Diagnostic yield of routine daily blood culture in patients on veno-arterial extracorporeal membrane oxygenation

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is increasingly used to support various causes of refractory shock [1]. Although it is life-saving support, it generates new issues and side effects. Emergent management, invasive procedures and devices, and intensive care unit (ICU)-acquired immunodepression increase infectious risk. Indeed, half of patients will further develop sepsis on V-A ECMO support [2]. Infectious complications are associated with an around 50% increase of mortality [3].

The diagnosis of sepsis in adult population supported by V-A ECMO is challenging. Body temperature cannot be interpreted because of blood exposure to heat exchanger. White blood cell count and common biomarkers lack of specificity in the setting of cardiogenic shock both on medical treatment and on V-A ECMO [4, 5]. To overcome diagnosis, routine blood cultures (BCs) are proposed [6, 7]. In a survey of the Extracorporeal Life Support Organization (ELSO), one-third of the American centers performed daily routine BCs [8]. However, this practice is still debated and has never been evaluated on V-A ECMO [9, 10]. According to the low incidence of poorly symptomatic BSIs and the high rate of contaminants leading to unnecessary antimicrobial therapy, we hypothesized that systematic BCs have a lowest interest than clinically guided BCs.

Beyond determining incidence, risk factors, and consequences of positive BCs, the aim of this study was to determine the respective contribution of routine versus on-demand BCs in a population of adult patients requiring V-A ECMO for refractory cardiogenic shock.

During the 4-year study period, 206 consecutive VA-ECMO were inserted for refractory cardiogenic shock or cardiac arrest. After exclusion of 56 V-A ECMO (9 patients with central V-A ECMO and 47 deaths within 24 h after implantation), 150 V-A ECMO were analyzed (Fig. 1). Patients who received two V-A ECMO during hospitalization (n = 3) were considered as independent cases.

In this 4-year series of 150 consecutive V-A ECMO, BSIs were observed in one-third of patients, with a rate of 34.5 BSI/1.000 days of V-A ECMO support. Routine BCs identified significantly less BSIs than on-demand BCs and led to a high proportion of contaminations with subsequent inappropriate antimicrobial therapy. In addition, performing routine BCs were negatively associated with BSIs diagnosis. However, one-third of BSIs would have been missed by a policy restricted to on-demand BCs. This argues for better selecting conditions of routine BCs prescription on V-A ECMO. Indeed, this study highlighted three independent risk factors for BCs positivity when routine BCs were performed: patient with V-A ECMO for graft failure after heart transplantation, BCs collected with ongoing antimicrobial therapy or renal replacement therapy.

A recent study of 220 V-A ECMO reported an incidence of nosocomial infections of 64%, with ventilator-associated pneumonia and BSI being the most frequent (55% and 18%, respectively) [2]. The specific burden of infectious complications is hard to evaluate, because the most severe patients die early, while the survivors experience prolonged ECMO support and ICU length of stay. For instance, V-A ECMO support duration, ICU, and hospital length of stay were significantly longer in patients with at least one BSI, but this link reflects a longer vulnerability period, prone to septic complications. This precludes comparison of the mortality of infected versus non-infected patients, in addition to discrepancies between definitions and differences of case mix between studies.

A few studies focused on the incidence of BSI on ECMO support. Unfortunately, mixture of veno-venous (V-V) and V-A ECMO, various indications of support (from acute respiratory distress syndrome to refractory cardiogenic shock), and various types of population (pediatric for the most of studies, or a mix of adult and children) creates heterogeneity [24‐28]. In addition, prophylactic anti-infective strategies and BCs contaminants varied between studies. Similarly, while the ELSO Infectious Disease Task Force does not recommend antibiotic prophylaxis on ECMO, 74% of centers reported performing it [29, 30]. The risk of BSIs and the well-established consequence of delayed or inappropriate antimicrobial therapy must be balanced with the negative impact of antibiotics on microbiota and subsequent infections [31].

Overall, a recent review (in pediatric and adult population with V-V and V-A ECMO) found a BSIs prevalence ranging from 3 to 18% and a incidence range from 3 to 31 episodes per 1.000 ECMO-days [3]. Regarding our BSIs rate, this large variation from a factor 1 to 10 prevents from drawing an “usual” rate of BSIs on ECMO. Our high rate of BSIs may be explained by (1) our daily routine BCs sampling protocol, (2) the inclusion of post-cardiac arrest patients who develop high rate of infectious complications, and (3) the extent of the study period up to 5 days after V-A ECMO withdrawal.

