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Diagnostic value of positron emission tomography combined with computed tomography for evaluating patients with septic shock of unknown origin
Journal of Critical Care (2012) 27, 316.e1–316.e7
Diagnostic value of positron emission tomography combined with computed tomography for evaluating patients with septic shock of unknown origin☆ Stefan Kluge MD a,⁎,1 , Stephan Braune MD a,1 , Axel Nierhaus MD a , Dominic Wichmann MD a , Thorsten Derlin MD b , Janos Mester MD b , Susanne Klutmann MD b a
Department of Intensive Care, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
b
Keywords: Severe sepsis; Septic shock; FDG-PET/CT; Outcome; Infection; Management
Abstract Purpose: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with computed tomography (CT) is a promising new tool for the identification of infectious foci. The aim of our work was to evaluate the diagnostic value of FDG-PET/CT in critically ill patients with septic shock of unknown origin. Methods: We performed a single-center, 6-year retrospective evaluation of the value of FDG-PET/CT in critically ill patients with severe sepsis or septic shock of unknown origin. Results: Eighteen patients underwent FDG-PET/CT. Microbiological tests (blood culture, urine, and respiratory secretions), chest x-rays, CT scans, and transesophageal echocardiography were performed on all patients before FDG-PET/CT scanning. Pathologic FDG accumulation could be demonstrated in 14 of 18 FDG-PET/CT scans. On a per-patient basis, 11 were “true positive,” 3 were “false positive,” 4 were true negative, and there were no false negatives. In 6 cases, the results of the PET/CT scan had direct therapeutic consequences (surgery, 2; pacemaker removal, 2; initiation of antibiotic therapy, 1; and prolonged antibiotic therapy, 1); 12 (66%) of the 18 patients survived to hospital discharge. Conclusions: The FDG-PET/CT is a valuable tool for the localization of infectious foci in critically ill patients with severe sepsis/septic shock in whom conventional diagnostic methods fail to detect these foci. Prospective studies with more patients are warranted to further evaluate the diagnostic accuracy and feasibility of this diagnostic tool in critically ill patients with severe sepsis. © 2012 Elsevier Inc. All rights reserved.
1. Introduction ☆ The authors declare that they have no competing interests. ⁎ Corresponding author. Tel.: +49 40 7410 57010; fax: +49 40 7410 57020. E-mail address: [email protected] (S. Kluge). 1 The first 2 authors contributed equally to this work.
0883-9441/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2011.10.004
Despite recent advances in our understanding of the pathophysiology and treatment of septic shock, the condition remains one of the leading causes of death in intensive care units (ICUs) with mortality rates of up to 50% to 60% [1-3]. In
316.e2 addition to early and adequate treatment, current guidelines recommend that all patients with severe sepsis should be evaluated for the source of infection with the aim of source control, for example, drainage of an abscess or removal of an infected device [4]. In most cases, a diagnosis can be reached on clinical, radiologic, or microbiological grounds. However, in a considerable number of cases, the source and focus of the infection cannot be found despite extensive diagnostic tests including computed tomography (CT). In recent years, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has become an established and well-studied imaging modality for the evaluation of inflammatory and infectious disorders [5-7]. The FDG is an indicator of increased intracellular glucose metabolism and may accumulate not only in malignant cells but also in cells involved in infectious and inflammatory processes, for example, macrophages. Several studies have documented the important role of FDG-PET in diagnosing patients with fever of unknown origin, chronic osteomyelitis, lower limb prostheses complications, diabetic foot problems, acquired immunodeficiency syndrome, vasculitis, and vascular graft infection [8-10]. An advanced application is the combination of PET technology with CT scanning in a single device. Hybrid imaging by FDG-PET/CT offers potential advantages by providing additional anatomical information and characterization of the detected lesion. To our knowledge, to date, there have been no published reports on the use of FDG-PET/CT to identify the source of infection in critically ill patients with septic shock. Therefore, we decided to assess the role of FDG-PET/CT in the detection of the source of infection in patients with septic shock of unknown origin.
2. Methods 2.1. Study design This retrospective observational study included all adult critically ill patients treated in the department of intensive care medicine of the University Medical Center HamburgEppendorf from January 2004 until December 2010 for severe sepsis or septic shock of unknown origin in whom an FDG-PET/CT had been performed for localization of an infectious focus. Severe sepsis was defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion. Septic shock was defined as sepsis-induced hypotension (systolic blood pressure b90 mm Hg or mean arterial pressure b70 mm Hg) persisting despite adequate fluid resuscitation [11]. The study was approved by the local clinical institutional review board and complied with the declaration of Helsinki. From the electronic patient data management system (Integrated Care Manager ICM; Dräger Medical, Lübeck, Germany), the following information was collected: demographics, severity of illness, diagnosis on admission, diagnosis
S. Kluge et al. on discharge (from ICU/hospital), duration of stay in the ICU/hospital, diagnostic procedures and treatment before FDG-PET/CT, transport-related complications, changes in clinical management after obtaining the results of the FDGPET/CT, and survival. All patients underwent a standardized diagnostic workup including microbiological evaluation (cultures of blood, urine, and respiratory secretions), chest x-rays, CT scanning, and transesophageal echocardiography according to the standard departmental protocol. The FDG-PET/CT was performed at the discretion of the attending intensivist when clinical signs and/or laboratory and/or imaging findings to identify the source of infection were inconclusive.
