Abstract
Background
Sepsis is the leading cause of mortality and morbidity in neonates. Blood cultures are the gold standard in diagnosing neonatal sepsis; however, there are currently no consensus guidelines for blood culture collection in neonates and significant practice variation exists in Neonatal Intensive Care Units (NICUs) globally.
Objective
To examine current practices in obtaining blood cultures in the evaluation of neonatal sepsis in NICUs across Canada.
Methods
A nine-item electronic survey was sent to each of the 29 level-3 NICUs in Canada, which are equipped to provide highly specialized care for newborns.
Results
Responses were received from 90% (26/29) of sites. Sixty-five percent (17/26) of sites have blood culture collection guidelines for the investigation of neonatal sepsis. Forty-eight percent (12/25) of sites routinely target 1.0 mL per culture bottle. In late-onset sepsis (LOS), 58% (15/26) of sites process one aerobic culture bottle, whereas four sites routinely add anaerobic culture bottles. In early-onset sepsis (EOS) in very low birth weight infants (BW <1.5 kg), 73% (19/26) of sites use umbilical cord blood, and 72% (18/25) use peripheral venipuncture. Two sites routinely collect cord blood for culture in EOS. Only one site applies the concept of differential time-to-positivity to diagnose central-line-associated bloodstream infection.
Conclusions
There is significant practice variation in methods used to obtain blood cultures in level-3 NICUs across Canada. Standardization of blood culture collection practices can provide reliable estimates of the true incidence of neonatal sepsis and help to develop appropriate antimicrobial stewardship strategies.
Keywords: Newborn, Neonatal sepsis, Blood culture
INTRODUCTION
Sepsis is the leading cause of mortality and morbidity in neonates (1–3). Worldwide, it is estimated to occur in approximately 22/1000 live births with a mortality rate of 11% to 19% (1). In Canada from 2019 to 2020, late-onset sepsis (LOS) among neonates <33 weeks had a mortality rate of 9% (4).
Blood cultures are the gold standard in the diagnosis of neonatal sepsis. The yield of blood cultures depends on many factors including blood volume, number of culture bottles, and sites of blood collection (5–10). Insufficient blood volumes increase the risk of false-negative culture results and are associated with a greater proportion of contaminants (5–10). Additional factors associated with blood culture contamination include insufficient disinfection of the skin, poor technique, and collection of blood through indwelling catheters (10,11). While only one blood culture is commonly collected in neonates, increasing the number of cultures can increase yield and help to distinguish true bacteraemia from contamination (5–10).
The exclusion of bacteraemia is important to prevent the unnecessary continuation of antibiotics (11). In a global point prevalence study, 48% of newborns in neonatal intensive care units (NICUs) received antibiotics to rule out sepsis or for culture-negative sepsis (12). The reliability of negative blood culture(s) may affect the management of the controversial culture-negative sepsis, and potentially contribute to the significant variation in antibiotic prescription practices across NICUs (13). Prolonged antibiotic use in neonates with negative blood culture results or necrotizing enterocolitis (NEC) is also associated with increased morbidity, mortality, and/or long-term neurodevelopmental outcomes (14–16).
Despite the important role of blood cultures in the diagnosis of neonatal sepsis, currently, there are no consensus guidelines for the collection of blood cultures in neonates with wide practice variation among NICUs globally (8,17). The objective of this study was to examine current practices in the collection of blood cultures across Canadian NICUs.
METHODS
Study population
The survey was conducted at level-3 NICUs across Canada through the platforms of the Canadian Neonatal Network (CNN) and Evidence-Based Practice for Quality Improvement (EPIQ), which conduct regular quality improvement activities to enhance neonatal outcomes. The survey was distributed to each neonatologist indicated as the site investigator for EPIQ projects.
Survey development and content
A nine-item survey (Supplementary Appendix 1) was developed, which assessed NICU practices for the collection of blood cultures in the investigation of neonatal sepsis. The following elements were examined: 1) volume of blood targeted per culture bottle; 2) number and type of culture bottles obtained in each episode of LOS work-up; 3) sites from which blood is drawn in the investigation of early-onset sepsis (EOS) in very low birth weight (VLBW) infants (BW <1.5 kg) and LOS; and 4) application of the concept of differential time-to-positivity (DTP—difference in time to have positive culture between two different samples) to diagnose central-line-associated bloodstream infection (CLABSI). The questions were primarily multiple choice in nature and sometimes included an option to provide a narrative response. The survey was tested by neonatologists, a neonatal nurse practitioner, a medical microbiologist, and an infection control practitioner, and was revised based on their feedback to ensure clarity of content and practical applicability.
