0031-3998/07/6102-0222

PEDIATRIC RESEARCH
Copyright 2007 International Pediatric Research Foundation, Inc.

Vol. 61, No. 2, 2007

Printed in U.S.A.

Heart Rate Characteristics and Clinical Signs in Neonatal Sepsis

M. PAMELA GRIFFIN, DOUGLAS E. LAKE, T. MICHAEL OSHEA, AND J. RANDALL MOORMAN
Departments of Pediatrics [M.P.G.], Internal Medicine [D.E.L., J.R.M.] and Molecular Physiology and Biological Physics [J.R.M.],
Cardiovascular Research Center, University of Virginia Health System, Charlottesville, VA 22908; Department of Pediatrics [T.M.O.],
Wake Forest School of Medicine, Winston-Salem, NC 27157; MedImmune Corporation [M.P.G.], Gaithersburg, MD 20878

tial false-negative rate, especially when based on small volumes of blood (37). Accordingly, the Centers for Disease
Control recognizes clinical sepsis in infants, which requires
only signs of illness with antibiotic therapy but no positive
blood culture (8). The NICHD Neonatal Research Network
found that both proven sepsis and clinical sepsis were associated with neurodevelopmental impairment in extremely low
birth weight (1000 g, ELBW) infants (9). The common
denominator is the systemic inflammatory response syndrome
(SIRS), the result of the host response to infectious and
noninfectious insults (10). Clearly, new approaches to the
early diagnosis of both proven and clinical neonatal sepsis are
required.
Before physician suspicion of sepsis and SIRS, neonates
have reduced heart rate variability and transient decelerations
similar to the findings in distressed fetuses (11,12). Heart rate
measures optimized to detect these abnormal heart rate characteristics (HRC) (11,1315) were used to develop an HRC
index at one NICU and then validated at another as a predictor
of neonatal infection and death (16 18).
Laboratory tests such as the I:T ratio add predictive information independent of the HRC index (19). Clinicians also
have ready access to many other sources of information about
the status of the infant such as the general appearance, vital
signs, apnea, oxygen requirement, and feeding tolerance. Our
goal in this work was to determine whether the HRC index
added to the clinical information that is already available to
physicians in the diagnosis of late-onset neonatal sepsis.
Accordingly, we developed a clinical illness score that was
specifically relevant to the diagnosis of neonatal sepsis. The
method for development followed that of the Richardson score
(20) for neonatal mortality or prolonged ventilation. Thus
armed, we examined the relationship between HRC and objective measures of clinical illness. The major hypothesis was
that HRC monitoring and clinical signs provide independent
information in the early diagnosis of late-onset clinical and
proven neonatal sepsis.

ABSTRACT: To test the hypothesis that heart rate characteristic

(HRC) monitoring adds information to clinical signs of illness in
diagnosing neonatal sepsis, we prospectively recorded clinical data
and the HRC index in 76 episodes of proven sepsis and 80 episodes
of clinical sepsis in 337 infants in the University of Virginia NICU
more than 7 d old. We devised an illness severity score based on
clinical findings and tests relevant to sepsis. Point scores were
derived from coefficients of multivariable regression models, and we
internally validated a total score. We determined relationships of the
HRC index with individual clinical signs, laboratory tests, and the
total score. We found highly significant correlations of the clinical
score and individual clinical signs with the HRC index. The clinical
score and HRC index added independent information in predicting
sepsis, and were similar in clinical and proven sepsis. The clinical
score and the HRC index rose before sepsis, and the HRC index rose
first. We conclude that clinical signs of illness and HRC monitoring
add independent information to one another in the diagnosis of
neonatal sepsis. (Pediatr Res 61: 222227, 2007)

