Septic shock with no diagnosis at 24 hours

Contou et al. Critical Care (2016) 20:360 DOI 10.1186/s13054-016-1537-5

RESEARCH  Open Access

: a pragmatic multicenter prospective cohort study

Damien Contou1,2*, Damien Roux3, Sébastien Jochmans4, Rémi Coudroy5, Emmanuel Guérot6, David Grimaldi7, Sylvie Ricome8, Eric Maury9, Gaëtan Plantefève10, Julien Mayaux11, Armand Mekontso Dessap1,2, Christian Brun-Buisson1,2 and Nicolas de Prost1,2

                     

 

Abstract

Background: The lack of a patent source of infection after 24 hours of management of shock considered septic is a common and disturbing scenario. We aimed to determine the prevalence and the causes of shock with no diagnosis 24 hours after its onset, and to compare the outcomes of patients with early-confirmed septic shock to those of others.

Methods: We conducted a pragmatic, prospective, multicenter observational cohort study in ten intensive care units (ICU) in France. We included all consecutive patients admitted to the ICU with suspected septic shock defined by clinical suspicion of infection leading to antibiotic prescription plus acute circulatory failure requiring vasopressor support.

Results: A total of 508 patients were admitted with suspected septic shock. Among them, 374 (74 %) had early- confirmed septic shock, while the 134 others (26 %) had no source of infection identified nor microbiological documentation retrieved 24 hours after shock onset. Among these, 37/134 (28 %) had late-confirmed septic shock diagnosed after 24 hours, 59/134 (44 %) had a condition mimicking septic (septic shock mimicker, mainly related to adverse drug reactions, acute mesenteric ischemia and malignancies) and 38/134 (28 %) had shock of unknown origin by the end of the ICU stay. There were no differences between patients with early-confirmed septic shock and the remainder in ICU mortality and the median duration of ICU stay, of tracheal intubation and of vasopressor support. The multivariable Cox model showed that the risk of day-60 mortality did not differ between patients with or without early-confirmed septic shock. A sensitivity analysis was performed in the subgroup (n = 369/508) of patients meeting the Sepsis-3 definition criteria and displayed consistent results.

Conclusions: One quarter of the patients admitted in the ICU with suspected septic shock had no infection identified 24 hours after its onset and almost half of them were eventually diagnosed with a septic shock mimicker. Outcome did not differ between patients with early-confirmed septic shock and other patients.

Keywords: Sepsis, Septic shock, Sepsis mimickers, Intensive care, Acute mesenteric ischemia

 

* Correspondence: damien.contou@aphp.fr
1Service de réanimation Médicale, Groupe de Recherche CARMAS, Centre Hospitalier Universitaire Henri Mondor, Assistance Publique-Hôpitaux de Paris, 51, avenue du Maréchal de Lattre de Tassigny, Créteil 94010, France 2INSERM U955, Institut Mondor de Recherche Biomedicale, Equipe 8, Faculté de Médecine de Créteil, Université Paris Est-Créteil, Créteil, France
Full list of author information is available at the end of the article

© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

             

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Background

The lack of a patent source of infection and/or the absence of microbiological documentation is not uncom- mon 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 in- tensive 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 sep- sis 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 ad- mitted 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 com- mon 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 docu- mentation 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 with- out early-confirmed septic shock.

Methods

Patients

We conducted a pragmatic, multicenter, observational, prospective cohort study in 10 ICUs in France. From November 2014 to June 2015 all consecutive patients with suspected septic shock requiring ICU admission were in- cluded. Suspected septic shock was defined by clinical sus- picion of infection leading to antibiotic prescription, plus acute circulatory failure requiring vasopressor support [9] (norepinephrine or epinephrine) for more than 1 mg/h and more than 1 h. Patients with post-chemotherapy neu- tropenia, hemorrhagic shock, obstructive or non-septic cardiogenic shock and patients developing post-operative shock or shock post cardiac arrest were excluded. Patients with ICU-acquired septic shock (i.e., occurring more than 48 h after ICU admission) were also excluded.

