February 11, 2013

Impact, ethics of surgery slammed

The consent form allowing UC Davis doctors to open Terri Bradley's skull and infect her with bowel bacteria was hand-delivered on a single page with a 300-word warning.

Second of two parts

The consent form allowing UC Davis doctors to open Terri Bradley's skull and infect her with bowel bacteria was hand-delivered on a single page with a 300-word warning.

"There is no proof that such treatment (for brain cancer) might be beneficial," the form read, "nor are there animal data to support it."

The ensuing infection might cause further harm to the patient, the form stated, including "paralysis, inability to speak or understand speech, inability to swallow, vegetative state, coma or death."

Terri and her daughter Janet signed the form that day in November 2010 in what the family now describes as a desperate Hail Mary attempt to save the woman's life.

But at what cost? family members now ask.

"I felt really pressured to sign it," said Janet, 26, who believes the experimental procedure only prolonged her mother's misery.

"There was no quality of life. None."

Terri Bradley was one of three patients who consented to the untested treatments for their life-threatening brain tumors, or glioblastomas, in 2010 and 2011.

Two of the patients developed sepsis and died within weeks of their procedures. Terri lived nearly a year, though "chronic meningitis" was found at autopsy, according to the pathology report.

Two UC Davis neurosurgeons, Dr. J. Paul Muizelaar and Dr. Rudolph J. Schrot, have been accused by the university and by federal investigators of violating numerous hospital policies and government regulations.

But questions about the cases go beyond the realm of hospital manuals and federal codes. In letters to the editor, in blogs, on message boards and radio talk shows, the doctors' actions – and the decisions by the three patients and their families – have stirred emotional debate.

Why, some ask, is the government so restrictive? Why shouldn't dying patients have easy access to untested drugs and procedures? If things go wrong, how can anyone at death's door legitimately complain? Why punish the doctors?

Others, including some of the nation's foremost bioethicists, contend that vulnerable patients desperate for a cure must be protected from flimsy experiments that offer little hope – and may actually cause harm.

How, they ask, can we forget the damage done by the Tuskegee experiment between 1932 and 1972, in which African American men with syphilis were intentionally left untreated by the government to test the disease's long-term effects? Or what of more contemporary scandals at Johns Hopkins University or the University of Pennsylvania, where volunteers died during poorly run research studies?

Without strict oversight, they ask, who will protect society's most fragile and desperate patients?

Today, more than a year after their mother's death, the Bradley daughters find their own questions spinning into focus.

"When you're dying, you'll pretty much do anything," said Regina Bradley, 28, a mother of two. "I don't want any other family to deal with what we had to go through."

Patient 2 is infected

Terri Bradley's surgery was scheduled for Nov. 19, 2010. It was a cool, overcast Friday, six days before Thanksgiving, and daughter Janet had checked her mom into the hospital the night before.

Terri, a single mother with four grown daughters and seven grandchildren, would turn 57 in four more days. The family had booked a trip that month to Hawaii, grandbabies and all, but Terri's severe reaction to chemo and radiation – and now this new scheduled surgery – had pre-empted those plans.

Here she was instead, at UC Davis Medical Center, preparing to undergo an unusual procedure her neurosurgeons were calling "probiotic intracranial therapy."

The procedure had been tried once before on a 56-year-old Reno man. Patient No. 1, as he came to be known, had been clinging to life for five weeks after allowing doctors on Oct. 15 to intentionally introduce bacteria into the tumor cavity.

Janet was aware of the other patient but said she knew nothing about any "bowel bacteria" being used in her mom. The consent form she and her mother signed describes the physicians' intent to use "live gram negative bacteria."

The bacteria they used, Enterobacter aerogenes, commonly found in the bowel, was not approved for use in humans in this fashion, investigators later determined.

The U.S. Food and Drug Administration had ordered the surgeons in 2008 to conduct rigorous animal studies before contemplating the bacteria's use in live patients. Muizelaar and Schrot had acquired the bacteria from a Virginia lab in 2009 for their proposed study involving lab rats.

Now, in November 2010, Muizelaar made a note in Terri's operation record of the plan to open her old surgical site, remove the tumor and place this same bacteria into the tumor bed and bone flap.

Janet had planted herself that morning in a fourth-floor waiting room but was too nervous to read, scooting outside intermittently to smoke.

"I was terrified," she said. "I kept wondering, 'Is Mom going to come out of this alive? Is she going to be in a coma? Will she be a vegetable?' These were all the things they had told us. "

The surgery began at 11:34 a.m., medical records show, and was completed by 2:18 p.m. The operating room nurses would later tell investigators they knew nothing about the procedure and did not know that live bacteria had come into the O.R.

The operating room record, electronically signed a day later by Muizelaar, described the placement of a small piece of Gelfilm, soaked in Enterobacter solution, inside the woman's tumor bed.

