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Louisville Medicine, October 2004

The Outcomes Research Institute at the University of Louisville

Inexpensive, low-risk, and simple. These adjectives define the treatments that the Outcomes Research Institute evaluates. They may be simple, but they are hardly unimportant: repeatedly, the group has shown that small changes in management — often costing just a few dollars — markedly improve patient outcome.

Take body temperature, for example. Core body temperature is normally controlled to within a few tenths of a degree. But all anesthetics markedly impair thermoregulatory control. The result is that unwarmed surgical patients become hypothermic by 2-3°C. Outcomes Research investigators have shown that a reduction in core temperature of only 1.5 to 2°C increases blood loss by a full unit during hip-replacement surgery, thus increasing transfusion requirement. They have also show that hypothermia reduces drug metabolism which prolongs immediate postoperative recovery. And perhaps most importantly, the group proved that mild hypothermia triples the risk of surgical wound infection and prolongs the duration of hospitalization by 20% (Kurz, et al. 1996. New England Journal of Medicine).

Surgical wound infections are the most common serious complication of surgery and anesthesia; the overall incidence is 2-3%, but infection occur in 10-15% of certain operations. Infected patients stay in the hospital an average of one week longer than uninfected patients, are twice as likely to require intensive care, and are twice as likely to die. The typical cost of treating surgical wound infections is $50,000 per patient. In contrast, maintaining normothermia only costs about $10 per patient and is virtually risk-free. Nearly all surgical patients are therefore kept warm with forced-air heating, a system that was validated and popularized by Outcomes Research.

The primary defense against surgical pathogens is oxidative killing by neutrophils. Oxygen is the substrate for this reaction, and the amount of killing is related to tissue oxygen partial pressure over the entire physiological range. One reason hypothermia promotes infections is that it triggers thermoregulatory vasoconstriction which, in turn, reduces tissue oxygenation.

Amongst the most important determinants of tissue oxygenation is inspired oxygen concentration. For example, tissue oxygenation is doubled when patients breath 80% oxygen rather than the more typical 30%. Based on this observation, Outcomes Research investigators demonstrated that supplemental oxygen halves the risk of surgical wound infection (Greif, et al. 2000. New England Journal of Medicine). It is important to note that the risk reduction resulting from supplemental oxygen is in addition to the reduction that results from maintaining normothermia. The two treatments together, thus reduce the risk of surgical wound infection by more than a factor of five. Supplemental oxygen is an attractive treatment because it is safe and costs only three cents per patient.

Another common complication of anesthesia and surgery is nausea and vomiting. One third of untreated patients suffer nausea and vomiting after surgery. Many patients consider it to be worse than surgical pain, and nausea and vomiting is the leading cause of unexpected hospital admission after planned day surgery. Vomiting also increases the risk of serious complications including aspiration and has been associated with suture dehiscence, esophageal rupture, and bilateral pneumothoraces. The cost of treating postoperative nausea and vomiting, just in the United States, is several hundred million dollars per year. Costs are high because many of the drugs used for prophylaxis and treatment of nausea and vomiting are expensive.

Until the definitive study was published by the Outcomes Research Institute, clinicians had little basis for determining which patients required treatment, how many interventions should be used in a particular patient, and which were best. This prospective, randomized study of 5,200 patients not only directly compared six prophylactic interventions, but evaluated the efficacy of all combinations of two and three treatments (Apfel, et al. 2004. New England Journal of Medicine). Ondansetron, dexamethasone, droperidol, and total intravenous anesthesia each reduced PONV risk by about 26%. Complications were rare and there were no important differences among the treatments. All interventions acted independently from each other and from the patients’ baseline risk.

Since each antiemetic intervention similarly reduced relative risk and acted independently, it is apparent that the least expensive or safest intervention(s) should be used first. Dexamethasone and droperidol, for example, cost only a dollar or two per dose whereas ondansetron is ten times more expensive. Antiemetic prophylaxis is rarely warranted in patients with a low baseline risk; patients at moderate risk will benefit from a single intervention; multiple interventions should be reserved for patients at high risk or in whom PONV is especially dangerous.

Twenty investigators work at the Institute’s headquarters at the University of Louisville. Thirty-five others are scattered in ten countries. The largest site outside Louisville is the University Bern where the Institute’s associate director, Professor Andrea Kurz, is chair of Anesthesiology. All together, the non-profit institute conducts more than 60 studies at any given time and publishes about 30 full research papers each year — for a total that now exceeds 300 full papers. This makes the Outcomes Research Institute (www.or.org) one of the world’s most prolific perioperative research groups.

While the treatments that the Outcomes Research Institute studies are inexpensive, their studies are not. Coordinating tightly-controlled multi-center trials with hundreds or thousands of patients is complicated and expensive. The Institute has recruited more than $7 million dollars in extra-mural funding, with more than half from the National Institutes of Health. Continued growth, though, will require additional funding. The Institute is thus conducting a concentrated fund-raising effort; the goal is establishment of several innovative endowed chairs, each of which will provide several years of non-clinical time (on a rotating basis) to junior investigators while they establish the credentials necessary to compete successfully for funding from the National Institutes of Health.

In summary, the focus of the Outcomes Research Institute is discovery and validation of inexpensive, low-risk, and simple treatments that markedly improve patient outcome. Treatments promulgated by the group include maintaining intraoperative normothermia, providing supplemental oxygen, and a rationale basis for selecting inexpensive anti-emetics tailored to individual patient needs.

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