Evidence Summaries

E.1. Non-sterile Gloves

Key Question 1. Does the use of non-sterile gloves after hand hygiene, compared with hand hygiene alone, prevent CLABSI in NICU Patients?

One RCT^[3] examined the efficacy of non-sterile glove use after hand hygiene, compared with hand hygiene alone in NICU patients. This study reported the outcomes of CLABSI, possible CLABSI, bloodstream infection (BSI), gram-positive BSI, and gram-negative BSI in NICU patients. This study reported no difference in the outcomes of CLABSI, BSI, and gram-negative BSI, but found a reduction in possible CLABSI and gram-positive BSI. Possible CLABSI was defined as "the detection ≥1 blood culture of any organism, and the presence of central line within 72 hours in the absence of another source of infection." Hand hygiene compliance was measured monthly and an overall 79% compliance was reported. This compliance was not reported according to study group. Product-related adverse events were not reported. This study may have been underpowered to detect a difference in CLABSI. The confidence in this evidence is moderate.

E.2. Central Line Type

Key Question 2: Does the use of one central line catheter type, compared with another, prevent CLABSI in NICU patients?

Eleven studies[6–15], [68] evaluated the impact of use of different catheter types on the risk of BSI in NICU patients using the outcomes of CLABSI,[9–11], [13–15], [68] catheter-associated BSI,[8], [12] nosocomial BSI,[7] nosocomial sepsis,[6] and late onset sepsis.[12] One study[13] evaluated the impact of different catheter types on infiltration.

Four studies[9], [10], [13], [15] evaluated the risk of BSIs among neonates with umbilical venous catheters (UVCs) or percutaneously inserted central venous catheters. Very low-quality evidence suggested no difference in infectious risk when comparing UVCs with percutaneously inserted central catheters. Two studies[15], [68] evaluating the incidence of CLABSI reported no difference in the incidence of CLABSI for UVCs compared with peripherally-inserted central catheters (PICCs). In one of these studies, patients with PICCs were of younger gestational age and lower birthweight at time of insertion and had longer catheter dwell times; in the smaller study the groups were well balanced in terms of these confounding factors.[15] Another study[11] found similar CLABSI rates in those with PICCs and UVCs, but reported a two-fold increase in the risk of CLABSI for UVCs compared with PICCs when adjusting for gestational age, birthweight, and catheter dwell time. The third study[12] reported no difference in adjusted catheter-associated BSI (CA-BSI) and late onset sepsis rates between UVCs and percutaneously inserted central catheters. Only one study[68] reported adverse events associated with UVCs and PICCs and reported no difference. UVCs are usually intended for short-term use and are removed or replaced by peripheral venous lines or percutaneously inserted central venous catheters if longer-term access is needed. Of note, two of these studies[12], [68] evaluated data that were collected before the United States focused on evidence-based CVC insertion and maintenance practices that have been shown to reduce CLABSIs. In the setting of current standard of care, the impact of prioritizing different catheter types is unknown.

Six studies[6–10], [13] evaluated the risk of BSIs among neonates with different central line types. Each study compared a different series of catheter types including umbilical arterial catheters, umbilical venous catheters, percutaneous arterial catheters, percutaneous venous catheters, peripherally inserted central catheters, intracath, phlebotomy catheters, and tunneled catheters. Very low-quality evidence did not allow for a clear determination about the BSI risk among neonates with different central line types. One study[9] compared UVCs, central venous catheters (CVCs), and PICCs, and found the lowest CLABSI incidence for UVCs. One large, multicenter study[10] reported a tunneled catheter CLABSI incidence that was 2.4 times as high as the CLABSI incidence for PICCs. Neither study reported an analysis for the confounding factor of dwell time on CLABSI incidence. The third study[13] compared the risk of CLABSI among umbilical arterial catheters (UACs), UVCs, short duration venous catheters (SDVCs), PICCs, and tunneled catheters, and found no difference. One study[8] reported the outcome of catheter-associated BSI and found a higher rate for PICCs than for other catheters, including UVC, intracaths, and phlebotomy catheters. One study[7] reported the outcome of nosocomial-BSIs and found higher infection rates associated with percutaneous venous and tunneled catheters compared with UVCs. One study6 compared the incidence of sepsis for tunneled catheters, percutaneous catheters (used primarily in pediatric patients), PICCs, and UVCs, and found the lowest incidence associated with umbilical catheters. This study did not adjust for the confounding factor of dwell time and reported a longer dwell time was associated with umbilical and tunneled catheters. Finally, one study[14] compared outcomes for extended dwell peripheral intravenous catheters (EVIP) also known as midline catheters, compared with PICCs in NICU patients, and found no difference in CLABSI rates between catheter types.

