Risk of morbidity following catheter removal among neonates with catheter associated bloodstream infection

Abstract

OBJECTIVE:

We hypothesized that infectious morbidities following percutaneously inserted central venous catheter (PICC) removal would be greater among neonates with central-line associated bloodstream infection (CLBASI).

STUDY DESIGN:

This retrospective cohort study, included all neonates who required a PICC over a ten-year period. Outcomes assessed following PICC removal included: late bloodstream infection, rule-out sepsis workups, need for a subsequent PICC and antibiotic days and PICC days after PICC removal. Odds ratios (OR) and 95% confidence intervals (CI) were determined for outcomes. Regression analyses were used to control for confounders.

RESULTS:

Two-thousand nine hundred and thirteen neonates required at least one PICC during the study period. After adjusting for confounders neonates with CLABSI were 3.4 (95% confidence interval (CI) 2.5, 4.6) and 2.2 (95% CI 1.2, 4.0) times more likely respectively to require a subsequent PICC or develop a late bloodstream infection after PICC removal. Neonates with CLABSI required 1.33 (95% CI 0.77, 1.89) more days of antibiotic treatment and 6.85 (95% CI 5.34, 8.37) more PICC days following PICC removal than neonates without a CLABSI.

CONCLUSIONS:

Neonates with CLABSI are at risk for additional infectious morbidities after PICC removal. Future intervention studies aimed at reducing CLABSI should evaluate whether morbidities following catheterization are also reduced.

Keywords

Central line associated bloodstream infection neonate percutaneously inserted central venous catheter bloodstream infection

1 Introduction

Percutaneously inserted central venous catheters (PICCs) are widely used for parenteral nutrition and antibiotic therapy in neonatal patients [1 –4]. One of the most common complications of PICCs in neonates is central line-associated bloodstream infection (CLABSI) which may increase length of hospital stay, hospital costs and potentially effect long-term outcome of very low birth weight infants [2 , 5–8]. The incidence of CLABSI among neonates has decreased dramatically since 2007 from an incidence of 4.9 to 1.5 CLABSI/1000 central venous catheter days [9]. The decline in the rate of CLABSI rate over the last eight years is likely in part due to application of Center for Disease Control (CDC) Guidelines for catheter care [10]. Through the use of “checklists” and “catheter care bundles” for catheter insertion and maintenance care, a number of groups, using time-sequence quality improvement initiatives, have shown that CLABSI rates could be reduced using the CDC evidence based guidelines for catheter care [11 –13].

Although a number of randomized and observational studies have examined risk factors for CLABSI as well as interventions to reduce their occurrence, few studies have examined associated morbidities that may occur after the PICC is removed. It is unlikely that the antibiotic course to treat a CLABSI is entirely responsible for the increased length of stay and hospital cost following a CLABSI. In addition to the course of antibiotics used to treat the CLABSI, neonates with CLABSI are at risk for circulatory and/or respiratory insufficiency that may require respiratory support, suspension of enteral feedings and red cell transfusions. Such treatments could result in additional morbidities that adversely affect the hospital course and the long-term outcome of neonates who experience a CLABSI [5]. Potential “CLABSI related morbidities” occurring during the hospital course following removal of a PICC among patients who have CLABSI may include: the need for a subsequent PICC placement, additional septicemia evaluations, additional bloodstream infections and an increased antibiotic days. Such morbidities could contribute to the increased in length of stay and hospital cost associated with a CLABSI.

The purpose of this four-center retrospective cohort study of neonates with PICCs was to determine if CLABSIs increased the risk of morbidities following PICC removal.