cute clinical deterioration of infants in the NICU occurs

frequently, especially in those of very low birth weight
(1500 g, VLBW), and late-onset bacterial sepsis is a common cause (1). Early diagnosis, before obvious clinical signs
of illness, is an important goal but is difficult to achieve. The
clinical signs of neonatal sepsis are neither specific nor uniform. Fanaroff et al. in the NICHD Neonatal Research Network found that increasing apnea, feeding intolerance, abdominal distension or guaiac-positive stools, increased respiratory
support, lethargy and hypotonia were the most common presenting signs of sepsis, but none were found to have high
predictive accuracy (2).
Diagnosis of late-onset neonatal sepsis is difficult even
when infants appear ill because blood cultures have a substanReceived June 28, 2006; accepted September 11, 2006.
Correspondence: J. Randall Moorman, M.D., Department of Medicine, Box 801395,
University of Virginia, Charlottesville, VA 22908; e-mail: [email protected]
Medical Predictive Science Corporation of Charlottesville, Virginia, has a license to
market technology related to heart rate characteristics monitoring of newborn infants,
supplied partial funding for this study, and aided in collection of data. The company
played no role in the study design, analysis and interpretation of data, writing of the
report, or the decision to submit the paper for publication. M.P.G., and J.R.M. have an
equity share in this company.
Additional support was provided by the American Heart Association, Mid-Atlantic
Research Affiliate; University of Virginia Childrens Hospital Research Fund; Virginias
Center for Innovative Technology; and NIGMS-64640 from the National Institute of
General Medical Sciences.
Presented in part at the Pediatric Academic Societies Meeting, May 3 6, 2003,
Seattle, WA.

METHODS
Patient population. We studied all admissions to the University of Virginia NICU from August 2001 to July 2003 who were 7 or more days of age
and had 7 or more days of HRC monitoring. The clinical research protocol

Abbreviations: HRC, heart rate characteristics; I:T ratio, ratio of immature

to total neutrophils; VLBW, very low birth weight; WBC, white blood cell
count

DOI: 10.1203/01.pdr.0000252438.65759.af

222

HRC AND SIGNS IN NEONATAL SEPSIS

was approved by the Human Investigation Committee of the University of
Virginia.
Clinical and HRC index database. We prospectively recorded clinical
signs and respiratory support into a relational events database (Microsoft
Access), and laboratory results were available from an electronic archive.
Each hospital course was divided into 6-h blocks beginning at midnight (n
41,769), and the HRC index and clinical score were noted for each block.
Healthcare personnel were not aware of the result of the HRC monitoring.
The HRC index reflects the degree of reduced variability and transient
decelerations in the prior 12 h. We record RR intervals in sets of 4,096,
approximately 20 to 25 min in duration, depending on the heart rate. For each
we calculate SD, sample asymmetry (the characteristic abnormality is increased asymmetry due to more decelerations and fewer accelerations (13))
and sample entropy (SampEn, and the characteristic abnormality is a reduction due to outliers (14,15,21)). We select the median SD and sample
asymmetry values over the preceding 12 h, and the 10th percentile lowest
SampEn value. These are used in a regression expression relating these
parameters to episodes of clinical illness that was developed at one center and
validated at another (16). The result is the probability of clinical illness in the
next 24 h. It is divided by the average probability and presented as the
fold-increase in risk of imminent clinical illness.
Proven sepsis and clinical sepsis events. We defined proven sepsis as
clinical signs of sepsis and a positive blood culture prompting five or more
days of antibiotic therapy. We defined clinical sepsis as clinical signs of sepsis
with a negative blood culture prompting five or more days of antibiotic
therapy (9). Recurrent episodes of sepsis were considered to be distinct if they
occurred 7 or more days apart.
Clinical illness score. We (1) identified candidate findings of neonatal
sepsis based on clinical experience, (2) made internally-validated regression
models relating these findings to proven and clinical sepsis (22), and (3) used
coefficients of the models to make an integer-based score (23).
The candidate findings that appeared in the final score were: Severe apnea
requiring positive pressure ventilation or 50% increase in apneic episodes
over 24 h in an extubated infant stable for three days; increased ventilatory
support and FiO2 by 25%; temperature instability (38C or 36.2C) twice
in 8 hours; lethargy or hypotonia; feeding intolerance (feedings held for 24
h) in an infant tolerant of advancing or full feeds for 3 days; immature/total
neutrophil (I:T) ratio 0.2; white blood cell count 25,000 or 5,000/mm3;
hyperglycemia (180 mg/dL).
Other findings that were considered but did not remain sufficiently associated with sepsis after taking all the other findings into account were: New
onset thrombocytopenia (100,000/mm3); severe hypotension requiring volume or pharmacologic support; increased support on nasal CPAP, nasal
cannula or hood oxygen.
We assigned clinical illness points a duration of 12 hours or until a follow-up
normal laboratory result or a change in the type of ventilatory support occurred.
Statistical analysis. We used multivariable logistic regression modeling
adjusted for repeated measures and a Wald 2 test of the hypothesis that
variables added independent information (16,17). Internal validation of the
predictive logistic regression models was performed using a bootstrapping
methodology that has been recommended as more efficient over traditional
split-sample approaches (22). Predictions for each infant were calculated
based on coefficients estimated using a training set of all other infants. We
evaluated the correlation of HRC measures with clinical signs using bootstrapped estimates of the p-value. Confidence intervals for the correlation
coefficients, also determined by bootstrap, were 0.03.

