# Characteristics and outcomes of ECMO cannula-related infections: a European multicenter retrospective study

Sofia Ortuno, Nicolas Massart, Charles Vidal, Etienne de Montmollin, Adrien Bouglé, Nicolas Nesseler, Frank Bidar, Benjamin Assouline, Paul Masi, Samuel Henri, et al.

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## To cite this version:

Sofia Ortuno, Nicolas Massart, Charles Vidal, Etienne de Montmollin, Adrien Bouglé, et al. Char- acteristics and outcomes of ECMO cannula-related infections: a European multicenter retrospective study. Annals of Intensive Care, 2025, 15 (1), pp.36. 10.1186/s13613-025-01446-y. hal-05025168

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# Characteristics and outcomes of ECMO cannula-related infections: a European multicenter retrospective study

Sofia Ortuno¹, Nicolas Massart², Charles Vidal³, Etienne de Montmollin⁴, Adrien Bouglé⁵, Nicolas Nesseler⁶,⁷,⁸, Frank Bidar⁹,¹⁰, Benjamin Assouline¹¹, Paul Masi¹²,¹³, Samuel Henri¹⁴, Sami Hraiech¹⁵, Hadrien Rozé¹⁶, Francesca Manicone¹⁷,¹⁸ and Charles-Edouard Luyt¹,¹⁹*

**Abstract**

**Objective** Only few data regarding epidemiology and management of ECMO cannula-related infections (ECMO-CRIs) exist. The aim of our study was to describe their epidemiology and prognosis, and to evaluate factors associated with outcome.

**Methods** We performed a multicenter retrospective study in 12 European ICUs, including patients with ECMO-CRI, defined as a clinical suspicion plus a positive bacterial sample of ECMO-cannulation site. Primary objective was to describe ECMO-CRI characteristics and outcomes. Secondary objectives were to evaluate the rates of infection recurrence, their risk factors, and to evaluate the impact of antimicrobial treatment duration on outcome.

**Results** During the study period, 109 patients with ECMO-CRI (78 having concomitant positive blood culture with the same pathogen) were included. Pathogens responsible for infections were predominantly Enterobacteriaceae, coagulase-negative Staphylococcus and Enterococcus spp., and 42% of episodes were polymicrobial. Rates of infection recurrence was 13% and ICU-mortality rate was 51%. Risk factors for death were concomitant blood-stream infection with same pathogen and septic shock. Patients with antibiotic course ≤ 8 days had similar infection recurrence rate and outcomes (including mortality) than patients with prolonged (> 8 days) antibiotic course.

**Conclusion** ECMO-CRIs are frequently associated with BSI and frequently polymicrobial. Duration of antimicrobial treatment for ECMO-CRI ≤ 8 days does not seem to be associated with an increased risk of recurrence or death, as compared to longer treatment.

**Keywords** ECMO, Cannula-related infection, Hospital-acquired infection, Bloodstream infection

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<footnote>*Correspondence:
Charles-Edouard Luyt
charles-edouard.luyt@aphp.fr
Full list of author information is available at the end of the article</footnote>
## Introduction

Extracorporeal membrane oxygenation (ECMO) is a complex therapy associated with potential life-threatening complications [1]. Infections are one of the main complications, occurring in 42–64% of ECMO patients [2–6]. Ventilator-associated pneumonia (VAP) is the most frequent one, but other ECMO-related infections (cannula-related infection (CRI), associated or not with bloodstream infection (BSI)) are frequent and may lead to increased morbidity/mortality. However, data regarding ECMO-CRI are scarce. In a retrospective large cohort of nosocomial infections in ECMO-patients, Schmidt et al. found that ECMO-CRI represents 10% of them [2], whereas Grasselli et al. found a 3% rate of CRI [5]. Discriminating cannula colonization from infection is sometimes challenging, since traditional clinical and biological signs of infection are frequently absent in ECMO patients.

Additionally, little is known about bacterial epidemiology of CRI, since published studies mostly focus on pediatric patients [7, 8]. In addition, no consensus on diagnostic criteria or management of ECMO-CRI exists, and little is known about their impact on prognosis. Data showed that long ECMO run (up to 10 days) were associated with increased rate of CRI, and that these infections were associated with prolonged hospital stay [8, 9]. Practices regarding treatment of these infections are heterogeneous [10], and optimal duration of antimicrobial treatment is unknown [11, 12].

We therefore design this study to describe the epidemiology, management and prognosis of ECMO-CRI, and to determine factors associated with outcomes, with a particular focus on the duration of antimicrobial treatment.

## Methods

### Centers

Thirteen high-volume ECMO centers (> 30 ECMO/year) were contacted and asked to participate. All were located in France, except 2 located outside France in Europe (Geneva and Brussels). Among the 13 centers contacted, 12 (10 in France and the 2 outside France) agreed to participate.

### Patients

Investigators from the 12 participating ICUs were invited to include their 10 most recent patients (starting from December 2022 and going back as far as January 2012) with ECMO-CRI (see definition below), that occurred either on veno-arterial- (VA) or veno-venous (VV)-ECMO. Since some centers had less than 10 CRI during the study period, other centers could include more than 10 patients.

## Study objectives

The primary objective was to describe the characteristics of ECMO-CRI, as defined hereafter, and its outcomes. Secondary objectives were to evaluate the rate of infection recurrence (see definition below), and to evaluate the impact of antimicrobial treatment duration on the outcome.