2 Methods

2.1 Study population

This retrospective cohort study used data taken from a database maintained at four community Level III neonatal intensive care units in Milwaukee, Wisconsin. The study was approved by the Institutional Review Boards at each center. An Access (Microsoft, Redmond Washington) database, developed in 1998 consists of demographic, clinical course and outcome data that provide real time data for quality improvement initiatives at each of the units. The data set includes a number of variables to evaluate morbidities and co-morbidities associated with PICC treatment. Dates of documented bloodstream infections and septicemia evaluations, as well as the antibiotics prescribed (type and dates of treatment) to treat all episodes are recorded for all neonates admitted to each of the units. Similar information is collected for episodes of clinically defined ventilator associated pneumonia [14], necrotizing enterocolitis (≥Bell Stage II) [15] and other infections requiring systemic antibiotic treatment.

‘Neonatal data used for this retrospective cohort trial was prospectively abstracted from each infant’s chart by dedicated neonatal nurses, nurse practitioners or trained quality improvement specialists from January 2000 to November 2010 into each unit’s data set. All neonates without major congenital anomalies who had a PICC in place for greater than 72 hours were included in the cohort.

2.2 Exposure

From 1998 to October of 2003 a CLABSI was defined by the presence of bacteria or fungus from one or more peripheral blood cultures obtained from a symptomatic neonate without an identifiable source who was treated with at least 6 days of systemic antibiotics. The CLABSI occurred during the time a PICC was in situ, or within 24 hours of a PICC removal. The CLABSI definition used in the data set differed slightly from the National Healthcare Safety Network definition in that a bloodstream infection was considered a CLABSI if it occurred up to 24 hours after PICC removal; the National Healthcare Safety Network definition includes a time frame of up to 48 hours after PICC removal. Since October 2003, as a part of an antibiotic stewardship initiative to limit vancomycin use in the neonatal units, the definition of CLABSI, more in-line with the National Healthcare Safety Network Criteria [14] has been used. From October 2003 to November of 2010 a CLABSI was defined by a positive peripheral blood culture growing a common pathogen or two peripheral blood cultures growing the same commensal organisms obtained from a symptomatic neonate without an identifiable source who was treated with at least 6 days of systemic antibiotics. CLABSI occurred during the time a PICC was in situ, or within 24 hours of a PICC removal rather than within the 48 hours of removal described in the National Healthcare Safety Network’s definition. Commensal organisms included diptheroids, Bacillus spp., Propionibacterium spp., coagulase-negative staphylococci, viridans group streptococci, Aerococcus spp., and Micrococcus spp.

2.3 Outcomes

2.3.1 Subsequent bloodstream infection

A subsequent bloodstream infection (SBSI) was defined by similar criteria as the initial CLABSI except that a central venous catheter did not have to be present and the SBSI occurred at least 6 days after the initial PICC was removed. Additionally any infant with a CLABSI during the initial PICC treatment period had to have received at least 7 day of appropriate antibiotic treatment prior to the subsequent SBSI. We chose at least 6 days following PICC removal to eliminate SBSIs that may have occurred around the time of PICC removal [16].

2.3.2 Septicemia evaluations

Septicemia evaluations included a peripheral blood culture, a complete blood count and at least 48 hours of systemic antibiotic treatment. The peripheral blood culture was negative. Initial septicemia evaluations done without a suspected source of infection or subsequent evaluations done at least 48 hours after a previous septicemia evaluation were counted as separate evaluations. Because septicemia evaluations are often done on neonates with and without a PICC who have begun appropriate treatment for an episode of pneumonia or necrotizing enterocolitis, we also included evaluations that occurred during the antibiotic course for these disease processes. In such cases a septicemia evaluation was counted if it occurred at least 48 hours after an infant was diagnosed and started on appropriate treatment for either pneumonia or necrotizing enterocolitis, and the antibiotics used to treat the suspected septicemia differed from those used to treat the infant’s necrotizing enterocolitis or pneumonia.