Three studies[13–15] reported adverse events. One study[15] reported no difference in obstruction or thrombosis, however events and sample sizes were small. The other study[13] reported the incidence of infiltration for UACs, UVCs, SDVCs, PICCs and tunneled catheters, and found PICCs were associated with a higher incidence of infiltration. Finally, one cohort study[14] reported a higher rate of obstruction, peritonitis, and premature ventricular contractions in infants with PICCs compared with EPIVs which are not typically used in this population, however infants with EPIVs received a higher incidence of hyaluronidase treated IV fluid extravasation.

Each study compared different catheter types and different outcome measures, and three of the studies[6–8] reported results from data collected prior to the implementation of bundles, which impeded the ability to draw conclusions as to the efficacy of one catheter type over another. In the setting of current standard of care, the impact of prioritizing different catheter types is unknown.

E.3. Central Line Insertion Site

Key Question 3: Does the use of one central line catheter insertion site, compared with another, prevent CLABSI in NICU patients?

Two studies[19], [20] compared the risk for catheter-related sepsis (CRS) between percutaneous catheters placed in femoral versus non-femoral sites. However, these studies examined the same NICU population during overlapping study periods. Very low-quality evidence suggested an increase in CRS in neonates with a percutaneous central catheter placed directly into the femoral vein compared to those placed in non-femoral sites. This was based on two studies which found that a significantly higher proportion of neonates with a percutaneous catheter placed at a femoral site developed CRS[20] or that neonates with a percutaneous catheter placed at a femoral site had an increase in the adjusted odds ratio for CRS.[19] The findings in both of these studies may have been biased by choosing non-femoral sites first. In these studies, femoral sites were used only if attempts to place a percutaneous catheter via a non-femoral site were unsuccessful. Additionally, duration of percutaneous catheter placement was also found to be a significant risk factor for infectious outcomes in both studies, which may have also confounded the results.

Non-infectious complications were assessed in both studies. One study[20] reported that the adjusted odds of a noninfectious complication in a neonate with a femoral central line placement did not differ significantly from neonates with a non-femoral site placement. In the study analyzing VLBW infants,[19] the proportion of patients that developed phlebitis, catheter site inflammation, or that required early percutaneous central catheter line removal was significantly higher for non-femoral central lines. This study did not assess adverse events. Of note, both studies were conducted at a time before the United States focused on evidence-based CVC insertion and maintenance practices that have been shown to reduce CLABSIs. In the setting of current standard of care, the impact of prioritizing femoral or non-femoral insertion sites is unknown. As a practical consideration related to care, there can be greater difficulty keeping central line dressings clean and dry when placed in the groin area; however, the studies did not report on cleanliness and ease of line management.

Three studies evaluated the risk of CLABSI,[24], [25] catheter-related sepsis[21] and catheter-associated infections[17] for surgically implanted central lines in neonates placed in the subclavian, jugular, or femoral sites. Low quality evidence from one case control study[24] suggested an increase in the odds of internal jugular placement among patients with CLABSI, and no difference in the proportion of subclavian, saphenous, external jugular, or brachial placement among NICU patients with CLABSI. A cohort[25] study examined tunneled CVCs and reported no difference in the incidence of CLABSI when comparing lines placed femoral sites with those in subclavian sites. Very low-quality evidence from one study[17] suggested an increased risk for catheter-associated infections among patients with central lines implanted in the internal jugular vein compared to those implanted in the subclavian vein. This difference remained significant after adjusting for confounding factors such as weight and age. Catheter removal due to obstruction of the CVC by kinking was significantly higher in infants with internal jugular catheters; however, there was no difference in clinical thrombosis and catheter dislocation between sites. Very low-quality evidence from one study[21] suggested a lower rate of catheter-related sepsis and accidental catheter removal in neonates with central lines placed at a femoral site when compared with central lines implanted in the neck, defined as either at the subclavian or the internal jugular site. This study did not define the criteria used to determine the outcomes of either catheter infection or catheter-related sepsis. In both studies, significant differences in weight may have impacted the site of successful catheterization. In both studies, the groups with lower weight had higher rates in infection. Of note, both studies were conducted before the widespread implementation of central line insertion and maintenance bundles in 2010. The impact of prioritizing different insertion sites is unknown in the context of the current standard of care.