2.2. The FDG-PET/CT All patients fasted for at least 4 hours before scanning; parenteral nutrition and all infusions containing glucose were also discontinued for that period. Blood glucose concentration was checked every hour before the application of 350 MBq of 18F-FDG. Administration of 18F-FDG was only performed at glucose levels less than 200 mg/dL. All patients were escorted by a qualified intensive care physician and a registered nurse and were fully monitored during transport and the procedure. The FDG-PET/CT was performed with a hybrid PET/CT scanner (Gemini GXL10; Philips, Best, Netherlands). The CT component of the examination was performed as a fully diagnostic CT with the use of intravenous contrast medium. All patients without elevated levels of serum creatinine (8 in our study) received 100 to 200 mL intravenous contrast agent (Imeron 300; Bracco Imaging, Konstanz, Germany) 90 seconds before starting the CT scan. The whole examination, including positioning of the patient, took between 30 and 45 minutes. Whole-body images were acquired in a craniocaudal direction. All PET scans were performed in 3-dimensional acquisition mode. Emission images were acquired for 1.5 minutes per bed position at the head, thorax, and abdomen and 60 seconds at the legs (effective axial field of view, 90 cm). The acquisition parameters were as follows: 120 kV, 150 mAs, slice thickness of 5 mm, no gap, pitch of 0.9, rotation time of 0.74 seconds, and matrix 512 × 512. Computed tomographic data extrapolated to 511 keV were used for low noise attenuation correction of PET data and for subsequent coregistration with attenuation corrected PET images. The PET, CT, and fused FDG-PET/CT images were available for review and were displayed in axial, coronal, and sagittal planes. The PET data were displayed as noncorrected and attenuation-corrected images and also as a rotating maximum-intensity projection.
2.3. Interpretation and analysis of contrast-enhanced FDG-PET/CT images An interdisciplinary team, including 4 radiologists who had knowledge of the patient's clinical history, evaluated all
PET/CT in sepsis of unknown origin studies. Initially, PET and CT images were read independently: PET images were evaluated by 2 specialists in nuclear medicine (one of them a senior consultant in nuclear medicine), and CT images were evaluated by 2 radiologists (one of them a senior consultant). Finally, the results of both parts of the investigation were obtained in a consensus conference of all 4 physicians resulting in a final written report for each FDG-PET/CT investigation. A focus of increased FDG uptake was considered abnormal if it was higher than the regional background in localizations outside the expected physiologic FDG distribution. The final clinical diagnosis, which served as the reference standard, was made retrospectively, taking all available clinical information into consideration. These sources of information included clinical course, physical examination, and laboratory, microbiology, and histology results as well as intraoperative findings and imaging results other than the FDG-PET/CT. The FDGPET/CT results were then compared with the final clinical diagnosis and interpreted as true or “false positive” and true or false negative. The FDG-PET/CT scan was considered • “true positive” if FDG-PET/CT results demonstrating a focal localized disease process were confirmed by further investigations as the cause of the sepsis; • false positive if FDG-PET/CT results demonstrating a focal localized disease process could not be confirmed as being the cause of the sepsis; • true negative if FDG-PET/CT produced a normal scan with further investigations or clinical follow-up excluding focal inflammation; and • false negative if FDG-PET/CT produced a normal scan, but focal inflammation was subsequently detected by other diagnostic modalities. We also evaluated whether the FDG-PET/CT results were essential to making a diagnosis or had therapeutic consequences. We also evaluated the impact of the FDG-PET/CT findings on further diagnostic procedures. In this context, truepositive scans were categorized as “helpful” for final diagnosis.
2.4. Statistical analysis The software used for statistical analysis was Statistica version 9.0 (StatSoft, Inc, Tulsa, Okla). Continuous variables are presented as means (±SD) for normally distributed data or as medians (with the range) for nonnormally distributed data.
3. Results 3.1. Patient characteristics During the study period, 19 FDG-PET/CT scans were performed on 18 adult ICU patients with severe sepsis or
316.e3 septic shock of unknown origin. One scan was excluded from the analysis because 2 scans were performed on 1 patient. Eleven patients were referred from the medical ICU, 3 from the neurologic ICU, 3 from the mixed ICU, and 1 patient from the surgical ICU. Demographics, mortality rates, and admission diagnoses of the study population are illustrated in Table 1. At the time of the FDG-PET/CT scan, all patients fulfilled the criteria for severe sepsis, 15 patients (83%) were in septic shock (requiring significant vasopressor support), and 12 patients (67%) were mechanically ventilated. In all 18 patients, microbiological tests (cultures of blood, urine, and respiratory secretions), chest x-rays, CT scans, and transesophageal echocardiography were performed before FDGPET/CT scanning. Of the 18 patients, 17 (94%) received antibiotic treatment, and 8 (44%) received antifungal therapy at the time of the FDG-PET/CT scan. In 12 patients (67%), blood cultures were positive. Staphylococcus aureus was identified in 4 patients, S epidermidis in 2 patients, Candida albicans in 2 patients, and Rhodococcus equi, Enterococcus durans, S hominis, and S haemolyticus each in 1 patient. The mean C-reactive protein level was 123 ± 72 mg/L; serum procalcitonin levels were measured in 13 patients (72%), and the median value was 4.3 g/mL (range, 0.4-14.3 g/mL). The median interval between ICU admission and FDG-PET/CT scan was 11 days (range, 1-42 days). No complications occurred during transportation to or from the ICU to the department of nuclear medicine. Adverse reactions to the tracer or the intravenous contrast agents were not observed; the investigation procedure was well tolerated by all patients.
3.2. Diagnostic value of FDG-PET/CT results Table 2 shows all diagnostic tests performed before FDGPET/CT, the final diagnosis, and correlation with FDGPET/CT findings. Pathologic FDG accumulations were found Table 1 Demographics, mortality rates, and admission diagnosis of the study population No. of patients Mean age (y) Sex (female/male) 28-d mortality ICU mortality Admission diagnosis Sepsis of unknown origin Pneumonia Acute liver failure Elective surgery Acute heart failure Acute pancreatitis Acute perimyocarditis
18 55.9 ± 17.8 4/14 0 (0) 6 (33) 7 (39) 4 (22) 2 (11) 2 (11) 1 (6) 1 (6) 1 (6)
Values in parentheses are percentages. Age is presented as mean ± SD.
316.e4
S. Kluge et al.
Table 2 Diagnostic tests before FDG-PET/CT, final diagnosis, and correlation with FDG-PET/CT in patients with septic shock and unknown source of infection Patient no.