2.3.3 Late antibiotic days

Systemic antibiotic days were defined by the total number of days an infant was given one or more systemic antibacterial or antifungal medications for a documented or suspected bloodstream infection, pneumonia, necrotizing enterocolitis or other infection. Days of antibiotics were subdivided into days that occurred up to the day of the initial PICC placement (early antibiotic days), those that occurred on the day of PICC placement and through the final day the PICC was in placed (PICC antibiotic days). For the purpose of the study antibiotic days that occurred after the PICC was removed that were judged to be a part of a course to treat a CLABSI or a suspected infection occurring prior to PICC removal were also counted as PICC antibiotic days. Late antibiotic days were defined by days of antibiotics after the catheter was removed less any antibiotic days that were considered part of a course to treat a CLABSI or suspected infection that occurred prior to PICC removal.

2.3.4 Subsequent PICC placement

Whether a subsequent PICC, placed after the initial PICC was removed, was documented for all neonates who were either discharged home or who died or were transferred to another institution at least two weeks after the initial PICC was removed.

2.3.5 Subsequent PICC days

Subsequent PICC days was defined by the number of days a PICC was in place following the removal of the initial PICC.

2.4 Clinical course variables

Demographic as well as clinical course data collected from the data set included year of birth, gender, race, location of birth, antenatal steroid treatment, route of birth, birth weight gestational age, Apgar scores, Score for Neonatal Acute Physiology [17], presence of respiratory distress syndrome at birth, surfactant treatment, presence of documented early onset septicemia, severity of intracranial hemorrhage and days of antibiotic treatment prior to the initial PICC placement.

3 Statistical analysis

Characteristics of infants with and without a CLABSI during initial PICC treatment were compared using chi-square testing for categorical variables and Student’s t test or a Wilcoxon rank sum test for continuous variables. Univariate analysis using chi-square testing was done to compare categorical outcomes such as SBSIs, placement of a subsequent PICC, and number of septicemia evaluation following the removal of the initial PICC among neonates with and without a CLABSI during the initial PICC treatment course. Wilcoxon rank sum test was used to compare days of systemic antibiotics following PICC removal as well as the number of subsequent PICC days during hospitalization following the removal of the initial PICC.

Multiple logistic, ordinal and linear regressions controlling for potential confounders were used to investigate the association between CLABSI and morbidities occurring after the removal of the PICC. We performed logistic regression for binary morbidities (i.e., subsequent PICC placement and SBSI); ordinal regression for ordinal morbidities (i.e., septicemia work-up); and linear regression for subsequent PICC days and late antibiotic days.

For each morbidity outcome we performed a two-stage backward stepwise regression on a set of demographic and clinical exposure variables (potential confounders) initially determined to be associated (P < 0.3) with the CLABSI and independently associated with the morbidity of interest. In the first stage, backward selection sequentially removed these potentially confounding variables one step at a time until the removal of a variable resulted in a significant (P < 0.1) decrease in the log-likelihood. The variable CLABSI was then entered into the model of the potentially confounding variables that remained in the model at the end of the first stage. Adjusted odds ratios (OR) and 95% confidence intervals (CI) of a morbidity among individuals with CLABSI prior to catheter removal compared to those without a CLABSI were calculated controlling for potential confounders. Birth weight, gestational age and NICU units were treated as categorical variables with the reference group being the highest birth weight or gestational age and Unit 1 respectively. Year of catheterization was also categorized, but was treated as an ordinal variable for the analyses.

4 Results

Two-thousand -nine hundred and thirteen neonates required at least one PICC for at least four days during the study period Initial PICCs placed in infants were in place for 17.3±12.1 days (50,515 total catheter days). Gestational age and birth weight of cohort neonates were 29.5±4.0 weeks and 1330±769 grams respectively. Four-hundred and seventy-seven neonates required at least one additional PICC after the initial PICC was removed.

