Downplay Sepsis at Your Peril

Sepsis is something of the redheaded stepchild in infection control – many other types of infection get more attention and resources. Ventilator-associated pneumonia and central line infections may garner more interest, but sepsis needs attention, too — it is the rabid dog sneaking up behind you while you’re focused on the tarantula in front of you.

One organization tackling this insidious intruder is the Surviving Sepsis Campaign (SSC), which is the product of a consortium composed of the European Society of Intensive Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine. The campaign aims to improve the management, diagnosis and treatment of sepsis.

Sepsis Defined

“Sepsis is the body’s reaction to infection,” explains says Mitchell Levy, MD, professor of medicine at Brown University and director of the medical intensive care unit at Rhode Island Hospital. “For example, a person can injure an elbow and initially have a simple cut, which over a short time worsens and begins to swell, turns red, and occasionally becomes hot. This is similar to sepsis. The body gets an infection, perhaps a pneumonia or bronchitis, and slowly, the body tries to heal. Sometimes, the organs in the body react to infection and begin to fail. In other words, what may start as a simple cold or bronchitis can eventually lead to a patient’s becoming unconscious, with very low blood pressure (shock) and kidney failure.”

Race has a surprisingly strong effect on who contracts sepsis and who survives it. A new study shows that African-American patients are twice as susceptible to sepsis and are more likely to die compared to Caucasian patients. But Hispanics have a lower incidence of severe sepsis than Caucasians, and African-Americans die more frequently of severe sepsis than both Caucasians and Hispanics.

Researchers write, “The difference in incidence was evident by age 20 and continued throughout the adult lifespan. After accounting for differences in poverty and geography, black race remained independently associated with higher severe sepsis incidence.”

Lead authors Amber E. Barnato, MD, MPH, MS, of the Center for Research on Healthcare at the University of Pittsburgh, and Sherri L. Alexander, PhD, of Genentech offered their findings in the February 2008 issue of the American Journal of Respiratory and Critical Care Medicine.

Barnato and colleagues conducted a retrospective population-based analysis of race-specific incidence and ICU case fatality rates for hospital-based infection and severe sepsis in Florida, Massachusetts, New Jersey, New York, Virginia and Texas. Using demographic and socioeconomic data from the 2000 U.S. census and clinical data for hospitalized severe sepsis cases from the hospitals’ discharge data, they compared incidence of severe sepsis, ICU admission and ICU case fatality among races, controlling for age and gender. The total analysis included more than 71 million people.

“Blacks do indeed have a higher rate of severe sepsis — almost double that of whites,” wrote Barnato. “Some, but not all, of this increase was explained by blacks’ more frequent residence in ZIP codes with higher poverty rates, suggesting that social rather than biological determinants, such as health behavior and access to primary care, may contribute to this disparity,” Barnato continued. “In contrast, Hispanic ethnicity appeared protective, conditional on similar regional urbanicity and poverty.”

The investigators considered several possible explanations of the results, including racial variation in susceptibility to particular types of infections or organ dysfunction, and overall health at baseline. “However, the severe sepsis syndrome characteristics were not markedly different among the groups with respect to the site of infection, microbiologic etiology and both the number and type of organ dysfunction,” wrote Barnato. Furthermore, “the burden of chronic conditions among severe sepsis cases did not differ substantially across racial groups.”

The study could not rule out unmeasured underlying differences such as behavior, pharmaceutical use, healthcare resources and within-hospital variations in treatment by race that may have contributed to the differences in case fatality observed, nor could they dismiss the possibility of a biological basis for racial disparities in susceptibility and outcome of severe sepsis, which could have “potentially important implications for treating sepsis.”

Despite possible explanations for the racial disparities that could not be ruled out, Barnato points out that “the overall mortality disparity among blacks could be partially ameliorated by focused interventions to improve processes and outcomes of care at the hospitals that are disproportionately black.”

Consequences of Sepsis

Sepsis is expensive. Just how expensive was addressed in another new study which found that sepsis is one of the most costly adverse events in children’s hospitals, and the authors of the study say that their findings target sepsis as a key intervention for hospitals.

“Among the areas in which children’s hospitals can address quality improvement, it is important to set priorities. This study provides some guidance,” says study leader Samir S. Shah, MD, an infectious diseases specialist at the Children’s Hospital of Philadelphia.