## Definitions

ECMO-CRI episodes were identified in each center by the investigator, based on patient's chart. In all centers, criteria for ECMO-CRI were either inflammatory signs at cannula site or general signs of infection (fever, leukocytosis, hemodynamic impairment) combined with a positive microbial sampling of cannula site. Details regarding the centers' procedures for infection prevention and methods for ECMO-CRI diagnosis are given in the online supplement. ECMO-CRI was considered complicated by BSI when the same pathogen (same species, same resistance profile) was retrieved from blood culture and cannula sampling at the same time (within a 48-h time window). Patients with infection of the cannulation site occurring after ECMO removal were not included. Patients with cannula-colonization (positive bacterial sampling of cannula and without local signs or without BSI) were not included. Patients with primary BSI (BSI without portal of entry and without bacteriologically-proven ECMO-CRI) were not included in the present study. Although ECMO cannula may be the hidden portal of entry of such infection, we choose not to include them since we wanted to focus on CRI and its management.

Recurrence of ECMO-CRI was defined as a new infection episode (same definition as first episode) in a patient having developed a first episode, whatever the pathogen responsible for the second episode. Second episodes occurring after ECMO removal were also considered as recurrences. In these patients, recurrence was defined as a new infection of the cannula site (purulent drainage of the orifice or cellulitis) confirmed by a positive bacteriological sample. Patients without second episode of ECMO-CRI were considered as cured from infection.

Duration of antimicrobial treatment for the first episode was defined as the total duration of antimicrobial treatment effective against the pathogen(s) responsible for ECMO-related infection, including time on antibiotics given for another infection than ECMO-related infection. Antimicrobial treatment was considered appropriate when the incriminated microorganism was susceptible to the antibiotic administered on antimicrobial susceptibility testing. As an example, if a patient
received amoxicillin for a ECMO-CRI due to wild-
type E. coli had to be switched at day 7 of amoxicillin
to a 7-day course of piperacillin-tazobactam for Pseu-
domonas aeruginosa VAP episode, he was considered
to have received 14 days of effective antibiotic treat-
ment for the initial ECMO-CRI.

Multi drug resistant organism (MDRO) was consid-
ered according to the definition of the European Soci-
ety of Clinical Microbiology and Infectious Disease,
as pathogens resistant to more than one antimicrobial
agent [13].

We also recorded local cannula site complications after
decannulation (hemorrhage, infection and thrombosis),
mortality rate before ECMO weaning, duration of ECMO
support and ventilatory support, length of ICU stays and
ICU mortality rate. We then determined factors associ-
ated with recurrence.

Statistical analysis

Categorical variables are expressed as percentages and
continuous variables as median and interquartile range
(IQR). Chi-Square test and Fisher exact test were used to
compare categorical variables and Mann-Whitney U test
or Wilcoxon test for continuous variables.

To determine factors associated with ICU-mortality, uni- and multivariable analysis of factors associated with ICU death were performed using a Cox proportional model. Proportional assumption for Cox model was tested using scaled Schoenfeld residuals. Variables with a p-value < 0.2 in univariable analysis were entered into the model.

To further explore the impact of antimicrobial treat-
ment duration of the first episode on outcome, we
selected the 94 patients who survived at least 8 days
after infection onset, and split them into 2 categories:
short duration of antimicrobial treatment, i.e. ≤ 8 days,
and long duration of treatment, i.e. > 8 days. To account
for inter-group imbalances of baseline characteristics
between patients with prolonged and short antibiotic
duration, a propensity score overlap weighted analy-
sis was performed [14]. Propensity score was calculated
using a non-parsimonious model including the follow-
ing variables: age, sex, comorbidities, reason for ECMO
cannulation, BMI, COVID-19 status, antibiotic at ECMO
cannulation, cardiac arrest at cannulation, type of ECMO,
SOFA at ECMO cannulation and a modified SAPS II (in
order to avoid redundancy with age, a modified SAPS II
score was calculated with exclusion of the variable age).
Propensity score ranked from 0 to 1 and corresponded
for each patient to its probability to received prolonged
antibiotic treatment. Then, in order to obtain 2 compa-
rable groups and using an overlap weighted analysis,

patients were attributed a weight of 1-PS (patients with
prolonged antibiotic duration) or PS (patients with short
treatment duration). Then the average effect of pro-
longed antibiotic duration was estimated by the differ-
ence between the overlap weighted populations. Analyses
were performed with an alpha risk of 5%. Statistical anal-
ysis was performed with the statistical software R 4.1.1.

Ethics

In accordance with current French law, informed writ-
ten consent for demographic, physiologic and hospital-
outcome data analyses was not obtained because this
observational study did not modify existing diagnostic or
therapeutic strategies. Nonetheless, patients and/or rela-
tives were informed about the anonymous data collection
and told that they could decline inclusion. The protocol
was approved by the ethics committee of the Société de
Réanimation de Langue Française on January, 15th, 2023
(registration no. CE-SRLF-22-074) for patients included
in France and in Belgium, and the ethics commit-
tee of the Geneva University Hospitals for the patients
included in Switzerland (registration n° 2023-00540).
The database is registered by the Commission Nationale
de l'Informatique et des Libertés (CNIL, registration no
2228484v 0).

Results

Between January 2012 and December 2022, 109 ECMO
patients with ECMO-CRI were included. Baseline
patients' characteristics are presented in Table 1. Patients
were predominantly male (68%), young (median (IQR)
age 52 (38–61 years), and 22 (20%) were immunosup-
pressed. We included higher number of patients with
VA-ECMO (n=77, 71%) than patients with VV-ECMO
(n=32, 29%).