Two hundred and ninety five neonates developed a CLABSI while the initial PICC was in place (5.8 infections/1000 catheters day). Gram positive organisms were responsible for 79% of CLABSI. Fifty-eight percent of all CLABSI were due to coagulase negative staphylococcus species. Gram negative organisms and fungal species were responsible for 14% and 7% of CLABSIs respectively. The type of organism responsible for CLABSI was not recorded in the databases for two cases. The rate of CLABSI among infants born prior to October 2003 (11.4 % [118/1039]) was not significantly different than the rate for those born after October 2003 (9.5 % [177/1874], P = 0.10). Similarly there were no differences in rates of CLABSI if the National Healthcare Safety Network definition was used to define a CLABSI; CLABSI occurring up to 48 hours after catheter removal vs up to 24 hours after catheter removal, as was used in the current study (10.7 vs 10.1%, P = 0.47).

Clinical characteristics of neonates who did and did not develop a CLABSI during their initial catheterization are shown in Table 1. Neonates with CLABSI during the initial PICC catheterization were more likely to require placement of a subsequent PICC and experience a subsequent bloodstream infection after removal of the PICC when compared to neonates without a CLABSI during the initial PICC catheterization (P < 0.0001, Table 2). Risk of a subsequent bloodstream infection after PICC removal among neonates who had a single central venous catheter during their hospital stay (n = 2436) were similar for neonates with (2/166, 1.2%) and without (14/2254, 0.62%) a CLABSI during initial PICC catheterization (P = 0.3). Neonates with a CLABSI during the time of the initial catheterization required more PICC days and days of antibiotic therapy as well as more septicemia evaluations following PICC removal (P < 0.0003, Table 2) than neonates who did not experience a CLABSI.

Table 1
Demographic and clinical characteristics among neonates without and with a central line associated bloodstream infection (CLABSI)

Neonates Neonates P Value

without CLABSI with CLABSI

(n = 2,618) (n = 295)

Sex - male (%) 55 55 0.97

Race (%)

White 46 40 0.35

Black 41 46

Hispanic 10 12

Other 3 2

Multiple (%) 24 27 0.27

Any antenatal steroids (%) 69 (n = 2600) 79 (n = 292) 0.001

Inborn (%) 90 93 0.19

Vaginal delivery (%) 43 43 0.77

Gestational age (%)

<25 weeks 10 28

25–28 weeks 27 41

28–32 weeks 40 28 <0.0001

>32 weeks 23 3

Birth weight (%)

<750 grams 16 39 <0.0001

750–1000 grams 20 31

1001–1250 grams 20 16

1251–1500 grams 16 9

>1500 grams 28 5

5 Minute Apgar (median, [25–75%]) 8(6–9) (n = 2609) 7(6–8) (n = 293) <0.0001

SNAP score (mean±standard deviation) 13.2±11 (n = 2040) 16.8±10 (n = 216) <0.0001

Surfactant treatment (%) 77 95 <0.0001

Respiratory distress at birth (%) 84 97 <0.0001

Patent ductus arteriosus (%) 31 48 <0.0001

Patent ductus arteriosus ligation (%) 10 21 <0.0001

Severe intracranial hemorrhage (Grade III/IV) (%) 5 (n = 2607) 12 (n = 293) <0.0001

Early onset septicemia (%) 2 1 0.37

Days of antibiotics before placement of central venous catheter (mean±standard deviation) 2.3±2.2 2.7±2.2 0.005

Days of initial PICC catheterization (mean±standard deviation) 16.7±12 23.3±14 <0.0001

Necrotizing enterocolitis (≥Stage II) (%) 5 9 0.003

Died during initial NICU course (%) 2 (n = 2613) 9 (n = 294) <0.0001

Level III NICU (%)

