Semin Neonatol 2002; 7: 325333 doi:10.1053/siny.2002.9125, available online at http://www.idealibrary.

com on

Preventing nosocomial bloodstream infection in very low birth weight infants

William H. Edwards

Department of Pediatrics, Childrens Hospital at Dartmouth, One Medical Center Drive, Lebanon, New Hampshire 03756, USA

Key words: infant, very low birth weight; cross infection; sepsis; infant, premature, diseases, infant, premature; intensive care, neonatal; total quality management; quality assurance, health care

Nosocomial sepsis is a frequent complication of caring for very low birth weight infants and incidence varies substantially among centres. Many cases are preventable. An organized approach to understanding the epidemiology of nosocomial sepsis within a unit, and implementing evidence-based practices can successfully reduce the incidence. Diagnostic accuracy is important to limit excess empiric antibiotic therapy. Instituting a hand hygiene program of education, monitoring, and consideration of waterless hand disinfectants to avoid hand transmission of organisms is essential. An emphasis on early achievement of enteral nutrition, preferably with human milk is important to reduce unnecessary exposure to central catheters and parenteral nutrition. Use of maximum sterile barrier precautions by personnel trained and skilled in central catheter insertion, followed by meticulous care in preventing catheter hub contamination will reduce the incidence of catheter related sepsis. Ultimately, the culture of the NICU needs to shift from a focus on early detection of infection to one of prevention.  2002 Elsevier Science Ltd. All rights reserved.

Introduction
Survival for very low birth weight (VLBW) infants has steadily improved. From 1988 to 1996, the National Institute of Child Health and Human Development (NICHD) neonatal network reported increased survival from 74% to 84% [1]. Increased morbidity has accompanied better survival rates, however. Nosocomial infection is frequent, and is not only a risk for mortality, but also adds to length of hospital stay and costs of care [24]. Multiple studies have identied risk factors associated with nosocomial bloodstream infections. Incidence of nosocomial sepsis is inversely related to birth weight and gestational age, higher in males, and directly correlates with severity of illness scores, ventilator days, length of stay, corticosteroid use, use of central catheters, and
Correspondence to: William H. Edwards, MD, Department of Pediatrics, Childrens Hospital at Dartmouth, One Medical Center Drive, Lebanon, New Hampshire 03756, USA. Tel.: 603 650-5828; Fax: 603 650-5458; E-mail: william.edwards@hitchcock.org

parenteral nutrition, especially intravenous lipids [510]. Comparing incidence rates for nosocomial infections in neonatal intensive care units is made more difficult by lack of standard denitions. The Center for Disease Controls National Nosocomial Infections Surveillance (NNIS) system denes laboratory-conrmed bloodstream infection as the recovery of a recognized pathogen from one or more blood cultures. Classication of common skin contaminants (e.g. diptheroids, Bacillus sp., Propionibacterium sp., coagulase-negative staphylococci, or micrococci) recovered from culture as a bloodstream infection requires symptoms (fever >38 C, hypothermia <37 C,* apnea, or bradycardia) and either two or more separate positive blood cultures or at least one positive blood culture from a patient with an intravascular line where the physician institutes appropriate antimicrobial therapy. Peripartum infections resulting from exposure to maternal ora, such as those due to Group B streptococci are considered to be nosocomial
*As dened in original publication.