Within the context of this pragmatic study reflecting real-life practice, the diagnostic work-up was not proto- colized, and microbiological and imaging studies were performed at the discretion of the attending physician (see Additional file 1). Serum biomarkers, including C- reactive protein or procalcitonin were not routinely measured. In the case of lethal shock of unknown origin, an autopsy was encouraged.

Patients’management
All patients were promptly treated with broad-spectrum antibiotic therapy, according to the source of suspected infection, previous antibiotic treatment, and known colonization with multidrug-resistant bacteria. Source control measures, such as surgery or removal of infected devices, were applied when necessary. Patients were treated according to the 2013 guidelines of the Surviving Sepsis Campaign [8]. Low-dose steroids (hydrocortisone) were prescribed at the discretion of the clinician.

Categorization of patients

The investigator of each center participating in the study was responsible for prospectively categorizing patients into two groups, according to data available at 24 h of in- clusion: (1) patients with proven septic shock (i.e., a likely source of infection was identified by clinical or imaging studies and/or microbiological documentation was ob- tained within the first 24 h) were categorized as having early-confirmed septic shock (EC-SS); and (2) patients with no definite infection identified (i.e., absence of both a source of infection and microbiological documentation within the first 24 h) were categorized as having non- early-confirmed septic shock (non EC-SS) (Fig. 1).

Definition of infection

Definitions of infection are provided in Additional file 1, and were used for the post-hoc classification of the sources of infection identified in patients with early-

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Fig. 1 Flow chart. *Shock with no source of infection nor microbiological documentation at 24 h of study inclusion

confirmed and late-confirmed septic shock. For all sources of infection, the absence of microbiological documentation did not per se exclude sepsis.

Collection of data

Details about collected data are available in Additional file 1.

Statistical analysis

Quantitative variables were expressed as median (25th– 75th percentiles) unless otherwise stated, and the nom- inal variables were reported as number (percentage). The quantitative variables were compared using the unpaired Student’s t test or the Mann-Whitney U test, and the nominal variables were compared using the chi- square (χ2) test or the Fisher exact test, as appropriate. The outcome of patients with EC-SS was compared to that of patients with non EC-SS. Mortality over the follow-up period was analyzed using a multivariable Cox model including variables yielding a p value <0.10 in univariable analysis. Potential interactions between vari- ables introduced in the model and centers were tested using the Mantel-Haenszel test of homogeneity of odds ratios; no significant interaction was detected. Follow up was censored at the date of latest information or at 60 days, whichever occurred first. Every effort was made to obtain the post-ICU/hospital discharge vital status from investigators at each site. Survival curves were generated using the Kaplan–Meier method and compared between patients with EC-SS and non EC-SS using the log-rank

test. Sensitivity analysis was performed to assess the validity of our results (i.e., proportion of patients with EC-SS and non EC-SS and Cox model for determining factors associated with mortality) in the subgroup of patients meeting septic shock criteria, as defined by the Third International Consensus Definitions for Sepsis and Septic Shock [10] (Sepsis-3). Missing data were retrieved from queries to the investigators. There was no imputation of missing data, except for data missing from comorbidities, which were then considered as absent. A two-way p value <0.05 was considered significant. Statis- tical analysis was performed using the statistical software package STATA version 13.1 (Stata Corp., College Station, TX, USA).

Results

One of four patients admitted in the ICU with a suspicion of septic shock had no infection identified at 24 h of shock onset
From November 2014 to June 2015, 508 patients with suspected septic shock were admitted to 10 ICUs. Among these 508 patients, 374 (74 %, 95 % CI 70–78) had EC-SS, whereas the remaining 134 (26 %, 95 % CI 22–30) lacked early confirmation (non EC- SS) (Fig. 1). There were no differences in demo- graphic data and associated comorbidities between patients with EC-SS and patients with non EC-SS, except for diabetes mellitus, which was more fre- quent in the latter group (Table 1).