Five studies evaluated the risk of a CLABSI,[16], [24] CRBSI,[18] sepsis,[23] and presumed sepsis[22] for CVCs in the upper extremity and lower extremity. Very low-quality evidence suggested the incidence of CLABSI, CRBSI, and presumed sepsis did not significantly differ between NICU infants in whom the PICC was placed in an upper extremity vein compared to those in whom the catheter was placed in a lower extremity vein. All four studies[16], [18], [22], [23] were conducted to assess PICC-related complications associated with PICC removal. The incidence of infiltration was significantly higher in neonates with PICCs placed in the upper extremity in one study.[16] Limited data[18] suggested an increase in the risk of phlebitis and significantly longer dwell time[16] for PICCs placed in the lower extremity. Finally, one case control study suggested an increase in the proportion of upper limb insertions among patients with CLABSI compared to those without CLABSI. Additionally, for PICCs placed in upper extremities, limited data suggested an increase in the proportion of patients developing cholestasis and dislodgement,[16], [23] and the time to first complication was shorter.[18] In one of these studies[23], the gestational age for patients with upper extremity placement was two weeks younger than patients with lower extremity placement, which may have been a source of bias in the adverse event data, however more studies are needed to determine if gestational age biases these results. In many of these studies, the choice of site was guided by healthcare personnel preference, which may or may not have been dictated by the needs of the patient as much as the preference of the inserting healthcare personnel and could also confound the results. Of note, all three of the five studies ([14], [15], [20]) evaluated data that were collected before the United States focused on evidence-based CVC insertion and maintenance practices that have been shown to reduce CLABSIs. In the setting of current standard of care, the impact of prioritizing different catheter insertion sites is unknown.

E.4. Number of Catheter Lumens

Key Question 4: Does the use of single-lumen, compared with double-lumen, umbilical venous catheters prevent CLABSI in NICU patients?

One randomized trial[26] and two observational studies reported on CLABSI,[24], [27] and catheter-related sepsis[21] between single- and double-lumen umbilical venous catheters. Low-quality evidence from two observational studies suggests an increase in the risk of CLABSI is associated with the use of double-lumen catheters. One cohort[27] reported a significant increase in the adjusted incidence rate ratio of CLABSI for patients with double-lumen UVCs compared with single lumen UVCs. The case control study also reported an increase in the odds of CLABSI for patients with double-lumen catheters compared with single lumen catheters. The RCT [21] reported no difference in the proportion of neonates with single- or double-lumen umbilical venous catheters that developed catheter-related sepsis. Of note, there were no infections reported in this study, and neonates in this study had catheters in place only for about 3 days.

The two observational studies noted an increase in complications was associated with double-lumen catheters; however, the patients in these studies were not matched by severity of illness and there are concerns for confounding by indication. The RCT reported no difference in mechanical complications between the two catheter types. Use of double-lumen catheters was associated with a significant reduction in the number of additional intravenous catheters required, however this RCT was not conducted in the current era of widespread implementation of catheter care bundles.

E.5. Skin Antisepsis for Catheter Insertion and Maintenance

Key Question 5: In NICU patients requiring skin antisepsis for catheter insertion and maintenance, does the use of alcoholic chlorhexidine, compared with alcoholic povidone-iodine, prevent CLABSI?

The literature search did not retrieve any articles comparing the use of any concentration of alcoholic chlorhexidine (CHX) with alcoholic povidone iodine (PI). One RCT[29] compared the use of 2% alcoholic chlorhexidine gluconate (CHG) with povidone iodine (PI) in an unspecified base to prepare skin for catheter insertion and maintenance. This study suggested no difference in CRBSI, CABSI, presumed BSI, or septicemia between study groups. This study was terminated early due to slow enrollment.