10842756/02/$-see front matter

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infections, although separately designated as maternally acquired [5,11]. The NICHD neonatal research network denes sepsis as positive results from one or more blood cultures, in the presence of clinical signs or symptoms suggestive of infection, and antibiotic treatment for 5 or more days. They further designate sepsis as early onset (positive culture obtained at <72 h age) or late onset [3]. The Vermont Oxford Neonatal Network database denition for sepsis and/or meningitis is recovery of a bacterial pathogen (from a pathogen list) from a blood and/or cerebrospinal uid culture. Coagulase-negative staphylococcal sepsis requires a positive blood culture or cerebrospinal uid culture and signs of generalized infection (such as apnea, temperature instability, feeding intolerance, worsening respiratory distress or hemodynamic instability) and treatment for 5 or more days with intravenous antibiotics. Early onset is dened as positive cultures obtained on or before day of life 3 [12]. Regardless of denition, there is great variation among centres in the incidence of bloodstream infections. The center-to-center variability in the incidence of late-onset sepsis in VLBW infants at 12 NICHD centres ranged from 11.5% to 32.4% [3]. The median incidence for late bacterial sepsis for 352 participating centres in the Vermont Oxford Network for the year 2000 was 21% (interquartile range 12% to 28%). The variation was even greater for babies with birth weights of 501750 grams (median 42%; interquartile range 2556%) [13]. As with many outcomes of VLBW infants, there is strong evidence that variation among centres in the incidence of nosocomial sepsis persists after adjusting for known risk factors and severity of illness, suggesting that some neonatal intensive care units are more successful preventing nosocomial sepsis than others [7]. A systematic approach using quality improvement techniques can successfully reduce the incidence of nosocomial sepsis [12,14,15]. This review will detail a variety of strategies for preventing nosocomial sepsis in VLBW infants along with the evidence supporting them. For this review, nosocomial sepsis will exclude maternally acquired, or early-onset sepsis. Other important nosocomial infection problems such as meningitis, pneumonia, necrotizing enterocolitis, urinary tract infections and wound infections will not be specically addressed, although many of the principles discussed will apply to prevention of these problems as well.

Figure 1.

Causal model
A schematic framework for understanding how prevention strategies may work is shown in Figure 1. In some cases of nosocomial sepsis, a virulent organism may gain direct access to the bloodstream, such as by infusing a contaminated intravenous solution [16]. However, in most cases bacteraemia is preceded by a variable period of colonization without signs of infection. Organisms responsible for nosocomial sepsis are typically those recovered from the skin and gastrointestinal tract of non-infected infants, and the distribution of organisms is remarkably consistent among reports [36]. Gram-positive organisms account for 7075% of cases, with over 50% caused by coagulase-negative staphylococci. Other frequent gram-positive organisms are coagulase-positive staphylococci and enterococci. There is particular concern that the incidence of enterococcal infections may be increasing, as well as resistance to vancomycin [1720]. Gram-negative organisms most commonly causing nosocomial sepsis are coliform organisms (Escherichia coli, Klebsiella sp. and Enterobacter sp.) which colonize the gastrointestinal

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tract. Infections due to Pseudomonas sp. are relatively less common, but may be difficult to control due to persistence in reservoirs in the environment [21,22]. Fungal organisms are commensal organisms that colonize the skin and gastrointestinal tract. Infections are related to disease severity and presence of invasive therapies, and prolonged exposure to antibiotics [23,24]. The incidence of fungal sepsis in VLBW infants is 23% [3,13], but has been reported to be as high as 20% for infants weighing less than 1000 grams at birth [25]. It is difficult to dissociate the morbidity caused by nosocomial infection from the underlying disease severity associated with problems of extreme prematurity. However, mortality rates associated with gram-negative and fungal sepsis are much higher than for gram-positive organisms. Case fatality rate in the NICHD neonatal research network for infections with all gram-positive organisms was 10.1%, compared to 39.6% for all gram-negatives and 28.1% for fungi. Mortality associated with Pseudomonas sepsis was 61.8% [3]. A clear understanding of the prole of organisms causing nosocomial sepsis in a neonatal intensive care nursery is vital to prioritizing strategies for prevention.

most often interpreted as the positive culture being a contaminant [29]. An alternative interpretation could be that in low colony count sepsis the additional sample increases the chances for detecting a true infection. Limiting unnecessary empiric antibiotic therapy should be a major motivation to accurately diagnose nosocomial sepsis. Frequent suspicion of sepsis along with the often subtle presenting clinical signs result in liberal use of broad-spectrum antibiotics. Antibiotic use then increases the risk of opportunistic infections in individual patients and the risk of developing antibiotic resistance in organisms over time [23,24,30,31]. Widespread vancomycin use to empirically cover coagulasenegative staphylococci may contribute to infections from more virulent gram-negative organisms and the emergence of vancomycin resistant enterococci [1820,32]. Improvements in blood culture systems with automated detection has reduced the time to positive results [33]. Empiric antibiotic therapy pending culture results should be no more than 48 h when such a system is in place.

