UB-Designed Ventilator Can Safely Sedate ICU Patients for Less

Device may also be a critical life-saving technology during pandemics

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A new, cost-effective ventilator invented by Bradley Fuhrman (shown) and Mark Dowhy promises to shorten patient stays in the intensive care unit (ICU) because it greatly reduces complications and habituation.

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Release Date: February 25, 2009

BUFFALO, N.Y. -- A new, recently licensed medical device developed by University at Buffalo researchers would introduce into intensive care settings the powerful and effective method of anesthetizing patients that works so well in the operating room.

The new UB ventilator has the potential to shorten the length of patient stays in the intensive care unit (ICU) because it will greatly reduce complications and habituation to sedatives used in the ICU. It also is expected to be more cost-effective than current methods of ventilating ICU patients.

The device also may have promising applications in treating large numbers of patients during pandemics or other events with mass casualties because it can safely enable multiple patients to share a single ventilator without the risk of cross-contamination.

The device is designed to cost effectively deliver to patients small amounts of powerful inhalation anesthetic agents as they breathe or are mechanically ventilated.

The portable patient ventilator was invented by Bradley Fuhrman, Ph.D., professor of pediatrics and anesthesiology and chief of critical care at Women & Children's Hospital of Buffalo, and Mark Dowhy, director of the Pediatric Critical Care Laboratory in the UB Department of Pediatrics; both are on staff in the UB School of Medicine and Biomedical Sciences.

The invention, which has been presented at numerous technology exhibitions, including the 2008 World's Best Technologies Showcase, was licensed from UB to Medical Conservation Devices (MCD) of Buffalo, located in UB's New York State Center of Excellence in Bioinformatics and Life Sciences.

Fuhrman and Dowhy are founding partners in MCD, and will receive the UB Entrepreneurial Spirit Award at the UB Inventors and Entrepreneurs Reception on March 5.

MCD is raising funds to further develop the prototype for FDA medical-device evaluation. Initial prototype devices have been validated in laboratory experiments. First Wave Technologies Inc. is a partial owner and manager of MCD. It is a technology-development company that partners with UB's Office of Science, Technology and Economic Outreach to expand the commercialization of early-stage university technologies utilizing private-sector resources.

A key advantage of inhaled anesthetics over intravenous sedation, which is the current approach in the ICU, is that inhaled anesthesia delivers and clears sedatives by way of the lungs, bypassing the metabolic and excretory systems. That's a critical factor, Fuhrman said, for patients who have sustained damage to their kidneys or livers, as a result of their illness.

When anesthesia is delivered through the lung, there is a much more rapid onset of effect and much quicker reversal once it is removed, an important consideration especially in patients who need to be frequently or abruptly awakened, such as children who have suffered trauma to the skull.

The invention addresses a problem common in ICU settings in which sedation must be deep enough that the patient is not aware of pain, but not so deep that it will cause withdrawal issues once the patient is no longer sedated.

"We administer significant amounts of narcotics and other agents to keep patients comfortable," explained Fuhrman. "But if we sedate them too well, we often face problems with withdrawal."

In those cases, patients can exhibit shakiness, combativeness and anxiety, symptoms that are then treated with methadone, usually requiring the patient to remain in the ICU for several more days.

By contrast, Fuhrman explained, patients in operating rooms are sedated using intravenous sedatives combined with precisely controlled concentrations of inhalation agents delivered by an expensive, specially designed anesthesia ventilator. An anesthesiologist or nurse anesthetist then monitors and controls a patient's vital signs and depth of anesthesia on a moment-by-moment basis.

"It's that kind of control that we are seeking to duplicate at each ICU bedside," said Fuhrman.

"With our ventilator, the patient is continually rebreathing the same anesthetic and oxygen mixture, so the amount of anesthetic that is used can be reduced by about 80 percent," he said.

The ventilator was developed with initial assistance from the UB Product Development Fund and the UB Center for Biomedical and Bioengineering Technology (CAT).

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. UB's more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.

Researchers Genetically Engineer Microorganisms into Tiny Factories

In work that could transform radically the ways in which many of these compounds are produced commercially, the UB researchers are genetically engineering microorganisms, such as E. coli, into tiny, cellular factories.

Several patents related to this work have been filed by UB. The team also is in discussions with companies in the U.S. and abroad.

