Bloodstream infection in children

Lucy Lum Chai See, MBBS, MD, MRCP

Objective: To establish the definitions of bloodstream infection

(BSI) in children for the purposes of identifying BSI for early
therapy, enrollment in sepsis trials, and epidemiology and surveillance studies.
Methods: Generalized medical literature search using various combinations of the terms bloodstream infection, children, and sepsis.
Results: The medical literature is sparse on these topics;
therefore, these recommendations are adapted from guidelines
designed for adults. BSI overlaps with other areas of sepsis, such
as catheter-related BSI, which will be covered separately. This

here is a large amount of literature on epidemiology and

burden of disease that addresses bloodstream infection
(BSI) in adults. The same, however, can
not be said of children. The few published
articles that are available address almost
exclusively nosocomial BSI (1). Hence,
the following recommendations are
adapted from guidelines that are designed
for adults.
Gray et al. (2) published a 3-yr survey
of bacteremia and fungemia in a pediatric
intensive care unit. They observed an incidence of 39.0 per 1,000 admissions, or 10.6
per 1000 bed days. Of these, 64.1% were
intensive care unitacquired and 20.6%
were community acquired. The rest of the
infections (15.3%) were acquired in other
areas of the hospital. Crude mortality in
children with BSI was 26.5%, compared
with 8.1% in those without BSI. In adults,
BSI accounts for 30% 40% of severe sepsis
and septic shock (3). However, the true
prevalence of BSI as a cause of severe sepsis
is probably underestimated in the hospital
setting. This is because blood cultures are

From the Department of Pediatrics, Faculty of

Medicine, University of Malaya, Kuala Lumpur, Malaysia.
This work was supported by the Mannion Family
FundCenter for the Critically Ill Child, Division of
Critical Care Medicine at Childrens Hospital Boston,
the PALISI Network, and the ISF.
Copyright 2005 by the Society of Critical Care
Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/01.PCC.0000161945.98871.52

S42

discussion focuses on BSI of unknown origin, also known as

primary BSI.
Conclusion: A BSI is the presence of a pathogen in the blood.
Its clinical significance should be determined by the presence of
the host response as defined by the modified criteria for systemic
inflammatory response syndrome SIRS in children or a clinically
recognizable syndrome. Definitions of BSI for the purposes of
sepsis trials may differ from those for epidemiologic or surveillance studies. (Pediatr Crit Care Med 2005; 6[Suppl.]:S42S44)
KEY WORDS: bloodstream infection; sepsis

frequently drawn from patients pretreated

with broad-spectrum antibiotics or are not
taken at all. In addition, smaller volumes
of blood are routinely taken in smaller
children, decreasing the sensitivity of the
cultures.
Definitions of BSI that have been used
by numerous investigators have been obtained from studies done in the 1980s and
1990s (4 6). In recent years, the definitions of nosocomial infections of the Centers for Disease Control and Prevention
(7) have been used in most epidemiologic
studies (2). Although widely used, they
are designed for nosocomial infections
and may need to be modified for community-acquired infections. In the 1999 document, BSI is divided into laboratoryconfirmed BSI and clinical sepsis for
which blood cultures are not performed,
not detected, or for which the physician
institutes treatment for sepsis. Although
it may be criticized that BSI should be
defined independently of a physicians decision whether to initiate antimicrobial
therapy, the real situation is that laboratory-based surveillance alone will underestimate the prevalence and the burden
of BSI. In addition, the Centers for Disease Control and Prevention guidelines
do not provide a definition for secondary
BSI, and they reference obsolete microbiological diagnostic tools such as antigen testing in the blood.
Bacteremia is the presence of a recognized pathogen in the blood. This presence may be indicated by a positive blood
culture, positive blood film (as in ma-