Age/sex
Days on ICU
Cultures R, B, and U
US
TTE/TEE
CT scan
Final diagnosis
Outcome
PET/CT result
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
52/M 67/M 80/M 51/M 22/M 58/M 51/M 71/M 80/M 48/M 62/M 85/F 30/M 50/F 78/F 62/M
45 34 30 23 1 20 20 40 65 57 59 9 111 39 7 22
+, +, + +, +, + +, +, + +, +, + −, +, + −, +, + +, +, + +, +, + +, +, + +, +, + +, +, + −, +, + +, +, + +, +, + −, +, + +, +, +
+ + − + + + + − − + + − + + + +
+/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+
Chest/abdomen Chest/abdomen Abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen
Died Survived Died Survived Survived Survived Survived Survived Died Died Died Survived Died Survived Survived Survived
TP TP TP TP TP TP TP TP TP TP TP TN TN TN TN FP
17
38/M
81
+, +, +
+
+/+
Chest/abdomen
Survived
FP
18
21/F
56
+, +, +
+
+/+
Chest/abdomen
Cervical abscess Pseudomembranous colitis Pacemaker infection Necrotizing pancreatitis Infected vena cava thrombosis Nocardiosis Pacemaker infection Pneumonia Infected vascular graft Pneumonia Spondylodiscitis Perimyocarditis Liver failure Pyoderma gangrenosum Sepsis of unknown origin Sepsis of unknown origin (PET/CT, paravertebral abscess) Cholangitis (PET/CT, chest wall abscess) Pneumonia (PET/CT: tongue abscess)
Survived
FP
In all patients, chest x-rays were performed; + indicates that the test was performed; −, test was not performed; R, respiratory secretions; B, blood; U, urine; US, abdominal ultrasound; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography; TP, true positive; FP, false positive; TN, true negative; FN, false negative.
in 14 (78%) of 18 PET/CT scans; there were 11 true positive, 3 false positive, 4 true negative, and no false negatives. In 5 patients, FDG-PET/CT was essential for the diagnosis because
no other investigation, including CT, provided sufficient diagnostic clues. These 5 cases were patients with pseudomembranous colitis (Fig. 1), an infected femoropopliteal bypass
Fig. 1 An FDG-PET/CT of a patient admitted to ICU with a diagnosis of nosocomial pneumonia. After stabilization, he developed fever, and blood cultures were positive for C albicans. Maximum intensity projection PET (A) and transaxial views of CT, PET, and fused PET/CT images (B and C). Increased uptake is noted in the colon (arrows) and around the central venous catheter (arrow). Colonoscopy revealed a pseudomembranous colitis that resulted in antibiotic treatment. The central venous catheter was removed after diagnosis of a catheter-related Candida sepsis.
PET/CT in sepsis of unknown origin
316.e5
Fig. 2 Maximum intensity projection PET (A) and transaxial views of CT, PET, and fused PET/CT images (B and C). A and B, Marked tracer uptake is noted around the femoral popliteal bypass (arrow). Corresponding CT image shows a small fluid collection, consistent with an infection. A and C, Subcutaneous and intramuscular foci of increased uptake are consistent with inflammation (arrowheads). Surgical removal of the bypass and subsequent microbiological evaluation confirmed the infection.
(Fig. 2), an infected vena cava thrombosis, an infected pacemaker, and a cervical abscess. In 6 cases, the results of the PET/CT scan led to a change of management (surgery, 2; pacemaker removal, 2; initiation of antibiotic therapy, 1; and prolonged antibiotic therapy, 1). Three FDG-PET/CT results were considered false positive. In the first patient (no. 16), FDG-PET/CT suggested the presence of a paravertebral abscess, but surgical exploration revealed that a hematoma and microbiological cultures remained sterile. The second patient (no. 17) had increased FDG uptake in the chest wall, suggesting an abscess formation. However, there were no clinical signs of abscess or focal inflammation, and ultrasound was negative. Therefore, the surgeon refused the request for surgical exploration. The third patient (no. 18) was a 21-year-old woman admitted with community-acquired pneumonia. Because of refractory septic shock during the course of her prolonged ICU stay, an FDG-PET/CT was performed that indicated an abscess in her tongue. However, subsequent surgical exploration revealed no source of infection.
3.3. Outcome Intensive care unit and hospital survival rate was 66% (12/18 patients). Three patients died during the course of prolonged respiratory weaning with multiple complications. One patient died because of septic shock with
multiple organ failure; 1 patient, because of acute liver failure; and 1 patient, because of severe acute respiratory distress syndrome due to pneumonia. In the latter case, an autopsy was performed, pneumonia was confirmed without any other source of infection, and the FDG-PET/CT results were judged as true positive.
