DETROIT—Sepsis severity can progress rapidly, leading to global tissue hypoxia, shock, organ failure, and death; frequently, this transition takes place before a patient can reach an intensive care unit (ICU). However, early administration of therapies formerly limited to the ICU can improve outcome. Using central venous oxygen saturation and pressure measured continuously via central venous cannulation to adjust cardiac preload, afterload, and contractility during the first six hours after presentation can significantly reduce mortality in patients with sepsis and septic shock.[1] This method of balancing systemic oxygen delivery and consumption can also improve subsequent oxygen delivery to tissues, pH, lactate, base deficit, and severity-of-illness scores.

Previous studies have demonstrated that hemodynamic optimization therapy initiated after ICU admission, when sepsis may be in advanced stages, fails to reliably improve outcome. This lack of efficacy may reflect irreversible organ damage due to early tissue hypoxia. In an effort to prevent such damage, Emmanuel Rivers, MD, MPH, and colleagues at Henry Ford Hospital attempted to diagnose and treat sepsis at much earlier stages.

“In our study, we took severely ill patients, of whom, with only standard treatment preceding ICU admission, 40% to 50% would be expected to die,” Dr. Rivers told PULMONARY REVIEWS. In their study, Dr. Rivers and collaborators went beyond standard emergency department (ED) enrollment therapy, which typically includes hemodynamic support and appropriate antibiotics.

They initiated additional measures to optimize cardiac preload, afterload, and contractility soon after patients presented to an ED with severe sepsis symptoms. “If you look at the criteria we use, it’s really no different than the Society of Critical Care Medicine and the American College of Chest Physicians consensus [treatment] recommendations, but what we decided to do is institute the measures as soon as patients come in. It’s not novel, it’s just more aggressive,” Dr. Rivers, an Assistant Professor of Emergency Medicine at Case Western Reserve University in Detroit, said of the early goal-directed therapy. “Mainly, the key is to look at three things: volume, pressure, and oxygen delivery (via central venous oxygen), which includes arterial oxygen saturation, hemoglobin and cardiac output.”

Dr. Rivers and colleagues randomized 263 patients presenting to an ED with sepsis or septic shock to receive either standard enrollment care or early goal-directed therapy. All patients received central venous and arterial catheters, and specimens were cultured to guide antimicrobial therapy. In early therapy patients, treatment was initiated at the same time as in patients receiving standard enrollment care, but, he noted, “the early group got more fluids, red cell transfusions, and inotropes in the first six hours.”

In patients receiving early therapy, central venous oxygen saturation (ScvO2) and pressure were monitored. Every half hour, a 500-mL bolus of crystalloid was administered until a central venous pressure (CVP) of 8 to 12 mm Hg was achieved. Using vasopressors and/or vasodilators, mean arterial pressure (MAP) was maintained between 65 and 90 mm Hg. If ScvO2 fell below 70%, the patient was given red blood cell transfusions to achieve a hematocrit of at least 30%. If ScvO2 remained below 70% after these measures were instituted, dobutamine (2.5–20 µg/kg/min) was administered to bring ScvO2 to 70%.

In-hospital mortality was also significantly lower in the early therapy group (30.5‰ vs 46.5‰); mortality differences remained significant at 28 and 60 days. Dr. Rivers’ team noted that, on average, standard therapy patients who survived until discharge remained in the hospital significantly longer than did those receiving early therapy during the first six hours (mean stay, 18.4 days vs 14.6 days).

BENEFITS OF EARLY DIAGNOSIS, INTERVENTION

After six hours, the 133 early therapy recipients had significantly higher CVP and MAP, Scvo2, and arterial pH than did the 130 patients receiving standard care. Patients given early therapy also had significantly lower lactate, base deficit, and severity-of-illness scores. Furthermore, most of these differences persisted during the 65 hours following the six-hour early therapy regimen, although early therapy CVPs declined slightly to overlap with values in the control group.

After six hours, the 133 early therapy recipients had significantly higher CVP and MAP, Scvo2, and arterial pH than did the 130 patients receiving standard care. Patients given early therapy also had significantly lower lactate, base deficit, and severity-of-illness scores. Furthermore, most of these differences persisted during the 65 hours following the six-hour early therapy regimen, although early therapy CVPs declined slightly to overlap with values in the control group.

ED CARE CHANGES WARRANTED

“It’s a paradigm shift for people to understand that early intervention is essential,” Dr. Rivers said. “Patients can die within a few hours of developing sepsis.”

Yet typical triage protocols may not allow early diagnosis of sepsis, which is necessary for early intervention and reducing mortality due to septic shock. “Traditionally, people in the ED look at vital signs. Vital signs are not very sensitive; they don’t tell you how well the heart is beating. Venous oxygen saturation is a better indicator,” he noted. Additionally, “current standards do not include measurement of lactate,” a key metabolic indicator of global tissue hypoxia that could be used to target patients for hemodynamic therapy, Dr. Rivers pointed out. “If patients’ lactate levels are greater than 4 mmol/L, we know they’re not going to do well without intervention.”

Understaffing may be an obstacle to instituting proactive sepsis therapy in the ED, according to Dr. Rivers. “People are in the ED up to 24 hours before ICU admission,” he pointed out. “The big thing is providing a higher level of care. There’s definitely a discrepancy: EDs in general are overcrowded,” with a typical patient:staff ratio of 4:1, versus 1:1 or 2:1 in the ICU, Dr. Rivers emphasized. And skills of individual emergency caregivers may come into play as well. “The ability to do even lactate levels is in the purview of every emergency room,” Dr. Rivers argued. “It comes down to whether you have the expertise in the ED or whether intensivists are immediately on hand to address the needs of these high-risk patients.”

SAVING LIVES—AND DOLLARS

The findings have important implications for allocation of hospital resources, Dr. Rivers emphasized, citing costs estimated for treating severe sepsis at Henry Ford: “When it comes to saying how this could impact on care, we did some hypothetical projections [assuming adoption of early care] as standard therapy in our institution. If we see 950 to 1,000 severe sepsis cases a year at Ford, this translated to a decrease in bed use of 4,000 bed-days,” Dr. Rivers noted. The resulting “decrease of about $13,000 per patient translates to about $13 million per year for the hospital,” he added. Presenting this cost analysis to hospital administrators, “we were able to get 30 more nurses for our ED,” said Dr. Rivers. “Basically, six hours of good, up-front nursing care is worth $13,000 per patient.”

—Mimi Zucker, PhD

Reference
1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345: 1368-1377.

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