Survey distribution
The electronic Qualtrics survey was sent via email to be completed by each NICU between May and July 2021. Email reminders were sent on June 28, 2021. Responses were collected until July 13, 2021. One response per site was received. This study was approved by the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board. Participation in the study was voluntary. Respondents provided informed consent in Qualtrics before proceeding to the survey questions.
Statistical analysis
Survey results were entered into an Excel spreadsheet (Microsoft Corporation, USA) and transferred to SPSS version 27 (IBM Corporation, USA) for statistical analysis. Descriptive statistics and frequency distributions were produced for all variables. The results are analyzed and presented with a denominator specific to each response received.
RESULTS
Responses were received from 90% (26/29) of level-3 NICUs in Canada. Sixty-five percent (17/26) of sites have formal guidelines for the collection of blood cultures in the investigation of neonatal sepsis.
Blood culture volume
The targeted blood collection volume was 1.0 mL per culture bottle at 48% (12/25) of sites. The gestational age was used to determine volume at 32% (8/25) of sites, and body weight was used to adjust the recommended blood volume at one site (Figure 1).
Figure 1.
Blood volume targeted per culture bottle in Canadian level-3 NICUs. Some sites that base blood volume on body weight indicated that they target 1.0 mL/kg. Other sites indicated that they have specific guidelines for minimum blood volume that varies based on the weight. The site that bases blood volume on gestational age indicated that they still target a minimum volume of 1.0 mL. Sites that selected “other” indicated that they have variable practices with regards to targeted blood volume.
Routine collection of anaerobic blood cultures
In LOS, 58% (15/26) of NICUs processed only one bottle. Four NICUs routinely process an additional anaerobic culture bottle from one or two sites (Table 1).
Table 1.
Blood culture collection practices in Canadian level-3 NICUs
| Number and type (aerobic or anaerobic) of blood culture bottles processed in LOS | Number of NICUs (n = 26) | Percentage of NICUs (n = 26) |
|---|---|---|
| One aerobic culture bottle | 15 | 58% |
| Two aerobic culture bottles from one site | 1 | 4% |
| Two aerobic culture bottles from two sites | 2 | 8% |
| One aerobic + one anaerobic culture bottle from one site | 3 | 12% |
| One aerobic + one anaerobic culture bottle from two sites | 1 | 4% |
| No standard method | 1 | 4% |
| Other1 | 3 | 12% |
| Central venous line and peripheral arterial line use for blood culture | Number of NICUs (n = 24) | Percentage of NICUs (n = 24) |
|---|---|---|
| Central venous line (when already present) | ||
| First-line option for blood culture collection | 1 | 4% |
| Only if culture from two different sites collected and one from a peripheral site is also taken | 2 | 8% |
| Only if no other access is available | 13 | 54% |
| Other2 | 8 | 33% |
| Peripheral arterial line (when already present) | ||
| First-line option for blood culture collection | 4 | 17% |
| Only if culture from two different sites collected and one from a peripheral site is also taken | 6 | 25% |
| Only if no other access is available | 12 | 50% |
| Other3 | 2 | 8% |
| Site of blood collection for culture in EOS in VLBW infants4 | Number of NICUs | Percentage of NICUs |
|---|---|---|
| Cord blood from placenta5 (n = 26) | 2 | 8% |
| Peripheral venipuncture (n = 25) | 18 | 72% |
| Umbilical lines (n = 26) | 19 | 73% |
| Other6 (n = 25) | 1 | 4% |
| Application of DTP | Number of NICUs (n = 23) | Percentage of NICUs (n = 23) |
|---|---|---|
| Only for coagulase-negative Staphylococci (CoNS) | 0 | 0% |
| For bacteria other than CoNs | 1 | 4% |
| Not applied | 11 | 48% |
| Not applicable as only one culture bottle is collected | 11 | 48% |
1Some sites indicated that they have specific guidelines that vary based on weight and gestational age for the number and type of blood culture bottles to be processed.
2Many sites indicated that they never use central venous lines when present to collect blood cultures. Some sites indicated that they will only use a central venous line if it is an appropriate size (not 1.2 Fr).
3Some sites indicated that they never use peripheral arterial lines when present to collect blood cultures.