4. Discussion Our findings show that FDG-PET/CT is a valuable investigation in the diagnostic workup of patients with septic shock of unknown origin. We were able to demonstrate that FDG-PET/CT was a decisive diagnostic step in a substantial proportion of patients for whom a standardized diagnostic workup including microbiological evaluation (cultures of blood, urine, and respiratory secretions), chest x-rays, CT scanning, and transesophageal echocardiography had failed to obtain a definitive diagnosis. To our knowledge, this is the first study investigating critically ill patients in septic shock with an unknown source of infection undergoing FDG-PET/CT. Conventional anatomical imaging modalities such as x-rays, ultrasound, and CT are normally used for the localization of infectious or inflammatory foci. However, especially in critically ill patients who are mechanically ventilated and sedated, the search for the source of infection may be very difficult. All of the conventional investigations
316.e6 cover only part of the spectrum of possible diagnoses, and therefore, their diagnostic accuracy for detecting the source of septic shock is limited. Nuclear medicine modalities using radiotracers may unmask previously unknown sites of inflammation or infection by providing functional information. This can add relevant information to conventional anatomical imaging modalities that only provide morphological information. The FDG-PET/CT may have a higher sensitivity than other nuclear medicine techniques for the diagnosis of infectious and inflammatory disease, partly owing to the fact that the spatial resolution of PET is much higher than the resolution of single positron emission computed tomography, allowing for the detection of smaller foci [5,8,12]. Despite that functional imaging techniques have been used for many years, few studies have actually assessed the value of nuclear medicine modalities for the identification of the primary infectious source in critically ill patients with sepsis [13-15]. Recently, Simons et al [16] reported a retrospective pilot study of 35 FDG-PET/CT scans in ICU patients for the evaluation of suspected infections. Twenty-one scans were true positive; 3, false positive; and 11, true negative. In 5 cases, the results of the scan had direct therapeutic consequences. However, it needs to be stressed that most patients in this study had fever of unknown origin without severe sepsis or septic shock and that only 2 of the 33 patients studied were in septic shock. Furthermore, less than 40% had additional diagnostic workup such as CT scans or cardiac ultrasound before FDG-PET/CT. This limits the validity and generalizability of this study. In our study, after a standardized and extensive diagnostic workup, the source of sepsis could be detected by FDGPET/CT in 11 (61%) of 18 patients, and in 6 cases, the results of the PET/CT scan led to a change of management. This emphasizes the potential value of this diagnostic technique for this specific population. However, some methodological characteristics have to be taken into account. The clinical importance of a true-negative PET/CT scan result lies in the exclusion of a focal infectious process requiring drainage or prolonged antibiotic treatment. A negative PET/CT scan per se cannot rule out sepsis or septic shock due to bacteremia without specific organ infiltration or involvement. Nevertheless, in these cases, no therapeutic measures would be missed, which go beyond adequate antimicrobial treatment. On the other hand, 3 of the 18 FDG-PET/CT gave falsepositive findings and led to further invasive exploration in 2 of the 3 cases. These 2 operations could not confirm the PET/CT diagnosis and put the patient at additional risk. These findings are consistent with the results of other publications describing false-positive PET/CT scans. Increased localized FDG uptake without an infectious cause has been explained as being related to recent surgery. However, our 3 false-positive cases were not in a postoperative state at the time of the PET/CT scan. Therefore, it needs to be emphasized that positive PET/CT scan results should be considered with caution, especially
S. Kluge et al. when resulting in invasive therapeutic consequences. In such cases, targeted additional investigations such as ultrasound, magnetic resonance imaging, or conventional radiologic studies of the region of interest should be performed. Furthermore, microbiological specimen from the identified area of interest should be obtained and cultured to confirm or exclude the diagnosis. We investigated a highly selected group of patients in whom no source of infection could be identified with conventional diagnostics. We believe that patients with sepsis and septic shock should undergo a standardized diagnostic workup. X-rays, ultrasound, CT, and echocardiography should be performed as a primary diagnostic imaging workup [17]. Only when these conventional imaging modalities are normal or inconclusive should an FDG-PET/CT scan be considered as a next or second level examination. The interpretation of the results of our study is limited by the retrospective design and the relatively small number of patients. However, to our knowledge, this is the first study addressing the value of FDG-PET/CT scans specifically in critically ill patients with severe sepsis and septic shock. Several difficulties in performing this diagnostic procedure in such patients need to be mentioned. First, transportation of patients in septic shock from the ICU to the department of nuclear medicine potentially puts these critically ill patients at risk. However, in our study, no complications related to transportation or the imaging itself were observed. Second, the intervention requires substantial resources in terms of both time and personnel as well as being relatively costly. Recently, Vos et al [18,19] analyzed the cost-effectiveness of FDG-PET/CT in patients with gram-positive bacteremia. Cost data were based on a cost-effectiveness analysis in a prospective FDG-PET/CT group and matched historical control group. Introduction of a diagnostic regimen including routine FDG-PET/CT detected metastatic infectious complications in a substantial proportion of patients and decreased morbidity and mortality. Costs per mortality case prevention of €48 325 were considered to be well within the range that is generally accepted as efficient. Finally, the associated exposure to radiation is potentially harmful but must be weighed against the diagnostic benefit in a patient population with an extreme high mortality rate. Last, the availability of PET/CT scanners is currently limited, although it is increasing.
5. Conclusion In our study, an FDG-PET/CT scan was categorized as “helpful for diagnosis” in 61% of patients with severe sepsis or septic shock of unknown origin and had a high negative predictive value (100%) regarding the exclusion of focal infection requiring drainage or prolonged antibiotic treatment. From these preliminary results, FDG-PET/CT scanning appears to be a valuable diagnostic tool in this patient
PET/CT in sepsis of unknown origin population when extensive prior diagnostic workup has been negative or inconclusive. Prospective multicenter studies with more patients are warranted to further evaluate the diagnostic accuracy and feasibility of FDG-PET/CT scanning in critically ill patients with severe sepsis.
Acknowledgments The authors thank Liz Wager for editing the manuscript.
References [1] Kreymann KG, de Heer G, Nierhaus A, et al. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med 2007;35:2677-85. [2] Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006;34:344-53. [3] Dombrovskiy VY, Martin AA, Sunderram J, et al. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 2007;35:1244-50. [4] Dellinger RP, Levy MM, Carlet JM. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296-327. [5] Gotthardt M, Bleeker-Rovers CP, Boerman OC. Imaging of inflammation by PET, conventional scintigraphy, and other imaging techniques. J Nucl Med 2010;51:1937-49. [6] Jasper N, Dabritz J, Frosch M. Diagnostic value of [(18)F]-FDG PET/CT in children with fever of unknown origin or unexplained signs of inflammation. Eur J Nucl Med Mol Imaging 2010;37:136-45.
