Early and Proper Diagnosis of Sepsis—Still a Problem and Matter of Controversy

Abstract

The disappointing results of new adjunctive therapies for sepsis in large clinical studies prompted the late Roger Bone to suggest that “we should spend more time to achieve an accurate diagnosis and less time for searching a magic bullet” [1]. However, not only important for valid clinical investigation, accurate and early diagnosis of sepsis may also help improve patient outcome. Because of the importance of the subject matter, we asked experts in the ~eld to discuss some new aspects and recent ~ndings that might be helpful in improving the diagnosis of sepsis. Sepsis is nowadays de~ned as a systemic response to severe infections [2]. Sepsis is diagnosed when clinical evidence of infection is accompanied by signs of systemic in_ammation. These statements have been translated to a set of clinical and laboratory criteria for the diagnosis of sepsis. For clinical purposes, the diagnostic criteria of sepsis should identify patients at an early stage of the syndrome, prompting clinicians to search for and treat infection, apply appropriate supportive therapy, and monitor for organ failure and other complications. For study purposes, the diagnostic criteria of sepsis should identify patients who would potentially bene~t from new (immunomodulatory) therapeutic approaches. Multicenter immunomodulatory trials of sepsis conducted 10 years ago started using uniform clinical diagnostic criteria for identifying septic patients [3]. These studies helped de~ne what sepsis means when certain clinical and laboratory criteria are used. Based on the characteristics of the patients included in these trials, Roger Bone published important clinical data regarding the epidemiology of sepsis (as de~ned by those criteria) and proposed using a set of criteria for “early detection and treatment of a group of very high-risk patients with sepsis” [4]. The term “sepsis syndrome” was coined for this group of patients. The “sepsis syndrome” was diagnosed when clinical evidence of infection was accompanied by evidence of in_ammation and poor organ perfusion or of organ dysfunction. Clinical evidence of infection meant that there was no longer a need to have bacteriological evidence such as positive blood cultures and that clinical criteria suf~ced [4,5]. To further clarify inadequacies arising from the de~nition of the sepsis syndrome, members of the American College of Chest Physicians and the American Society of Critical Care Medicine (ACCP/SCCM) provided a new set of de~nitions for both clinical and experimental applications [2]. The “systemic in_ammatory response syndrome” (SIRS) was de~ned as the presence of two or more of the following diagnostic criteria: changes in body temperature (fever or hypothermia), changes in white blood cell counts (leukocytosis or leukopenia or increases in immature neutrophils), tachycardia, and tachypnea. Sepsis was then de~ned as the systemic in_ammatory response to an infection, severe sepsis as sepsis associated with organ dysfunction, hypoperfusion, or hypotension, and septic shock as persistence of hypoperfusion or hypotension despite _uid resuscitation. The diagnostic criteria thus comprises signs of in_ammation and evidence of infection to diagnose sepsis and signs of remote organ failure to address the severity of the in_ammatory response. Some points are of importance: First, common signs of in_ammation such as changes in body temperature, changes in leukocyte count, changes in neutrophil granulation, tachycardia etc. may have an infectious or non-infectious etiology and are neither speci~c nor sensitive for sepsis. Of note, only two signs, namely changes in leukocyte counts and changes in body temperature can be directly related to in_ammation whereas tachycardia and tachypnea cannot. Second, the disappointing results of immunomodulatory trials in septic patients have raised doubts as to whether clinical and laboratory criteria alone may suf~ce in identifying groups of patients who would most likely bene~t from such therapies. We note that the diagnosis of sepsis, an important ~rst step for both clinicians and clinical investigator, still has many pitfalls. These shortcomings of the de~nitions and diagnostic criteria call for new diagnostic tools and parameters. Some parameters may be needed in early clinical identi~cation of such patients, others may be important in gauging the in_ammatory response and monitoring the immune status of the patient, still others may help identify subgroups of septic patients who may bene~t from proor anti-in_ammatory therapies. In this issue of the journal, parameters and markers of the septic response and their scienti~c and clinical