Unit 1 48 42 0.25

Unit 2 25 29

Unit 3 16 18

Unit 4 12 11

	Neonates	Neonates	P Value
Sex - male (%)	55	55	0.97
Race (%)
White	46	40	0.35
Black	41	46
Hispanic	10	12
Other	3	2
Multiple (%)	24	27	0.27
Any antenatal steroids (%)	69 (n = 2600)	79 (n = 292)	0.001
Inborn (%)	90	93	0.19
Vaginal delivery (%)	43	43	0.77
Gestational age (%)
<25 weeks	10	28
25–28 weeks	27	41
28–32 weeks	40	28	<0.0001
>32 weeks	23	3
Birth weight (%)
<750 grams	16	39	<0.0001
750–1000 grams	20	31
1001–1250 grams	20	16
1251–1500 grams	16	9
>1500 grams	28	5
5 Minute Apgar (median, [25–75%])	8(6–9) (n = 2609)	7(6–8) (n = 293)	<0.0001
SNAP score (mean±standard deviation)	13.2±11 (n = 2040)	16.8±10 (n = 216)	<0.0001
Surfactant treatment (%)	77	95	<0.0001
Respiratory distress at birth (%)	84	97	<0.0001
Patent ductus arteriosus (%)	31	48	<0.0001
Patent ductus arteriosus ligation (%)	10	21	<0.0001
Severe intracranial hemorrhage (Grade III/IV) (%)	5 (n = 2607)	12 (n = 293)	<0.0001
Early onset septicemia (%)	2	1	0.37
Days of antibiotics before placement of central venous catheter (mean±standard deviation)	2.3±2.2	2.7±2.2	0.005
Days of initial PICC catheterization (mean±standard deviation)	16.7±12	23.3±14	<0.0001
Necrotizing enterocolitis (≥Stage II) (%)	5	9	0.003
Died during initial NICU course (%)	2 (n = 2613)	9 (n = 294)	<0.0001
Level III NICU (%)
Unit 1	48	42	0.25
Unit 2	25	29
Unit 3	16	18
Unit 4	12	11

Table 2

Morbidity following central line removal among neonates without and with a CLABSI during initial catheterization

Outcome	Neonates without	Neonates with	P Value
	CLABSI	CLABSI
	(n = 2,618)	(n = 295)
Number of rule out sepsis evaluations and antibiotic treatment (%)^a	0 93	86
	1 3	6
	≥2 4	8	0.0003
Placement of second central catheter following removal of initial catheter (%)	13	43	<0.0001
Neonates with a bloodstream infection without a source following catheter removal (%)	2	6	<0.0001
Days of antibiotics following catheter removal^b (mean±standard deviation)	1.3±4.4	3.7±7.1	<0.0001
Days of subsequent PICC therapy after catheter removed (mean±standard deviation)	4.0±12.4	13.8±20.1	<0.0001

^aRule out sepsis evaluations included a complete blood cell count, blood culture and≥2 days of systemic antibiotic treatment. ^bDays of antibiotic treatment following catheter removal less days that were a part of an antibiotic course to treat a CABSI or presumed infection occurring prior to catheter removal.

Table 3 and 4 summarizes multivariate analyses of the association between CLABSI and the need for a subsequent PICC (Table 3), or subsequent bloodstream infection following the catheter removal (Table 4) while controlling for confounding variables. Risk for subsequent PICC placement declined from the start of the cohort to the end. (P = 0.01, Table 3). Neonates with CLABSI were 3.4 (95% confidence interval (CI) 2.5, 4.6) times more likely to require a subsequent PICC when compared to neonates without a CLABSI, even after controlling for potential confounders such as days of catheterization, presence of necrotizing enterocolitis and year of birth (Table 3). CLABSI during initial catheterization increased risk of a subsequent bloodstream infection following catheter removal 2.0 fold (95% CI 1.06, 3.8), after controlling for confounders (Table 4). Year of birth (born prior to October 2003 vs after) was not included in the modelling as it was not a confounder of the CLABSI/ subsequent bloodstream infection association.