laria), or a positive serological response

in the presence of a compatible clinical
syndrome associated with a high probability of infection (as in enteric fevers,
leptospirosis, meningococcemia). This
definition, however, is not perfect. It excludes clinically well-recognized syndromes that are associated with sepsis,
such as toxic shock syndrome, which is
caused by the exotoxin secreted by Staphylococcus aureus. Frequently, BSI is
strongly suspected without microbiological confirmation. Classification, however, usually depends on identification of
bacteremia.
Not all positive blood cultures, however, are true BSIs. In the study by Weinstein et al. (8), 41.5% of inpatient positive
blood culture episodes were judged to
represent contamination, and another
5.3% were of indeterminate clinical significance. Thus, only half of all positive
cultures represented true BSI. These
rates might be explained by the use of
intravascular devices such as arterial or
central venous catheters for the purpose
of obtaining blood cultures. The rate of
contamination might be higher in children, in whom obtaining blood cultures
from an indwelling device may be
thought to prevent the trauma of a venipuncture. Distinguishing between true
contamination and local infection of the
device (catheter colonization) is also difficult in children if peripheral blood cultures are not obtained.
In critically ill adult patients in whom
paired blood culture specimens were obPediatr Crit Care Med 2005 Vol. 6, No. 3 (Suppl.)

tained through a central venous catheter

and a peripheral venipuncture, the sensitivity was 82.4% and 64.7%, respectively,
and specificity was 92.5% and 95.9% (9).
The positive predictive value was 58.3%
for catheter-obtained samples and 66.7%
for peripheral venipuncture samples, and
the respective negative predictive values
were 97.6% and 95.5%. Although the
negative predictive value of blood samples obtained by both techniques is good,
the sensitivity of blood samples obtained
by either catheter draw or peripheral venipuncture alone is not adequate to recommend the elimination of blood samples obtained from the other site. In
children, smaller volumes of blood are
usually drawn (3 mL in children vs. 10
mL in adults), leading to a markedly
lower sensitivity. Peripheral blood samples may be valuable when interpreting
positive blood culture results for common skin or central venous catheter contaminants.
Given the caveats described above, the
following consensus definitions are proposed for BSI in children after the newborn period (separate definitions are being proposed for newborns).

Definite BSI
1. Microbiological confirmation of the
presence of recognized pathogens
that are not common to skin flora,
or
2. Isolation of organisms that are common skin flora together with clinical
signs and symptoms of infection,
from
a. Two or more separate blood cultures,
b. One blood culture and another site,
or
c. One blood culture in a patient with
an intravascular device in whom
there is resolution of clinical signs
and symptoms after removal of the
device or after appropriate therapy.
Catheter-related BSI will be discussed
in more detail elsewhere. A definite BSI
can be further divided into:
1. Primary BSI: a BSI not related to an
identifiable focus of infection or an
intravascular catheter-related BSI.
2. Secondary BSI: A BSI caused by microorganisms related to an infection
at another site (e.g., pneumonia, intraabdominal abscess).
Pediatr Crit Care Med 2005 Vol. 6, No. 3 (Suppl.)

Probable BSI
Presence of systemic inflammatory response syndrome (SIRS) or a clinically
compatible syndrome with a negative
blood culture plus a non culture-positive
marker of inflammation, such as increased C-reactive protein level or increased procalcitonin level, plus a serological response to immunoglobulin M in
the acute phase of infection.