Cutaneous absorption of chlorhexidine was found in half of the infants who were monitored for this outcome; however, no significant systemic side effects were noted. This study also reported no dermatitis at CHG application sites. The confidence in this evidence is very low. This study was published prior to the widespread implementation of insertion and maintenance bundles in 2010. The impact of this intervention in the current standard of care is unknown.

E.6. Chlorhexidine Bathing

Key Question 6: Does chlorhexidine bathing, compared with no bathing or bathing with placebo, prevent CLABSI in NICU patients?

One RCT [30] and three observational studies) [31–33] examined the use of chlorhexidine bathing for neonatal patients. The RCT[30] compared a single bath using 0.25% chlorhexidine-impregnated washcloths with a single bath using saline impregnated cloths or no baths in NICU patients. The two observational studies[31], [33] compared specific bathing regimens based on birthweight, gestational age and chronologic age, using 2% CHG impregnated washcloths compared with using soap33 or no baths.[31] One of the observational studies compared a bath with 2% CHG in water with no bath.[32] Three of the four studies reported the outcomes of product-related adverse events, including hypothermia[30] and skin reactions.[30], [31, [33]

One RCT[30] examining the safety and efficacy of a single bath using 0.25% chlorhexidine-impregnated washcloths compared with saline impregnated washcloths or no bath, reported the outcomes of culture positive sepsis and clinical sepsis. This study suggested no difference in the incidence of culture-positive sepsis or the incidence of clinical sepsis at one week between groups. The confidence in this evidence is low.

Two observational studies examining the safety and efficacy of using 2% CHG washcloths compared with using soap[33] or no baths[31] reported the outcomes of CLABSI. These studies suggested a clinically meaningful[33] or significant[31] decrease in the rate of CLABSI in NICU patients. Both studies were conducted in facilities with high baseline CLABSI rates. While both studies reported adding chlorhexidine bathing to existing standard of care, and both were conducted in the era of widespread implementation of insertion and maintenance bundles in the United States, it is unclear if the study conducted in an international setting[31] implemented insertion and maintenance bundles for the prevention of CLABSI. The confidence in this evidence is low.

Finally, one cohort[32] study suggested a reduction in laboratory-confirmed sepsis and culture-negative for patients who received at least one bath in the first three days of life. These reductions reached statistical significance during the intervention period for laboratory-confirmed sepsis. This evidence as rated as very quality.

The RCT[30] reported on the effects of 0.25% chlorhexidine-impregnated washcloths on axillary temperature and skin reactions. This study reported no instances of moderate hypothermia (<36°C) and no difference in the incidence of cold stress (36.0° – 36.4 1°C) between groups of NICU patients. This study reported no adverse product-related skin reactions for a single chlorhexidine-impregnated washcloth bath, including skin erythema, fissuring, or crusting in NICU patients or adverse effects on skin condition in neonates. The confidence in this evidence is low.

Two observational studies[31] reported on the effects of 2% CHG impregnated washcloths on skin reactions. Both studies reported no adverse product-related events associated with using 2% CHG impregnated washcloths, including local or systemic adverse events[31] and dermatitis or other adverse events.[33] The confidence in this evidence is very low.

One of the studies[30] included in this section was published prior to the widespread implementation of insertion and maintenance bundles in 2010.

E.7. Catheter Hub Manipulation

Key Question 7: In NICU patients with central line catheters does minimizing the number of times central line hubs are accessed prevent CLABSI?

One study evaluated the effect of catheter hub manipulations and blood draws through the catheter on catheter-associated BSIs.[34] Very low-quality evidence suggested that more frequent central line hub manipulations requiring disinfection (e.g., disconnection of the infusion set from a central line) or drawing blood through a central line increases the risk of catheter-associated BSIs. These findings were based on an increase in the odds of catheter-associated BSI in a multivariate model. Of note, drawing arterial blood through an arterial catheter for a blood gas was not associated with an increase in the odds of BSI.