Table 3

Results of logistic regression analysis of association between CLABSI and subsequent PICC placement

Risk factors	Beta Coefficient	P value	Adjusted OR (95% CI)
CLASI during initial catheterization	1.23	<0.001	3.4 (2.53, 4.63)
Time period of catheterization	–0.11	0.01	0.90 (0.93, 0.98)
site(2)	0.011	0.939	1.01 (0.76,1.34)
site(3)	–0.033	0.851	0.97 (0.69, 1.37)
site(4)	0.579	0.005	1.78 (1.19, 2.67)
Birth weight (grams)
<750	0.908	<0.001	2.48 (1.83, 3.36)
750–1000	0.410	0.002	1.51 (1.17, 1.94)
1001–1250	0.004	0.976	1.00 (0.77, 1.30)
1251–1500	–0.281	0.102	0.76 (0.54, 1.06)
Gestational age (weeks)
<25	0.958	<0.001	2.61 (1.82, 3.74)
25–28	0.565	<0.001	1.76 (1.33, 2.32)
29–32	–0.276	0.042	0.76 (0.58, 0.99)
Surfactant treatment	0.475	0.056	1.61 (0.99, 2.61)
Grade III/IV intraventricular hemorrhage	–0.465	0.045	0.63 (0.40, 0.99)
Surgical ligation of ductus arteriosus	0.757	<0.001	2.13 (1.52, 2.99)
History of necrotizing enterocolitis	1.891	<0.001	6.63 (4.39, 10.01)
Days of catheterization	–0.062	<0.001	0.94 (0.93, 0.95)

Table 4

Results of logistic regression analysis of association between CLABSI and a subsequent bloodstream infection following catheter removal

Risk factors	Beta coefficient	P value	Adjusted OR (95% CI)
CLASI during initial catheterization	0.694	0.033	2.0 (1.06, 3.79)
site(2)	0.737	0.021	2.1 (1.1, 3.9)
site(3)	0.751	0.085	2.1 (0.91, 5.0)
site(4)	0.605	0.250	1.8 (0.65, 5.13)
Gestational age (weeks)
<25	1.479	0.000	4.4 (2.5, 7.8)
25–28	0.796	0.002	2.2 (1.3, 3.7)
29–32	–0.711	0.027	0.49 (0.27, 0.90)
Presence of patent ductus arteriosus	–0.712	0.022	0.49 (0.27, 0.90)

Differences in septicemia evaluations among neonates with and without CLABSI was no longer significant (P = 0.21) after controlling for potential confounders using ordinal regression.

Neonates who had a CLABSI during initial PICC therapy required 1.33 (95% CI 0.772, 1.891) more days of antibiotic treatment and 6.85 (95% CI 5.34, 8.37) more PICC days following PICC removal than neonates without a CLABSI during initial PICC catheterization (Tables 5, 6) after adjusting for potential confounders with linear regression. Again, year of birth (prior to October 2003 vs after) was not included in the modelling as it was not a confounder of the CLABSI/ antibiotic days or CLABSI/PICC days association.

Table 5

Linear regression analysis of association between CLABSI and days of antibiotics

Risk factors	Coefficient	Lower bound	Upper bound	P value
CLABSI during initial catheterization	1.331	0.772	1.891	<0.001
Antenatal steroids	–0.511	–0.898	–0.125	0.010
Gestational age category (4 categories)	–0.924	–1.243	–0.605	<0.001
Birth weight category (5 categories)	–0.474	–0.670	–0.277	<0.001
Apgar at 5 minutes	–0.109	–0.209	–0.010	0.032
Days of antibiotics prior to catheter placement	0.067	–0.012	0.146	0.095
Surgical ligation of patent ductus arteriosus	1.341	0.757	1.926	<0.001
Days of catheterization	–0.071	–0.087	–0.054	<0.001
Presence of necrotizing enterocolitis	3.568	2.824	4.313	<0.001

Neonates who had a CLABSI during initial PICC therapy required 1.33 (95% CI 0.772, 1.891) more days of antibiotic treatment.