Possible BSI
Presence of SIRS or a clinically compatible syndrome, plus laboratory markers of inflammation, such as an increased
C-reactive protein level or an increased
procalcitonin level, but a negative blood
culture or a negative serological response
of a particular pathogen. The difference
between probable and possible BSI is that
indirect evidence of a pathogen (positive
serology) is present, which is absent in
possible BSI.
For the purpose of enrolling children
in sepsis trials, the diagnosis of BSI is
often a tentative diagnosis until definitive
culture results are available together with
a confirmed absence of infection from
other sources. To decrease the probability
of patients without BSI being enrolled
into clinical sepsis trials, those patients at
highest risk of BSI should be considered
eligible. A clinically significant BSI
should have a laboratory-confirmed presence of a pathogen and be accompanied
by a host response, which manifests itself
in physiologic disturbances, including a
nonspecific inflammatory process as defined in SIRS.
The SIRS criteria were developed for
use in the adult population (10) and
therefore contained a number of clinical
signs and laboratory values not appropriate for children. A number of modifications of these criteria for the pediatric
population have been proposed. The most
recent one was used in the Recombinant
Human Protein C study in children (11),
which was based on a variation of the
Bones Sepsis Syndrome Definitions (12).
These criteria were further refined by the
International Pediatric Sepsis Consensus
Conference (13). These modified criteria
for SIRS in children include the presence
of at least two of the following four criteria, one of which must be abnormal
temperature or leukocyte count:
1. Core temperature of 38.5C or
36C
2. Tachycardia, as defined as a mean

heart rate of 2 SD above normal for

age in the absence of external stimulus, chronic drugs, or painful stimuli;
or otherwise unexplained persistent
elevation for a 0.5- to 4-hr time period, or for children 1 yr old, bradycardia, defined as a mean heart rate
less than the tenth percentile for age
in the absence of external vagal stimulus, beta-blocker drugs, or congenital heart disease; or otherwise unexplained persistent depression for a
0.5-hr time period.
3. Mean respiratory rate 2 SD above
normal for age or mechanical ventilation for an acute process not related to
an underlying neuromuscular disease
or the administration of general anesthesia.
4. Leukocyte count elevated or depressed
for age (not secondary to chemotherapyinduced leucopenia) or 10% immature neutrophils.
For the evaluation of trials involving
BSI, a clinically significant BSI (i.e., a
laboratory-confirmed presence of a
pathogen plus the presence of the SIRS
criteria or a recognized clinical syndrome
compatible with an infection) should be
considered the gold standard. Although a
bacterial infection in the blood may often
be confirmed by positive blood cultures
or other methods, other pathogens, such
as infections of viral or rickettsial origins,
may not be positively confirmed. It
should be borne in mind that some of
these infections may directly affect the
leukocyte count in a way that the leukocyte count in the SIRS criteria may not
be fulfilled.
For the purpose of identifying BSI for
epidemiologic and surveillance studies,
the Centers for Disease Control and Prevention guidelines that are designed for
nosocomial infections may be applicable
for community-acquired infections with
some modifications.
1. The definition should be modified to
include infections that cannot be diagnosed by positive blood cultures but
are accompanied by a clinically recognizable syndrome such as typhoid fever, leptospirosis, Epstein-Barr virus,
and rickettsial infections.
2. For clinical sepsis, the definition is
modified to include at least two of the
four SIRS criteria, and blood cultures
are negative or are not drawn, there is
no apparent infection at another site,
and physician institutes treatment for
sepsis.
S43

A BSI is regarded as hospital-acquired

if the initial positive blood culture is obtained 48 hrs after admission to the
hospital. Likewise, BSI is considered to
have been acquired in the intensive care
unit when the initial positive culture is
obtained 48 hrs after admission to the
unit. A community-acquired BSI is a diagnosis of exclusion of the above.
Epidemiologic surveillance of BSI
should include both laboratory and clinical surveillance. Laboratory surveillance
will identify laboratory-confirmed BSI,
which by itself does not give any indication of its clinical significance and as to
whether it is a true or contaminated sample. We recommend that for epidemiologic surveillance, BSIs should be captured as separate entities of:
1. Laboratory-confirmed BSI with no
clinical significance.
2. Laboratory-confirmed BSI with clinical significance.
3. Clinical sepsis.

recognition of the pediatric SIRS criteria,

clinicians must be equipped with sufficient knowledge of clinical syndromes
that have high association with infections. A detailed history may identify risk
factorsfor example, swimming in rivers
(leptospirosis), playing in muddy fields
(Chromobacterium violaceum), visiting
endemic areas of diseases (malaria, typhoid), consuming food from food handlers
(typhoid)and will guide appropriate antibiotic therapy. Clinical examination may
reveal petechial or purpuric rash or purpura fulminans and other organ involvement that are clinically recognizable. A
comprehensive knowledge of the epidemiology of nosocomial infections in the institution or the ward will be necessary to
recognize and control outbreaks of nosocomial infections. Careful consideration of
the choice and duration of antimicrobial
therapy is necessary to prevent the emergence of multiresistant organisms in the
institution.