316.e7 [7] Keidar Z, Gurman-Balbir A, Gaitini D. Fever of unknown origin: the role of 18F-FDG PET/CT. J Nucl Med 2008;49:1980-5. [8] Basu S, Chryssikos T, Moghadam-Kia S. Positron emission tomography as a diagnostic tool in infection: present role and future possibilities. Semin Nucl Med 2009;39:36-51. [9] Miceli MH, Jones Jackson LB, Walker RC. Diagnosis of infection of implantable central venous catheters by [18F]fluorodeoxyglucose positron emission tomography. Nucl Med Commun 2004;25:813-8. [10] Zerizer I, Tan K, Khan S. Role of FDG-PET and PET/CT in the diagnosis and management of vasculitis. Eur J Radiol 2010;73:504-9. [11] American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-74. [12] Kumar R, Basu S, Torigian D. Role of modern imaging techniques for diagnosis of infection in the era of 18F-fluorodeoxyglucose positron emission tomography. Clin Microbiol Rev 2008;21:209-24. [13] Kao CH, Wang YL, Liao SQ. Tc-99m HMPAO labelled WBCs in the detection of occult sepsis in the intensive care unit. Intensive Care Med 1992;18:15-9. [14] Minoja G, Chiaranda M, Fachinetti A. The clinical use of 99m-Tclabeled WBC scintigraphy in critically ill surgical and trauma patients with occult sepsis. Intensive Care Med 1996;22:867-71. [15] Kaya Z, Kotzerke J, Keller F. FDG PET diagnosis of septic kidney in a renal transplant patient. Transpl Int 1999;12:156. [16] Simons KS, Pickkers P, Bleeker-Rovers CP. F-18-fluorodeoxyglucose positron emission tomography combined with CT in critically ill patients with suspected infection. Intensive Care Med 2010;36:504-11. [17] Barkhausen J, Stoblen F, Dominguez-Fernandez E. Impact of CT in patients with sepsis of unknown origin. Acta Radiol 1999;40:552-5. [18] Vos FJ, Bleeker-Rovers CP, Sturm PD. Cost-effectiveness of FDGPET/CT in patients with Gram+ bacteraemia. J Nucl Med 2011;52(Supplement 1):67 (abstract). [19] Vos FJ, Bleeker-Rovers CP, Sturm PD, et al. 18F-FDG PET/CT for detection of metastatic infection in gram-positive bacteremia. J Nucl Med 2010;51:1234-40.
Diagnostic value of positron emission tomography combined with computed tomography for evaluating patients with septic shock of unknown origin☆ Stefan Kluge MD a,⁎,1 , Stephan Braune MD a,1 , Axel Nierhaus MD a , Dominic Wichmann MD a , Thorsten Derlin MD b , Janos Mester MD b , Susanne Klutmann MD b a
Department of Intensive Care, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
b
Keywords: Severe sepsis; Septic shock; FDG-PET/CT; Outcome; Infection; Management
Abstract Purpose: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with computed tomography (CT) is a promising new tool for the identification of infectious foci. The aim of our work was to evaluate the diagnostic value of FDG-PET/CT in critically ill patients with septic shock of unknown origin. Methods: We performed a single-center, 6-year retrospective evaluation of the value of FDG-PET/CT in critically ill patients with severe sepsis or septic shock of unknown origin. Results: Eighteen patients underwent FDG-PET/CT. Microbiological tests (blood culture, urine, and respiratory secretions), chest x-rays, CT scans, and transesophageal echocardiography were performed on all patients before FDG-PET/CT scanning. Pathologic FDG accumulation could be demonstrated in 14 of 18 FDG-PET/CT scans. On a per-patient basis, 11 were “true positive,” 3 were “false positive,” 4 were true negative, and there were no false negatives. In 6 cases, the results of the PET/CT scan had direct therapeutic consequences (surgery, 2; pacemaker removal, 2; initiation of antibiotic therapy, 1; and prolonged antibiotic therapy, 1); 12 (66%) of the 18 patients survived to hospital discharge. Conclusions: The FDG-PET/CT is a valuable tool for the localization of infectious foci in critically ill patients with severe sepsis/septic shock in whom conventional diagnostic methods fail to detect these foci. Prospective studies with more patients are warranted to further evaluate the diagnostic accuracy and feasibility of this diagnostic tool in critically ill patients with severe sepsis. © 2012 Elsevier Inc. All rights reserved.
1. Introduction ☆ The authors declare that they have no competing interests. ⁎ Corresponding author. Tel.: +49 40 7410 57010; fax: +49 40 7410 57020. E-mail address: [email protected] (S. Kluge). 1 The first 2 authors contributed equally to this work.
0883-9441/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2011.10.004
Despite recent advances in our understanding of the pathophysiology and treatment of septic shock, the condition remains one of the leading causes of death in intensive care units (ICUs) with mortality rates of up to 50% to 60% [1-3]. In
316.e2 addition to early and adequate treatment, current guidelines recommend that all patients with severe sepsis should be evaluated for the source of infection with the aim of source control, for example, drainage of an abscess or removal of an infected device [4]. In most cases, a diagnosis can be reached on clinical, radiologic, or microbiological grounds. However, in a considerable number of cases, the source and focus of the infection cannot be found despite extensive diagnostic tests including computed tomography (CT). In recent years, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has become an established and well-studied imaging modality for the evaluation of inflammatory and infectious disorders [5-7]. The FDG is an indicator of increased intracellular glucose metabolism and may accumulate not only in malignant cells but also in cells involved in infectious and inflammatory processes, for example, macrophages. Several studies have documented the important role of FDG-PET in diagnosing patients with fever of unknown origin, chronic osteomyelitis, lower limb prostheses complications, diabetic foot problems, acquired immunodeficiency syndrome, vasculitis, and vascular graft infection [8-10]. An advanced application is the combination of PET technology with CT scanning in a single device. Hybrid imaging by FDG-PET/CT offers potential advantages by providing additional anatomical information and characterization of the detected lesion. To our knowledge, to date, there have been no published reports on the use of FDG-PET/CT to identify the source of infection in critically ill patients with septic shock. Therefore, we decided to assess the role of FDG-PET/CT in the detection of the source of infection in patients with septic shock of unknown origin.
