Background
Central venous catheter (CVC)-associated complications are a prevalent and significant problem in the intensive care unit (ICU) [
1]. Catheter-related bloodstream infection (CRBSI) is considered the leading cause of morbidity and mortality in patients with CVCs [
2,
3], but CRBSI contributes only modestly and has a better prognosis than other ICU-acquired infections in terms of overall mortality [
4‐
7]. Prompt catheter removal with delayed placement of a new catheter is recommended by the Infectious Diseases Society of America (IDSA) in patients with CRBSI [
8], and an expert statement suggests that immediate removal of suspected intravascular catheters is always urgent as a means of source control in patients with septic shock [
9]. However, among options that include CVC replacement using a guidewire, insertion of a new CVC, and watchful waiting, the optimal strategy for the management of patients with suspected but unconfirmed CRBSI remains unclear [
10]. In clinical practice, the diagnosis of CRBSI is challenging until microbiological culture results are available [
10]. A common management strategy for CRBSI is prompt catheter removal followed by immediate reinsertion of a new catheter (IRINC), which prevents interruption of treatments because CVCs provide important access for medical and fluid therapy in critically ill patients [
11], especially those who need vasoconstrictive agents [
12]. However, catheter insertion increases the risk of complications, including mechanical complications [
13], deep vein thrombosis [
13,
14], and secondary infections, which are associated with subsequent mortality [
4]. Therefore, the decision of whether to remove and reinsert CVCs in critically ill patients with suspected CRBSI has been a debated issue in the management of ICU patients [
5,
8,
10,
15], in whom suspected and confirmed CRBSI are one entity and initial management is usually identical. To date, only a few studies have directly or indirectly compared the benefit and harm between reinsertion and no reinsertion in patients whose CVCs have been removed [
16‐
18]. For example, an observational study of 60 cancer patients reported that catheter removal and reinsertion were associated with a moderate to severe symptom burden [
16]. A randomized trial showed that mortality did not differ between the catheter removal group and the watchful waiting group in 64 patients with suspected CRBSI [
17]. Another randomized controlled trial showed that among 52 patients with suspected CRBSI, the mortality rate in patients who underwent immediate reinsertion and delayed reinsertion of new catheters was not different [
18]. Studies with small sample sizes cannot provide strong evidence regarding the association between CVC reinsertion and mortality. Considering the need to maximize benefits in the complex situation of clinical practice, the consequences of a missed catheter-related infection for patients with suspected CRBSI were thought to be more important than the risk of unnecessary catheter removal [
17]. Our previous retrospective cohort study showed that catheter removal and IRINC may be associated with 30-day mortality in suspected CRBSI [
7]; however, a more comprehensive assessment is needed because it did not meet clinical significance. Therefore, by consensus, we hypothesized that IRINC reduces mortality in patients with suspected CRBSI. In this better-executed cohort study with a larger sample size, we sought to determine the impact of IRINC on 30-day mortality after CVC removal for suspected CRBSI.
Discussion
Interestingly, we found that IRINC was associated with increased 30-day mortality in patients after prompt catheter removal due to suspected CRBSI, which was consistent across several analytic approaches and robust to multiple sensitivity analyses. This association was apparent regardless of physical/disease status, ICU admission, comorbidities, treatment interventions, clinical symptoms, disease severity with suspected infection, or causative pathogens in CRBSI. However, in subgroups of patients with CRBSI, there was no significant difference in the 30-day mortality rate between patients with and without IRINC.
The association between IRINC and an increased risk of 30-day mortality that was observed in the patient-level analysis could be due to the selection of patients or to unmeasured confounding factors, as patients who are evenly matched for the causative pathogens can still have significant adverse outcomes depending on what the offending agent is. For example, antibiotic use guided by inflammatory variables did not result in a reduced use of antibiotics compared with usual care among patients with suspected infection [
29]. Some specific antibiotic agents have been found not to reduce mortality at 28 days without microbial sensitivity tests [
30]. In addition, propensity score matching to balance antibiotics by use (types > 2) or not (types ≤ 2) may reduce antibiotic selection pressure without a negative impact on mortality, and an expert statement recommends de-escalation from a broad‑spectrum to a narrow‑spectrum antimicrobial [
9]. Similar, perhaps, to unmeasured confounding factors is the use of vasoconstrictor agents [
31], corticosteroids [
32], anticoagulants [
33], renal replacement therapy [
34], and mechanical ventilation [
35]. Finally, the competing risk analysis confirmed that the results of the propensity score-matched analysis were not subject to patient selection bias.