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Table 1 Baseline characteristics of patients admitted to the ICU with suspected septic shock (n = 508) and comparison between patients with early-confirmed septic shocks (EC-SS) and other patients (non EC-SS)

    

Age and gender Age, years Male gender

Comorbidities
Chronic respiratory disease
Chronic heart failure
Chronic kidney disease
Cirrhosis
Recent malignant hemopathy Recent cancer
Diabetes mellitus
HIV infection
Obesity
Cerebrovascular disease Immunosuppressive therapy Immunosuppression statusa
No coexisting comorbid conditions

All patients (n = 508)

68 (59–79) 297 (58)

21 (4) 34 (7) 46 (9) 49 (10) 34 (7) 63 (12) 132 (26) 17 (3) 71 (14) 55 (11) 54 (11) 132 (26) 154 (30)

EC-SS (n = 374)

67 (58–80) 219 (59)

17 (5) 22 (6) 33 (9) 35 (9) 27 (7) 43 (11) 87 (23) 11 (3) 54 (14) 37 (10) 41 (11) 95 (25) 119 (32)

38.4 (37.4 − 39.1) 36.2 (35.4–37.0) 15 (12–15)
58 (45–72)

2 (0–7) 0 (0–1) 0 (0–2) 2 (1–2) 2 (2–3)

17.1 (9.8–24.9) 156 (81–45) 178 (110 − 288) 19.6 (3.7–56.5) 13.6 (8.7–20.0) 187 (115–275) 58 (42–72)

3.4 (2.0–6.1)

Non EC-SS (n = 134) P

68 (61–78) 0.81 78 (58) >0.99

4 (3) 0.44 12 (9) 0.22 13 (10) 0.76 14 (10) 0.71 7 (5) 0.43 20 (15) 0.30 45 (34) 0.019 6 (4) 0.40 17 (13) 0.62 18 (13) 0.26 13 (10) 0.68 37 (28) 0.62 35 (26) 0.22

37.9 (36.9 − 38.6) <0.0001 36.0 (34.6–36.8) 0.006 13 (9–15) 0.002 59 (50–75) 0.34

1 (0–4) 0.33 0 (0–1) 0.28 0 (0–2) 0.59 2 (1–2) 0.09 2 (1–3) 0.050

15.9 (9.9–23.0) 0.62 155 (92–236) 0.72 108 (48–179) <0.0001 1.6 (0.7–7.8) <0.0001 16.0 (9.1–24.0) 0.16 198 (107–347) 0.13

56 (38–72) 0.72

3.6 (2.0–10.0) 0.13

Clinical data within 24 h of inclusion and antibiotic therapy

Maximal temperature, °C Minimal temperature, °C Glasgow Coma Scale SAPS2

Delay admission-inclusion, hours Delay inclusion -ATB1, hours
Delay inclusion -ATB2, hours Number of ATB administered at 3 h Number of ATB administered at 24 h

Biological data within 24 h of inclusion Leukocyte count, 103.mm−3
Platelets count, 103/mm−3
C-reactive protein, mg/Lb Procalcitonin, ng/mLc

Serum urea, mmol/L Serum creatinine, μmoL/L Prothrombin time, % Arterial lactate, mmol/L

38.2 (37.3–39.0) 36.1 (35.2–37.0) 14 (11–15)
58 (47–73)

1 (0–6) 0 (0–1) 0 (0–2) 2 (1–2) 2 (2–3)

16.5 (9.9–24.6) 156 (85–243) 166 (87 − 265) 7.6 (1.3–37.9) 14.0 (8.7–21.7) 187 (114–296) 58 (41–72)

3.5 (2.0–7.0)

Categorical variables are expressed as number (%) and continuous variables as median (IQR 25–75). aImmunosuppression status includes patients with HIV or malignant hemopathy or recent cancer, or under immunosuppressive therapy. bValue available for 248 patients. cValue available for 128 patients. ATB antibiotic therapy, h hour, HIV human immunodeficiency virus, SAPS2 Simplified Acute Physiology Score, WBC white blood count

Patients with non EC-SS underwent more diagnostic testing
Patients with non EC-SS underwent more imaging procedures, including computed tomography (CT) of the chest and abdomen and echocardiography, during the first 24 h of shock management, as

compared to those with EC-SS (see Additional file 1: Table S1). Likewise, among the microbiological tests performed, urine, pleural and lumbar cultures were more frequently obtained in patients with non EC-SS as compared to those with EC-SS (Additional file 1: Table S1).