2. Methods 2.1. Study design This retrospective observational study included all adult critically ill patients treated in the department of intensive care medicine of the University Medical Center HamburgEppendorf from January 2004 until December 2010 for severe sepsis or septic shock of unknown origin in whom an FDG-PET/CT had been performed for localization of an infectious focus. Severe sepsis was defined as sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion. Septic shock was defined as sepsis-induced hypotension (systolic blood pressure b90 mm Hg or mean arterial pressure b70 mm Hg) persisting despite adequate fluid resuscitation [11]. The study was approved by the local clinical institutional review board and complied with the declaration of Helsinki. From the electronic patient data management system (Integrated Care Manager ICM; Dräger Medical, Lübeck, Germany), the following information was collected: demographics, severity of illness, diagnosis on admission, diagnosis
S. Kluge et al. on discharge (from ICU/hospital), duration of stay in the ICU/hospital, diagnostic procedures and treatment before FDG-PET/CT, transport-related complications, changes in clinical management after obtaining the results of the FDGPET/CT, and survival. All patients underwent a standardized diagnostic workup including microbiological evaluation (cultures of blood, urine, and respiratory secretions), chest x-rays, CT scanning, and transesophageal echocardiography according to the standard departmental protocol. The FDG-PET/CT was performed at the discretion of the attending intensivist when clinical signs and/or laboratory and/or imaging findings to identify the source of infection were inconclusive.
2.2. The FDG-PET/CT All patients fasted for at least 4 hours before scanning; parenteral nutrition and all infusions containing glucose were also discontinued for that period. Blood glucose concentration was checked every hour before the application of 350 MBq of 18F-FDG. Administration of 18F-FDG was only performed at glucose levels less than 200 mg/dL. All patients were escorted by a qualified intensive care physician and a registered nurse and were fully monitored during transport and the procedure. The FDG-PET/CT was performed with a hybrid PET/CT scanner (Gemini GXL10; Philips, Best, Netherlands). The CT component of the examination was performed as a fully diagnostic CT with the use of intravenous contrast medium. All patients without elevated levels of serum creatinine (8 in our study) received 100 to 200 mL intravenous contrast agent (Imeron 300; Bracco Imaging, Konstanz, Germany) 90 seconds before starting the CT scan. The whole examination, including positioning of the patient, took between 30 and 45 minutes. Whole-body images were acquired in a craniocaudal direction. All PET scans were performed in 3-dimensional acquisition mode. Emission images were acquired for 1.5 minutes per bed position at the head, thorax, and abdomen and 60 seconds at the legs (effective axial field of view, 90 cm). The acquisition parameters were as follows: 120 kV, 150 mAs, slice thickness of 5 mm, no gap, pitch of 0.9, rotation time of 0.74 seconds, and matrix 512 × 512. Computed tomographic data extrapolated to 511 keV were used for low noise attenuation correction of PET data and for subsequent coregistration with attenuation corrected PET images. The PET, CT, and fused FDG-PET/CT images were available for review and were displayed in axial, coronal, and sagittal planes. The PET data were displayed as noncorrected and attenuation-corrected images and also as a rotating maximum-intensity projection.
2.3. Interpretation and analysis of contrast-enhanced FDG-PET/CT images An interdisciplinary team, including 4 radiologists who had knowledge of the patient's clinical history, evaluated all
PET/CT in sepsis of unknown origin studies. Initially, PET and CT images were read independently: PET images were evaluated by 2 specialists in nuclear medicine (one of them a senior consultant in nuclear medicine), and CT images were evaluated by 2 radiologists (one of them a senior consultant). Finally, the results of both parts of the investigation were obtained in a consensus conference of all 4 physicians resulting in a final written report for each FDG-PET/CT investigation. A focus of increased FDG uptake was considered abnormal if it was higher than the regional background in localizations outside the expected physiologic FDG distribution. The final clinical diagnosis, which served as the reference standard, was made retrospectively, taking all available clinical information into consideration. These sources of information included clinical course, physical examination, and laboratory, microbiology, and histology results as well as intraoperative findings and imaging results other than the FDG-PET/CT. The FDGPET/CT results were then compared with the final clinical diagnosis and interpreted as true or “false positive” and true or false negative. The FDG-PET/CT scan was considered • “true positive” if FDG-PET/CT results demonstrating a focal localized disease process were confirmed by further investigations as the cause of the sepsis; • false positive if FDG-PET/CT results demonstrating a focal localized disease process could not be confirmed as being the cause of the sepsis; • true negative if FDG-PET/CT produced a normal scan with further investigations or clinical follow-up excluding focal inflammation; and • false negative if FDG-PET/CT produced a normal scan, but focal inflammation was subsequently detected by other diagnostic modalities. We also evaluated whether the FDG-PET/CT results were essential to making a diagnosis or had therapeutic consequences. We also evaluated the impact of the FDG-PET/CT findings on further diagnostic procedures. In this context, truepositive scans were categorized as “helpful” for final diagnosis.
2.4. Statistical analysis The software used for statistical analysis was Statistica version 9.0 (StatSoft, Inc, Tulsa, Okla). Continuous variables are presented as means (±SD) for normally distributed data or as medians (with the range) for nonnormally distributed data.
3. Results 3.1. Patient characteristics During the study period, 19 FDG-PET/CT scans were performed on 18 adult ICU patients with severe sepsis or
316.e3 septic shock of unknown origin. One scan was excluded from the analysis because 2 scans were performed on 1 patient. Eleven patients were referred from the medical ICU, 3 from the neurologic ICU, 3 from the mixed ICU, and 1 patient from the surgical ICU. Demographics, mortality rates, and admission diagnoses of the study population are illustrated in Table 1. At the time of the FDG-PET/CT scan, all patients fulfilled the criteria for severe sepsis, 15 patients (83%) were in septic shock (requiring significant vasopressor support), and 12 patients (67%) were mechanically ventilated. In all 18 patients, microbiological tests (cultures of blood, urine, and respiratory secretions), chest x-rays, CT scans, and transesophageal echocardiography were performed before FDGPET/CT scanning. Of the 18 patients, 17 (94%) received antibiotic treatment, and 8 (44%) received antifungal therapy at the time of the FDG-PET/CT scan. In 12 patients (67%), blood cultures were positive. Staphylococcus aureus was identified in 4 patients, S epidermidis in 2 patients, Candida albicans in 2 patients, and Rhodococcus equi, Enterococcus durans, S hominis, and S haemolyticus each in 1 patient. The mean C-reactive protein level was 123 ± 72 mg/L; serum procalcitonin levels were measured in 13 patients (72%), and the median value was 4.3 g/mL (range, 0.4-14.3 g/mL). The median interval between ICU admission and FDG-PET/CT scan was 11 days (range, 1-42 days). No complications occurred during transportation to or from the ICU to the department of nuclear medicine. Adverse reactions to the tracer or the intravenous contrast agents were not observed; the investigation procedure was well tolerated by all patients.
