smoking was found in 29 retrospective and 7 prospective studies in 1964.
3. Specificity. This is established when a single putative cause produces a specific effect. This is considered by some to be the weakest of all the criteria. Lung cancer attributed to cigarette smoking does not meet this criterion because the death rate of smokers is higher from other causes in addition to lung cancer. When specificity of an association is found, it provides additional support for a causal relationship. However, absence of specificity in no way negates a causal relationship.
4. Temporality. Exposure always precedes the outcome. If a factor is believed to cause a disease, then the factor must precede the occurrence of the disease. This is the only absolute criterion. In the case of lung cancer, cigarette smoking invariably occurs before the development of the cancer.
5. Biological gradient. By this Bradford Hill means a dose-response relationship. The death rate from lung cancer increases as the number of daily cigarettes smoked increases.
6. Plausibility. The association agrees with currently accepted understanding of pathological processes. In 1965, it was known that tobacco tar induced cancer when painted on the skin of mice (8).
7. Coherence. The association should be compatible with existing knowledge. Both the incidence of lung cancer and cigarette smoking rose beginning after World War I. In 1964 both the incidence of lung cancer and cigarette smoking were lower in women than in men.
8. Experiment. The condition can be prevented or ameliorated by an appropriate experimental regimen. The incidence of lung cancer can be lowered by quitting smoking.
9. Analogy. In judging whether a reported association is causal, it is necessary to determine the extent to which researchers have taken other possible explanations into account and have effectively ruled out such alternate explanations. For example, in their investigations Doll and Bradford Hill were careful to match lung cancer patients with controls to eliminate any potential bias related to exposure to occupational or environmental toxins. A questionnaire was designed to identify potential confounding variables including whether cigarette holders and petrol lighters were used, occupation, residence near a gasworks, exposure to different types of home heating, and previous respiratory illnesses and shown to be independently unrelated to lung cancer.

Bradford Hill pointed out that no formal tests of significance could answer the above questions. During his career, he used the simplest mathematical techniques. It is remarkable that as a statistician he relied so little on statistics and he often pointed out that he had no formal training in medicine or statistics. His success was due to a combination of factors but probably most importantly communication of honest experimental and statistical concepts in a way that nearly all could understand.

Hill died in 1991 a few months short of his 94^th birthday. Up until the time of his death he continued to collect a 100%, war-related, disability pension from the British Government. In hindsight, his development of tuberculosis may have been a fortuitous occurrence for medical investigation. Despite his disability, he did rather well and should be remembered for his courage in standing up for honest, unbiased research.

Richard A. Robbins, MD

References

1. Raschke RA. May 2012 critical care journal club. Southwest J Pulm Crit Care 2012;4:178-9.
2. Robbins RA. Profiles in medical courage: evidence-based medicine and Archie Cochrane. Southwest J Pulm Crit Care 2012;5:?-?.
3. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295-300.
4. Hill AB. Principles of Medical Statistics. London: Lancet, 1937.
5. Hill AB. Suspended judgement, memories of the British streptomycin trial, the first randomised clinical trial. Control Clin Trials 1990;1:77-79.
6. Medical Research Council. Streptomycin treatment of pulmonary tuberculosis: a report of the Streptomycin in Tuberculosis Trials Committee. British Medical Journal 1948;2:769-82.
7. Doll R and Hill AB.  A study of the aetiology of carcinoma of the lung.  Br Med J 1952;2:1271-86.
8. Croninger AB, Graham EA, Wynder EL. Experimental production of carcinoma with tobacco products. V. Carcinoma induction in mice with cigar, pipe, and all-tobacco cigarette tar. Cancer Res 1958;18:1263-71.

Reference as: Robbins RA. Profiles in medical courage: causation and Austin Bradford Hill. Southwest J Pulm Crit Care 2012;5:115-20. (Click here for PDF version)