RESULTS
Clinical and HRC database. Demographics of the patient
population are shown in Table 1. We prospectively recorded
Table 1. Demographics of the study population, and episodes of
acute neonatal illness
Total

1500 g

No. of infants
337
172
Birth weight
1,460 (910, 2, 539) 915 (715, 1, 177)
Gestational age
30 (27, 35)
27 (25, 28)
Male (%)
56
55
Illness events
Positive blood culture (infants)
76 (63)
67 (55)
Negative blood culture (infants)
80 (63)
67 (53)
Results are presented as median (25th, 75th percentiles) or episodes (patients).

223

more than 57,000 clinical observations in 337 infants. There

were 76 episodes of proven sepsis and 80 episodes of clinical
sepsis. As expected, the majority of cases of sepsis occurred in
VLBW infants.
Descriptions of illustrative cases. Figure 1 shows graphical
displays of clinical data and HRC index for the hospital
courses of three infants. The top half of each panel shows the
presence of selected clinical signs, and the shade of the bar
reflects the severity of the sign and the clinical point score
associated with it. The bars representing blood cultures have
duration equal to the antibiotic therapy. The bottom half
shows the HRC index (solid line) and the clinical score
(dashed line).
Figure 1A shows the benign course of an infant born at
gestational age 29 wk and birth weight 1,149 g. After the first
several days of life, there were no major clinical events or
major HRC abnormalities during the nearly 8 wk course. The
infant was intubated for about 1 wk and on other oxygen
support until day 45. Blood and urine cultures were drawn late
on day 20 because of increasingly frequent episodes of apnea
followed by temperature instability. Laboratory results of
WBC, I:T ratio, platelet count blood glucose were normal.
Cultures were negative, and antibiotics were administered
for 2 d.
Figure 1B shows the course of an infant of gestational age
29 wk and birth weight 1,285 g who had an episode of
late-onset neonatal sepsis. On day 18, Klebsiella sepsis was
diagnosed and manifest by feeding intolerance and need for
intubation and mechanical ventilation. On day 21, he failed
extubation and required re-intubation. On day 40, there was an
increase in the clinical score due to temperature instability,
frequent apnea and feeding intolerance, but this was not
accompanied by a rise in HRC index, positive blood culture,
prolonged antibiotic therapy or abnormal laboratory tests.
Panel C shows the course of another infant, gestational age
26 wk and birth weight 715 g, who had an episode of
late-onset neonatal sepsis. On day 30 there was an episode of
Klebsiella sepsis with hyperglycemia and need for intubation
and mechanical ventilation. On day 107, an abrupt rise and fall
of the HRC index marks the time of bilateral inguinal herniorrhaphy and circumcision under anesthesia.
From inspection of graphical records of individual patients,
we hypothesized that both HRC and clinical signs report on
neonatal sepsis. If the hypothesis is true, then HRC and
clinical illness should rise before the clinical diagnosis, HRC
and at least some clinical signs should be correlated, and HRC
and clinical signs should predict sepsis.
A clinical score for neonatal sepsis. The performance of
predictive models depended on the time window of the training set. Clinical signs are the usual means for suspecting the
diagnosis of neonatal sepsis, and are thus clustered around
episodes of illness. If the time window for model-training
included the time of diagnosis (that is, the time of the blood
culture), model performance was improved. If the time window was just before, but did not include the time of the blood
culture, signs were sparse and model performance deteriorated. In either case, there was highly significant association
with feeding intolerance, increased frequency and severity of