3.2. Diagnostic value of FDG-PET/CT results Table 2 shows all diagnostic tests performed before FDGPET/CT, the final diagnosis, and correlation with FDGPET/CT findings. Pathologic FDG accumulations were found Table 1 Demographics, mortality rates, and admission diagnosis of the study population No. of patients Mean age (y) Sex (female/male) 28-d mortality ICU mortality Admission diagnosis Sepsis of unknown origin Pneumonia Acute liver failure Elective surgery Acute heart failure Acute pancreatitis Acute perimyocarditis
18 55.9 ± 17.8 4/14 0 (0) 6 (33) 7 (39) 4 (22) 2 (11) 2 (11) 1 (6) 1 (6) 1 (6)
Values in parentheses are percentages. Age is presented as mean ± SD.
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Table 2 Diagnostic tests before FDG-PET/CT, final diagnosis, and correlation with FDG-PET/CT in patients with septic shock and unknown source of infection Patient no.
Age/sex
Days on ICU
Cultures R, B, and U
US
TTE/TEE
CT scan
Final diagnosis
Outcome
PET/CT result
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
52/M 67/M 80/M 51/M 22/M 58/M 51/M 71/M 80/M 48/M 62/M 85/F 30/M 50/F 78/F 62/M
45 34 30 23 1 20 20 40 65 57 59 9 111 39 7 22
+, +, + +, +, + +, +, + +, +, + −, +, + −, +, + +, +, + +, +, + +, +, + +, +, + +, +, + −, +, + +, +, + +, +, + −, +, + +, +, +
+ + − + + + + − − + + − + + + +
+/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+ +/+
Chest/abdomen Chest/abdomen Abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen Chest Chest/abdomen Chest/abdomen Chest/abdomen Chest/abdomen
Died Survived Died Survived Survived Survived Survived Survived Died Died Died Survived Died Survived Survived Survived
TP TP TP TP TP TP TP TP TP TP TP TN TN TN TN FP
17
38/M
81
+, +, +
+
+/+
Chest/abdomen
Survived
FP
18
21/F
56
+, +, +
+
+/+
Chest/abdomen
Cervical abscess Pseudomembranous colitis Pacemaker infection Necrotizing pancreatitis Infected vena cava thrombosis Nocardiosis Pacemaker infection Pneumonia Infected vascular graft Pneumonia Spondylodiscitis Perimyocarditis Liver failure Pyoderma gangrenosum Sepsis of unknown origin Sepsis of unknown origin (PET/CT, paravertebral abscess) Cholangitis (PET/CT, chest wall abscess) Pneumonia (PET/CT: tongue abscess)
Survived
FP
In all patients, chest x-rays were performed; + indicates that the test was performed; −, test was not performed; R, respiratory secretions; B, blood; U, urine; US, abdominal ultrasound; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography; TP, true positive; FP, false positive; TN, true negative; FN, false negative.
in 14 (78%) of 18 PET/CT scans; there were 11 true positive, 3 false positive, 4 true negative, and no false negatives. In 5 patients, FDG-PET/CT was essential for the diagnosis because
no other investigation, including CT, provided sufficient diagnostic clues. These 5 cases were patients with pseudomembranous colitis (Fig. 1), an infected femoropopliteal bypass
Fig. 1 An FDG-PET/CT of a patient admitted to ICU with a diagnosis of nosocomial pneumonia. After stabilization, he developed fever, and blood cultures were positive for C albicans. Maximum intensity projection PET (A) and transaxial views of CT, PET, and fused PET/CT images (B and C). Increased uptake is noted in the colon (arrows) and around the central venous catheter (arrow). Colonoscopy revealed a pseudomembranous colitis that resulted in antibiotic treatment. The central venous catheter was removed after diagnosis of a catheter-related Candida sepsis.
PET/CT in sepsis of unknown origin
316.e5
Fig. 2 Maximum intensity projection PET (A) and transaxial views of CT, PET, and fused PET/CT images (B and C). A and B, Marked tracer uptake is noted around the femoral popliteal bypass (arrow). Corresponding CT image shows a small fluid collection, consistent with an infection. A and C, Subcutaneous and intramuscular foci of increased uptake are consistent with inflammation (arrowheads). Surgical removal of the bypass and subsequent microbiological evaluation confirmed the infection.
(Fig. 2), an infected vena cava thrombosis, an infected pacemaker, and a cervical abscess. In 6 cases, the results of the PET/CT scan led to a change of management (surgery, 2; pacemaker removal, 2; initiation of antibiotic therapy, 1; and prolonged antibiotic therapy, 1). Three FDG-PET/CT results were considered false positive. In the first patient (no. 16), FDG-PET/CT suggested the presence of a paravertebral abscess, but surgical exploration revealed that a hematoma and microbiological cultures remained sterile. The second patient (no. 17) had increased FDG uptake in the chest wall, suggesting an abscess formation. However, there were no clinical signs of abscess or focal inflammation, and ultrasound was negative. Therefore, the surgeon refused the request for surgical exploration. The third patient (no. 18) was a 21-year-old woman admitted with community-acquired pneumonia. Because of refractory septic shock during the course of her prolonged ICU stay, an FDG-PET/CT was performed that indicated an abscess in her tongue. However, subsequent surgical exploration revealed no source of infection.
3.3. Outcome Intensive care unit and hospital survival rate was 66% (12/18 patients). Three patients died during the course of prolonged respiratory weaning with multiple complications. One patient died because of septic shock with
multiple organ failure; 1 patient, because of acute liver failure; and 1 patient, because of severe acute respiratory distress syndrome due to pneumonia. In the latter case, an autopsy was performed, pneumonia was confirmed without any other source of infection, and the FDG-PET/CT results were judged as true positive.