The decision about whether to recommend immediate or later CVC removal in this population is controversial because source control by immediate removal of suspected intravascular catheters is always urgent in patients with septic shock [
5,
9,
11,
15]. Moreover, a prospective observational study conducted in 18 ICUs in Spain showed that patients with immediate CVC removal had a higher rate of 30-day mortality than those with later CVC removal in suspected CRBSI [
5]. However, they did not evaluate the association of reinsertion of new catheters and mortality, which may underlie the risk of iatrogenic injuries, because rigorous quality-controlled randomized controlled trials in France showed that the rate of bloodstream infection was 0.5% to 1.2% (averaging 1.0%), the rate of mechanical complications was 0.7% to 2.1% (averaging 1.4%), and the rate of deep-vein thrombosis was 0.5% to 1.4% (averaging 0.9%), varying according to the insertion site [
13]. A control study demonstrated that CVC was a more significant exposure for a composite of mortality than midline catheters [
36]. We attempted to maximize the benefit to patients by considering the serious consequences of CRBSI. In reality, the evidence from our data and other previous reports has supported the idea that watchful waiting may be more reasonable than CVC removal and IRINC in patients with suspected CRBSI [
5], which is a clinical practice recommended by the IDSA [
10].
For patients with CRBSI in the subgroup, we did not find that mortality was higher in patients with IRINC than in those with delayed replacement or no replacement of the catheter. One can argue that the sample size of the patients with CRBSI who did not undergo IRINC was relatively small, as there were only 42 deaths, which may mean that the mortality analysis had limited power to detect a between-group difference. However, the hazard ratio that we observed was similar to that of all patients. Theoretically, CVC removal and reinsertion can remove the source of infection. In fact, CVC removal and reinsertion increase the risks of catheter recolonization and introduce other risks of complications [
13,
16]. It has been reported that prompt CVC removal may not be necessary for all patients [
5]. In addition, this study could not identify a certain proportion of catheter colonization after bacteraemia in all patients with CRBSI. We used bloodstream infections in general as an independent risk factor for attributed mortality risk in the subgroup and sensitivity analyses. These bloodstream infections may be associated with a good prognosis compared to other infections, and we may have overestimated the mortality risk of CRBSI among all patients with sepsis [
4,
6,
7]. However, given that this study was an exploratory study based on hypotheses and that this association was apparent, we need to be cautious because of the risk of a lack of a causal relationship due to the inherent limitations of the observational study. Therefore, this association can inform future clinical trials seeking to prevent insertion complications with mortality as an end point, as they can be avoided in the great majority of cases [
9] by preventing unnecessary catheter removals [
5,
17] and frequent changes and reinsertion of catheters in critically ill patients.
A major limitation of the present study is our inability to explain why IRINC was associated with increased 30-day mortality based on clinical data regarding related complications. Previous studies have shown that unnecessary catheter removal is common [
1,
5,
7], although routine replacement of CVCs has not been recommended in international clinical guidelines to prevent CRBSI [
8,
9,
37]. A recent systematic review reported that catheter removal and reinsertion may be associated with discomfort, complication risks, and possible disruption or delay in the administration of other treatments to critically ill patients [
11]. Additionally, there was an increase in the number of complications related to the insertion and use of intravascular catheters [
13,
38]. Therefore, CVC insertion was a significant risk factor for a series of catheter-related complications, including high symptom burden [
16,
36], secondary infection [
4], severe injurious complications [
13,
39], and other associated harms (e.g., air embolisms, dislodgement of thrombi, haemorrhage/bruising and arterial complications) [
40‐
42]. Although ultrasound-guided CVC placement can easily be performed with training and it is recommended that subclavian venous catheters be inserted with ultrasound guidance to decrease the mechanical complication rate, the superiority of this strategy over another cannot be clearly demonstrated [
37]. Unfortunately, our study did not provide data on the use of ultrasound guidance and related complications in each patient with IRINC. Therefore, this issue may need to be approached with caution, as unmeasured variables may have an impact on the outcome.
Another limitation of this study, as a single-centre cohort study, was that it used data covering a period of more than 12 years, and many clinical practices can possibly change in terms of care for CVC over such a long period. In addition, the exclusion of patients without catheter tip culture may mean that this cohort might not be sufficiently representative of real-world clinical practice. However, since 2009, our medical team has adhered to the guidelines that catheter cultures are not routinely obtained for all patients with CVC replacements [
10]; therefore, this study population is deemed homogeneous and uniform over the study period. A homogeneous sample may be more important than representativeness, and it is possible to generalize trial results to target populations even in the absence of representative data on the target population using a single-centre study [
43]. Finally, we acknowledge that the positivity assumption required for using counterfactual methods such as propensity score might not be verified in some cases. Although most of ICU patients require a CVC during their stay in the ICU, the indication for IRINC or not is complex and very dependent of the physician in charge of the patient.
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