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GRIFFIN ET AL.

Figure 1. Graphical representations of the hospital course of three infants. In the upper half of each panel, the bars represent clinical findings listed on the right
axis, and darker shading reflects more severely abnormal findings and higher clinical point scores (light gray 0 points, gray 1 point, black 2 points). In the bottom
half, the noisy line is the HRC index and the dashed lines are the clinical score.

apnea, abnormal I:T ratio, need for increased support on

mechanical ventilator, and temperature instability with the
diagnosis of sepsis. Hyperglycemia and abnormal WBC were
significantly associated with sepsis only when the time window included the time of the blood culture. Conversely, the
finding of hypotonia and lethargy was significantly associated
with sepsis only when the time window preceded the blood
culture. Based on the regression coefficients, we assigned the
point score shown in Table 2. Systematic analysis of changing
each coefficient confirmed that the final score was optimal.
Several clinical findings commonly associated with sepsis
did not appear in the final score. Severe hypotension is
certainly a sign of sepsis, but occurred very infrequently in
this population only 3% of infants with sepsis had this sign.
Thus it failed to reach sufficient significance in our scheme to
warrant a point. New-onset thrombocytopenia is also a finding
in sepsis, but did not reach sufficient association with sepsis
after taking everything else into account.
HRC index and clinical score increase at the time of
neonatal sepsis. Figure 2 shows the mean HRC index and
clinical scores as a function of time relative to the 156
episodes of proven or clinical neonatal sepsis. The plots have
been scaled to allow comparison of the changes near the time
of sepsis. Asterisks mark data points that differed significantly
from 24 h prior (p 0.05, t-test). The HRC index rises first,
and shows significant increases over the 24 h before clinical
suspicion.

HRC correlates with clinical signs of sepsis. The mean

HRC index, taken over the entire hospital course for each
infant, was highly significantly correlated with the mean
clinical score (r 0.55, n 337 infants, p 0.001). In
addition, the 6-hourly HRC index measurements (n 41,769)
were highly significantly associated with the corresponding
6-hourly clinical scores, with correlation coefficient r 0.27
(95% confidence interval 0.24 0.30). Each of the candidate
signs was significantly correlated with the HRC index (p
0.01). The highest correlation was with increased ventilatory
support, with r 0.24 (95% confidence intervals 0.21 0.27).
Correlations with the laboratory tests led to r values between
0.14 and 0.16, and correlations with the other signs led to r
values between 0.04 and 0.07.
HRC and clinical scores predict sepsis. Individually, both
the clinical score and the HRC index were predictive of sepsis
in the next 24 h (ROC areas 0.62 and 0.67, respectively, p
0.001). Knowledge of both led to higher association with
imminent sepsis (ROC area 0.70, p 0.001), and the HRC
index added significantly to the clinical score (p 0.001). The
performance of models that included data from the time of
diagnosis was better, with ROC areas of 0.80 (clinical score),

Table 2. Point score for imminent neonatal sepsis

Signs

Points

Feeding intolerance (feedings held for greater than 24

hours) in an infant who had been tolerating advancing
or full feeds for three days
Severe apnea requiring positive pressure ventilation
50% increase in number of apneic episodes over a 24
hour period in an infant who had been extubated and
stable for three days
Immature/total neutrophil (I:T) ratio greater than 0.2
Increase in ventilatory support and FiO2 by 25% from
baseline
Lethargy or hypotonia
Temperature instability (38oC or 36.2oC); two
episodes within an eight hour period
Hyperglycemia (180 mg/dL)
Abnormal white blood cell count (25,000 or 5,000)

2
2

2
1
1
1
1
1

Figure 2. Changes in clinical score () and HRC index (e) in relation to

episodes of neonatal sepsis. Asterisks mark points that were statistically
significantly increased compared with 24 h prior. The plots are scaled to have
the same baseline and peak to allow comparison of the changes before the
clinical illness.