E.8. Central Line Antimicrobial Locks

Key Question 8: In NICU patients with central line catheters, does the use of central line antimicrobial locks, compared with standard of care, prevent CLABSI?

Three studies of neonates evaluated the effect of central line antimicrobial locks on catheter-related BSIs.[35–37] There was high-quality evidence that the use of catheter locks prevented catheter-related BSIs. This was based on studies of three different antimicrobial locks (vancomycin,[36] amikacin,[37] or fusidic acid,[35] in combination with heparin) that were used at least once per day that demonstrated a decrease in definite CRBSIs. No evidence was retrieved regarding the use of ethanol locks. None of the three studies reported a significant decrease in suspected or probable CRBSIs. The definition of CRBSI differed slightly across the studies.

The presence of a lock results in the disconnection of glucose infusion to a neonate and can result in the development of hypoglycemia. Hypoglycemia was evaluated in all three studies and was not found to be higher in the antimicrobial lock group as compared with the control saline-heparin-only locks. The rate of hypoglycemia was more than 10% in these studies, presumably because of the disconnection of the glucose infusion as a result of the lock. The development of antimicrobial resistance over the short term was evaluated in two of the studies,[36], [37] and no instances of resistance to the agent used in the antimicrobial lock were detected. The incidence of bleeding complications was not evaluated in any of the studies. Of note, all three studies were conducted before the widespread implementation of central line insertion and maintenance bundles that have been shown to reduce CLABSIs, which may be why the rates of catheter-related BSIs were very high in the non-intervention groups. In the setting of current standard of care, the impact of central line antimicrobial locks is unknown.

E.9. Optimal Umbilical Arterial and Venous Catheter Dwell Time

Key Question 9: What is the optimal duration of umbilical artery and umbilical venous catheters to prevent CLABSI in NICU patients?

Six studies evaluated the risk of a BSI outcome for patients with umbilical catheters (6 venous, 1 arterial).[6], [11], [27], [38–40] (add Levit 2020) Low-quality evidence suggested that the longer an umbilical arterial or venous catheter was in place, the higher the odds or risk of a BSI-related outcome. While the catheter dwell time break points varied among studies, three studies suggested an optimal UVC duration of up to 7 days.[3–5] One cohort suggested low risk in the first week of central line use, followed by a three-fold increase in risk at day 14 of use.[27] Two studies[11], [39] found that longer use of an umbilical venous catheter was associated with an increase in the risk of CLABSI. One study reported an increase in risk of CLABSI for UVCs in situ for >7 days,[39] and the other study[11] reported the risk of CLABSI increased beyond 3-4 days of dwell time for UVCs, and that risk doubled every 2 days thereafter if the UVC was followed by PICC insertion. One study[6] reported an increase in the incidence of sepsis in UVCs in situ for 4-6 days when compared with those in situ for 1-3 days, but this difference was not noted as significant. This study also found the incidence of sepsis was higher in umbilical artery catheters in situ for ≥8 days when compared with those in situ for ≤7 days. One study,[40] conducted after the widespread implementation of central line insertion and maintenance bundles in 2010, implemented a quality improvement initiative in uncomplicated NICU patients without congenital anomalies, with a gestational age of ≥27 weeks or weighing >1000g at birth. This study found no increase in CLABSI in infants with UVCs that were replaced by PICCs at 7 days compared with infants with UVCs replaced at 5 days. This study may have been underpowered. In an 11-year observational cohort study (2008-2018), CLABSIs occurred at a mean of 9.8 days (range 5 to 18). The risk began to rise in the second week, from <1% at day 7 to 3.6% at day 14.

One RCT evaluated the effect of routinely removing umbilical venous catheters and replacing them with a percutaneous central catheter after seven to ten days compared with replacement at up to 28 days.[38] There were no significant differences in the two study arms for time to catheter-related infection and the duration of catheter use before infection. However, while the overall incidence of catheter sepsis was not significantly different between groups, the study reported more than twice the incidence of infections in the long-term UVC group compared with the group in which UVCs were replaced by percutaneous central catheters. This study also reported no significant difference between the two groups in measured complications, including development of a thrombus.