ECMO-CRI characteristics

ECMO-CRI characteristics (clinical presentation, path-
ogens responsible for infection and management of
infection) are displayed in Table 2. Median [IQR] time
between ECMO implantation and ECMO-CRI was 7
[5–13] days in patients having surgical cannula insertion,
and 9 [6–15] days in patients with percutaneous cannula
insertion (p=0.08 for between-groups comparisons).
Among the 109 episodes of ECMO-CRI, 78 (72%) had
blood culture positive that yielded the same pathogen
that the one retrieved at the cannula site. Although the
majority (65%) had inflammatory signs at cannula inser-
tion site, 41 had ECMO-CRI with concomitant BSI but
without local sign of infection. Pathogens responsible for
ECMO-CRI are shown on Table 2: Enterobacteriaceae
<table><caption>**Table 1** Baseline characteristics according to ICU</caption><thead><tr><th></th><th>Overall population<br>n = 109</th><th>Alive<br>n = 53</th><th>Death in ICU<br>n = 56</th><th>p</th></tr></thead><tbody><tr><td>Baseline characteristics</td><td></td><td></td><td></td><td></td></tr><tr><td>Male sex</td><td>74 (67.9)</td><td>36 (67.9)</td><td>38 (67.9)</td><td>1.0</td></tr><tr><td>Age, years</td><td>52 [38–61]</td><td>50 [37–58]</td><td>55 [39–62]</td><td>0.29</td></tr><tr><td>BMI, kg/m² *</td><td>28 [25–34]</td><td>28 [25–33]</td><td>28.5 [26–35]</td><td>0.69</td></tr><tr><td>Pre-existing conditions</td><td></td><td></td><td></td><td></td></tr><tr><td>Chronic cardiac disease</td><td>39 (36)</td><td>18 (34)</td><td>21 (38)</td><td>0.85</td></tr><tr><td>Chronic renal disease</td><td>15 (14)</td><td>6 (11)</td><td>9 (16)</td><td>0.58</td></tr><tr><td>Chronic respiratory disease</td><td>15 (14)</td><td>4 (8)</td><td>11 (20)</td><td>0.12</td></tr><tr><td>Diabetes mellitus</td><td>34 (31)</td><td>17 (32)</td><td>17 (30)</td><td>1.0</td></tr><tr><td>Peripheral vascular disease</td><td>20 (18)</td><td>7 (13)</td><td>13 (23)</td><td>0.27</td></tr><tr><td>Immunocompromised †</td><td>22 (20)</td><td>9 (17)</td><td>13 (23)</td><td>0.57</td></tr><tr><td>Ongoing pregnancy</td><td>1 (1)</td><td>0</td><td>1 (2)</td><td>1.0</td></tr><tr><td>Admission SAPS2</td><td>41 [29–57]</td><td>42 [29–56]</td><td>41 [30–61]</td><td>0.75</td></tr><tr><td>Admission SOFA score</td><td>9 [4–12]</td><td>9 [6–11]</td><td>9 [4–12]</td><td>0.79</td></tr><tr><td>ECMO characteristics</td><td></td><td></td><td></td><td></td></tr><tr><td>Veno-venous ECMO</td><td>32 (30)</td><td>12 (23)</td><td>20 (36)</td><td>0.19</td></tr><tr><td>Percutaneous cannulation</td><td>64 (66)</td><td>29 (67)</td><td>35 (65)</td><td>0.96</td></tr><tr><td>Ongoing antibiotics at ECMO start</td><td>44 (40)</td><td>17 (32)</td><td>27 (48)</td><td>0.13</td></tr><tr><td>SARS-Cov2 infection</td><td>22 (20)</td><td>8 (15)</td><td>14 (25)</td><td>0.29</td></tr><tr><td>Indication of ECMO</td><td></td><td></td><td></td><td>0.56</td></tr><tr><td>Cardiogenic shock</td><td>58 (53)</td><td>29 (55)</td><td>29 (52)</td><td></td></tr><tr><td>ARDS</td><td>32 (29)</td><td>13 (25)</td><td>19 (34)</td><td></td></tr><tr><td>Post-cardiotomy</td><td>11 (10)</td><td>5 (9)</td><td>6 (11)</td><td></td></tr><tr><td>Septic shock</td><td>1 (1)</td><td>1 (2)</td><td>0 (0)</td><td></td></tr><tr><td>E-CPR</td><td>5 (5)</td><td>4 (8)</td><td>1 (2)</td><td></td></tr><tr><td>Other</td><td>2 (2)</td><td>1 (2)</td><td>1 (2)</td><td></td></tr><tr><td>Cannulation by mobile unit</td><td>24 (23)</td><td>12 (24)</td><td>12 (22)</td><td>1.0</td></tr></tbody></table>

Data are expressed as median (IQR) or n (%)

BMI: Body Mass Index; SAPS2: Simplified acute physiology score 2; SOFA: Sepsis-related organ failure assessment; ECMO: Extra-corporeal membrane oxygenation; E-CPR: Extracorporeal cardiopulmonary resuscitation

* Data available for 101/109 patients

† Solid organ transplant recipients, active hematological malignancy or receiving immunosuppressant drug (including corticosteroids at a dose ≥ 0.5 mg/kg/d for ≥ 1 month)

were the most common pathogen responsible for these infections, followed by coagulase-negative *Staphylococcus* and *Enterococcus* spp.. Interestingly, 42 (39%) of episodes were polymicrobial. Regarding coagulase-negative *Staphylococcus*, 26 out of the 32 ECMO-CRI due to coagulase-negative *Staphylococcus* were associated with BSI with the same coagulase-negative *Staphylococcus*, and the 6 other were polymicrobial, coagulase-negative *Staphylococcus* being not the only pathogen responsible for ECMO-CRI.