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Patients with non EC-SS had predominantly non- infectious disease
Only 37 (28 %) of the 134 patients with non EC-SS had infectious etiology, which was identified after a median delay of 2 (IQR 1–2) days following inclusion (late- confirmed septic shocks (LC-SS)), whereas 59 patients (44 %) had non-infectious etiology identified within 2 (1–4) days (septic shock mimickers (SSM)) and 38 patients (28 %) remained with no diagnosis by the end of the ICU stay (shock of unknown origin (SUO)) (Fig. 1 and Table 2). Causes of shock in patients with non EC-SS are shown in Table 2.

For patients with confirmed infection (i.e., the EC-SS and LC-SS groups), the source of infection and the mi- croorganisms isolated are reported in Additional file 1: Tables S2, S3 and S4). In both the EC-SS and LC-SS groups, the main source of infection identified was pleuro-pulmonary (Additional file 1: Table S2), including 33 % of patients (n = 65/195) having no microbiological documentation. Among patients (n = 313) who were not diagnosed with pleuro-pulmonary infection, 52 (17 %) presented with pulmonary infiltrates on chest x-ray. There was no significant difference observed between EC-SS and non EC-SS patients in the proportion of patients with leucocytes in otherwise sterile body fluids (Additional file 1: Table S5).

Day-60 mortality was not different between EC-SS and non EC-SS patients
Patients with EC-SS developed acute respiratory distress syndrome (ARDS) more frequently thanthe other patients, although the requirement of mechanical venti- lation did not differ between EC-SS and non EC-SS pa- tients. Conversely, the non EC-SS group required renal replacement therapy more frequently (Table 3). There were no differences between these two groups in ICU mortality, duration of ICU stay and duration of mechan- ical ventilation or of vasopressor support (Table 3).

The median follow up of patients included in the cohort was 33 (6–98) days in the whole cohort and 93 (55–144) days in survivors. Among patients who sur- vived to ICU discharge (n = 320), 74 had follow up of under 60 days (median 36 (26–53) days) and were censored at the time of the latest follow up. The Kaplan–Meier plot of the probability of survival from inclusion to day 60 showed no significant difference between patients with EC-SS and patients with non EC- SS (Fig. 2; p = 0.41, log-rank test), which was confirmed by the multivariable Cox model after adjusting for covar- iates associated with mortality and taking into account the center effect (Table 4). However, when patients with non EC-SS were categorized as LC-SS, SSM or SUO, those from the latter subgroup had a lower probability of survival than the others (Additional file 1: Figure S1;

Table 2 Causes of shock in the 134 patients with non-early- confirmed septic shock (non EC-SS, i.e., patients with shock but no source of infection or microbiological documentation at 24 h after onset of shock)

Causes
Late-confirmed septic shock (LC-SS), n/total study sample (%)

Pleuro-pulmonary
Urinary tract
Abdomen
Liver and biliary tract
Primary bloodstream infection Skin and soft tissues Endocarditis

Bone-joint
Central nervous system Endovascular stent infection

Septic shock mimickers (SSM), n/total study sample (%) Adverse effects of drugs

Metformin

Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers

β-blockers Propofol Othersa

Vascular
Acute mesenteric ischemia

Arterial

Venous Malignancies

Lymphoma
Solid tumor (including one Marastic endocarditis) Tumor lysis syndrome

Inflammatory diseases
Hemophagocytic lymphohistiocytosis
Drug rash with eosinophilia and systemic symptoms Catastrophic antiphospholipid syndrome Cholesterol embolization syndrome