4. Discussion Our findings show that FDG-PET/CT is a valuable investigation in the diagnostic workup of patients with septic shock of unknown origin. We were able to demonstrate that FDG-PET/CT was a decisive diagnostic step in a substantial proportion of patients for whom a standardized diagnostic workup including microbiological evaluation (cultures of blood, urine, and respiratory secretions), chest x-rays, CT scanning, and transesophageal echocardiography had failed to obtain a definitive diagnosis. To our knowledge, this is the first study investigating critically ill patients in septic shock with an unknown source of infection undergoing FDG-PET/CT. Conventional anatomical imaging modalities such as x-rays, ultrasound, and CT are normally used for the localization of infectious or inflammatory foci. However, especially in critically ill patients who are mechanically ventilated and sedated, the search for the source of infection may be very difficult. All of the conventional investigations
316.e6 cover only part of the spectrum of possible diagnoses, and therefore, their diagnostic accuracy for detecting the source of septic shock is limited. Nuclear medicine modalities using radiotracers may unmask previously unknown sites of inflammation or infection by providing functional information. This can add relevant information to conventional anatomical imaging modalities that only provide morphological information. The FDG-PET/CT may have a higher sensitivity than other nuclear medicine techniques for the diagnosis of infectious and inflammatory disease, partly owing to the fact that the spatial resolution of PET is much higher than the resolution of single positron emission computed tomography, allowing for the detection of smaller foci [5,8,12]. Despite that functional imaging techniques have been used for many years, few studies have actually assessed the value of nuclear medicine modalities for the identification of the primary infectious source in critically ill patients with sepsis [13-15]. Recently, Simons et al [16] reported a retrospective pilot study of 35 FDG-PET/CT scans in ICU patients for the evaluation of suspected infections. Twenty-one scans were true positive; 3, false positive; and 11, true negative. In 5 cases, the results of the scan had direct therapeutic consequences. However, it needs to be stressed that most patients in this study had fever of unknown origin without severe sepsis or septic shock and that only 2 of the 33 patients studied were in septic shock. Furthermore, less than 40% had additional diagnostic workup such as CT scans or cardiac ultrasound before FDG-PET/CT. This limits the validity and generalizability of this study. In our study, after a standardized and extensive diagnostic workup, the source of sepsis could be detected by FDGPET/CT in 11 (61%) of 18 patients, and in 6 cases, the results of the PET/CT scan led to a change of management. This emphasizes the potential value of this diagnostic technique for this specific population. However, some methodological characteristics have to be taken into account. The clinical importance of a true-negative PET/CT scan result lies in the exclusion of a focal infectious process requiring drainage or prolonged antibiotic treatment. A negative PET/CT scan per se cannot rule out sepsis or septic shock due to bacteremia without specific organ infiltration or involvement. Nevertheless, in these cases, no therapeutic measures would be missed, which go beyond adequate antimicrobial treatment. On the other hand, 3 of the 18 FDG-PET/CT gave falsepositive findings and led to further invasive exploration in 2 of the 3 cases. These 2 operations could not confirm the PET/CT diagnosis and put the patient at additional risk. These findings are consistent with the results of other publications describing false-positive PET/CT scans. Increased localized FDG uptake without an infectious cause has been explained as being related to recent surgery. However, our 3 false-positive cases were not in a postoperative state at the time of the PET/CT scan. Therefore, it needs to be emphasized that positive PET/CT scan results should be considered with caution, especially
S. Kluge et al. when resulting in invasive therapeutic consequences. In such cases, targeted additional investigations such as ultrasound, magnetic resonance imaging, or conventional radiologic studies of the region of interest should be performed. Furthermore, microbiological specimen from the identified area of interest should be obtained and cultured to confirm or exclude the diagnosis. We investigated a highly selected group of patients in whom no source of infection could be identified with conventional diagnostics. We believe that patients with sepsis and septic shock should undergo a standardized diagnostic workup. X-rays, ultrasound, CT, and echocardiography should be performed as a primary diagnostic imaging workup [17]. Only when these conventional imaging modalities are normal or inconclusive should an FDG-PET/CT scan be considered as a next or second level examination. The interpretation of the results of our study is limited by the retrospective design and the relatively small number of patients. However, to our knowledge, this is the first study addressing the value of FDG-PET/CT scans specifically in critically ill patients with severe sepsis and septic shock. Several difficulties in performing this diagnostic procedure in such patients need to be mentioned. First, transportation of patients in septic shock from the ICU to the department of nuclear medicine potentially puts these critically ill patients at risk. However, in our study, no complications related to transportation or the imaging itself were observed. Second, the intervention requires substantial resources in terms of both time and personnel as well as being relatively costly. Recently, Vos et al [18,19] analyzed the cost-effectiveness of FDG-PET/CT in patients with gram-positive bacteremia. Cost data were based on a cost-effectiveness analysis in a prospective FDG-PET/CT group and matched historical control group. Introduction of a diagnostic regimen including routine FDG-PET/CT detected metastatic infectious complications in a substantial proportion of patients and decreased morbidity and mortality. Costs per mortality case prevention of €48 325 were considered to be well within the range that is generally accepted as efficient. Finally, the associated exposure to radiation is potentially harmful but must be weighed against the diagnostic benefit in a patient population with an extreme high mortality rate. Last, the availability of PET/CT scanners is currently limited, although it is increasing.
5. Conclusion In our study, an FDG-PET/CT scan was categorized as “helpful for diagnosis” in 61% of patients with severe sepsis or septic shock of unknown origin and had a high negative predictive value (100%) regarding the exclusion of focal infection requiring drainage or prolonged antibiotic treatment. From these preliminary results, FDG-PET/CT scanning appears to be a valuable diagnostic tool in this patient
PET/CT in sepsis of unknown origin population when extensive prior diagnostic workup has been negative or inconclusive. Prospective multicenter studies with more patients are warranted to further evaluate the diagnostic accuracy and feasibility of FDG-PET/CT scanning in critically ill patients with severe sepsis.
Acknowledgments The authors thank Liz Wager for editing the manuscript.
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