Details on treatment are reported in Table 2: median (IQR) duration of antimicrobial treatment was 10 (7–15)

days, similar in patients with and without concomitant BSI (median (IQR) durations of 11 (7–15) and 10 (7–15) days, respectively, p = 0.4); 24 patients (22%) were treated using combination therapy during all the duration of antimicrobial treatment, 32 (29%) had surgery for their ECMO-CRI, and 22 (20%) had change of cannulation site for the infection.

## Outcomes

Among the 109 patients, 14 had a second episode of infection that occurred after a median (IQR) of 6 (0–10) days after the end of antimicrobial treatment of the first
<table><caption>**Table 2** First ECMO-related infection episode characteristics</caption><thead><tr><th></th><th>Overall population<br>n = 109</th><th>Alive<br>n = 53</th><th>Death in ICU<br>n = 56</th><th>p</th></tr></thead><tbody><tr><td>Time between ECMO insertion and first episode, days</td><td>8 [6–15]</td><td>8 [5–13]</td><td>9 [6–19]</td><td>0.21</td></tr><tr><td>Concomitant BSI</td><td>78 (72)</td><td>31 (59)</td><td>47 (84)</td><td>0.006</td></tr><tr><td>Septic shock</td><td>61 (57)</td><td>17 (33)</td><td>44 (79)</td><td>&lt; 0.001</td></tr><tr><td>Inflammatory sign at cannula insertion site</td><td>68 (65)</td><td>31 (61)</td><td>37 (69)</td><td>0.53</td></tr><tr><td>Pathogen</td><td></td><td></td><td></td><td></td></tr><tr><td>Staphylococcus aureus</td><td>5 (5)</td><td>3 (6)</td><td>2 (4)</td><td>0.67</td></tr><tr><td>Methicillin resistant</td><td>0</td><td>0</td><td>0</td><td>-</td></tr><tr><td>Coagulase-negative Staphylococcus</td><td>32 (29)</td><td>13 (25)</td><td>19 (34)</td><td>0.3</td></tr><tr><td>Streptococcus spp</td><td>4 (4)</td><td>3 (6)</td><td>1 (2)</td><td>0.35</td></tr><tr><td>Enterococcus spp</td><td>33 (30)</td><td>16 (30)</td><td>17 (30)</td><td>1.0</td></tr><tr><td>Vancomycin resistant</td><td>0</td><td>0</td><td>0</td><td>-</td></tr><tr><td>Enterobacteriaceae</td><td>55 (51)</td><td>28 (53)</td><td>27 (48)</td><td>0.77</td></tr><tr><td>ESBL-producer</td><td>13 (12)</td><td>4 (8)</td><td>9 (16)</td><td>0.28</td></tr><tr><td>Carbapenem resistant</td><td>3 (3)</td><td>1 (2)</td><td>2 (4)</td><td>1.0</td></tr><tr><td>Non fermenting Gram-negative bacilli</td><td>20 (18)</td><td>11 (21)</td><td>9 (16)</td><td>0.7</td></tr><tr><td>Multiresistant NF-GNB</td><td>5 (5)</td><td>2 (4)</td><td>3 (5)</td><td>1.0</td></tr><tr><td>Anaerobe</td><td>5 (5)</td><td>2 (4)</td><td>3 (5)</td><td>1.0</td></tr><tr><td>MDRO</td><td>18 (17)</td><td>6 (11)</td><td>12 (21)</td><td>0.25</td></tr><tr><td>Polymicrobial</td><td>42 (39)</td><td>22 (42)</td><td>20 (36)</td><td>0.67</td></tr><tr><td>Time from diagnostic to empiric treatment, days</td><td>0 [0–0]</td><td>0 [0–0.5]</td><td>0 [0–0]</td><td>0.57</td></tr><tr><td>Appropriate empiric antimicrobial treatment</td><td>66 (69)</td><td>31 (62)</td><td>35 (76)</td><td>0.21</td></tr><tr><td>Time from infection onset to appropriate antimicrobial treatment, days</td><td>1 [0–2]</td><td>2 [1, 2]</td><td>0.50 [0–2]</td><td>0.01</td></tr><tr><td>Duration of antimicrobial treatment of first CRI, days *</td><td>10 [7–15]</td><td>11.50 [7–16]</td><td>10 [7–14]</td><td>0.12</td></tr><tr><td>Combination antimicrobial treatment</td><td>24 (22)</td><td>13 (25)</td><td>11 (20)</td><td>0.70</td></tr><tr><td>Oxygenator change during infection</td><td>27 (25)</td><td>13 (25)</td><td>14 (25)</td><td>1.0</td></tr><tr><td>Cannula site change for infection</td><td>22 (20)</td><td>10 (19)</td><td>12 (21)</td><td>0.93</td></tr><tr><td>Surgery needed for cannula site infection</td><td>32 (29)</td><td>18 (34)</td><td>14 (25)</td><td>0.41</td></tr><tr><td>ECMO-CRI recurrence</td><td>14 (13)</td><td>8 (15)</td><td>6 (11)</td><td>0.69</td></tr><tr><td>Time to recurrence, days †</td><td>6 [0–10]</td><td>7 [2–12]</td><td>0 [0–8]</td><td>0.09</td></tr></tbody></table>

Data are expressed as median [IQR] or n (%)

ECMO, Extra-corporeal membrane oxygenation. ICU, intensive care unit. CRI, Cannula related infection. ESBL, extended spectrum beta-lactamase. NF-GNB, Non fermenting Gram-negative bacilli. MDRO, multidrug resistant organism. BSI, bloodstream infection

* Data available for 108/109 patients

† Time from end of antimicrobial treatment of first episode to second episode onset

episode. Details regarding the outcomes and pathogens responsible for the second episode of infection are reported in Table 3. Among these recurrences, 7 (50%) occurred after ECMO removal, with a median [IQR] time from ECMO removal to recurrence of 5 [1–8] days.

