The lack of a patent source of infection and/or the absence of microbiological documentation is not uncommon during the first hours of management of patients presenting with a clinical phenotype of septic shock. Study of a large series of patients with sepsis in the intensive care unit (ICU) [1–3] reveals that approximately 5 % of patients with shock initially deemed to be septic had neither source of infection nor microbiological documentation retrieved by the end of the ICU stay, raising the question whether these patients truly had an underlying infection. In a monocentric study, Heffner et al. [4] showed that 18 % of patients diagnosed with sepsis had in fact a non-infectious condition that mimicked sepsis (sepsis mimicker). Two previous retrospective studies [5, 6] both showed that 13 % of the patients admitted to the ICU with suspected sepsis had in fact no infection identified; interestingly, these patients had a higher mortality rate as compared with those having an identified infection. The causes of sepsis mimickers are numerous and typically include adrenal insufficiency, acute pancreatitis, drug adverse effects, lymphoma, hemophagocytic lymphohistiocytosis or tumor lysis syndrome [4, 7].

The presence of an infectious process is by definition necessary to discriminate between sepsis and sepsis mimickers. However, patients with sepsis mimickers have a clinical phenotype that resembles that of patients with sepsis, so that antimicrobial agents are usually administered within the first hours of recognition of shock [8], until infection is ruled out and an alternative non-infectious diagnosis is made.

Managing a patient with a clinical phenotype of septic shock and with no clear diagnosis (lack of both a source of infection and microbiological documentation) within the first 24 hours of vasopressor introduction is a common but disturbing and challenging clinical scenario reflected by the often quoted question “what does my patient have?” heard during morning rounds in many ICUs. To our knowledge, the prevalence, the causes and the prognosis of suspected septic shock with no early (i.e., 24 h after vasopressor introduction) etiological diagnosis (i.e., non-early-confirmed septic shock) have never been assessed in a large series.

We conducted a pragmatic, prospective, multicenter, observational cohort study including patients initially considered to have septic shock, in which we aimed to: (1) determine the prevalence of non-early-confirmed septic shock, as defined by the lack of a definite source of infection and microbiological documentation within 24 h of shock onset; (2) identify the main causes of non-early-confirmed septic shock; and (3) compare the outcome of patients with and without early-confirmed septic shock.

The main results of our pragmatic study are as follows: (1) a quarter of patients admitted to ICUs with suspected septic shock had no infection identified at 24 h after onset of shock and almost half of them had a septic shock mimicker; (2) septic shock mimickers were mostly due to acute mesenteric ischemia or adverse effects of drugs; and (3) outcomes did not differ between EC-SS and non EC-SS patients.

We reported a high rate (26 %) of patients admitted to the ICU with suspected septic shock and no clear diagnosis 24 h after its onset. This 24-h time point was defined a priori because we believed it relevant to the management of patients with sepsis syndromes, as it practically corresponds to the end of the initial management phase of critically ill patients admitted to the ICU and the time when most patients receive a probable/confirmed diagnosis. We also show that in almost three quarters of these cases (i.e., patients with SUO and SSM, accounting for 19 % of the whole cohort), sepsis was not eventually identified, despite an extensive diagnostic work-up with more imaging procedures and microbiological investigations, which is consistent with the 18 % rate reported by Heffner et al. [4] in the emergency department. Interestingly, the prevalence of diabetes mellitus was higher in patients with non EC-SS as compared to those with EC-SS, likely because of the large proportion of patients with metformin intoxication, which might also explain the higher rate of renal replacement therapy observed in this group. Conversely, the rate of ARDS was higher in patients with EC-SS, consistent with the fact that pulmonary sepsis, known to be one of the main risk factors for ARDS [11, 12], was the source of infection in half of cases in this group.

Our results thus suggest that the lack of either a source of infection or microbiological documentation, identified at 24 h after vasopressor introduction in patients admitted to and treated in the ICU on clinical suspicion of septic shock, should encourage practitioners to consider the possibility of a sepsis mimicker, which in the current study accounted for almost half of the patients in that group. In other words, more than 90 % of patients with confirmed septic shock were diagnosed within 24 h of the onset of shock and infection was secondarily confirmed in only 28 % of patients with shock having no clear diagnosis at 24 h. Our study illustrates the wide differential diagnostic spectrum of patients presenting with a clinical phenotype of septic shock.

Practically, when the etiology of a sepsis syndrome appears unclear, our series provides managing physicians with a useful working list of the main sepsis mimickers among medical admissions. The main causes of sepsis mimickers found in our study were classic [7], with a high proportion of adverse drug reactions, acute mesenteric ischemia, malignancies and inflammatory diseases.