Metabolic disorders
Acute adrenal insufficiency Diabetic ketoacidosis

Acute pancreatitis Miscellaneous

Abdominal compartment syndrome Air embolismb
“Reventilation” syndrome

Shock of unknown origin (SUO), n/total study sample (%)

Number (%) 37/134 (28) 13/37 (35) 6/37 (16) 4/37 (11) 4/37 (11) 4/37 (11) 2/37 (5) 1/37 (3) 1/37 (3) 1/37 (3) 1/37 (3) 59/134 (44) 22/59 (37) 10

4

2
2
4
12/59 (20) 12

10
2
9/59 (15)
3
4
2
5/59 (8)
2
1
1
1
4/59 (7)
2
2
4/59 (7)
3/59 (5)
1
1
1
38/134 (28 %)

  

Categorical variables are expressed as n (%). aIncluding neuroleptic (n = 1), lithium (n = 1), intravenous immunoglobulins (n = 1), sorafenib (n = 1).
bAir embolism was clinically suspected and confirmed by autopsy

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Table 3 Organ support and outcomes in patients admitted to the ICU with suspected septic shock (n = 508) and comparison between patients with early-confirmed septic shock (EC-SS) or non-early confirmed septic shock (Non EC-SS)

    

Tracheal intubation
ARDS
Renal replacement therapy
Steroids for septic shocka
ECMO
Duration of tracheal intubation, days Duration of vasopressors support, days Duration of ICU stay, days
ICU mortality
Follow-up duration, days
Mortality over the follow-up period

All patients (n = 508)

397 (78) 167 (33) 145 (28) 197 (39)
8 (2) 4(1−9) 3(2−5)
7 (4−14) 188 (37) 29(7−96) 232 (46)

EC-SS (n = 374)

294 (79) 143 (38) 95 (25) 143 (38)
5 (1) 4(1−9) 3(2−5)
7 (4−24) 139 (37) 30(8−91) 166 (44)

Non EC-SS (n = 134) P

103 (77) 0.67
24 (18) <0.0001 50 (37) 0.009 54 (40) 0.67
3 (2) 0.44
4 (0 − 6) 0.19
3 (2 − 6) 0.55
7 (4−21) 0.69
49 (37) 0.90
25 (6 − 113) 0.75
66 (49) 0.33

Categorical variables are expressed as n (%) and continuous variables as median (IQR 25–75). aIncludes eight patients receiving either steroids or placebo because of clinical trial enrolment.
ARDS acute respiratory distress syndrome, ECMO extra-corporeal membrane oxygenation, ICU Intensive Care Unit

p = 0.014, log-rank test). The multivariable Cox model confirmed that patients categorized as having SUO had higher risk of mortality (Additional file 1: Table S6).

Sensitivity analysis assessing the validity of the results in the subgroup of patients meeting the criteria of the Sepsis-3 definition
Among the 508 included patients with septic shock ac- cording to the 1992 definition [9], 369 (73 %) had serum lactate levels greater than 2 mmol/L and thus met the septic shock criteria of the Sepsis-3 definition [10]. In this subgroup, the distribution of patients with EC-SS (n=272 (74 %), 95 % CI 69–78) and non EC-SS (n= 97 (26 %), 95 % CI 21–30) was remarkably similar with that of the whole cohort. Moreover, among pa- tients with non EC-SS, the proportion of those with LC-SS (n=23 (24 %), 95 % CI 15–32), SSM (n=43 (44 %), 95 % CI 34–54), and SUO (n=31 (32 %), 95 % CI

23–41) was also consistent with that observed in the whole cohort (Additional file 1: Table S7).

A multivariable Cox model was run in this subgroup and displayed results consistent with those in the whole cohort, with no significant relationship between non EC- SS and day-60 mortality (Additional file 1: Table S8). Also, when patients with non EC-SS were categorized as LC-SS, SSM or SUO, those from the latter sub- group had higher risk of mortality than the other patients (Additional file 1: Table S9), consistent with the results obtained in the whole cohort.