Other outcomes are reported in Table 3. ICU-mortality rate was 51%. Uni- and multivariable analyses of factors associated with mortality are shown in Table 4: concomitant BSI and septic shock complicating ECMO-CRI were associated with ICU-mortality.

### Impact of antimicrobial treatment duration

To explore the impact of antimicrobial treatment duration of the first episode on outcome, we selected the 94 patients who survived at least 8 days after infection onset, and analyze them according to the duration of antimicrobial treatment, i.e. ≤ 8 days vs. > 8 days. Results of this analysis are presented in the online supplement: 31 patients had a short (≤ 8 days) duration of antimicrobial treatment and 63 had a long (> 8 days) duration of antimicrobial treatment; with median (IQR) durations of treatment of 7 (6–8) and 15 (11–18) days, respectively. Characteristics of patients were similar between patients
<table><caption>**Table 3** Outcomes</caption><thead><tr><th></th><th>Overall population<br>n=109</th></tr></thead><tbody><tr><td>Recurrence of infection</td><td>14 (13)</td></tr><tr><td>Time to new infection, days*</td><td>6 [0–10]</td></tr><tr><td>Pathogen responsible for second episode</td><td></td></tr><tr><td><em>Staphylococcus aureus</em></td><td>0</td></tr><tr><td>Coagulase-negative <em>Staphylococcus</em></td><td>3 (21)</td></tr><tr><td><em>Streptococcus</em> spp.</td><td>1 (7)</td></tr><tr><td><em>Enterococcus</em> spp.</td><td>6 (43)</td></tr><tr><td>Enterobacteriaceae</td><td>5 (36)</td></tr><tr><td>Non fermenting Gram-negative bacilli</td><td>2 (14)</td></tr><tr><td>MDRO</td><td>7 (50)</td></tr><tr><td>Polymicrobial</td><td>9 (64)</td></tr><tr><td>Complications on cannula site after decannulation</td><td></td></tr><tr><td>Arterial thrombosis</td><td>6 (6)</td></tr><tr><td>Hemorrhage</td><td>4 (4)</td></tr><tr><td>Duration of ECMO support, days</td><td>15 [9–23]</td></tr><tr><td>Duration of invasive mechanical ventilation, days</td><td>20 [10–34]</td></tr><tr><td>ICU length of stay, days</td><td>26 [18–41]</td></tr><tr><td>Death on ECMO</td><td>33 (30)</td></tr><tr><td>ICU mortality rate</td><td>56 (51)</td></tr></tbody></table>

Data are expressed as median (IQR) or n (%)

ECMO, Extracorporeal membrane oxygenation. ICU, intensive care unit. MDRO, multidrug resistant organism

* Time from end of antimicrobial treatment of first episode to second episode onset

with short or long duration of treatment (see eTable 1, online supplement). Data regarding infection characteristics, microbiological data and management of infection according to duration of antimicrobial treatment are presented in eTable 2 (online supplement). Patients with long duration of treatment had more frequently surgery on cannulation site than patients with short duration; however the outcomes were similar between the 2 groups; particularly the recurrence rates and ICU mortality rates were similar.

Then, as detailed in the method section, a propensity score was constructed to reduce imbalance between groups, in order to evaluate through an overlap weighting analysis, the effect of prolonged (>8) versus standard (≤8 days) duration of antimicrobial treatment. Weighted groups were well balanced and standardized mean differences were <0.1 for all variables (see eFigure 1, online supplement). Considering a Cox proportional hazard model with propensity score overlap weighting, patients treated for more than 8 days exhibited significantly higher hazard of ICU mortality compared to those treated for 8 days or less, with an HR of 1.72 (95% CI, 1.02–2.90; p=0.043).

## Discussion

In this multicenter study of 109 patients with ECMO-CRI, we found that more than 2/3 of patients with cannula-related infection had associated BSI due to the same pathogen. Main pathogens responsible for ECMO-CRI were *Enterobacteriaceae*, coagulase-negative *Staphylococcus* and *Enterococcus* spp., and 39% of these infections involved more than one pathogen. Outcomes of ECMO-CRI were globally poor, since 13% experienced infection recurrence and 51% died in the ICU. Factors associated with death were associated bloodstream infection and ECMO-CRI complicated by septic shock. Interestingly, patients with a short duration of antimicrobial treatment (≤8 days) seem to have better outcomes than patients with long duration of antimicrobial treatment (>8 days). Unfortunately, the small number of recurrences (n=14) did not allow us to explore factors associated with recurrence.

This is the largest multicenter cohort regarding ECMO-CRI in adults, and the first that describes its epidemiology and outcomes. Among the previous observational studies evaluating infection in ECMO patients, small case series showed that *Enterobacteriaceae* and non-fermenting Gram negative bacilli were the most frequent pathogen involved in ECMO-associated infection [8, 11, 15], while other highlighted the central role of *Enterococcus* spp. in nosocomial infections [2, 5]. However, most infections recorded in these studies were not specifically ECMO-related, i.e., included VAP or urinary tract infection [2, 5]. Among them, only few ECMO-CRIs were documented [2, 5, 15, 16]. Nevertheless, our findings are in agreement with these results, since the main pathogens responsible for ECMO-CRI were *Enterococcus* spp. and *Enterobacteriaceae*. Of note, coagulase-negative *Staphylococcus* represented 30% of CRI in our study, whereas a previous study that included 21 ECMO-CRI episodes reported a 19% rate of coagulase-negative *Staphylococcus* [2]. Last, pathogens responsible for infections in our study were less frequently MDRO than in others, [5], probably related to the relatively low rate of MDRO in French ICUs, as compared to other European countries.