Another important finding of the current study is that 7 % of the patients admitted to the ICU with suspected septic shock had shock of unknown origin and that both the ICU mortality and the 60-day mortality rates in these patients were higher than in other patients, including those with a septic shock mimicker. This 7 % rate is comparable to the 5 % rate of patients with no source of infection or microbiological identification reported in previous large sepsis studies [1–3], raising the question whether these patients truly had an underlying infection.

The reason for the higher risk of mortality observed in the SUO subgroup likely involves the lack of available etiological diagnosis and consequently, the impossibility of promptly initiating targeted treatment to reverse shock. In the ICU setting, autopsy studies [13–15] have been performed to assess the discrepancies between clinical and post-mortem diagnoses. Nevertheless, there is scant information in the literature on the rates of autopsy performed to identify the etiology of lethal shock. Unfortunately, none of our patients who died of shock of unknown origin underwent post-mortem imaging and only one of the three autopsies performed allowed a definite diagnosis (air embolism). Previous autopsy studies suggest that patients with lethal shock of unknown origin may have died from an undiagnosed vascular disease or acute hemorrhage, which are the main causes of missed diagnoses in the ICU setting [13]. In the context of a worldwide decline in the autopsy rate [16, 17], virtual autopsy involving post-mortem multidetector CT or magnetic resonance imaging (MRI) combined with 3D visualization may be a new alternative to medical autopsy [17, 18].

Our study has several limitations. First, the 24-h delay after onset of shock that was used to categorize patients into the EC-SS or the non EC-SS groups may be considered too short as definitive cultures of microbiological samples are not available by then. However, this delay had been defined a priori for its practical clinical relevance and eventually, only 9 % of patients with septic shock were confirmed after 24 h.

Second, patients with acute mesenteric ischemia were categorized as having SSM, which may be questionable. Nevertheless, 10 of the 12 patients diagnosed with acute mesenteric ischemia in the current series underwent surgery and had no evidence of digestive perforation or peritonitis. Moreover, all 12 patients had blood cultures drawn, none of which was positive, and 4 of 10 patients who underwent surgery had peritoneal cultures tested, and all remained sterile. Interestingly, a large recent observational study [19] showed that antibiotic therapy, although widely prescribed, is not associated with reduction of mortality in patients with acute mesenteric ischemia, thus downplaying the role of infection during acute mesenteric ischemia.

Third, a few causes of SSM may appear questionable, including ketoacidosis, reventilation syndrome or propofol-associated hypotension not meeting the diagnostic criteria for propofol infusion syndrome [20]; however, all these patients received antibiotics on clinical suspicion of sepsis and none of them had either microbiological documentation or a source of infection identified.

Fourth, one cannot rule out the possibility that some of the patients eventually diagnosed with SUO had in fact an unidentified infection [1, 21]. However, these patients had no source of infection or microbiological documentation identified by the end of the ICU hospitalization in spite of a comprehensive diagnostic work-up. We acknowledge that conventional microbiological methods frequently fail to identify a microorganism due to various reasons related to technical issues or intrinsic to the microorganism. Using polymerase chain reaction methods might have improved the early diagnosis of sepsis and helped rule out infection within 6 h of ICU admission [22, 23]. Of note, despite the limited number of patients investigated in this regard, plasma procalcitonin levels were lower in patients with SUO, suggesting the absence of an infectious process. Moreover, Combes et al. [13] previously showed that cardiovascular disease was the leading cause of missed clinical diagnoses, as opposed to infectious disease, which accounted for only 10 % of the autopsy-identified missed clinical diagnosis.

Last, the current study was designed two years before the publication of the Sepsis-3 definition [10], and the inclusion of patients was closed before its publication [10]. Thus, the quick version of the sequential organ failure assessment (SOFA) was not collected upon admission. Additionally, although all patients met the criteria for the previous definition of septic shock [9], approximately one fourth (n = 139) of the included patients had no hyperlactacidemia (i.e., serum lactate >2 mmol/L) upon ICU admission and would thus not have met the criteria for the Sepsis-3 definition. In any case, sensitivity analysis was performed in the subgroup of patients meeting the Sepsis-3 criteria and yielded remarkably consistent findings with those obtained from the analysis of the whole cohort.

Our study showed that using conventional microbiological methods, one quarter of the patients admitted to the ICU with clinical presentation of septic shock had no infection identified 24 h after introduction of vasopressors, and almost half of these patients had a non-infectious diagnosis that mimicked sepsis. We identified several causes of septic shock mimickers for which patients with suspected septic shock of no apparent etiology should be screened. Outcomes did not differ between patients with early-confirmed septic shock and other patients. Seven percent of the patients admitted on suspicion of septic shock had no cause identified by the end of ICU stay. Further studies are needed to assess the diagnostic yield of molecular detection methods in this subgroup of patients.