Unit culture Diagnosis

Making an accurate diagnosis of sepsis in VLBW infants is sometimes difficult. Some episodes of sepsis have low quantitative counts of organisms in the blood, although the actual incidence of low colony count sepsis by organism type is not known [26]. The relationship between culture volume and detection of sepsis in adults is clearly established [27]. Concern about excessive blood losses from testing and technical difficulties obtaining sufficient blood volume from arterial or venous punctures often result in small volumes of blood for culture. A reasonable recommendation is to obtain a minimum of 1 ml of blood for culture [28]. Positive cultures obtained from indwelling arterial or venous catheters may reect colonization of the catheter or the hub rather than bloodstream infection. To improve diagnostic accuracy, it is often recommended to obtain two culturesone from the indwelling catheter and a second from direct arterial or venous puncture. Concordance between the two cultures, either positive or negative, increases condence in diagnosing or ruling out sepsis. Discordant results from two cultures are One of the most important strategies for preventing nosocomial sepsis, at the same time most difficult to study and quantify, is the role of unit culture. During a quality improvement project to reduce nosocomial sepsis rates in VLBW infants, site visits were made to two NICUs with the lowest incidence of nosocomial sepsis in the Vermont Oxford Network [12]. Two attributes of these benchmark units were apparent: the staffs of the units were both aware and proud of their low nosocomial sepsis rate, and they believed nosocomial infection was preventable. When an infant developed an infection, it was considered a breakdown in care. Two conceptual models for a units beliefs about nosocomial sepsis are proposed in Table 1, a model of entitlement, and one of prevention. In the entitlement model, there is a fatalistic belief that nosocomial sepsis is inevitable due to factors beyond the control of the care team. VLBW infants have inherent deciencies in immunity, and risks associated with necessary and life-saving care, such as invasive lines, parenteral nutrition and ventilator support are unavoidable. The focus of the care team is on detecting early signs of infection and starting treatment early. The

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Table 1. Two conceptual models for nosocomial sepsis in VLBW infants Entitlement Causality Unavoidable inherent risk from poor immune function and necessary invasive care Early detection Chance or unavoidable Babys vulnerability Fatalistic, inevitable Prevention Preventable in most instances Prevention Breakdown in ideal care Care team Challenge to continually improve

Focus of care team Why did it happen? Responsibility Motivation for improvement

team may take pride in its ability to detect subtle presenting clinical signs, and sepsis work-ups and empiric courses of antibiotics pending culture results are frequent. Ultimately, no connection is made between a lapse in ideal care, for example leading to colonization and infection of a central line, and the event of sepsis. Lack of ownership is further hampered by the interval between the care failure and the downstream event, making it difficult to even suspect such a connection. In contrast to the entitlement model, in the prevention model the inherent risk due to impaired immunity is also acknowledged, but the focus is on developing care practices that minimize the risk. An episode of nosocomial sepsis prompts a review to determine whether any events or breaks in ideal care practices might have contributed. Most important, belief that nosocomial sepsis is preventable leads to motivation to improve. Because nosocomial infections are multifactorial in origin (Fig. 1), it is particularly important for all team members to understand the units goal of nosocomial infection prevention, and their role in adhering to ideal care practices and encouraging creativity in proposing potential improvements in care.

Hand hygiene
Endemic strains of bacteria or fungi may persist in NICUs over months to even decades, and are transmitted to new patients by hand transmission [3436]. The importance of hand transmission in nosocomial infections has been emphasized in multiple recent reviews, and many guidelines exist [3740]. Evidence-based reviews of hand hygiene have been recently published [41,42]. Health care providers generally acknowledge the importance of handwashing, but overestimate their own compliance [43]. If it is clearly important, but care