Few data regarding outcomes of patients with ECMO-CRI are available. A small single center cohort study showed that ECMO patients who developed infection had significantly higher mortality rate than patients without infection (40.4% vs. 20.0%, respectively, p=0.037). However this study reported only 3 ECMO-CRIs and 5 BSIs [5]. Moreover, these results were not confirmed in others [2, 11, 15]; Schmidt et al., in their cohort study of 220 ECMO patients, found that infected and non-infected patients had similar mortality rate (51% vs. 62%, respectively, p=0.15). Although our study was not designed to compare patients with and without CRI,
<table><caption>**Table 4** Proportional Cox uni and multivariable analysis of factors for death in the 109 patients with cannula-related infection</caption><thead><tr><th rowspan="2">Variables</th><th colspan="3">Univariable analysis</th><th colspan="3">Multivariable analysis</th></tr><tr><th>HR</th><th>95% CI</th><th>p</th><th>HR</th><th>95% CI</th><th>p</th></tr></thead><tbody><tr><td>Age. per year</td><td>1.01</td><td>0.99-1.03</td><td>0.19</td><td>1.00</td><td>0.98-1.02</td><td>0.27</td></tr><tr><td>Male sex</td><td>0.98</td><td>0.56-1.72</td><td>0.95</td><td></td><td></td><td></td></tr><tr><td>Body mass index. per point</td><td>1.01</td><td>0.97-1.04</td><td>0.79</td><td></td><td></td><td></td></tr><tr><td>Indication for ECMO</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Cardiogenic shock</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Acute respiratory distress syndrome</td><td>1.06</td><td>0.59-1.89</td><td>0.85</td><td></td><td></td><td></td></tr><tr><td>Post-cardiotomy</td><td>1.46</td><td>0.6-3.51</td><td>0.40</td><td></td><td></td><td></td></tr><tr><td>Septic shock</td><td>0</td><td>0-∞</td><td>0.99</td><td></td><td></td><td></td></tr><tr><td>E-CPR</td><td>0.3</td><td>0.04-2.23</td><td>0.24</td><td></td><td></td><td></td></tr><tr><td>Other</td><td>0.72</td><td>0.1-5.28</td><td>0.75</td><td></td><td></td><td></td></tr><tr><td>SARS-CoV2 infection</td><td>1.16</td><td>0.63-2.13</td><td>0.62</td><td></td><td></td><td></td></tr><tr><td>Pre-existing conditions</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Chronic cardiac disease</td><td>1.21</td><td>0.7-2.07</td><td>0.49</td><td></td><td></td><td></td></tr><tr><td>Chronic renal disease</td><td>1.44</td><td>0.71-2.94</td><td>0.32</td><td></td><td></td><td></td></tr><tr><td>Chronic respiratory disease</td><td>2.01</td><td>1.04-3.89</td><td>0.03</td><td>1.49</td><td>0.74-3.00</td><td>0.51</td></tr><tr><td>Diabetes mellitus</td><td>0.95</td><td>0.54-1.68</td><td>0.86</td><td></td><td></td><td></td></tr><tr><td>Peripheral vascular disease</td><td>1.54</td><td>0.83-2.88</td><td>0.17</td><td>1.27</td><td>0.62-2.60</td><td>0.94</td></tr><tr><td>Immunocompromised*</td><td>1.33</td><td>0.71-2.47</td><td>0.37</td><td></td><td></td><td></td></tr><tr><td>Pregnancy</td><td>2.4</td><td>0.33-17.51</td><td>0.39</td><td></td><td></td><td></td></tr><tr><td>Admission SAPS II score</td><td>1.00</td><td>0.99-1.02</td><td>0.68</td><td></td><td></td><td></td></tr><tr><td>Admission SOFA score</td><td>1.01</td><td>0.95-1.07</td><td>0.86</td><td></td><td></td><td></td></tr><tr><td>Veno-venous ECMO†</td><td>1.21</td><td>0.7-2.1</td><td>0.49</td><td></td><td></td><td></td></tr><tr><td>Cardiac arrest during cannulation</td><td>0.66</td><td>0.28-1.55</td><td>0.34</td><td></td><td></td><td></td></tr><tr><td>Site of cannulation</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Femoro-jugular</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Femoro-femoral</td><td>0.80</td><td>0.46-1.39</td><td>0.43</td><td></td><td></td><td></td></tr><tr><td>Other</td><td>1.76</td><td>0.41-7.52</td><td>0.45</td><td></td><td></td><td></td></tr><tr><td>Implantation by mobile unit</td><td>0.99</td><td>0.52-1.89</td><td>0.99</td><td></td><td></td><td></td></tr><tr><td>Percutaneous cannulation</td><td>0.95</td><td>0.54-1.66</td><td>0.85</td><td></td><td></td><td></td></tr><tr><td>Ongoing antibiotics at ECMO start</td><td>1.46</td><td>0.86-2.47</td><td>0.16</td><td>0.98</td><td>0.54-1.76</td><td>0.94</td></tr><tr><td>Associated bloodstream infection‡</td><td>2.7</td><td>1.32-5.51</td><td>0.006</td><td>2.33</td><td>1.09-5.00</td><td>0.03</td></tr><tr><td>Time from ECMO start to infection onset, per day</td><td>1.03</td><td>1-1.05</td><td>0.04</td><td>1.03</td><td>0.99-1.06</td><td>0.052</td></tr><tr><td>Inflammatory sign at cannula insertion site</td><td>1.08</td><td>0.61-1.92</td><td>0.79</td><td></td><td></td><td></td></tr><tr><td>Septic shock</td><td>4.78</td><td>2.51-9.1</td><td>&lt;0.001</td><td>4.10</td><td>2.07-8.10</td><td>&lt;0.001</td></tr><tr><td>Time from diagnostic to empiric treatment, per day</td><td>0.89</td><td>0.70-1.13</td><td>0.35</td><td></td><td></td><td></td></tr><tr><td>Time from infection onset to appropriate antimicrobial treatment, per day</td><td>0.83</td><td>0.69-1.00</td><td>0.05</td><td>0.95</td><td>0.78-1.15</td><td>0.58</td></tr><tr><td>Combination therapy</td><td>0.78</td><td>0.4-1.51</td><td>0.46</td><td></td><td></td><td></td></tr></tbody></table>