4This question allowed multiple responses to be selected.
5The term refers to umbilical cord blood culture (UCBC).
6One site indicated that umbilical lines were only used to collect blood cultures on insertion of the line.
Sites of blood culture collection
Unless no other access is available, 54% (13/24) of sites do not draw blood for culture from a central venous line when it is present (Table 1). One site routinely collects blood from a central venous line as the first option in suspected LOS. Fifty percent (12/24) of sites do not draw blood for culture from a peripheral arterial line when it is present unless no other access is available. Four sites routinely collect blood from a peripheral arterial line as a first-line option.
In EOS in VLBW infants, 73% (19/26) of sites routinely draw blood for culture from umbilical lines, and 72% (18/25) of sites routinely use peripheral venipuncture (Table 1). Two sites routinely collect cord blood for culture.
Differential time-to-positivity
Only one site applies the concept of DTP to determine whether a blood culture is indicative of infection or colonization (Table 1).
DISCUSSION
To our knowledge, this is the first study to evaluate blood culture collection practices in the investigation of neonatal sepsis in Canadian NICUs. We found that blood culture collection practices vary widely and that approximately one-third of sites do not have established blood culture collection guidelines. Given that there are no global consensus guidelines for blood culture collection in neonates, our findings are not surprising (8,17).
We found that approximately half of level-3 NICUs in Canada routinely target 1.0 mL of blood per culture bottle, while other sites estimate adequate blood volume using gestational age or weight (e.g., 1 mL/kg). Adequate blood volume is imperative to increase yield and to reduce the likelihood of contamination (5–10,18). A narrative review of blood volume in paediatric cultures recommended a minimum of 1 mL to 1.5 mL of blood be collected in children weighing <2 kg (5). Even when pathogen concentrations are low (colony count <4 colony-forming units per millilitre), blood cultures from 1 mL of blood have a reported sensitivity of 98% in neonates (18). The paediatric blood culture bottles manufactured by Becton, Dickinson and Company in the USA (BD BACTECTM Peds PlusTM/F) can be cultured with 0.5 mL to 5 mL of blood but achieve optimum recovery of isolates with 1 mL to 3 mL (19). However, due to technical difficulties and the possibility of exsanguination in preterm and VLBW infants, it may be challenging to collect 1 mL of blood (5,6).
A single aerobic culture bottle is often recommended in the investigation of neonatal sepsis unless the collected blood volume exceeds the optimal volume for one bottle or indications for anaerobic cultures are present, including cellulitis, chorioamnionitis, and NEC (5,7,20,21). A retrospective study of EOS in VLBW infants identified that pathogens were isolated at a rate of 20.5 infections/1000 infants, of which 16.7% were obligate anaerobes, most frequently Bacteroides (20). In another retrospective study of neonatal sepsis, clinically significant organisms were isolated from 9.7% of culture sets, with 33.9% of those organisms being isolated from an anaerobic bottle alone and one (0.2%) obligate anaerobic bacterium (Clostridium symbiosum) was identified (21). In addition, the increasing use of probiotics to prevent NEC may place neonates at a higher risk of anaerobic infections, especially Bifidobacterium (22). In our study, we found that most sites collected a single bottle for aerobic cultures, while only four sites routinely added anaerobic cultures.
When CLABSI is suspected in neonates, the most cultured organism is coagulase-negative Staphylococcus (CoNS), but it may be difficult to determine contamination versus true infection. The CDC recommends drawing blood on two separate occasions or from two separate sites in children ≤1 year of age to confirm infection with skin commensals (23). Collecting two or more blood culture sets can increase yield and help to differentiate between contaminants and true pathogens (5,7). However, getting adequate blood culture volume can be challenging in small infants due to both technical restraints and small circulating volume (5,6). In a prospective study of neonates with suspected sepsis where two blood cultures were collected, cultures from the second site did not substantiate a diagnosis of CoNS in 5% of babies (24). The use of two blood cultures compared to one in this study reduced antibiotic use by 8.2% (24). However, another prospective study of EOS and LOS found that each of the 9.2% of neonates with culture-proven sepsis had the same organisms with similar sensitivity patterns isolated from two different peripheral sites, indicating that one blood culture may be sufficient in diagnosing neonatal sepsis (25). We found that most level-3 NICUs in Canada do not collect blood from multiple sites.