5.

6.

7.

8.

9.

10.

Clinical significance is identified by

the presence of two or more of the four
criteria of pediatric SIRS. The epidemiology, morbidity, and economic costs of
each of these entities may differ significantly (14).
For the purpose of identifying BSI for
diagnosis and optimal therapy, we recommend early recognition for the presence
of BSI and early institution of therapy.
Before initiation of antibiotic therapy, the
sample of blood drawn for culture should
be as large of a volume as possible, and
the laboratory confirmation of pathogens
plus adequate cultures from other suspected sites of infection, such as central
venous catheters, surgical wounds or
urine, should be done. Apart from the

S44

REFERENCES
1. Slonim AD, Kurtines HC, Sprague BM, et al:
The cost associated with nosocomial blood
stream infections in the pediatric intensive
care unit. Pediatr Crit Care Med 2001;
2:170 174
2. Gray J, Gossain S, Morris K: Three-year survey of bacteremia and fungemia in a pediatric
intensive care unit. Pediatr Infect Dis J 2001;
20:416 421
3. Bochud PY, Glauser M, Calandra T: Antibiotics in sepsis. Intensive Care Med 2001; 27:
S33S48
4. Weinstein MP, Murphy JR, Reller LB, et al.
The clinical significance of positive blood
cultures: A comprehensive analysis of 500
episodes of bacteremia and fungemia in
adults. II: Clinical observations, with special

11.

12.

13.

14.

reference to factors influencing prognosis.

Rev Infect Dis 1983; 5:54 70
Bates DW, Cook EF, Goldman L, et al: Predicting bacteremia in hospitalized patients: A
prospectively validated model. Ann Intern
Med 1990; 113:495500
Pittet D, Wenzel RP: Nosocomial bloodstream infections: Secular trends in rates,
mortality, and contribution to total hospital
deaths. Arch Intern Med 1995; 155:
11771184
National Nosocomial Infection Surveillance.
Atlanta, Center for Disease Control and Prevention, 1999
Weinstein MP, Towns ML, Quartey SM, et al:
The clinical significance of positive blood
cultures in the 1990s: A prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and
fungemia in adults. Clin Infect Dis 1997;
24:584 602
Beutz M, Sherman G, Mayfield J, et al: Clinical utility of blood cultures drawn from central venous catheters and peripheral venipuncture in critically ill medical patients.
Chest 2003; 123:854 861
Levy M, Fink M, Marshall J, et al: 2001
SCCM/ESICM/ACCP/ATS/SIS International
Sepsis Definitions Conference. Crit Care Med
2003; 31:1250 1256
Barton P, Kalil AC, Nadel S, et al: Safety,
pharmacokinetics, and pharmacodynamics
of drotrecogin alfa (activated) in children
with severe sepsis. Pediatrics 2004; 113:717
Samson LM, Allen UD, Creery WD, et al:
Elevated interleukin-1 receptor antagonist
levels in pediatric sepsis syndrome. J Pediatr
1997; 131:587591
Goldstein B, Giroir B, Randolph A: International Pediatric Sepsis Consensus Conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med
2005; 6:2 8
Hugonnet S, Sax H, Eggimann P, et al: Nosocomial blood stream infection and clinical
sepsis. Emerg Infect Dis 2004; 10:76 81

Pediatr Crit Care Med 2005 Vol. 6, No. 3 (Suppl.)