Of note, 4 of the 6 studies included in this analysis were conducted using data collected prior to the implementation of catheter insertion and maintenance bundles.[6], [11], [38], [39] In the setting of current standard of care, there is limited understanding of the impact of umbilical catheter dwell time on CLABSI, CRBSI, and CA-BSI.

E.10. Optimal Peripherally Inserted Central Catheter Dwell Time

Key Question 10: What is the optimal duration for peripherally inserted central catheters to prevent CLABSI in NICU patients?

Eight studies[10], [11], [41–46] evaluated the risk of BSI over time for PICCs. Very low-quality evidence suggested that the longer a percutaneous central catheter was in place, the odds or risk of developing a CLABSI, CRBSIs, or catheter-related sepsis increased, although the time periods analyzed varied across studies. Three studies[11], [42], [46] reported increases in CLABSIs with increasing dwell time; however, none was able to pinpoint a clear inflection point for removal or replacement of PICC to reduce CLABSI risk. One study[10] reported an increased risk of CLABSI in the first week of dwell time and found that no other duration of catheter stay was associated with increased risk of CLABSI. Three studies[41], [44], [45] reported the outcome of CRBSI. Two studies[41], [44] found an increase in CRBSI with increasing dwell time; however, this increase did not reach significance in one study.[44] Almost all PICCS in this study were removed within two weeks of insertion. One study[45] found no difference in PICC dwell time between patients with CRBSI and those that did not develop CRBSI. One study[43] found significant increases in catheter-related sepsis in patients with peripherally-inserted central catheters in place for >9 days compared to those in place for ≤9 days. No product-related adverse events were reported in relation to PICC dwell time.

Of note, 6 studies[11], [41–44], [46] were conducted using data collected prior to the widespread implementation of central line insertion and maintenance bundles in 2010. One of these studies[42] conducted data analyses to account for this change in infection prevention and control practices; however, the others did not. In the setting of current standard of care, the impact of PICC dwell time on CLABSI, CRBSI, and CA-BSI is unknown.

E.11. Dedicated Catheter Care Team

Key Question 11: Does the use of dedicated catheter care teams compared with standard of care, prevent CLABSI in NICU patients?

Two observational studies reported the effect of a dedicated catheter care team on CLABSI[48] and CRBSI[69] One observational study[48] reported on the effect of a dedicated central line maintenance team on CLABSI in a NICU. This study reported a reduction in CLABSI that remained significant after adjustment for the NHSN CLABSI definition change. The other observational study[47] evaluated the effect of a dedicated PICC team on CRBSIs in extremely low birth weight NICU patients. Implementation of the PICC team was compared to previous standard of care and reported no difference in the risk of CRBSI. A duration stratification analysis showed a reduction in CRBSIs for NICU patients with indwelling central lines ≥30 days was associated with implementing catheter care teams. However, no difference was reported for patients with indwelling central lines <30 days. Adverse events attributable to catheter care teams were not reported. While the evidence suggests a benefit to implementation of catheter care teams when baseline rates are high, catheter care teams are a prevention measure, and not solely a reactive measure. Use of a catheter care team can prevent high CLABSI rates in addition to reducing them. The confidence in this evidence is very low due to imprecision.

E.12. Central Line Insertion and Maintenance Bundles

Key Question 12: What are the optimal elements of central line insertion and maintenance bundles to prevent CLABSI in NICU patients?

Three observational studies[50] implemented a central venous catheter insertion and maintenance bundle and measured concurrent compliance as part of a NICU-specific[50] or hospital-wide[51], [52] quality improvement initiative. Possible adverse events attributable to the implementation of an insertion only bundle or insertion and maintenance bundle were not assessed.

All three studies[50–52] reported reductions in CLABSI. All three studies also measured healthcare personnel bundle compliance and reported an increase in insertion and maintenance compliance from the baseline throughout the intervention period. Compliance reporting was required for all bundle elements in order for the data to be included in the analysis. Although CLABSI decreased, none of the studies examined the possible association between bundle compliance and the reduction in CLABSI.

No studies were retrieved that directly compared the efficacy of different bundles.

E.13. Prophylactic Antimicrobial Administration

Key Question 13: What is the efficacy of prophylactic antimicrobials, compared with standard of care, to prevent CLABSI in NICU patients?

