Sepsis
A four-year-old boy with a fever and complaining of a "sore tummy" is brought into the emergency department. His condition is not considered serious and, after waiting a couple of hours without seeing a doctor, his mother takes him home. Twelve hours later he is back—with a ruptured appendix and bacteria in his belly. His appendix is removed, and he is transferred to the pediatric critical-care unit. Approximately eight hours later he suffers a cardiac arrest and dies.
Although this case happened in Alberta, healthcare professionals around the world deal with similar cases and ask the same question: What went wrong?
The culprit is sepsis—a life-threatening inflammation caused by the body's system-wide immune response to bacterial infection. It causes severe problems throughout the body, problems that can lead to failure of the lungs, kidneys, liver, and heart. Doctors don't know why one patient develops this response and another doesn't.
Only trauma kills more North American children than sepsis. In adults, sepsis is one of the top ten killers, affecting 18 million patients every year worldwide; specifically, 750,000 North Americans and 30,000 Canadians. Only 50% of adults survive one year after having sepsis, and only 60% of those survivors return to a normal lifestyle.
"Critical-care groups around the world have been looking at sepsis for decades—billions of dollars have been spent on research," says Dr. Christopher Doig, a critical-care physician at Calgary's Foothills Hospital. "And still we don't have many answers. People keep getting sick and dying. Mortality associated with sepsis has not improved in adults over the last 40 years. A group of us in Alberta became convinced we needed to take a different approach to sepsis research."
Enter the Alberta Sepsis Network, a team of 25 researchers from the universities of Calgary, Alberta, Lethbridge, and Toronto. The network includes both basic researchers—immune experts, microbiologists, and biochemists—and bedside physicians such as infectious-disease specialists and intensive-care doctors.
Rather than looking for a blockbuster drug to treat sepsis—the strategy that has been pursued for decades—the research team believes that understanding the complexity of sepsis will provide clues to more effective treatment. Sepsis can be caused by many different bacteria, and each of these can provoke a different immune response. This immune reaction causes inflammation throughout the body, which can lead to irreparable organ damage. The critical step, therefore, is to stop the inflammation as soon as possible: identify the infection early, and treat it quickly with the appropriate antibiotics, along with intravenous fluids and other therapies aimed at reducing inflammation and organ damage.
This is easier said than done, notes Dr. Doig. "Often it's not immediately obvious that a patient has an infection, because they don't have typical symptoms. And even when sepsis is diagnosed, we frequently don't know the actual cause. Is that right-side pain from a bacterium in the urinary tract or from pneumonia? To complicate matters, microbiological tests for bacteria often come back negative, even though we know there is infection somewhere. We need to look more closely at the immune response in septic patients."
The team plans to collect blood samples from children and adults with serious infections that lead to severe sepsis or septic shock (when the infection leads to life-threatening low blood pressure). The blood samples will be analyzed using the "new science" of metabolomics. It uses nuclear magnetic resonance (NMR) technology to rapidly identify metabolites (the waste products of chemical reactions in the cell). In this case, metabolomic analysis will look for the chemical fingerprints of the infection and the cell's immune response. All the information gained from metabolomic analysis will be placed in a province-wide database. Once enough data is collected, it should be possible to identify common features and patterns among groups of patients.
AHFMR Scientist Dr. Paul Kubes, a basic scientist who studies infection and inflammation, is convinced that this information will lead to better treatment of sepsis. "To date, clinical trials for sepsis drugs have been unsuccessful because, I believe, they are looking for a single drug for all septic patients. Think of cancer; we don't use one drug for all kinds of cancer. We want to use a similar approach to sepsis. The good news is that we don't need to find new drugs. I know from my laboratory work that there are already drugs that should work in certain types of patients. Our goal is to identify the main subgroups of patients. Then we can start clinical trials of drugs in specific subgroups of patients."
For Dr. Ari Joffe, a pediatric intensive-care unit (ICU) physician at the University of Alberta Hospital, one advantage of the database is that it will provide information on both adults and children. "With greater numbers and greater diversity in the patients we enrol, we increase our chances of finding differences among patients that may be associated with how well they respond to treatment. From my perspective in the ICU, one key outcome would be the ability to quickly identify patients who are likely to have severe sepsis, so we can start treatment early. I can't emphasize enough how important this is. In the case of the little boy with appendicitis, it could have been the difference between life and death."