Table 6

Linear regression analysis of association between CLABSI and subsequent picc days

Risk factors	Coefficient	Lower bound	Upper bound	P valule
CLABSI during initial catheterization	6.851	5.335	8.366	<0.001
Antenatal steroids	–1.727	–2.772	–0.681	0.001
Gestational age category (4 categories)	–3.341	–4.199	–2.484	<0.001
Birth weight category (5 categories)	–1.656	–2.187	–1.125	<0.001
Apgar at 5 minutes	–0.380	–0.649	–0.110	0.006
Severe IVH (Grade III, IV)	–2.655	–4.557	–0.752	0.006
Surgical ligation of patent ductus arteriosus	4.724	3.142	6.306	<0.001
Days of catheterization	–0.312	–0.356	–0.268	<0.001
Presence of necrotizing enterocolitis	12.927	10.917	14.937	<0.001

Neonates with CLABSI required 6.85 (95% CI 5.34, 8.37) more PICC days following PICC removal than neonates without a CLABSI during initial PICC catheterization.

5 Discussion

Several authors have shown that CLABSI increases hospital cost and length of stay [6 –8]. Most recently Goudie et al. [7] reported that hospital charges and length of stay attributable to neonatal CLABSI were $55,646 and 19 days, respectively. The authors do not speculate as to the reasons for the additional cost and length of stay. In our study we noted neonates who developed a CLABSI during initial PICC therapy were more likely to require placement of an additional PICC, have a second bloodstream infection at least a 6 days following the removal of the initial PICC and require more antibiotic days and PICC days following the removal of the initial PICC. Each of these hospital morbidities can increase hospital cost among neonates with CLABSI and are likely partially responsible for the increased hospital cost and length of stay among neonates with CLABSI that has been reported by others.

Though the increased risk for second PICC as well as increased PICC days following a CLABSI has not been widely reported, it is not an unexpected finding. In most cases treatment of neonatal CLABSIs requires PICC removal for adequate treatment [18, 19]. The antibiotic course required to treat a CLABSI frequently requires an additional PICC if intravenous access is limited or the neonates is having feedings difficulties secondary to the CLABSI. The need for an additional PICC as well as additional PICC days following a CLABSI was increased even and after controlling for potential confounders, including birth weight and gestational age.

Because PICCs increase the risk of bloodstream infections, the need for a subsequent PICC placement and additional PICC treatment days is likely a major contributor to the increased risk of a subsequent bloodstream infection following PICC removal among neonates who have a CLABSI during the time the initial PICC was in place. However, not all subsequent bloodstream infections occurred in neonates who required a subsequent PICC following initial PICC removal, suggesting that other risk factors among neonates with a CLABSI or perhaps treatments required for the CLABSI may have contributed to the subsequent bloodstream infection risk following PICC removal.

We used criteria outlined by others to define a subsequent bloodstream infection following removal of a central venous catheter [20]. We further limited the definition to bloodstream infections occurring at least 6 days after catheter removal to assure the infections were unrelated to the initial catheter infection or secondary to biofilm contamination during the process of removing the PICC [16]. In a retrospective cohort study Van Den Hoogen et al. [16] noted bacteremia in 26% of neonates with PICCs; 44% of the cases occurred after the catheter was removed. Sixty percent of the sepsis episodes occurred within 5 days of catheter removal. They speculate that when the catheter is removed the biofilm from the catheter is stripped off, resulting in an influx of bacteria into the bloodstream. They further speculate that even the cases of bacteremia occurring greater than 5 days after catheter removal may be due to a low level of bacteria released from the biofilm when the catheter is removed [16]. Neonates receiving antibiotics at time of catheter removal were less likely to have an episode of sepsis following catheter removal, suggesting that infant with an episode of CLABSI requiring antibiotic treatment after catheter removal would have a lower rate of subsequent bloodstream infections following catheter removal when compared to neonates without a CLABSI during the time of catheterization. However, this was not the case in our study. Increased risk of subsequent bloodstream infections following PICC removal remained among neonates who had experienced a CLABSI during their initial PICC even after controlling for gestational age, birth weight and presence or absence of necrotizing enterocolitis during the hospital course.