" (A)nd on purpose we did not rinse the bone flap, hoping for a chronic infection."

Terri Bradley was now officially Patient No. 2. Unbeknownst to her family, Patient No. 1 would die at the hospital three days later after going into septic shock.

A life prolonged

Terri Bradley was destined to become the surgeons' so-called success story – the one patient who lived nearly a full year after having her brain infected with bowel bacteria.

In university documents and medical records, she is held up as the one patient who had a "positive response" and "improved," showing signs before her death of tumor regression. A report on her autopsy, conducted at UC Davis, noted that she "had improved with regards to daily functioning" after the wound-infection surgery, but still required skilled-nursing care.

University officials, responding to a critical report from federal regulators about the procedures, pointed out that "Patient 2's life was prolonged as a result of the innovative care."

Terri's daughters remember things differently, describing how their mother's quality of life ended after she consented to "probiotic therapy."

"It didn't really do any good," said Janet. " Regardless of what anyone may think – yeah, she lived 18 months. But that was 18 months of hell."

After the infection surgery, medical records show, Terri became increasingly depressed, apathetic and moody. She wouldn't eat. Medical staff and her daughters noted a worsening of expressive aphasia, an inability to speak or communicate.

In the months following the controversial treatment, Terri required at least three more significant surgeries at UC Davis. In April 2011, she underwent an operation to relieve hydrocephalus, or a buildup of fluid inside her skull. Gamma knife radiosurgery followed in July for a recurrent tumor identified away from the primary site.

The procedures were taking a serious toll, her daughters say.

For a while, she could answer questions with a simple thumbs-up, thumbs-down, but that didn't last. Where once she allowed Janet to hold her hand or tweeze her eyebrows, she now began to reject her daughter's touch.

She ultimately seemed a vacant shell, housed in a nursing home and oblivious to visitors.

"She was gone," Janet said. "She was Mom, but she had no idea who I was. She would look right past me.

"I was a ghost to her. I wasn't her girl anymore."

Christina, the youngest daughter, recalled how her mother "would look off into space" in those final months.

"I don't know if I'll ever get the answer to this, but my real question is, 'Was she in pain at the end?' I just want to know. "

The family's ordeal culminated with yet another operation in October 2011 to clean out Terri's infected head wound and administer antibiotics, which had been withheld to promote infection.

Janet remembered how the oozing, quarter-sized hole in her mom's skull had failed to close, creating a sickening odor.

Muizelaar took note of his patient's decline but seemed pleased overall with the wound-infection results.

"Her life expectancy was basically only two months when we started treating her," Muizelaar told The Bee last July. "For a good part of the 1 1/2 years, she was in pretty good condition.

"But later she started to deteriorate, and unfortunately also, her wound started to smell bad, so that was one of the reasons we started to treat her infection."

Some of the symptoms described by Terri's daughters are typical of end-stage disease. One 2009 study of patients with high-grade gliomas found that the majority experienced loss of consciousness and difficulty swallowing, often shortly before death.

Many patients also suffered seizures, along with progressive neurological deficits, incontinence and headaches.

But federal regulators, who recently examined all three cases, put much of the responsibility for Terri's deteriorating condition on the doctors and their novel treatment.

"Patient 2 experienced worsening of her abilities to move and speak, which required placement in a nursing home," according to the report released in November by the Centers for Medicare and Medicaid Services. "Over the coming year, increased pressure in the brain and chronic drainage from a wound infection of the original surgical site required additional surgical interventions.

"Patient 2 did not experience significant functional benefit," investigators concluded, "and upon her death recurrences of the tumors and chronic infection of the brain were identified."

Ethics debated

Amid the controversy, no one seems to dispute that all three patients and their families agreed to the experimental treatments. All of them signed consent forms, according to the university.

"I think it's important indeed that all the patients themselves, plus their families, gave their consent," Muizelaar told The Bee. "We made it totally clear to them that this had never happened before."

All were "of sound mind," he said, and their disease did not affect their judgment.

Schrot told The Bee in an email last year that all three patients "requested the treatment after an exhaustive informed consent process. "

Rabecca Rich, the Reno widow of Patient No. 1, could not be reached for this story. But in a letter published last month in The Bee, she said that she is grateful to the UC Davis doctors.

"There were no choices left except hospice and a slow deplorable end of life," she wrote. "My husband was a vibrant, loving and extremely intelligent man who lived life to the fullest and went into this surgery with full knowledge that he might not survive, but potentially would be part of work that would in the future shed light and potential cure to a disease that currently has none.

"From a family's perspective, one who has firsthand experienced this disease, I can only say thank you to the staff at UC Davis, including Drs. Muizelaar and Rudolph J. Schrot."

