Clinical Laboratory Strategies: June 9, 2011
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Evaluating BUN as a Risk Predictor in Acute Pancreatitis

Analyte Also Found Useful in Guiding Resuscitation Efforts
By Genna Rollins

Only a minority of acute pancreatitis (AP) cases result in serious illness, but those that do can cause significant complications, including death. Numerous biomarkers and clinical algorithms have been proposed to readily identify patients at highest risk, but for a variety of reasons have not proven particularly effective in routine clinical practice. Now, a consortium of researchers has reported using blood urea nitrogen (BUN) as a risk predictor in AP, and proposed and validated a BUN-based assessment algorithm, findings examined in this issue of Strategies.

Although most cases of AP are self-limited, about 20% cause severe, even life-threatening, illness. For decades, researchers have been on the hunt to find objective ways to accurately assess early AP, with the aim of enabling clinicians to instigate appropriate management, particularly aggressive fluid resuscitation in patients most likely to have worse outcomes. Numerous algorithms and biomarkers have been proposed, but algorithms such as the Acute Physiology and Chronic Health Enquiry (APACHE) II score tend to be complicated, involving multiple variables, and are not easily used in day-to-day clinical practice. Likewise, many proposed biomarkers aren’t readily available or don’t change significantly until the patient’s condition already has worsened.

A consortium of researchers at Brigham and Women’s Hospital in Boston, University Medical Center Utrecht in The Netherlands, and the University of Pittsburgh Medical Center (UPMC) recently investigated an objective approach to early clinical assessment of AP based on serial BUN measurements (Arch Intern Med 2011;171:669-76). The investigators also sought to develop an algorithm based on early BUN changes that would help guide clinicians in their early resuscitation efforts.

“Identifying more relevant prognostic indicators in the early course of acute pancreatitis has been a long-standing issue and area of research in the field,” explained lead author Bechien Wu, MD, MPH, an instructor of medicine at Harvard Medical School and associate physician at Brigham and Women’s Hospital. “Several candidate biomarkers have been proposed, including routine lab tests, as well as clinical scoring systems. We wanted to use tools that are readily available at the bedside to help guide doctors in tracking the progress of patients with acute pancreatitis.”

Wu also emphasized that early fluid resuscitation still is the mainstay treatment for AP, but that clinicians need better means to gauge the level of fluid resuscitation in individual patients. “There are dangers both to overly aggressive resuscitation as well as too little. That’s where having a marker for assessing response to those initial efforts can be useful,” he said. “It’s been long-held in animal models and retrospective studies that under-resuscitation may be a risk for necrosis and other complications, so that’s where another layer of granularity can help make sure patients are receiving the right amount of fluids.” Wu and his colleagues previously found serial BUN measurement to be more accurate than hematocrit as an early predictor of mortality in AP.

The researchers concurrently conducted three prospective cohort studies of AP using the same diagnostic criteria. While all three study centers evaluated the use of serial BUN measurements as part of an early AP clinical assessment, the investigators used data from Brigham and Women’s Hospital to develop a BUN-based assessment algorithm, and validated the algorithm with data from The Netherlands and UPMC studies.

Across all three centers, 1,043 AP patients were included in the final analysis. BUN levels were measured upon admission and after 24 hours. In a pooled analysis, the investigators found that patients with BUN levels ≥20 mg/dL had four times higher risk for mortality. Patients admitted with an elevated BUN level but in whom there was at least a 5 mg/dL decrease in BUN level after 24 hours were at significantly reduced risk of mortality. In addition, a rise in BUN level at 24 hours was associated with an odds ratio of 4.3 for death. Even a rise as small as 2 mg/dL was associated with increased mortality among patients who had normal BUN levels at admission. BUN levels proved to be as accurate as serum creatinine measurements or APACHE II score, with an area under the curve of 0.84 versus 0.79 for serum creatinine and 0.80 for APACHE II. The researchers speculate that BUN levels may reflect several physiological processes at work in the early stages of AP, including renal insufficiency, depleted intravascular volume status, and negative nitrogen balance.

This study reflects the progression of science in AP and has important clinical implications, according to Scott Tenner, MD, MPH, director of medical education and research for the gastroenterology division at Maimonides Medical Center in Brooklyn. “The findings go along with a lot of research that’s occurred over the last decade, when we’ve learned that hydration of patients with acute pancreatitis is the single most important factor in preventing morbidity and mortality. We’ve been using hematocrit but it has not been the most reliable predictor for a variety of reasons, so it makes sense that a better lab marker would be BUN,” he said. “It’s very important that this drives home the message of how important aggressive hydration is in the early course of acute pancreatitis. The study’s of great importance, and BUN should be used clinically to help manage patients with acute pancreatitis.” Tenner also is associate professor of medicine at the State University of New York - Health Sciences Center in Brooklyn.

Wu, Tenner, and Stuart Gordon, MD, all agreed that the findings are particularly important given the ease of obtaining BUN measurements. “BUN is readily available in any emergency department or lab, it’s relatively inexpensive, and it’s something that everybody understands,” noted Gordon, who is director of gastrointestinal endoscopy at Dartmouth-Hitchcock Medical Center and associate professor of medicine at Dartmouth Medical School in Hanover, NH. “A lot of these patients are seen in smaller, community emergency departments, so the simpler you can make it for busy clinicians, the better. You don’t want someone with potentially severe pancreatitis languishing in the hospital because it wasn’t apparent to the physician that the patient was at risk.”

“Our take home message is that there are ways we can optimize resources that are already available to enhance patient care,” added Wu. “It’s ironic that so much work has been done on biomarkers and other targeted measures of inflammation in acute pancreatitis, yet we can gain so much information from this routine lab test.”

Tenner suggested that labs consider adding an interpretative comment to BUN results. “It would be wonderful if labs informed clinicians that if a patient clinically appears to have acute pancreatitis and their BUN is 20 mg/dL or higher, based on current research, the clinician should consider aggressive hydration,” he said.

Based on this study, Wu and his colleagues have developed and are evaluating in a randomized trial a goal-directed protocol. The investigators hope that it will provide further guidance around fluid resuscitation efforts in acute pancreatitis.

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