BMI. body mass index. ECMO. extracorporeal membrane oxygenation. SAPS 2. Simplified acute physiology score 2. SOFA. Sepsis-related organ failure assessment. E-CPR. Extracorporeal cardiopulmonary resuscitation. SARS-CoV-2: severe acute respiratory syndrome coronavirus-2. MDRO: multi-drug resistant organism

* Solid organ transplant recipients. active hematological malignancy or receiving immunosuppressant drug (including corticosteroids at a dose ≥ 0.5 mg/kg/d for ≥ 1 month)

† As compared to veno-arterial ECMO

‡ As compared to cannula-related infection without associated bloodstream infection
ICU-mortality rate of our patients was similar to that observed in the Schmidt study [2]. One of the originalities of our work was to focus on other outcomes, and in particular infection recurrence. Although we were unable to explore factors associated with infection recurrence, due to the small number of patients with recurrence, we show here that recurrences were also frequently polymicrobial,

Management of ECMO-CRI may be challenging, with specific issues regarding antimicrobial treatment duration and need for cannula change to cure infection. To date, no data focusing on these issues exist in the literature. We showed here that neither antimicrobial treatment duration, nor combination therapy, nor cannula change were associated with an increased risk of mortality. Specifically, patients with short duration of antimicrobial treatment (≤ 8 days) seem to have better outcome than patients with prolonged (> 8 days) duration of antimicrobial treatment. This observation is in line with recent data on infections in ICU patients, which showed that short durations of antimicrobial treatment, even for severe infections, are not associated with worse outcomes, but may even be associated with better outcomes [17].

Our study has several limitations that should be underlined. Firstly, selection of patients with ECMO-CRI was performed retrospectively, based on patient's chart, therefore some ECMO-CRI episodes could have been missed, and we are unable to calculate the incidence of ECMO-CRI. However, this was not the purpose of our study. Secondly, due to its retrospective design, we cannot be sure that all parameters recorded in the present study were reported in the patient chart, including clinical data regarding the ECMO-CRI episode (inflammatory signs at ECMO cannulation site...). Moreover, the retrospective design limits the interpretation of outcomes. Therefore, our results should be interpreted cautiously. Thirdly, there is no clear definition of CRI and no consensus on the diagnosis process (which sample, which type of sampling...). We used criteria described in previous papers, but these criteria may vary from one study to another [2, 18–20], and were different among centers having included patients. Additionally, center effect was not taken into account in our study. However, since all included patients had either ECMO-CRI concomitant BSI or local signs of infection, our population is homogenous, without patients with ECMO-cannula colonization. On the other side, patients developing BSI without local signs (at the cannula insertion site) may have ECMO-CRI. Since we excluded patients who were not sampled, we could have missed some patients with ECMO-CRI.

Fourthly, we excluded patients with primary BSI and therefore could have miss some patients with ECMO-CRI: indeed, some patients with primary BSI could have in fact ECMO-CRI (not diagnosed for several reasons). However, we preferred to include only patients with bacteriologically proven ECMO-CRI. Fifthly, we had a large proportion of patients with CRI due to coagulase-negative *Staphylococcus*, that could be considered as colonization rather than infection. However, 26 out of the 32 ECMO-CRI due to coagulase-negative Staphylococci were associated with BSI with the same coagulase-negative *Staphylococcus*, and the 6 other were polymicrobial, coagulase-negative *Staphylococcus* being not the only pathogen responsible for ECMO-CRI. Therefore, we believe that all episodes reported here due to coagulase-negative Staphylococci were actually due to this pathogen (alone or in combination with others). Sixthly, the relationship between duration of antimicrobial treatment and outcome should be interpreted with caution: indeed, treatment duration might depend on factors as the time on ECMO after treatment initiation, possibly on the responsible pathogens, association of soft tissue infection, time to surgery, and other cofounding factors. Finally, even if this is a multicenter cohort, our study mostly performed in French ICUs. We cannot be sure that similar results would be observed in ICUs with different bacterial ecologies.

## Conclusion

ECMO-CRI is frequently polymicrobial, mainly due to Enterobacteriaceae, coagulase-negative *Staphylococci* and *Enterococcus* spp, and frequently associated with BSI. ECMO-CRI management, and more specifically duration of antimicrobial treatment does not seem to influence mortality.