First Wave Technologies, Inc., a technology development company based in UB's New York State Center of Excellence in Bioinformatics and Life Sciences, which is collaborating with the UB group, recently received a highly competitive Phase I Small Business Innovation Research (SBIR) grant from the National Science Foundation to focus on the biosynthesis of a popular group of flavonoids called isoflavonoids.

"Ultimately, we want to be able to take a designed E. coli off of the shelf and drop into it the enzymes that constitute a particular biosynthetic pathway in order to make exactly the product we want," said Mattheos A. G. Koffas, Ph.D., assistant professor of chemical and biological engineering in the School of Engineering and Applied Sciences and leader of the UB team.

The UB approach to synthetic chemistry addresses some of the major challenges in conventional industrial production of specialty chemicals.

Through the use of specially adapted bacteria, specialized enzymes and natural feedstocks, microbial biosynthesis reduces or eliminates the need for petrochemical sources, elevated temperatures, toxic heavy metal catalysts, extremes of acidity and dangerous solvents, Koffas said.

In addition, the natural enzymes the UB researchers are using can facilitate chemical reactions that are difficult to accomplish through conventional chemistry, such as chiral synthesis, glycosylations and targeted hydroxylations, common but challenging steps in many syntheses.

"We are finding out how we can actually 'train' microbial systems to produce high yields of chemicals to be used as pharmaceuticals and to make production processes more efficient, less expensive and more environmentally friendly," Koffas said.

As with any commercial endeavor, process efficiency is a critical concern, he noted.

In work published in Applied and Environmental Microbiology in June, Koffas and his colleagues produced about 400 milligrams of flavonoids per liter of cell culture, far above the next highest yield of about 20 milligrams per liter produced by other microbial synthesis efforts.

"We have done this by increasing the amount of precursor available and re-engineering the native microbial metabolism," he explained, adding that they have taken different approaches to identifying the pathways that lead to the biosynthesis of precursors for desired compounds.

"Further improvement of production yields are possible and various approaches are being pursued by our team at this time," he said.

Another major challenge for microbial biosynthesis is that the enzymes required for certain chemical steps have special requirements that the host cell cannot meet efficiently, Koffas said. In some cases, the enzyme needs to be re-engineered, while in others the host cell needs modification.

Koffas' lab recently achieved the functional expression in E. coli of P450 monooxygenases, enzymes that are used widely in nature, but are not readily expressed in most industrially important microorganisms.

"P450 is very important in the synthesis of natural products," said Koffas. "For example, both Taxol, the breast cancer drug that is currently produced from plant cultures, and artemisinin, the anti-malaria drug, have P450 enzymes in their biosynthetic pathways."

The Koffas lab has introduced ways to modify both the P450 monooxygenase enzymes and the host cell, thereby improving their yield of flavonoids.

Microbial biosynthesis methods also are making it easier to create analogs of existing drugs, as well as new molecules for a broad range of therapeutics.

The UB researchers are particularly interested in developing novel molecules that can be used to treat chronic diseases, such as type II diabetes and obesity.

They also are using the methods to produce specialty compounds, such as natural pigments, that could replace chemical dyes in food.

Koffas' goal is to employ these microbial synthesis methods for a wide variety of applications.

Flavonoids, which are of interest to pharmaceutical companies because of their antioxidant and anti-carcinogenic properties, are difficult to produce using currently available methods.

Microbial synthesis strategies also are being adapted by the UB researchers for the biosynthesis of other commercially significant classes of compounds, including vitamins, anti-cancer drugs, anti-parasitic drugs, dyes and food supplements.

The UB group is working on boosting yields further and hopes to achieve pilot scale production of flavonoids by the end of this year.

For further information on commercialization of this technology, please contact Mike Fowler, commercialization manager for bioinformatics and health sciences, in UB's Office of Science, Technology Transfer and Economic Outreach (STOR) at mlfowler@buffalo.edu.

For information on commercialization of SBIR-funded research on the biosynthesis of isoflavonoids, please contact Jack Daiss, technical director, First Wave Technologies at jack@firstwavetechnologies.com.

Koffas's research has received funding from the National Science Foundation, UB's New York State Center of Excellence in Bioinformatics and Life Sciences and the Independent Research and Development Fund of the UB Office of the Vice President of Research.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. UB's more than 27,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.