According to the study, published in the June 2008 issue of Pediatrics, the researchers analyzed information from more than 430,000 discharges from 38 pediatric hospitals in the United States that participated in the Pediatric Health Information Systems database in 2006. They searched the database for 12 different adverse patient safety events, designated pediatric-specific quality indicators (PDIs) by the federal Agency for Healthcare Research and Quality (AHRQ). The adverse events included infections and other complications that occurred as unintended consequences of treatment and hospitalization.

The total number of adverse events was 6,656, or approximately 1.5 percent of the sample. Overall, the most frequent adverse events in hospitalized children were infection due to medical care, respiratory failure following surgery and postoperative sepsis (an infection in the bloodstream).

The excess length of hospital stay from PDI events ranged from 2.8 days for accidental puncture and laceration to 23.5 days for postoperative sepsis. Excess overall charges ranged from $34,884 for accidental puncture and laceration to $337,226 for in-hospital mortality after pediatric heart surgery. Among excess charges, the largest were for laboratory, room and nursing charges. The researchers adjusted charges to reflect geographical differences in prices and wages.

“Our findings may help guide physicians and hospital administrators toward changes in practices where even modest improvements could have a high impact in patient safety and in more efficient, less costly healthcare,” says Shah. “For instance, focusing quality improvement efforts on reducing postoperative sepsis and infection due to medical care could create large cost savings and reduction in length of hospitalization. Additional studies should focus on determining specific safety measures and practices that pediatric hospitals can implement in the most appropriate areas.”

Shah adds that such quality improvement programs are all the more important in light of a recent decision by the Centers for Medicare and Medicaid Services (CMS) to begin denying payments to hospitals for patients who develop preventable complications during hospitalization.

Innovative Solutions and Global Campaigns

Sepsis is beginning to garner a lot of attention, says Levy. “The Surviving Sepsis Campaign, a global initiative for reducing mortality in sepsis, is associated with two ‘sepsis bundles’, similar to the approach used for prevention of ventilator-associated pneumonia (VAP). Several states (including Rhode Island and New Jersey) now have statewide initiatives targeted at reducing mortality in sepsis. The attention to sepsis is likely to increase as the results of these efforts are made public,” Levy adds.

The campaign is currently in 30 countries and 250 hospitals, with 18,000 patients in the SSC database, he continues. For more information about the management of sepsis, including the most recent 2008 Surviving Sepsis Campaign guidelines, visit the following site: http://www.survivingsepsis.org/

One study from Spanish researchers demonstrated the efficacy of the campaign; a national educational effort in Spain to promote appropriate care for severe sepsis and septic shock has shown an association with a lower rate of sepsis deaths in hospitals and improved guideline adherence, although the improvement in compliance with some resuscitation procedures diminished after one year, according to a study in the May 21, 2008, issue of JAMA.

“Sepsis is one of the most prevalent diseases and one of the main causes of death among hospitalized patients. Severe sepsis accounts for 1 in 5 admissions to intensive care units (ICUs) and is a leading cause of death in non-cardiac ICUs,” the authors write.

The Surviving Sepsis Campaign (SSC) guidelines were developed as part of a plan to reduce severe sepsis mortality. For improving sepsis care, the SSC and the Institute for Healthcare Improvement recommend implementing two bundles of guidelines, similar to the bundles that have been successfully implemented to fight VAP.

Ricard Ferrer, MD, of the Universidad Autónoma de Barcelona in Spain, and colleagues conducted a study to determine whether a national educational program based on the SSC guidelines could improve compliance with recommended processes of care in severe sepsis at 59 Spanish ICUs. All ICU patients were screened daily and enrolled if they fulfilled severe sepsis or septic shock criteria. A total of 854 patients were enrolled in the pre-intervention period, 1,465 patients during the post-intervention period, and 247 patients during the long-term follow-up period one year later.

The educational program consisted of training physicians and nursing staff from the emergency department, wards, and ICU in the definition, recognition, and treatment of severe sepsis and septic shock as outlined in the guidelines. Treatment was organized in two bundles: a resuscitation bundle (six tasks to begin immediately and be accomplished within six hours) and a management bundle (four tasks to be completed within 24 hours).