## Abbreviations

BSI Bloodstream infection

CRI Cannula-related infection

ECMO Extracorporeal membrane oxygenation

ICU Intensive care unit

IQR Interquartile range

VAP Ventilated-associated pneumonia

VA Veno-arterial

VV Veno-venous

## Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13613-025-01446-y.

Additional file 1

## Contributors

Groupe Hospitalier Pitié-Salpêtrière, Paris, France: Juliette Chommeloux, Guillaume Hékimian, Alain Combes, Nima Djavidi, Aymeric Lancelot, Pauline Dureau, Guillaume Lebreton. CH de Saint-Brieuc, France: Pierre Fillatre. Centre
Hospitalier Universitaire de La Réunion, Saint Denis, France: Laura Rivoire, Nicolas Allou, Radj Cally. *Hôpital Bichat-Claude Bernard, Paris, France:* Hermann Do Rego, Mariem Dlela, Marc Doman. *Centre Hospitalier universitaire de Rennes: Christophe Camus, Erwan Flecher. Hôpital Louis Pradel, Lyon, France:* Jean-Luc Fellahi, Matteo Pozzi, Matthias Jacquet-Lagreze. *Hôpitaux Universitaires de Genève, Genève, Switzerland:* Raphaël Giraud, Karim Bendjelid. *Hôpital Henri Mondor, Créteil, France:* Keyvan Razazi, Armand Mekontso-Dessap. *Hôpital universitaire de Lille, Lille, France:* Anahita Rouzé, Saed Nseir, Thibault Duburcq. *Hôpital Nord, Marseille, France:* Christophe Guervilly, Jean-Marie Forel. *Hôpital Haut Leveque, Pessac, France:* Eline Bonnardel. *Hôpital Universitaire de Bruxelles, Bruxelles, Belgium:* Fabio S Taccone.

**Author contributions**

SO and CEL designed the study, collected, compiled, analyzed and interpreted the data and wrote the manuscript. SO, NM, CV, EdM, NM, SH, AB, PM, FB, SH, BA, HR and CEL collected data. NM performed statistical analysis, analyzed and interpreted the data. All authors approved the final version of the manuscript.

**Funding**

None.

**Availability of data and materials**

The datasets generated during the current study are available from the corresponding author on reasonable request.

**Declarations**

**Ethics approval and consent to participate**

In accordance with current French law, informed written consent for demographic, physiologic and hospital-outcome data analyses was not obtained because this observational study did not modify existing diagnostic or therapeutic strategies. Nonetheless, patients and/or relatives were informed about the anonymous data collection and told that they could decline inclusion. The protocol was approved by the ethics committee of the Société de Réanimation de Langue Française (registration no. CE-SRLF-22-074) and the database is registered by the Commission Nationale de l'Informatique et des Libertés (CNIL, registration no 2228484v 0).

**Consent for publication**

Not applicable.

**Competing interests**

C.-E. L. received lecture fees from Merck, Aerogen and AdvanzPharma, and grant from Eumedica and Merck, all outside the submitted work. The other authors have no conflicts of interest to declare in relationship to this manuscript.

**Author details**

¹Service de Médecine Intensive-Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpétrière, Sorbonne Université, Assistance Publique-Hôpitaux de Paris, 47-83, Boulevard de L'Hôpital, 75651 Paris Cedex 13, France. ²Service de Réanimation, CH de Saint-Brieuc, Saint-Brieuc, France. ³Réanimation Polyvalente, Centre Hospitalier Universitaire de La Réunion Site Félix Guyon, Saint-Denis, France. ⁴Service de Médecine Intensive-Réanimation, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France. ⁵Département d'Anesthésie-Réanimation, GRC 29, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpétrière, Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Paris, France. ⁶Department of Anesthesia and Critical Care, Pontchaillou, University Hospital of Rennes, Rennes, France. ⁷Univ Rennes, CHU Rennes, Inserm, CIC 1414 (Centre d'Investigation Clinique de Rennes) Rennes, France. ⁸Univ Rennes, CHU de Rennes, Inra, Inserm, Institut NUMECAN - UMR_A 1341, UMR_S 1241, Rennes, France. ⁹Service d'Anesthésie-Réanimation, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France. ¹⁰EA 7426, Pathophysiology of Injury-Induced Immunosuppression, Hospices Civils de Lyon-Biomérieux-University, Claude Bernard Lyon 1, Lyon, France. ¹¹Division of Intensive Care, Geneva University Hospitals, the Faculty of Medicine, University of Geneva, Geneva, Switzerland. ¹²AP-HP, Service de Médecine Intensive Réanimation, Hôpitaux Universitaires Henri-Mondor, Créteil, France.

¹³Univ Paris Est Créteil, CARMAS, 94010 Créteil, France. ¹⁴Service de Médecine Intensive-Réanimation, Hôpital Universitaire de Lille, Lille, France. ¹⁵Service de Médecine Intensive-Réanimation, AP-HM, Hôpital Nord, Marseille, France. ¹⁶Service de Réanimation Polyvalente, Centre Hospitalier Côte Basque et Service d'Anesthésie Réanimation Thoraco-Abdominale, CHU de Bordeaux, Université de Bordeaux, Bordeaux, France. ¹⁷Department of Intensive Care, Hôpital Universitaire de Bruxelles (HUB), Brussels, Belgium. ¹⁸Experimental Laboratory of Intensive Care, Université Libre de Bruxelles, Brussels, Belgium. ¹⁹INSERM Umr_1166-Ican, Institute of Cardiometabolism and Nutrition, Paris, France.

Received: 9 September 2024 Accepted: 10 February 2025

Published online: 20 March 2025

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