HRC AND SIGNS IN NEONATAL SEPSIS

225

Figure 5. HRC index measurements in the 6 h before the diagnosis of clinical

sepsis (n 77 of 80 episodes) or proven sepsis (75/76) compared with control
measurements (n 211). B. Clinical scores. Neither HRC measurements nor
clinical scores differ between clinical and proven sepsis, though both are
highly significantly higher than control.

Figure 3. Odds ratios for clinical findings and the HRC index in the
prediction of clinical and proven sepsis in the next 24 h. Horizontal lines are
95% confidence limits. The inset above shows the time window for training
the models the 24 h preceding, but not including, the time of the blood
culture obtained for suspicion of sepsis (BC).

0.75 (HRC index), and 0.86 (both). Internal validation of the

performance of these models via bootstrapping resulted in
95% confidence intervals less than 0.04 around the observed
ROC areas.
Odds ratios for prediction and diagnosis of neonatal sepsis
are shown in Figures 3 and Figure 4. They were determined
from multivariable regression models taking all the variables
into account. In Figure 3, the time window for training
multivariable regression models was the 24 h before the event.
In Figure 4, the time window was a 24-h period including the
time of diagnosis, and the evaluation is of clinical findings and

Figure 4. Odds ratios for clinical findings and the HRC index at the time of
diagnosis of clinical and proven sepsis. Horizontal lines are 95% confidence
limits. The inset above shows the time window for training the models the
6 h preceding and 18 h following the time of the blood culture obtained for
suspicion of sepsis (BC).

HRC index in diagnosing the symptomatic infant. The major

finding is that clinical signs and tests are less useful in the time
window preceding sepsis, because they are present much less
often. This is expected once findings are present, we expect
the diagnosis to be suspected and tested for promptly. Here we
categorized the HRC index into low: 70% lowest values, less
than 1-fold increase in risk; intermediate: 70th to 90th percentile values, 1- to 2-fold increase (not shown); and high-risk:
10% highest values, more than 2-fold increase groups (19).
After taking all other information into account, feeding intolerance was the most predictive clinical sign of neonatal sepsis.
Similarity of HRC and clinical signs in clinical and
proven neonatal sepsis. Figure 5A shows box plots of the
HRC index for the 6-h period just before the diagnosis of
clinical sepsis or proven sepsis. Control values were chosen 1
wk before event, or randomly from infants who did not have
events. The HRC index values before proven or clinical sepsis
were significantly different from control, but not from each
other.
Figure 5B shows bar graphs of clinical scores for the same
infants. Infants with clinical or proven sepsis had higher
scores than controls, but were not distinguishable from each
other. More detailed inspection of individual clinical signs
failed to reveal distinctive differences between infants with
clinical and proven sepsis (not shown).
A risk assessment tool for early diagnosis of imminent
neonatal sepsis. Figure 6 shows a table for bedside use in
estimating the risk of impending sepsis in the NICU using a

Figure 6. A risk assessment card for neonatal sepsis based on clinical signs
and HRC monitoring.