providers fail to do it, is there any hope that hand hygiene can be improved? Several studies hold promise. Better accessibility of sinks is associated with improved handwashing, while installation of automated sinks have little lasting benet [44,45]. Waterless hand rub sanitizers have been shown to be effective in decontaminating hands and are generally well tolerated [46]. Introducing these products has led to improved hand decontamination in some, but not all trials [4750]. Use of waterless hand rubs may reduce time required for traditional handwashing, making compliance more likely and cost-effective [51]. A variety of educational strategies have improved hand disinfection, but without ongoing monitoring, the effect is transient [45,52]. An innovative approach has been taken of educating patients about the importance of handwashing, and asking that they remind their caregivers to wash. For adult medical and surgical patients, compliance with handwashing was increased by 34% and 50% in two studies [53,54]. All patients asked nurses to wash hands, but only 35% asked physicians [54]. The possibility of including parents as partners ensuring compliance with hand decontamination guidelines in NICUs should be studied. Protecting the hands against irritation and breakdown is important. A small study showed that nurses with hand irritation had greater numbers of colonizing species [55]. Recently, articial nails have been implicated as potential risk factors for transmission of gram-negative bacteria, particularly Pseudomonas aeruginosa, and should be prohibited from use in the NICU [21,56,57].

Nutrition
Besides the widely held belief that better nutrition enhances immune function and helps resist

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infection, nutrition care practices may relate to nosocomial infection risk in other ways. Nosocomial sepsis incidence correlates with parenteral nutrition, especially intravenous lipids, as well as with the central lines often placed primarily for giving parenteral nutrition [3,4,69]. Although it is reasonable to assume that limiting exposure to central lines and parenteral nutrition by earlier establishment of enteral nutrition might reduce the incidence of nosocomial sepsis, there are no specic trials with that primary hypothesis. There is evidence that early initiation of enteral feedings while an umbilical artery catheter is in situ is safe, and results in fewer days on parenteral nutrition [58]. In a systematic review of minimal enteral nutrition, or trophic feedings, dened as providing < =25 kcal/kg/day for > =5 days, infants in the study groups reached full enteral feeds sooner, with fewer days total days feedings were held. The incidence of necrotizing enterocolitis was not signicantly different among groups. Nosocomial sepsis was not a reported outcome [59]. The possibility that human milk feedings reduce risk of nosocomial sepsis has been suggested in several small studies and is reviewed more extensively in this issue by Hanson [6062]. Feeding studies with pre-term mothers breast milk compared to premature infant formula are difficult to conduct due to the lack of random allocation, lack of ability to blind care providers, and need to supplement breast milk with formula when supply is inadequate. el-Mohandes and co-workers considered infants to be human milk-fed if they received only human milk as an enteral nutrient for > =1 week, or if human milk accounted for at least 40% of their total enteral caloric intake. By that denition, 59 were fed human milk and 114 formula. The odds ratio for sepsis in the human milk-fed group compared with formula was 0.38 (95% condence interval 0.150.95, P=0.04). In the Schanler study, the human milk group was dened as receiving an average of > =50 ml/kg/day of human milk during hospitalization. There were 62 infants in the human milk group and 46 in the formula group. The incidence of sepsis was not signicantly different (31% vs 48%, P=0.07), but the combined incidence of sepsis and/or necrotizing enterocolitis was less in the human milk group compared to the formula group (31% vs 54%, P<0.01). Hylander and co-workers compared VLBW infants receiving any human milk (n=123) to those receiving only formula (n=89). The human milk-fed infants had a lower incidence of nosocomial sepsis or

meningitis than those fed formula (19.5% vs 32.6%, P=0.04). Glutamine supplementation has been suggested to potentially reduce nosocomial sepsis incidence in VLBW infants. Neither a systematic review nor a preliminary report of a large multicenter randomized clinical trial demonstrated any benet of glutamine supplementation in reducing nosocomial sepsis [63,64].