Four studies evaluated the effect of systemic prophylactic antibiotics on BSIs among patients with central lines.[53–56] Moderate-quality evidence did not suggest a clear net benefit to systemic prophylactic antibiotics to reduce total BSIs, although prophylactic vancomycin did appear to result in a decrease in BSIs due to coagulase-negative staphylococci (CoNS). This was based on three studies[54–56] that evaluated the use of prophylactic vancomycin and one that evaluated prophylactic amoxicillin.[53] The first,[56] a randomized trial, found a decrease in coagulase-negative staphylococcal BSIs among infants that had vancomycin added to doses of TPN. It was not clear in this study if this approach resulted in a significant change in overall catheter-related sepsis. A second pre-post study[55] evaluated the administration of prophylactic low-dose vancomycin (25 mcg/ml) through neonates' catheters and found an overall significant decrease in gram-positive infections, but no change in the percent of neonates with gram-negative or fungal infections. The third study[54] (pre-post) compared a period in which prophylactic vancomycin was provided with parenteral nutrition infusions to the period that followed, during which vancomycin was used only for treatment. This study found an overall significant decrease in positive blood cultures in the vancomycin group that was primarily due to a significant decrease in positive blood cultures for CoNS. The number of patients exposed to vancomycin decreased between the first and second periods, although the total amount of vancomycin use increased. The fourth study[53] (randomized trial) evaluated prophylactic amoxicillin daily and did not find statistically significant differences in proven septicemia or suspected septicemia in neonates receiving prophylactic amoxicillin. There did not appear to be large differences in mechanical and thrombotic complications between the two groups.

Three studies reported on antibiotic resistance. Two studies[55], [56] reported on vancomycin resistance, and one on amoxicillin resistance.[53] One study[56] reported no incidences of vancomycin resistance, and CoNS susceptibility patterns did not change; further, vancomycin-resistant strains of CoNS were not detected. One study[55] reported that no incidences of vancomycin resistance were observed during the study period; however, in the two years following the study, four cases of CoNS resistance to vancomycin appeared. The study evaluating prophylactic amoxicillin[53] reported one incidence of amoxicillin-resistant Staphylococcus epidermidis in the control group. The long-term development of antimicrobial resistance was not adequately evaluated in any of these studies, nor was impact on the infant microbiome. None of the studies included in this analysis were conducted using data collected after the widespread implementation of central line insertion and maintenance bundles. In the setting of current standard of care, the impact of prophylactic antimicrobials on CLABSI, CRBSI, and CA-BSI is unknown. In contrast, prolonged antibiotic exposure in uninfected neonates has been associated with adverse outcomes, including NEC and death.[70] In VLBW infants, each increased day of antibiotic exposures has been associated with an increased risk of bronchopulmonary dysplasia.[71] The current standard of care in NICUs is to limit unnecessary antimicrobial exposure.

E.14. Prophylactic Anticoagulant Administration

Key Question 14: What is the efficacy of prophylactic anticoagulant infusions, compared with standard of care, to prevent CLABSI in NICU patients?

Four studies[57–60] evaluated the effect of heparin infusions on BSI-related outcomes. Moderate-quality evidence suggested that neither continuous infusions of heparin, nor heparin added to or infused with TPN, resulted in significant reductions in catheter-related sepsis. This conclusion was based on four studies[57–60] that showed no decrease in catheter-related sepsis or definite catheter-related sepsis among neonates with PICCs receiving infusions of heparin. One study[57] suggested no difference in the incidence of probable or possible catheter-related sepsis, and another study[60] reported no difference in the incidence of septicemia.

Adverse events were evaluated in all four studies. Two studies[59], [60] demonstrated a significant reduction in catheter occlusion; the other two[57], [58] did not find a significant difference in this outcome. Three studies[57], [58], [60] reported no difference in the incidence of intraventricular hemorrhage between the two groups; however, a small number of infants was assessed for this outcome, limiting the confidence in these results. Of note, sepsis outcome definitions and heparin preparations were heterogeneous across studies. All of the studies were conducted using data collected prior to the widespread implementation of central line insertion and maintenance bundles in 2010. The effect of prophylactic anticoagulant on central line infections with the current standard of care is unknown.

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