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GRIFFIN ET AL.

clinical score and HRC monitoring. When neither is measured, the fold-increase in risk of illness is 1.0. The clinical
score alone differentiates infants across a spectrum of risk, as
does the HRC index. Knowledge of both allows greater
refinement in the estimation of risk. For example, an infant
with a clinical score of 0 generally has lower risk of illness,
but the concurrent finding of a high-risk HRC index identifies
a subset with 2.5-fold increase in risk. For infants with 2
points or more, that is, with clinical findings of illness, knowledge of the HRC index adds little and even a low-risk HRC
index does not cancel out the clinical presentation. This is in
keeping with the idea that the HRC index is adjunctive to
clinical information, and is not a standalone substitute for
medical personnel.
DISCUSSION
We studied heart rate characteristics (HRC) and objective
findings of clinical illness in infants in a tertiary care NICU.
The major findings were (1) a validated HRC index was
correlated with clinical signs of illness and abnormal laboratory tests as well as a composite score of clinical illness
severity, and (2) the HRC index added significantly to clinical
signs and abnormal laboratory tests in predicting imminent
sepsis.
The mechanism by which sepsis leads to reduced variability
and transient decelerations of heart rate is not known, though
we speculate that circulating cytokines may interfere with
normal signal transduction in sinus node pacemaker cells.
There is substantial evidence that sepsis causes large increases
in the circulating levels of many cytokines (24), and that these
changes are evident before the clinical diagnosis of illness in
newborn infants (25). Sepsis is not the only illness in the
NICU that alters cytokine levels, and we know that the HRC
index also increases with illnesses such as necrotizing enterocolitis, intracranial hemorrhage and respiratory failure, and at
the time of surgery. Sepsis remains the focus of our work with
HRC monitoring as it is common, and it seems reasonable that
earlier diagnosis and therapy might improve outcome.
Inclusion of infants with negative blood cultures in studies of neonatal sepsis. Stoll et al. (9) in the NICHD Neonatal
Research Network recently reported on neurodevelopmental
impairment (NDI) in extremely low birth weight (1000 g,
ELBW) infants. The major finding was that infants who had
one or more episodes of infection had a 50% increase in the
already high rate of NDI. Importantly, NDI was equally
increased in infants with clinical sepsis, that is, sepsis-like
illness warranting five or more days of antibiotics despite negative blood cultures. This finding justifies inclusion of these
patients in evaluating novel means for early diagnosis of
neonatal sepsis, and it is reasonable to suspect that some of
them had bacterial sepsis that was not detected by blood
culture, an imperfect test. Certainly the NICHD Neonatal
Research Network clinicians must have believed the clinical
presentation more than the blood culture, as prolonged courses
of antibiotics were administered. Our findings of similar HRC
and clinical signs in proven and clinical sepsis are consistent
with our earlier work (11,16).

A clinical illness score relevant to neonatal sepsis. Neonatal sepsis is suspected because of clinical signs of illness.
When signs are severe enough, prolonged antibiotic therapy is
administered even if the blood culture is negative; this is
clinical sepsis. Thus using a clinical score to predict neonatal sepsis is circular since the signs are the diagnosis, they
will never fail as a diagnostic test. Laboratory tests are also
problematic, as they are much more frequently available near
the time of sepsis (19). A more stringent test of the utility of
clinical signs in early diagnosis is to analyze them before the
clinical diagnosis of sepsis, when subtle signs might be attributed to benign causes. This is the approach we used in
developing the HRC index, where the outcome of interest was
the 24 h before, but not including, the quarter-day in which the
diagnosis was made.
Here we developed and validated internally a clinical score
following a method similar to that used by Escobar and
coworkers to produce the Richardson score for neonatal mortality or prolonged ventilation (20). We began with clinical
signs that we knew were associated with sepsis, and optimized
their weighting. As expected, these signs were more predictive
of sepsis when observed at the time of diagnosis. There were,
however, highly significant associations in the preclinical
phase as well. The most predictive findings were feeding intolerance, hypotonia and lethargy, abnormal I:T ratio, severe or
increased apnea, need for increased support on mechanical ventilator, and temperature instability. The finding that I:T ratio was
the most robust independent predictor of sepsis confirms our
recent finding in a superset of this population (19).
We found a small increase in the clinical score in the 24 h
before the clinical diagnosis of illness. This finding, which
further validates the score, is not surprising since sepsis and
SIRS are preceded by a period during which cytokines are
elevated though symptoms are subtle or absent (25). This
finding confirms that of Fanaroff et al. (2) that clinical signs
were increased before the diagnosis of proven sepsis, and
extends it by combining them into a clinical illness severity
score and demonstrating similar changes before clinical sepsis. However, clinical experience teaches that the early diagnosis of neonatal sepsis and SIRS using clinical signs and
laboratory findings alone is unsatisfactory, and that new diagnostic measures are badly needed (1,26).
Surprisingly, up to 40% of infants with clinical and proven
sepsis had 0 points. Several factors could contribute to this
finding. First, several of our signs required the presence of an
abnormal clinical sign or lab test for 8 or 24 h. Thus a very
acute illness would not score points. Second, infants might
have had values near but not quite exceeding the threshold for
points. For example, an infant with a 40% increase in apnea,
18 h of feeding intolerance, one episode of temperature instability and an I:T ratio of 0.18 would have 0 points despite an
overall clinical presentation that could represent impending
sepsis. Different thresholds and different tests would lead to
different results, but scoring systems with hard cutoffs all
suffer this shortcoming.
HRC index is correlated with clinical signs of illness and
abnormal laboratory tests. We found that the HRC index was
highly significantly associated with objective clinical findings