Even so, several prominent bioethicists and patient advocates have expressed alarm over the three cases.

Dr. Michael Carome, an expert on the protection of human research subjects, said he regarded the patients' treatments as "highly experimental, untested, unproven and likely to be highly risky."

Carome, a physician and a former top official with the federal Office for Human Research Protections, said the neurosurgeons appeared to "take advantage of highly vulnerable patients who are easily susceptible to suggestions for things that might give them a glimmer of hope."

The UC Davis surgeons approached their patients with a theory in hand that they wanted to prove, Carome said, so "you're motivated to try to push people toward this."

Carome helped lead the federal government's investigation more than a decade ago into Duke University Medical Center, which temporarily lost its federal funding because of violations involving human research.

"To do something that has not been tested at all – for which you've been told you need to do rigorous animal studies first – is extraordinarily serious and unethical," said Carome, now deputy director of Public Citizen's Health Research Group, a nonprofit consumer organization with offices in Washington, D.C., and Austin, Texas.

Carome and others said the three families' cooperation, and the signing of the consent forms, do not exonerate the surgeons.

While consent forms are standard procedure for any hospital, the matter gets more complex where human research subjects are involved.

At UC Davis and other institutions, federal regulations require that any research involving human subjects be reviewed and monitored by an institutional review board, or IRB. UC Davis has three IRB committees charged with protecting the rights and welfare of humans involved in research studies.

The campuswide committees, which include members from the general public, have the authority to approve, modify or reject all research activities that fall within their jurisdictions. As part of their work, they are closely involved with the drafting and approval of consent forms.

Both doctors have defended their actions, saying they were providing "innovative treatment," not conducting research.

The university initially concluded in October 2011 that all three procedures were improper, and that the treatments of Terri Bradley and Patient No. 3 "constituted human subjects research without IRB review and approval."

The university since has revised its findings, saying that none of the surgical cases constituted "research," but that the second and third surgeries still lacked appropriate approvals. University officials recently adopted a new "innovative care" policy "to prevent similar unusual occurrences in the future."

Elizabeth Woeckner, who heads a nonprofit group to improve protections for human subjects in research, said a clean IRB process is critical. Getting a patient or family to sign a consent form does not necessarily grant an ethical green light, she said.

"Terminal patients don't have special rights to access experimentation," said Woeckner, founder and director of Citizens for Responsible Care and Research. "The regulations apply to all of us, and the reason they're there is to keep everyone safe.

"My heart goes out to these people, but that's the way it is."


Terri Lee Bradley died in a Citrus Heights nursing home at 4:05 p.m. on Nov. 28, 2011. She was 58.

Daughter Regina had left the facility several hours earlier after a brief visit. Janet, who had accompanied her mom to every medical appointment and visited her daily, had just arrived in the parking lot when a staff member called with the news.

"I was a minute away ," she lamented.

But the doctors weren't finished.

As a dying wish, Terri had asked that her brain be donated to science. Janet notified Schrot, who was anxious to acquire Terri's body as soon as possible, she said.

Terri's brain was examined that evening at UC Davis, her medical records show. The pathologist identified a Grade IV glioblastoma, while also noting a finding of "chronic meningitis."

Schrot shared the findings with Janet by phone. She has not spoken with the surgeons since.

After The Bee first wrote about the controversial procedure last July, federal regulators descended on the medical center, issuing a report that questioned the safety of all patients at the hospital.

Since then, the university has found itself both condemning and defending the surgeons' actions.

"While we agree that the surgeons did not obtain appropriate approvals , we also believe that all of these surgical cases were physician-driven efforts to prolong the patients' lives," the university told federal regulators in a written response to their critical report.

In November, Dr. Claire Pomeroy, dean of the UC Davis School of Medicine, announced her resignation. University officials also announced that Muizelaar would be taking a voluntary leave of absence from providing patient care, while a peer committee reviews four new malpractice claims involving the surgeon.

The doctors' rat study is ongoing, and Schrot said in an email that "the initial results looked promising."

The Bradleys are considering a lawsuit, but legal experts have advised that their mother's yearlong survival poses challenges.

Today, Janet says, she remains burdened by feelings of regret, guilt and a mental chorus of if-onlys.

"She was my world and my best friend," Janet said. " I didn't make her do the surgery, but she looked to me for advice."

Terri Bradley's death certificate was, as her daughter similarly described the surgical consent form, short and simple. Under cause of death, the physician filled out only one line: Brain cancer.

"I was terrified. I kept wondering, 'Is Mom going to come out of this alive? Is she going to be in a coma? Will she be a vegetable?'"

JANET BRADLEY, 26, daughter of Terri Lee Bradley, who provided family photographs below

"She was gone. She was Mom, but she had no idea who I was. She would look right past me. I was a ghost to her. I wasn't her girl anymore."


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