Differences in circulating biomarkers distinguished blunt trauma patients who improved over time from those who instead developed serial persistent infections and multiple organ failures in a single-center retrospective cohort study published online in Annals of Surgery.
The distinctly different patterns in biomarkers were already becoming apparent in blood samples taken at admission to the ICU, and they evolved over the first week of hospitalization. The patterns in patients who went on to develop infections and organ failures most likely reflect an excessive inflammatory response to injury, which caused further immune dysregulation and impairment of host physiological function that rendered patients susceptible to severe infection.
“We propose that a combination of traditional parameters of inflammation, such as white blood cell differential, combined with a novel subset of circulating biomarkers measured upon presentation and over the initial 24 hours, could be used to stratify ICU patients for either more or less intensive care and monitoring,” wrote the investigators. This would optimize both resource utilization and patient outcomes, wrote the investigators, led by Dr. Rami A. Namas of the department of surgery and Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh (Ann. Surg. 2014 Nov. 3).
They analyzed blood test results from 472 adults who survived severe blunt trauma and were admitted to the emergency department of a trauma center during an 8-year period. A total of 127 (27%) went on to develop persistent nosocomial infections – including 79 cases of pneumonia, 39 of urinary tract infections, 15 of bloodstream infections, 5 of wound infections, 2 of empyema, and 1 of Clostridium difficile infection – and organ failure. The study participants had undergone blood sampling via central venous or arterial catheters at least three times during the first 24 hours in the ICU, as well as at frequent intervals for at least a week. Samples were tested for the levels of 26 inflammatory biomarkers.
The investigators then performed a case-control analysis differentiating the blood test results between a subgroup of 44 patients who never developed nosocomial infections from 44 who had. They excluded patients who received blood transfusions or underwent emergency surgery within the first 24 hours, “to avoid the confounding impact of these interventions on the overall inflammatory response.” They also selected only patients whose trauma was caused by a motor vehicle accident, to avoid confounding factors related to the mechanism of injury. The two study groups were rigorously matched for patient age, patient sex, and Injury Severity Score.
Overall, injury severity was comparable between the two study groups. The severity of brain injury in particular, as reflected in Glasgow Coma Scores, was not significantly worse for patients who developed persistent infections. Both groups also showed a virtually identical pattern of elevation in the chemokines MIG/CXCL9, IL-8/CXCL8, and eotaxins, beginning at admission and continuing throughout the first week of ICU care. This suggests that these mediators are a component of a normal immune response to injury.
However, patients who developed persistent infections had “larger and more highly connected networks of systemic inflammation biomarkers” than did the other patients, suggesting that “mounting an adequately robust inflammatory response is essential for effective restoration of homeostasis after injury, [but] an overly exuberant and sustained immune response may be detrimental,” the investigators said.
At admission, the patients who later developed persistent infections had much higher levels than did the patients who recovered of the biomarkers IL-6, MCP-1/CCL2, HMGB1, and IL-1RA. “The early peak suggests that these mediators are produced in response to preexisting factors or variables associated with injury mechanism/pattern or prehospital management that are not revealed in our analysis. It is unclear, for example, if this pattern reflects the higher incidence of thoracic trauma in the [persistent infection] group,” Dr. Namas and his associates wrote.
After 12 hours, this pattern of biomarkers gave way to an increase in cytokines either produced by lymphoid cells or involved in the regulation of lymphocyte responses. This relatively early engagement of the lymphocyte response correlated with the development of multiple organ dysfunction beginning on day 2, which progressed over time in the infection group but rapidly resolved in the group that had an uncomplicated recovery. “We speculate that the gradual elevations of cytokines such as IL-1beta and TNF-alpha ... could reflect the response to microbes in the early phases of infection, though further studies are needed to test this hypothesis,” the researchers said. Compared with the patients who recovered, those who developed persistent infections also showed significant elevations in total leukocyte counts and polymorphonuclear neutrophils percentage, beginning at admission and continuing throughout the first week. They showed sustained lymphopenia from admission through 2 weeks of ICU care. This suggests that lymphocyte depletion “plays a detrimental role in the evolution of nosocomial sepsis-induced multiple organ failure after traumatic injury,” they noted.