In suspected EOS, blood can be drawn for culture by venipuncture, from an umbilical line, or from the umbilical cord (26–30). A prospective study showed that peripheral blood cultures (PBCs) are no more likely to be contaminated than umbilical line cultures, and that they have similar yields (26). Umbilical cord blood culture (UCBC) is a convenient option that does not require an invasive procedure, allows larger volumes of blood to be collected to increase yield, and may be especially important in neonates who were given prophylactic antibiotics before blood collection for culture (27,28). In a prospective study, UCBCs were 100% sensitive and 94.9% specific for EOS (28). In addition, a recent systematic review found that UCBCs had higher sensitivity and comparable specificity for EOS compared to PBCs (29). However, contamination can be an issue with UCBCs unless strict and proper sterile techniques are followed (30). We found that most level-3 NICUs in Canada routinely draw blood for culture from peripheral veins and umbilical lines, while only two centres use cord blood.
In suspected LOS, it is recommended that blood should be collected for culture by venipuncture, rather than from an indwelling catheter, to reduce the risk of contamination (8–10). A systemic review and meta-analysis of nine studies in adult and paediatric patients showed a 2.69-fold increase in contamination rates of blood cultures from an indwelling catheter compared to venipuncture (10). Catheters can be colonized with skin commensals, such as CoNS, which result in false-positive blood cultures (9). Here, we found that approximately half of level-3 NICUs in Canada do not collect blood for culture from an existing catheter unless no other access is available and only a handful of centres routinely draw from catheters as a first-line option in LOS.
Paired blood samples can be obtained from the catheter and a peripheral vein to assess DTP in suspected CLABSI in neonates (9,31–33). DTP can confirm whether a colonized catheter is the true source of infection without having to remove the catheter itself (9,31–33). A positive central-line culture at least 2 hours prior to a positive peripheral vein culture likely indicates CLABSI (31,32). However, the small lumens of central catheters may not allow for blood collection and DTP has not yet been validated in neonatal studies. We found that only one level-3 NICU in Canada routinely applies the concept of DTP.
The main limitation of our current study is that it exclusively surveyed blood culture collection practices in level-3 NICUs in Canada and thus our results may not be representative of practices in non-tertiary NICUs and other countries. Future studies should examine practices at level-1 nurseries and level-2 NICUs, correlate practices to blood culture positivity rates, contaminations rates, and antibiotic use rates, and qualitatively assess barriers to standardization of blood culture collection practices in NICUs.
In summary, there is wide variation in blood culture collection practices in the investigation of neonatal sepsis across Canadian NICUs, which may affect the accuracy of detection of bacteraemia, comparability of infection rates across sites, and antibiotic use rates. Standardized and evidence-based blood culture collection guidelines are needed to increase the reliability of blood culture findings and to support antimicrobial stewardship in NICUs across Canada. Key considerations to be addressed in future blood culture collection guidelines include the following: 1) adequate blood volume per culture bottle, that is, to consider using calculations based on gestational age or weight to ensure yield while minimizing blood use; 2) number and type of culture bottles in each episode of septic work-up, that is, to consider two bottles with one being anaerobic; 3) sites of blood collection, that is, to consider the use of UCBC for detection of EOS, particularly in preterm infants with strict aseptic collection protocols.
SUPPLEMENTARY DATA
Supplementary data are available at Paediatrics & Child Health Online by searching for pxac112.
ACKNOWLEDGEMENTS
The authors acknowledge the valuable contributions of members of the Canadian Neonatal Network (CNN) and Evidence-Based Practice for Quality Improvement (EPIQ).
Contributor Information
Nicole Hajjar, Department of Pediatrics, Queen’s University, Kingston, Ontario, Canada.
Joseph Y Ting, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
Prakesh S Shah, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
Kyong-Soon Lee, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
Michael S Dunn, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
Jocelyn A Srigley, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Faiza Khurshid, Department of Pediatrics, Queen’s University, Kingston, Ontario, Canada.
FUNDING
There are no funders to report.
CONFLICT OF INTERESTS
NH reports support from Queen’s School of Medicine for a summer studentship and for travel reimbursement. MSD reports payment received as faculty for Vermont Oxford Network NICQ and received travel reimbursement as a speaker at the Canadian Paediatric Society annual conference. MSD is also a Data and Safety Monitoring Board member of the OPTIMIST Trials, which is an unpaid position. JAS reports participation on the COVID-19 Immunity Task Force and Worksafe BC. There are no other disclosures. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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