HRC AND SIGNS IN NEONATAL SEPSIS

of illness and with abnormal test results. There were correlations with individual signs and tests, and with the composite
clinical score whether measured at each 6 h time point or
averaged over the entire hospital course. Correlations were
moderate or weak in degree.
Summary. In summary, we have devised an internally
validated point score system relevant to late-onset neonatal
sepsis. We found that heart rate characteristics (HRC) monitoring is correlated with this score, adds independent information to it, and becomes abnormal before it, among infants
with clinical and proven neonatal sepsis. Since the HRC index
is continuous and in real time, it does not require any new
contact with the patient, and is significantly associated with
imminent clinical neonatal illness, we feel that it may have a
favorable impact on clinical care. While it will not replace
clinical assessment by the physician, blood cultures or other
laboratory tests, HRC monitoring can add information to
conventional measures in the early diagnosis of neonatal
sepsis.
REFERENCES
1. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, Lemons
JA, Donovan EF, Stark AR, Tyson JE, Oh W, Bauer CR, Korones SB, Shankaran S,
Laptook AR, Stevenson DK, Papile LA, Poole WK 2002 Late-onset sepsis in very
low birth weight neonates: the experience of the NICHD Neonatal Research
Network. Pediatrics 110:285291
2. Fanaroff AA, Korones SB, Wright LL, Verter J, Poland RL, Bauer CR, Tyson JE,
Philips JB, Edwards W, Lucey JF, Catz CS, Shankaran S, Oh W 1998 Incidence,
presenting features, risk factors and significance of late onset septicemia in very low
birth weight infants. The National Institute of Child Health and Human Development
Neonatal Research Network. Pediatr Infect Dis J 17:593598
3. Kellogg JA, Ferrentino FL, Goodstein MH, Liss J, Shapiro SL, Bankert DA 1997
Frequency of low level bacteremia in infants from birth to two months of age. Pediatr
Infect Dis J 16:381385
4. Schelonka RL, Chai MK, Yoder BA, Hensley D, Brockett RM, Ascher DP 1996
Volume of blood required to detect common neonatal pathogens. J Pediatr 129:275
278
5. Neal PR, Kleiman MB, Reynolds JK, Allen SD, Lemons JA, Yu PL 1986 Volume
of blood submitted for culture from neonates. J Clin Microbiol 24:353356
6. Pierce JR, Merenstein GB, Stocker JT 1984 Immediate postmortem cultures in an
intensive care nursery. Pediatr Infect Dis 3:510513
7. Squire E, Favara B, Todd J 1979 Diagnosis of neonatal bacterial infection: hematologic and pathologic findings in fatal and nonfatal cases. Pediatrics 64:6064

