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Vol. LXI, No. 18
September 4, 2009

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Good News from the CC Anesthesia Front

Dr. Zenaide Quezado Dr. Andrew Mannes

Grand Rounds recently featured reports from Drs. Zenaide Quezado (l) and Andrew Mannes.

There was actually good news about pain at the final Clinical Center Grand Rounds of the season on June 24 as two anesthesiologists from the department of anesthesia and surgical services (DASS) at the hospital presented studies.

In an 8-year study of the risk of sedation/anesthesia in pediatric patients at the CC, which involved more than 600 patients and about 1,500 administrations of anesthesia, there was not a single serious adverse event, reported Dr. Zenaide Quezado, chief of DASS.

“Believe me, when you’ve got a kid who has to spend 2 hours in an MRI machine, trying to be still, anesthesia is necessary,” she quipped.

In her half of the Grand Rounds hour, Quezado demonstrated that the safety of anesthesia, not just in the relatively delicate case of children but in all patients, is improving.

As recently as the 1980s, she reported, the mortality rate for anesthesia procedures was 2 in 10,000; the rate is now 1 in 100,000 to 200,000 according to the Institute of Medicine. “Safety has improved significantly,” she said.

Part of the improvement may be related to the use of standard monitoring and the development of safer anesthetic drugs. It is also important, Quezado said, to understand the staging of patients according to American Society of Anesthesiology (ASA) classifications, which rank patients for procedures from 1 (in good health) to 5 (burdened with an assortment of serious health issues) as it can be associated with complications during anesthesia. Most of the patients in her study (70 percent) had genetic disease, brain tumors or inborn errors of metabolism, and hence were ASA-3 (severe systemic disease with some functional deficit). Most were ages 2-8 and were being administered anesthesia in advance of MRI procedures.

A total of 98 events took place during the 1,500 procedures, involving 63 patients, about 12 percent of whom had airway abnormalities to begin with. “Most events were respiratory, followed by cardiovascular events, but none were serious,” she said.

Most events took place during induction of anesthesia, or what Quezado referred to as “when the plane takes off.” The higher the patient’s ASA classification, the more common the incidence of an event, she found. Other factors increasing risk were the duration of the procedure and the presence of an airway abnormality.

Age, she found, had a protective effect; the older kids tended to do better. And IV administration [the most common drug is propofol], versus inhalation, was also better tolerated.

The second 30 minutes offered hope to that percentage of us who may one day face the specter of severe, intractable cancer pain, which happens to be the research focus of Dr. Andrew Mannes, a DASS anesthesiologist since 2001.

Speaking on “Recent Innovations in Pain Management,” he briefly sketched three promising new approaches to anesthesia: resiniferatoxin (RTX), an Investigational New Drug on which Mannes is the principal investigator; substance P fusion protein, which blocks protein synthesis in cells that sense pain, leading to cell death; and herpes-mediated gene transfer, targeted to dorsal root ganglia, which transmit pain signals.

“Pain is the second most common reason for hospital admission, next to fever,” Mannes reported. “Sixty to 80 percent of advanced cancer patients have pain, and dying in pain is not uncommon. Around 1,500 people per day die of cancer—it’s the second most common cause of death.”

Most cancer patients in pain get effective relief from opioids such as morphine, but 5-15 percent don’t respond well, reporting constipation among other problems, Mannes said. Hence the need for new therapies.

RTX is derived from a succulent plant native to Morocco and is 1,000 times more potent than the hottest chili pepper (whose active ingredient is capsaicin). It doesn’t burn the tongue of cancer cells though, but acts to prop open calcium channels within cells that form pain-sensing fibers, inducing rapid cell death. It goes right to the cells that transmit pain and ablates them forever. “The response is lifelong,” said Mannes. “The cells are gone.”

Mannes showed trial data and videos demonstrating the remarkable effectiveness of RTX in animals such as dogs and Nubian goats. “We have shown efficacy in all species tried so far,” he said. His study is now recruiting patients for human trials.

The second approach, substance P, is an 11-amino acid protein that ablates pain-sensing neurons.

The third innovation, gene therapy, employs a nonreplicating herpes virus as a vector and is now in clinical trials, said Mannes. Injected cutaneously, it works in small regions, not systemically. “It’s not so good in coverage of the whole body,” he cautioned. This therapy has been in development for two decades, including 8 years of animal studies.

Noting that morphine has supplied reliable analgesia for more than 5,000 years, Mannes said the new innovations represent “an exciting time for pain treatments. We are expecting great progress in the next 5 to 10 years.”

In his view, RTX may hold the most promise of the three treatments for severe cancer pain he described but the relative efficacy and benefit of these novel therapies have to await completion of the clinical trials.. NIHRecord Icon

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