Executive Summary: Guidelines for Evaluating New Fever in Adult Patients in the ICU

Fever is frequently an early indicator of infection and often requires rigorous diagnostic evaluation. The range of potential etiologies of fever is vast and includes both infectious and noninfectious causes. Noninfectious causes of fever should be considered in the differential diagnosis, but because early treatment initiation may improve patient outcomes of infections, initial evaluation of patients with new-onset fever is usually directed at potential microbial causes, and this is the primary focus of this guideline. It should be noted that not all febrile episodes dictate a need for investigation (i.e., those in which a noninfectious etiology is obvious such as fever occurring immediately in the postoperative state). For those fevers that do require investigation, a good history and physical examination will often reveal potential sources of infection. Diagnostic studies should then be sent with those potential sources in focus rather than reflexively sending cultures for all possible sources. Although much of this document and its recommendations may be applicable to severely immunocompromised patients, such as organ transplant recipients and those with severe neutropenia, these populations are not directly addressed here. The variability and complexities of different types of immunocompromise make this a task that cannot be accomplished in the context of a generally applicable guideline. This document is an update of the 2008 Infectious Diseases Society of America (IDSA) and Society of Critical Care Medicine (SCCM) guideline for the evaluation of new onset fever in adult ICU patients without severe immunocompromise. The SCCM and the IDSA have previously defined fever in ICU patients as the presence of a single temperature measurement of greater than or equal to 38.3°C, and we used this definition of fever for this guideline. In contrast to the 2008 document, this update uses the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. It addresses the approach to the diagnosis of the cause of fever in adults receiving intensive care in which onset of fever occurs after ICU admission. It includes recommendations for microbiologic studies, imaging procedures and use of biomarkers, as well as the use of antipyretics. In contrast to the previous guideline, the current guideline includes more specific recommendations regarding imaging procedures (particularly ultrasonography and CT), the microbiologic diagnosis of central venous access infection, and the use of rapid molecular tests for the diagnosis of viral infections, including those due to severe acute respiratory syndrome coronavirus 2. Readers will find rationales for 24 recommendations or statements derived from actionable Population, Intervention, Comparison, Outcome questions, or best practice statements in which GRADE methodology was not used. The supplemental digital figures and tables provide background on how the questions were developed, profiles of the evidence, the evidence-to-decision tables used to develop the recommendations, and the voting results (1). We also acknowledge the evidence gaps that exist which allow for only weak recommendations and preclude addressing all clinical priority questions. GRADE RECOMMENDATIONS The consensus recommendations are summarized and listed in Table 2 of the full guidelines document (1). Selected recommendations that are new or require special attention are listed here in Table 1. There have been only limited advances in the available evidence since the previous guideline, and we highlight three areas of importance below. TABLE 1. - Consensus Recommendations 1) Central temperature monitoring methods, including thermistors for pulmonary artery catheters, bladder catheters, or esophageal balloon thermistors, are preferred when these devices are in place or accurate temperature measurements are critical to diagnosis and management. For patients without these devices in place, we suggest using oral or rectal temperatures over other temperature measurement methods that are less reliable (such as axillary or tympanic membrane temperatures, noninvasive temporal artery thermometers, or chemical dot thermometers) (Weak recommendation, very low quality evidence). 2) For critically ill patients with fever and no abdominal signs or symptoms or liver function abnormalities, and no recent abdominal surgery, we recommend against the routine use of a regular abdominal ultrasound or POCUS as an initial investigation (Best practice statement). 3) In patients with fever and recent abdominal surgery or in any patient with either abdominal symptoms or suspicion of an abdominal source (e.g., abnormal physical examination/POCUS, increased transaminases, or alkaline phosphatase, and/or bilirubin, we recommend performing a formal bedside diagnostic ultrasound of the abdomen) (Best practice statement). 4) For ICU patients with fever without an obvious source and who have a central venous catheter, we recommend simultaneous collection of central venous catheter and peripherally drawn blood cultures to allow calculation of differential time to positivity (Best practice statement). 5) In patients with fever in the ICU in whom central venous catheter cultures are indicated, we recommend sampling at least two lumens (Best practice statement). 6) When performing blood cultures in adult ICU patients, we recommend collecting at least two sets of blood cultures (ideally 60 mL of blood total) one after the other, from different anatomical sites, without a time interval between them (Best practice statement). POCUS = point of care ultrasound. Measurement of Temperature Central temperature monitoring methods, including thermistors for pulmonary artery catheters, bladder catheters, or esophageal balloon thermistors, are preferred when these devices are in place or accurate temperature measurements are critical to diagnosis and management. For patients without these devices in place, we suggest using oral or rectal temperatures over other temperature measurement methods that are less reliable (i.e., axillary temperature measurement, tympanic membrane thermometers, noninvasive temporal artery thermometers, or chemical dot thermometers). We highlight this recommendation because of the ubiquitous use of tympanic membrane thermometers in many ICUs. Although the recommendation is weak, it is worth noting that tympanic membrane thermometers have a wide range of temperature inaccuracy ranging from –1.42°C to +1.26°C, are relatively expensive to purchase, and must be maintained and calibrated according to manufacturer’s recommendations, or more frequently if you suspect the thermometer is not measuring temperature accurately. When these devices are used one should maintain a high index of suspicion regarding the accuracy of the temperature measurement if the measurement is discordant with other clinical signs and symptoms of infection. Ultrasonography The use of ultrasound technology has proliferated in the ICU setting and is generally recommended when it is available and sufficient expertise exists on site to view and interpret the images. Many intensivists are skilled in performing point-of-care ultrasonography at the bedside, while many institutions rely on more formal diagnostic ultrasound imaging performed by radiologists. Ultrasonography can be viewed as useful complement to the physical examination, however, diagnostic abdominal ultrasound has not been studied in the evaluation of fever in critically ill patients, and the impact of its routine use when abdominal symptoms or liver test abnormalities are absent is incompletely defined. Conversely when signs or symptoms of abdominal pathology are present (elevated transaminases and or bilirubin, abnormal abdominal examination) a formal abdominal ultrasound may be useful and has some advantages over a CT scan including a lack of radiation, safety, low cost, and often no need for patient transport. Abdominal ultrasound can potentially diagnose acalculous cholecystitis, cholelithiasis, liver or kidney abscesses, perforated bowel, ascites, and/or appendicitis as potential sources of fever. In surgical patients, it can also identify surgical wound abscesses, and determine if they are amenable to drainage. Ultrasound imaging views may be more limited than views obtained by a CT scan, so determination of which imaging procedures are most useful will depend on clinical circumstances. Blood Cultures At least two sets of blood cultures sampling a total of 60 mL of blood should be performed; the samples should be obtained at the same time and from different anatomical sites. Blood cultures collected through central venous catheters are associated with higher rates of contamination than those collected by venipuncture. However, in many ICU patients, multiple peripheral venipunctures are not feasible. If bacteremia arising from a central venous access device is suspected, blood for culture should be obtained from at least two device lumens and peripheral venous blood should be simultaneously sampled to determine the differential time-to-positivity and to determine whether the device is the source of bloodstream infection. Rapid diagnostic tests such as nucleic acid amplification for detection of bacteremia should only be used as an adjunct to routine blood cultures. CONCLUSIONS While important advances have been made in dealing with patients with new onset of fever while receiving critical care, our knowledge gaps remain multiple and large. This demonstrates the need for rapid advancement of research in all aspects of this issue—specifically better noninvasive methods to measure core body temperature, the use of diagnostic imaging and its role in patients with fever, advances in microbiology including rapid molecular testing, and the role of biomarkers in diagnosing infection.