Intravascular catheters
A correlation between nosocomial sepsis in VLBW infants and centrally placed lines has been reported in numerous studies [5,7,9,65]. Indwelling catheters are a particular factor for infection with coagulasenegative staphylococci [36,66]. Since the introduction of percutaneously inserted central catheters, the use of surgically placed catheters has decreased in most NICUs. Practical issues such as relative benets of umbilical versus percutaneously placed central lines, when to remove umbilical lines and clear risk-benet analysis of indications for placing central lines need further study. Excellent reviews of the evidence base for preventing central line infections have been recently published [42,67]. Although these reviews analyse more adult studies, many of the recommendations are relevant to preventing catheter-related bloodstream infections in neonates. Strategies related to the insertion of central lines include using maximal barrier precautions and aseptic technique during placement and developing a limited team of skilled persons to consistently perform the procedure. In a randomized clinical trial of 343 adult oncology patients, catheter-related infections were 6.3 times more likely when only sterile gloves and small drapes were used compared with maximal sterile barrier precautions during catheter insertion [68]. Education of physicians-intraining in catheter insertion also reduced primary bloodstream and catheter-related infections by 28% (P<0.01) in adult ICUs [69]. Using maximal barrier precautions in a before and after analysis of a quality improvement prevention program in neonates was also associated with a decrease in central venous catheter bacteraemias (RR 0.27, 95% CI 0.150.51; P<0.001) [15]. The portals of entry for organisms causing catheter-related sepsis are the skin insertion site and the catheter hub. The importance of contamination of the hub in the sequence of catheter

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colonization leading to infection has been described in several adult and neonatal studies [7072]. Saltzman and co-workers studied 113 catheters in 88 neonates. In 10 of 28 episodes of catheterrelated sepsis, the organism isolated from blood was isolated from a culture of the catheter hub prior to the onset of clinical sepsis, and in 5 additional episodes, simultaneously. The common sense preventive measure of limiting the number of connecting hubs is suggested by a prospective randomized clinical trial where episodes of catheter-related sepsis were more common with triple lumen than with single lumen catheters [73]. Carefully devised techniques of maintaining hub sterility during line changes and active decontamination of the catheter hub may be effective in limiting hub colonization [15,74]. Saltzman and co-workers developed an in vitro model to study hub disinfection and emphasized the importance of mechanical friction, which was 99% effective in hub decontamination. The use of 70% alcohol completed the disinfection [75]. There is promise that with better understanding of the epidemiology of catheter colonization, new designs may be effective in reducing catheter-related sepsis [76,77]. Antibiotic impregnated catheters have strong evidence for efficacy in preventing catheter-related sepsis in adults, and research in developing similar materials for use in neonates should be encouraged [42]. Since by far the most common organism associated with neonatal catheter-related sepsis is coagulase-negative staphylococcus, a number of clinical trials have been conducted using vancomycin prophylaxis, and the practice has been the subject of a critical review [78]. Although effective in reducing the incidence of coagulase-negative staphylococcal sepsis, the lack of proven benet for other important clinical outcomes of mortality and length of stay along with concern for the development of vancomycin resistance in other organisms are reasons for caution in recommending widespread use of this strategy [20,78].

terials and skin punctures for blood sampling. Nopper and Lane in a study designed to measure the effects of an emollient ointment on insensible water loss, found an unexpected reduction in the incidence of nosocomial sepsis in the group treated with twice a day application of the ointment for two weeks [79]. A randomized clinical trial of infants weighing 5011000 grams at birth of similar design failed to conrm a benet of reduced nosocomial sepsis. The group receiving prophylactic application of emollient ointment actually had a higher incidence of nosocomial infection [80]. Additional reports have associated ointments with infection. Campbell and co-workers in a casecontrol study demonstrated a potential relationship between the topical application of petrolatum ointment and systemic candidiasis in infants weighing <1500 grams [81]. Ramsey and co-workers reported contamination of Aquaphor as a potential source of nosocomial infection [82]. Currently the practice of prophylactic application of emollients for an extended time to prevent infection cannot be recommended.

Conclusion
The incidence of nosocomial sepsis in VLBW infants varies greatly among NICUs. Comparative data from similar centres using the same denitions are helpful in identifying problems and measuring results of improvement initiatives. Quality improvement methods are effective in reducing the incidence of nosocomial sepsis [12,14,15]. Reasons for developing nosocomial sepsis are multifactorial, and may be unit specic. Specic targets for improvement should be based on understanding the epidemiology of nosocomial sepsis within the units own environment. Many practices with strong evidence for efficacy are incompletely implemented in most NICUs. Although practices of using prophylactic antibiotics may be effective, they should not be substitutes for a high quality prevention program. References

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