Discussion

The main results of our pragmatic study are as follows: (1) a quarter of patients admitted to ICUs with sus- pected 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 diag- nosis 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 manage- ment 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 microbio- logical investigations, which is consistent with the 18 %

  

Fig. 2 Kaplan–Meier plot of the probability of survival from inclusion to day 60 in patients with early-confirmed septic shock (EC-SS, blue curve) and other patients (Non EC-SS, red curve)

 

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Table 4 Factors associated with day-60 mortality in univariable and multivariable Cox models

Variables

Categorization of shock EC-SS

Non EC-SS Cirrhosis

No

Yes Cancer

No

Yes
Chronic respiratory failure

No

Yes
Age >68 years

No

Yes SAPS2 > 58

No

Yes
PT ratio <50%

No

Yes
Mechanical ventilation

No

Yes
Lactate, per point in mmol/L

Univariable analysis HR(95%CI)

1
0.87 (0.65–1.16)

1
2.04 (1.42–2.93)

1
1.62 (1.15–2.28)

1
2.16 (1.30–3.59)

1
1.47 (1.14–1.91)

1
3.01 (2.28–3.96)

1
1.96 (1.50–2.55)

1
3.65 (2.33–5.72) 1.09 (1.07–1.11)

Multivariable analysisa P HR(95%CI)

0.34

1
<0.0001 2.45 (1.63–3.69)

1
0.006 1.91 (1.32–2.75)

1
0.003 2.45 (1.41–4.26)

1
<0.0001 1.73 (1.30–2.30)

1
<0.0001 1.94 (1.43–2.64)

1
<0.0001 1.41 (1.05–1.91)

1
<0.0001 2.53 (1.57–4.09)

<0.0001 1.06 (1.04–1.09)

P

<0.0001

<0.001

0.002

<0.0001

<0.0001

0.024

<0.0001

<0.0001

      

Patients were categorized as having early-confirmed (i.e., within 24 h of vasopressor initiation) septic shock (EC-SS) or not (non EC-SS). aAdjusted for center. CI confidence interval, HR hazard ratio, PT prothrombin time, SAPS2 simplified acute physiology score 2

rate reported by Heffner et al. [4] in the emergency de- partment. Interestingly, the prevalence of diabetes melli- tus was higher in patients with non EC-SS as compared to those with EC-SS, likely because of the large propor- tion 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 pa- tients 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 sec- ondarily 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 pre- senting with a clinical phenotype of septic shock.

Practically, when the etiology of a sepsis syndrome appears unclear, our series provides managing physi- cians 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 re- actions, 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 mor- tality rates in these patients were higher than in other

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patients, including those with a septic shock mim- icker. This 7 % rate is comparable to the 5 % rate of patients with no source of infection or microbio- logical 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 avail- able etiological diagnosis and consequently, the im- possibility of promptly initiating targeted treatment to reverse shock. In the ICU setting, autopsy studies [13–15] have been performed to assess the discrepan- cies between clinical and post-mortem diagnoses. Nevertheless, there is scant information in the litera- ture 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 under- went post-mortem imaging and only one of the three autopsies performed allowed a definite diagnosis (air embolism). Previous autopsy studies suggest that pa- tients 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 consid- ered 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 rele- vance 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 ques- tionable. 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 posi- tive, 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 pre- scribed, is not associated with reduction of mortality in patients with acute mesenteric ischemia, thus downplaying the role of infection during acute mesen- teric ischemia.

Third, a few causes of SSM may appear question- able, including ketoacidosis, reventilation syndrome or

propofol-associated hypotension not meeting the diag- nostic 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 microbio- logical documentation identified by the end of the ICU hospitalization in spite of a comprehensive diag- nostic work-up. We acknowledge that conventional microbiological methods frequently fail to identify a microorganism due to various reasons related to tech- nical issues or intrinsic to the microorganism. Using polymerase chain reaction methods might have im- proved 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 inves- tigated in this regard, plasma procalcitonin levels were lower in patients with SUO, suggesting the ab- sence 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 be- fore 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 se- quential 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.

