Is Procalcitonin-Guided Therapy Associated With Beneficial Outcomes in Critically Ill Patients With Sepsis?

Critical Care Medicine www.ccmjournal. org 811 The rapid initiation of appropriate antibiotics is unquestionably the most effective treatment intervention to reduce mortality in critically ill patients with sepsis (1–3). Standing in contrast to this is the accumulating evidence of the harmful effects of unnecessary prolonged use of antibiotics, which includes serious drug side effects, development of Clostridium difficile colitis, emergence of antibiotic resistance, and high costs for both patients and society (4–6). The use of bedside signs and symptoms and traditional laboratory data has shown to be of little help to define the optimal antibiotic duration in patients with sepsis; thus, the search for serum biomarkers has vigorously grown in the last 10–15 years. One of these biomarkers, which increases with a severe infection and decreases with its resolution, is procalcitonin (PCT) (7). Previous studies have attempted to shed light on the role of this biomarker in the care of patients with sepsis (8), but the overall picture has remained cloudy, often due to the difficulty of even defining the entity of sepsis and its underlying etiology, as well as due to the statistical power limitations of single studies. Also, a retrospective study based on International Classification of Diseases, Ninth Edition, codes by Chu et al (9) suggested that PCT was not associated with improved antibiotic use; however, only less than one-third of patients had serial PCT measurements, and PCT levels were not available. This issue of Critical Care Medicine brings two studies that analyze the current evidence and shed further light on the utility of PCT-guided antibiotic therapy in critically ill patients. PCTguided therapy, as evaluated in these two studies, is defined by serial measurements of serum PCT to assist clinicians in antibiotic decision making. These decisions may include both initiation and duration of therapy and are always coupled with thoughtful evaluation by a clinician. Generally, when the PCT levels do not rise above (or fall below) a cutoff level (e.g., < 0.5 μg/mL) or are reduced 80–90% compared with the peak level at the beginning of the infection process, antibiotic de-escalation is advised. In this issue of Critical Care Medicine, Iankova et al (10) sought to evaluate the published evidence related to the use of PCT guidance to optimize antibiotic treatment in patients with sepsis. They performed a systematic review and meta-analysis that included 10 randomized controlled trials with a total of 3,489 patients. PCT utilization in addition to clinical judgment was associated with a 1.5-day significant shorter antibiotic duration compared with no PCT guidance. Also, the safety evaluation did not show differences in adverse events such as mortality or length of ICU stay. The strengths of this study reside on the large sample size and the selection of randomized trials. However, a limitation is related to the high heterogeneity found in most of the analyses. For instance, the main analysis (Fig. 2 in [10]) showed an I-squared of 81%; this means that only 19% of the study heterogeneity was due to random error, and that 81% of the study heterogeneity was associated with factors pertaining to the specific studies selected for the analysis. Several clinical reasons could potentially have led to this high heterogeneity: different patient populations, sepsis definitions, baseline disease severity, varying compliance with PCT algorithms, or different PCT cutoffs to guide antibiotic discontinuation. An additional statistical reason for the increased heterogeneity may be the imputation of means based on study arms interquartile range. Despite these limitations, this study suggests, as a previous one have (8), the serial measurement of PCT coupled with physician judgment can be used to safely guide antibiotic utilization and reduce unnecessary antibiotic exposure to patients with sepsis. Also in this issue of Critical Care Medicine, Lam et al (11) also performed a systematic review and meta-analysis, but focused on different outcomes: they aimed to evaluate the short-term mortality effect of PCT guidance on different phases of sepsis antibiotic use: initiation, cessation, or a combination of both (mixed). It is important to explore these applications of PCT as its utility may be different in different phases of care. Although PCT use has been shown to safely decrease antibiotic use in lower respiratory tract infections such as exacerbations of chronic bronchitis and pneumonia, patients with sepsis have higher mortality rates, and bacterial infection is more common, raising the “stakes” of therapeutic decisions. Their analysis included 15 randomized trials with a total of 3,037 patients. While no outcome difference was observed when all studies were pooled together, the relative risk of mortality outcome was significantly decreased by 13% (95% CI, 2–23%) with PCT guidance compared with no PCT guidance in the analysis of antibiotic cessation studies. In addition, a significant antibiotic duration decrease of 1.3 days was *See also p. 684 and 691.