Patients in the post-intervention group had a statistically significant lower risk of hospital mortality (44.0 percent vs. 39.7 percent) and 28-day mortality (36.4 percent vs. 31.1 percent) compared with the pre-intervention group. Compliance with the process-of-care variables improved after the intervention in the sepsis resuscitation bundle (5.3 percent vs. 10.0 percent) and in the sepsis management bundle (10.9 percent vs. 15.7 percent). The percentage of patients in whom care complied with all resuscitation and all management measures improved significantly after the educational program. However, evidence from the one-year follow-up indicated that compliance with the resuscitation bundle returned to baseline, but that compliance with the management bundle and mortality remained stable with respect to the post-intervention period.

“The decreased mortality observed in our study and other studies might derive from better identification of patients with severe sepsis or from improved compliance with quality indicators, including earlier administration of antibiotics, or both,” the authors write.

Customized Treatments

Another innovative solution is customizing treatments for sepsis, utilizing a blood test and a decision algorithm, rather than standard hospital protocols, to determine the appropriate length of antibiotic therapy in patients with severe sepsis or septic shock. This procedure can reduce duration of treatments, shorten ICU stays, and lower hospital costs — all without adverse effects on patients, according to a press release about new research published in the March 1, 2008 issue of the American Journal of Respiratory and Clinical Care Medicine.

“We have shown that it is possible to customize antibiotic treatment duration in patients with septicemia based on a reliable and robust blood test,” says Jérôme Pugin, MD, of the intensive care unit at the University Hospital in Geneva, Switzerland.

The researchers randomized 79 patients to receive a treatment course of antibiotics either according to standard treatment protocols administered by the treating physicians, or according to the decision algorithm based on measured blood levels of procalcitonin (PCT), a marker for severe bacterial infection in patients with suspected sepsis. For patients randomized to the PCT-based treatment, there were predetermined “stopping rules” based on circulating PCT levels, at which point investigators encouraged treating physicians to discontinue antibiotic therapy, although the treating physician retained the ultimate decision-making power.

In the analysis that included all 79 patients, the median treatment time for the PCT group was 3.5 fewer days than that of the control group, although the difference was not significant. However, once the investigators controlled for early drop-outs, previously undiagnosed infections, and patients whose physicians declined to stop antibiotic treatment when the algorithm would have dictated it, they found that patients treated by the PCT algorithm had a significantly shorter treatment time at six days than patients treated according to standard protocols, who averaged 12.5 days on antibiotics.

“Our study is the first randomized clinical trial in which a surrogate biochemical parameter was used to reduce the duration of antibiotic therapy in a population of critically ill patients admitted to the ICU for severe sepsis and septic shock,” wrote Pugin. “Despite the relatively short duration of treatment in bacteremic patients assigned to the PCT group, no case of recurrence of infection was observed in these patients.”

And, according to the researchers, following the PCT algorithm had another benefit — patients randomized to the PCT treatment had significantly shorter stays in the ICU than control patients: an average of three days versus five.

Customizing treatment does more than simply save hospitals money and patients precious days in the ICU, Pugin says. Overuse of antibiotics can result in antibiotic resistance. “Given the diversity of the types of infections, bacterial strains and levels of host immune defense, every infected patient should benefit from a personalized treatment, and particularly, a personalized treatment duration,” he says.

The investigators express the hope that customized treatments will continue to improve care for sepsis patients around the world. “We have now implemented this new algorithm based on procalcitonin guidance in our ICU for patients presenting with severe sepsis and septic shock, and are following the outcome of those patients,” says Pugin. “Currently, three large multi-center trials are ongoing in France, Denmark and Germany, with a design similar to that of our study. Results from these studies will be important to determine whether such a protocol of procalcitonin guidance is definitely safe and can be generalized worldwide.”

Nutraceuticals’ Role in Sepsis Prevention

Even green tea has proven helpful, according to a new study by Haichao Wang, PhD, of the Feinstein Institute for Medical Research. Wang and his colleagues found that an ingredient in green tea rescued mice from lethal sepsis — findings that may lead to clinical trials in humans.

Wang had previously discovered a late mediator of sepsis called HMGB1, a substance expressed in the late stages of lethal sepsis. The researchers found a way to block this substance, which they felt would prevent the sepsis process from moving forward.

In the latest study, Wang’s group gave a substance in green tea called EGCG to mice with severe sepsis. The dose was equivalent to 10 cups in a human. Survival jumped from 53 percent in controls to 82 percent in those who received the green tea substance. “Clinically, even if we could save 5 percent of patients, that would be huge,” says Wang. “In this study, we saved 25 percent more animals with the green tea.”

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