Conclusion

Our study showed that using conventional microbio- logical 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 vaso- pressors, 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

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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.

Key messages

 One quarter of the patients admitted to the ICU on suspicion of septic shock had no infection identified 24 h after onset of shock.

 Almost half of the patients with no infection identified 24 h after onset of shock had a non-infectious disease that mimicked sepsis.

 The main causes of septic shock mimickers were adverse effects of drugs, malignancies, acute mesenteric ischemia and inflammatory diseases.

 Outcomes did not differ between patients with and without early-confirmed septic shock.

 Seven percent of the patients admitted to the ICU on suspicion of septic shock had shock of unknown origin.
Additional file
Abbreviations
ARDS: acute respiratory distress syndrome; CT: computed tomography; EC-SS: early-confirmed septic shock; ICU: intensive care unit; LC-SS: lately-confirmed septic shock; SSM: septic shock mimicker; SUO: shock of unknown origin
Acknowledgements
The authors are grateful to Juliette Palle, Patricia Villié, Priscille Baudin, Ségolène Périneau, Tomas Urbina, Yann N’Guyen and Maxens Decavele, who contributed to data collection.
Funding
This study did not receive funding from external or internal sources.
Availability of data and materials
Not applicable.
Authors’ contributions
DC conceived the study, acquired the data and drafted the manuscript. NDP conceived the study, performed the statistical analysis and revised the manuscript. CBB performed the statistical analysis and revised the manuscript. AMD participated in the design of the study and helped to revise the manuscript. DR, SJ, RC, EG, DG, SR, EM, GP and JM acquired the data and helped to revise the manuscript. All authors read and approved the final manuscript.
Authors’ information Not applicable.
Competing interests
The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

The study was conducted in accordance with French law as standard care, and received approval from the Comité de Protection des Personnes Ile de France VI, Paris, France, in September 2014. As per French law, the need for patient approval was waived because of the observational nature of the study.

Author details

1Service de réanimation Médicale, Groupe de Recherche CARMAS, Centre Hospitalier Universitaire Henri Mondor, Assistance Publique-Hôpitaux de Paris, 51, avenue du Maréchal de Lattre de Tassigny, Créteil 94010, France. 2INSERM U955, Institut Mondor de Recherche Biomedicale, Equipe 8, Faculté de Médecine de Créteil, Université Paris Est-Créteil, Créteil, France. 3Service de réanimation médico-chirurgicale, Centre Hospitalier Universitaire Louis Mourier, Assistance Publique-Hôpitaux de Paris, 178 rue des Renouillers, Colombes 92700, France. 4Service de réanimation, Centre Hospitalier Marc Jacquet, 2 rue Fréteau de Peny, Melun 77011, France. 5Service de réanimation médicale, Centre Hospitalier Universitaire de Poitiers, 2 rue de la Milétrie, Poitiers 86021, France. 6Service de réanimation médicale, Centre Hospitalier Universitaire Georges Pompidou, Assistance Publique-Hôpitaux de Paris, 20 rue Leblanc, Paris 75015, France. 7Service de réanimation médico-chirurgicale, Centre Hospitalier André Mignot, 177 rue de Versailles, Le Chesnay 78150, France. 8Service de réanimation, Centre Hospitalier Robert Ballanger, Boulevard Robert Ballanger, Aulnay-sous-Bois 93600, France. 9Service de réanimation médicale, Centre Hospitalier Universitaire Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 184 rue du Faubourg Saint-Antoine, Paris 75012, France. 10Service de réanimation polyvalente, Centre Hospitalier Victor Dupouy, 69 rue du Lieutenant-Colonel Prudhon, Argenteuil 95107, France. 11Service de réanimation médicale, Centre Hospitalier Universitaire Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris, 47-83 Boulevard de l’Hôpital, Paris 75013, France.

Received: 13 June 2016 Accepted: 19 October 2016

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