Discussion

In this retrospective, case–control study of ICU CLABSI at a large, quaternary children’s hospital over a six-year period, we identified that higher number of days with a CVC in place, receiving a continuous non-opioid sedative infusion, and having a chronic CVC while also receiving parenteral nutrition were independently associated with increased odds of CLABSI.

Many of our results align with work done at our institution over a decade ago, with similar findings despite modifications of our CVC insertion and maintenance bundles in accordance with updated guidelines and standards. ^{Reference Lyren, Brilli, Zieker, Marino, Muething and Sharek8,Reference Wylie, Graham and Potter-Bynoe12,Reference Costello, Graham, Morrow, Potter-Bynoe, Sandora and Laussen17,Reference Buetti, Marschall and Drees31} The repeat identification of several risk factors in this new study that are similar to prior predictors highlights that despite routine modification of prevention bundles, there are patient characteristics associated with increased risk for CLABSI that offer potential opportunities for further prevention efforts. Additionally, the Solutions for Patient Safety Network recently showed that attaining >95% reliability to the CVC maintenance bundle was associated with lower CLABSI rates. ^{Reference Tripathi, McGarvey and Lee9} It is possible that our results could be different if we were able to achieve this level of reliability. BCH, like most peer institutions, is continuously working to improve bundle reliability with the hopes of decreasing CLABSI rates. Even so, we (and many other hospitals) have observed decreased CLABSI rates over the last decade, including among ICU patients, but we continue to strive to reduce rates as low as possible. Our work highlights the need to continue to improve compliance with current bundles, but also to consider additional approaches that might further reduce CLABSI rates in critically ill children.

Parental nutrition is a known risk factor for CLABSI. ^{Reference Woods-Hill, Srinivasan, Schriver, Haj-Hassan, Bezpalko and Sammons10,Reference Wylie, Graham and Potter-Bynoe12–Reference Advani, Reich, Sengupta, Gosey and Milstone14} Previous work has also suggested that intraabdominal pathology and gastrointestinal dysfunction are associated with increased CLABSI risk. ^{Reference Woods-Hill, Srinivasan, Schriver, Haj-Hassan, Bezpalko and Sammons10,Reference Wylie, Graham and Potter-Bynoe12,Reference Dahan, O’Donnell and Hebert15,Reference Seddik, Tian, Nespor, Kerner, Maldonado and Gans32,Reference Paioni, Kuhn, Strässle, Seifert and Berger33} Many of these patients also receive parenteral nutrition for varying periods of time. To assess whether certain subgroups of patients receiving parental nutrition were at greater risk for CLABSI, composite variables were developed. We found that the composite risk factor of chronic CVC (CVC in place for >21 days) and administration of parenteral nutrition was associated with increased risk of CLABSI. Additionally, we assessed other markers of gastrointestinal tract function including the presence of an ostomy, the presence of single and multiple invasive gastric devices, or the presence of gut ischemia, ileus, or insufficiency, but these variables were not significantly associated with CLABSI in this study. Our results indicate that despite current CLABSI prevention bundles, patients receiving parenteral nutrition remain at high risk for CLABSI, and those who also have a chronic CVC in place are at even greater risk. Additionally, 46% of the patients who qualified for our chronic CVC and parenteral nutrition composite variable also qualified for having GI insufficiency suggesting that this specific population is at greater risk. Large, multicenter studies are needed to assess parenteral nutrition parameters such as osmolarity and anticoagulants as well as glucose, amino acid, and lipid content and their potential association with CLABSI risk. Such further work to characterize differences among patients receiving parenteral nutrition who develop CLABSI compared with those who do not can help clinicians identify children at highest risk and guide new strategies to reduce their risk. While this work is being done, interventions at the bedside to mitigate the increased risk of CLABSI in patients receiving parenteral nutrition could include use of peripheral access points for intermittent medications and collection of blood draws at the time the CVC is being accessed to administer a new bag of parenteral nutrition.

Surprisingly, we found that patients with a CVC and a concurrent endotracheal tube or Foley catheter, as well as those receiving continuous neuromuscular blockade or stress ulcer prophylaxis with histamine blockers had a decreased odds of CLABSI. We speculate that a possible explanation is that intubated patients, especially those receiving continuous neuromuscular blockade, are more likely to have a nurse with fewer patient assignments (1 nurse to 1 patient or 1 nurse to 2 patients across the ICUs at BCH), facilitating higher reliability with all elements of the CVC maintenance bundle. ^{Reference Buetti, Marschall and Drees31,Reference Saman, Kavanagh, Johnson and Lutfiyya34,Reference Fridkin, Pear, Williamson, Galgiani and Jarvis35} The role of stress ulcer prophylaxis in critically ill pediatric patients remains largely unknown but it is more commonly used in the sickest patients who also usually have a lower nurse to patient ratio which might facilitate higher CVC maintenance bundle reliability. ^{Reference Green, Abdel-Latif, Jones, Lui and Osborn36,Reference Weiss, Peters and Alhazzani37} Additionally, patients receiving continuous neuromuscular blockade may be less likely to self-contaminate their CVC or tamper with the dressing. Finally, some bloodstream infections in patients with endotracheal tubes or Foley catheters may meet criteria to be considered secondary to pneumonia or urinary tract infection, respectively, leading to them not being categorized as CLABSI. ⁴