The increased risk for a subsequent bloodstream infection following the initial CLABSI is particularly concerning given the fact that several authors have shown that bloodstream infections in low birth weight infants are associated with and increased risk of developmental delay, attention deficit hyperactivity disorder and cerebral palsy [5, 21]. Rand et al. [21] noted that even neonates with coagulase negative Staphylococcus bloodstream infections were at increased risk of severe motor impairment and attention deficit hyperactivity disorder Furthermore neonates with more than one bloodstream infections during their stay were at even greater risk of motor and cognitive impairment in follow-up when compare to neonates who had a single bloods stream infection or did not have a bloodstream infection during their nursery stay [21].

The CLABSI rate (5.8/1000 catheter days) we noted in our study was greater than rates currently reported, although similar to those noted by others prior to 2007 [9]. The study period spanned over 10 years and although efforts were made at each institution to reduce the CLABSI infection rate it wasn’t until the study NICUs were a part of a 13 state initiative involving 141 NICUs [11] to reduce CLABSI that the CLABSI rate dropped to a rate that is closer to what others have recently reported [22, 23]. During the initiative time period (October, 2011-July, 2013) the CLABSI rate was reduced to 1.88 /1000 catheter days and two of the study NICUs went without a CLABSI for over a year. We speculate that the CLABSI reduction initiative not only reduced the CLABSI rate, but may also have reduced subsequent antibiotic and PICC days, subsequent bloodstream infections, and the need for subsequent PICC placement following removal of the initial PICC, when compared to neonates born in the years prior to the initiative. We are just beginning to evaluate whether the initiative to reduce CLABSI also reduce CLABSI associate morbidities.

The study size, the use of prospectively collected data and standardized definitions for exposure variables and outcomes are facets of the study design that strengthen the findings of this work. There were several limitations to the study. The definition of CLABSI due to coagulase negative staphylococcus changed during the time of the study. All prospective or retrospective cohort studies looking at CLABSI rate changes have had to contend with the change in CLABSI definition that occurred in 2008 [14]. Beginning early in 2003 the study nurseries changed practices and began requiring two blood cultures prior to beginning intravenous vancomycin for a presumed CLABSI, thus the study nurseries were employing the 2008 definition in 2003. In the study nurseries the rates of CLABSI before and after the change in the definition were similar and birth year was noted to confound only the relationship between CLABSI and subsequent PICC placement, and thus was included in the regression modelling of the CLABSI/ subsequent PICC placement association (Table 3). Although we attempted to control for severity of illness with SNAP scores [17], gestational age, birthweight and the need for surfactant treatment, it is possible that differences in severity of illness remained between neonates with and without CLABSI. As this was an observational study there was a potential for bias. Clinicians may have been more likely to look for infections among neonates who already had a CLABSI because they considered them to be a higher risk for a subsequent infection. This bias would likely have a greater effect on differences in septicemia work-up and less effect on differences in subsequent bloodstream infections as most neonates with bloodstream infections are symptomatic (fever, apnea, tachypnea) prompting clinicians to obtain a blood culture. Thus it is unlikely bias was responsible for differences in subsequent bloodstream infection rates among neonates with and without CLABSI.

We have demonstrated that neonates with a CLABSI during PICC treatment were more likely to require a subsequent PICC, have an episode of late onset septicemia following the removal of the initial PICC and require a greater number of days of systemic antibiotics and PICC treatment days following PICC removal than infants without a CLABSI during PICC treatment. Future intervention studies to reduce CLABSI should evaluate whether morbidities following catheterization are also reduced..

Conflict of interest

The authors declare no conflict of interest. None of the authors have potential or actual financial interests relevant to the topics discussed in the manuscript.

Footnotes

Acknowledgments

Partial funding for study provided by the Wheaton Franciscan Foundation-St Joseph Foundation.

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