To deal with the challenging issue of diagnosis of infection on ECMO, routine BCs sampling is sometimes advocated but is still debated [6, 32]. According to ELSO surveys, between 34 and 49% of centers reported performing routine BCs, with variable intervals [8, 30]. As far as we are aware, this is the first study focusing on the interest and impact of a policy of routine BCs on V-A ECMO.

Multiple and non-clinically oriented routine BCs could increase the probability of diagnosing paucisymptomatic BSIs, but also the risk of positivity with contaminants. Our contamination rate was 2.5%; a rate within previously reported contamination ranges from 0.6 to 6% [33]. This raises several points of concern. First, the isolation of positive BC with potential contaminants generates an additional cost of hospitalization of around $8000 per patient, an increase of antibiotic prescription, and length of stay [34, 35]. It has been demonstrated than half of patients with contaminated BCs were inappropriately treated with antibiotics, one-third receiving vancomycin [17]. In our unit, antimicrobial therapy was deemed a posteriori inadequate in only 14% of cases, thanks to a rigorous anti-antimicrobial therapy policy and daily rounds with infectious diseases specialists. This may counterbalance our high rate of BSIs and contaminated BCs. Second, collecting 20 ml of blood per BC on the top of others daily blood samples exposes to progressive anemia [36]. On the contrary, a policy of reduction of blood laboratory tests reduced red blood cell transfusion, hospitalization costs, without impacting ICU outcome [37].

Our results question the optimal policy of BC practices. Our results could mean that BSIs are often symptomatic in this population, with either worsening shock or clinical/radiological signs of sepsis. Alternatively, physicians may have not prescribed on-demand BCs, knowing the fact that routine BCs had been sampled a few hours before. This subjective point may have lowered the diagnosis yield of on-demand BCs. Aiming to identify the clinical settings that increase the putative contribution of systematic BCs, we highlighted three risk factors for BC positivity. ECMO support after cardiac transplantation raises the question of performing systematic daily BC, as immunodepression increases the risk of BSI, and thus, the suitability of routine BC. Similarly, ongoing renal replacement therapy denotes higher severity and thus higher risk of nosocomial infections. Alternatively, the need for intravascular dialysis catheter may be a supplementary BSI risk factor. At least, BC sampling during ongoing antimicrobial therapy may reveal creeping bacteremia that are uncompleted treated by antibiotics. Overall, we propose a mitigated strategy, i.e., performing daily BC in adult patients on V-A ECMO with risk factor. This approach could be an acceptable compromise between an aggressive BC collection policy leading to an excess of contaminant identification and blood depletion, and a sparing policy missing clinically relevant BSI.

Our work presents limitations. First, in the absence of consensual definition of contaminated BCs in the present particular clinical setting, the CDC definition was applied [18, 38]. Second, our study population mixed patients with post-cardiotomy shock, acute heart failure, and refractory cardiac arrest. The latter is more prone to infectious complications, notably BSI [39]. Third, in case of death on V-A ECMO support, BC may not have been sampled the day of death. Fourth, the retrospective design of this study did not allow us to assess formally that all BCs taken between 4 and 7 a.m. were all routine sampling. Fifth, the reason of performing on-demand BC was not collected. We also acknowledge that providers who know their patients will receive daily BCs in the morning might be less likely to order on-demand cultures, or consider that the routine BCs were enough for diagnosing infection, even in the setting of new signs or symptoms. In addition, ongoing antimicrobial therapy was analyzed as a yes/no variable, but it may have different impact according to the duration of treatment. Also, we did not extract biological variables at each BC sampling but only those at V-A ECMO implantation, i.e., at day 0. Similarly, location and number of intravascular catheters were not collected, whereas they are per se a major risk factor for BSI. Sixth, BC was considered as the gold-standard of BSI diagnostic method. However, BC detect only culturable bacteria. Innovative techniques like bacterial DNA detection in rapid molecular assays such as PCR or more recently metagenomic next-generation sequencing (mNGS) test using cell-free DNA from blood could be promising tools for diagnosis supplementary BSI [40, 41]. Finally, the temporal window of BCs collection is debatable. Indeed, the time frame of ECMO-related BSIs advocated by some authors is from the day of V-A ECMO implantation up to two days after withdrawal [2, 42]. However, risk of delayed V-A ECMO-related BSIs persists several days after withdrawal. Our results confirm this recent finding, arguing for large BCs sampling after V-A ECMO withdrawal [43].

We describe for the first time the consequences of BC practices policy in an adult population supported by V-A ECMO. Whereas routine daily BCs were less clinically relevant than on-demand BCs and lead to a significant proportion of inappropriate antimicrobial therapy, a restricting policy of BCs sampling misses a significant proportion of BSIs. We suggest daily BCs sampling on V-A ECMO support when easy-to-identify positive BCs risk factors are present. Further prospective studies should test these criteria.