227

8. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM 1988 CDC definitions for
nosocomial infections, 1988. Am J Infect Control 16:128140
9. Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, Higgins
RD 2004 Neurodevelopmental and growth impairment among extremely low-birthweight infants with neonatal infection. JAMA 292:23572365
10. American College of Chest Physicians/Society of Critical Care Medicine Consensus
Conference Committee (ACCP/SCCM) 1992 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for
sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.
Crit Care Med 20:864874
11. Griffin MP, Moorman JR 2001 Toward the early diagnosis of neonatal sepsis and
sepsis-like illness using novel heart rate analysis. Pediatrics 107:97104
12. Moorman JR, Lake DE, Griffin MP 2006 5 Heart rate characteristics monitoring in
neonatal sepsis. IEEE Trans Biomed Eng 53:126132
13. Kovatchev BP, Farhy LS, Cao H, Griffin MP, Lake DE, Moorman JR 2003
Sample asymmetry analysis of heart rate characteristics with application to
neonatal sepsis and systemic inflammatory response syndrome. Pediatr Res 54:
892898
14. Lake DE, Richman JS, Griffin MP, Moorman JR 2002 Sample entropy analysis of
neonatal heart rate variability. Am J Physiol Regul Integr Comp Physiol.Am J Physiol 283:R789R797
15. Richman JS, Moorman JR 2000 Physiological time series analysis using approximate entropy and sample entropy. Am J Physiol Heart Circ Physiol.Am J Physiol
278:H2039H2049
16. Griffin MP, OShea TM, Bissonette EA, Harrell FE Lake DE, Moorman JR 2003
Abnormal heart rate characteristics preceding neonatal sepsis and sepsis-like illness.
Pediatr Res 53:920926
17. Griffin MP, OShea TM, Bissonette EA, Harrell FE Jr, Lake DE, Moorman JR 2004
Abnormal heart rate characteristics are associated with neonatal mortality. Pediatr
Res 55:782788
18. Griffin MP, Lake DE, Bissonette EA, Harrell FE Jr, OShea TM, Moorman JR 2005
Heart rate characteristics: novel physiomarkers to predict neonatal infection and
death. Pediatrics 116:10701074
19. Griffin MP, Lake DE, Moorman JR 2005 Heart rate characteristics and laboratory
tests in neonatal sepsis. Pediatrics 115:937941
20. Escobar GJ, Shaheen SM, Breed EM, Botas C, Greene JD, Yoshida CK, Zupancic
J, Newman TB 2004 Richardson score predicts short-term adverse respiratory
outcomes in newborns 34 weeks gestation. J Pediatr 145:754760
21. Richman JS, Lake DE, Moorman JR Sample entropy. Methods Enzymol
2004;384:172184
22. Steyerberg EW, Harrell FE, Borsboom GJ, Eijkemans MJ, Vergouwe Y, Habbema
JD 2001 Internal validation of predictive models: Efficiency of some procedures for
logistic regression analysis. J Clin Epidemiol 54:774781
23. Moons KG, Harrell FE, Steyerberg EW 2002 Should scoring rules be based on odds
ratios or regression coefficients? J Clin Epidemiol 55:10541055
24. Anderson MR, Blumer JL 1997 Advances in the therapy for sepsis in children.
Pediatr Clin North Am 44:179205
25. Kuster H, Weiss M, Willeitner AE, Detlefsen S, Jeremias I, Zbojan J, Geiger R,
Lipowsky G, Simbruner G 1998 Interleukin-1 receptor antagonist and interleukin-6
for early diagnosis of neonatal sepsis 2 days before clinical manifestation. Lancet
352:12711277
26. Stoll BJ, Gordon T, Korones SB, Shankaran S, Tyson JE, Bauer CR, Fanaroff AA,
Lemons JA, Donovan EF, Oh W, Stevenson DK, Ehrenkranz RA, Papile LA, Verter
J, Wright LL 1996 Late-onset sepsis in very low birth weight neonates: a report from
the National Institute of Child Health and Human Development Neonatal Research
Network. J Pediatr 129:6371