Over the last two decades, much CLABSI research has assessed line characteristics and their relationship to CLABSI. It is well established that temporary, non-tunneled CVCs are associated with greater CLABSI risk. ^{Reference Woods-Hill, Srinivasan, Schriver, Haj-Hassan, Bezpalko and Sammons10,Reference Wylie, Graham and Potter-Bynoe12,Reference Niedner, Huskins and Colantuoni38} Interestingly, in our multivariable analysis, the presence of a non-tunneled CVC was associated with a significantly decreased odds of CLABSI. It is standard in all ICUs at our institution for an emergent, non-tunneled CVC to be transitioned to a PICC as soon as possible (as suggested by a prior multicenter QI study), resulting in shorter duration of non-tunneled CVC dwells which could explain this finding. ^{Reference Niedner, Huskins and Colantuoni38} Additionally, a substantial proportion of our non-tunneled CVCs are placed in the operating room as opposed to at the bedside in the ICU. Finally, we found that the use of an upper extremity vein, most commonly for PICC placement, is associated with a significantly decreased odds of CLABSI.

We also found that patients transported out of the ICU to radiology had a decreased odds of CLABSI and those receiving continuous non-opioid sedative infusions had an increased odds of CLABSI. The first finding may reflect the fact that patients need to have some degree of clinical stability to leave the ICU, and therefore, they may be less ill and at lower risk of bloodstream infection. It is also common practice in our institution that when these patients are being cared for in non-ICU locations by other providers, such as anesthesia, their CVCs are not routinely accessed for intermittent medications, thereby decreasing risk of introduction of bacteria into the bloodstream. Our finding that patients receiving continuous non-opioid sedative infusions (primarily dexmedetomidine and/or midazolam) have increased odds of CLABSI warrants further study. It could be explained by our institutional practice of weaning continuous sedative infusions rather than transitioning to equivalent enteral medications (which can lead to prolonged infusions). Other possibilities include immune suppression by these agents, including the recently described inhibition of bacterial phagocytosis of Gram-negative bacilli in vitro by dexmedetomidine. ^{Reference Maisat, Han, Koutsogiannaki, Soriano and Yuki39,Reference Caroff, Szumita and Klompas40}

In our multivariable analyses, there was no significant association between the administration of packed red blood cells or other blood products and CLABSI development; this potential association was only evaluated for patients who did not experience extracorporeal membrane oxygenation support during their ICU admission. Multiple prior studies have demonstrated a relationship between the administration of blood products and the development of CLABSI. ^{Reference Woods-Hill, Srinivasan, Schriver, Haj-Hassan, Bezpalko and Sammons10,Reference Wylie, Graham and Potter-Bynoe12,Reference Costello, Graham, Morrow, Potter-Bynoe, Sandora and Laussen17} This unexpected finding might be explained by recent changes in practice, including preferentially administering blood products through peripheral access points, different leukocyte depletion methods, and more frequent changing of needleless connectors. ^{Reference Buetti, Marschall and Drees31}

As with all case–control studies, our study has limitations. One limitation is generalizability, as our patient population may not be representative of other pediatric ICUs. It is also possible that there is unmeasured confounding related to the absence of certain variables influencing CLABSI risk (such as ICU capacity or proportion of nurses in traveler roles). The use of automated data introduces the possibility of incorrect and/or missing data. We attempted to mitigate this limitation through our random, manual data validation. Our data also depended on the completeness and accuracy of the original documentation. We were unable to assess several known risk factors (such as race, primary language, and number of line accesses) in this study due to substantial missing data. There are practice differences among our four ICUs, resulting in some variables (such as illness severity scores) being available for only certain patients. Our population included a few subgroups of interest (patients who have had a history of a stem cell transplant, patients who have had multiple CLABSI with different lines) with relatively small numbers, such that no meaningful conclusions about risk factors within these patient groups could be reached. Additionally, we chose not to match controls on age to evaluate it as a risk factor, to avoid similarity between cases and controls on other risk factors which could have made identification of significant risk factors more challenging, and to improve generalizability of our findings to critically ill children of all ages (given that >75% of cases were younger than 5 years).

In summary, our work demonstrates that pediatric ICU patients with a greater number of CVC days, those receiving parenteral nutrition in the presence of a chronic CVC, and those receiving continuous non-opioid sedative infusions are at increased risk for CLABSI in the context of high but imperfect adherence to current prevention measures. Improving reliability of practice for core CVC bundle elements and developing novel strategies to further reduce CLABSI risk in the current era should be prioritized. Further research should focus on characterizing the differences in patients receiving parenteral nutrition who develop CLABSI compared with those who do not.