A New Marker of Sepsis Post Burn Injury?
*
Jennifer D. Paratz, PhD, FACP1,2,3; Jeffrey Lipman, MBBCh, FCICM, MD1,2; Robert J. Boots, PhD, FCICM1,2;
Michael J. Muller, MMedSc, FRACS1,4; David L. Paterson, PhD, FRACP, FRCPA5
Objectives: Accurate diagnosis of sepsis is difficult in patients post
burn due to the large inflammatory response produced by the major
insult. We aimed to estimate the values of serum N-terminal pro-B-
type natriuretic peptide and procalcitonin and the changes in hemo-
dynamic variables as markers of sepsis in critically ill burn patients.
Design: Prospective, observational study.
Setting: A quaternary-level university-affiliated ICU.
*See also p. 2137.
1
Burns, Trauma and Critical Care Research Centre, The University of
Queensland, Brisbane, QLD, Australia.
2
Department of Intensive Care Medicine, Royal Brisbane and Womens
Hospital, Brisbane, QLD, Australia.
3
Department of Rehabilitation Sciences, Griffith University, Brisbane,
Australia.
4
Professor Stuart Pegg Burn Unit, Royal Brisbane and Womens Hospital,
Brisbane, QLD, Australia.
5
University of Queensland Centre for Clinical Research, Brisbane, QLD,
Australia.
Supported, in part, by Royal Brisbane and Womens Hospital Research
Foundation.
Dr. Paratz consulted for Edwards Lifesciences; is employed by Uni-
versity of Queensland; and received support for travel from Australian
and New Zealand Intensive Care Society, South African Burns Soci-
ety, and Australian Physiotherapy Association. Her institution received
grant support from National Health and Medical Research Council
(NIHMRC), Office of Health Medical Research, NHMRC Equipment
grants, Royal Brisbane Hospital Research Foundation, and Office
Medical Research; received provision of equipment from Edwards
Lifesciences (equipment lent free of cost to ICU); and lectured for
University of Queensland, Australian Catholic University. Dr. Lipmans
institution received grant support from the Royal Brisbane and Wom-
ens Hospital Research Foundation; received provision of equipment
from Edwards Lifesciences (equipment lent free of cost to ICU); served
as board member for Bayer European Society Council Intensive Care
Medicine Advisory Board; consulted for Merk Sharp Dohme (Aust) Pty
Ltd, Pfizer Australia, and AstraZeneca; received grant support from
AstraZeneca; and lectured for AstraZeneca and Pfizer Australia Pty
Ltd. Dr. Boots institution received grant support from Royal Brisbane
and Womens Hospital Research Foundation and received provision of
equipment from Edwards Lifesciences (equipment lent free of cost to
ICU). Dr. Mullers institution received grant support from Royal Bris-
bane and Womens Hospital Research Foundation, received provision
of equipment from Edwards Lifesciences (equipment lent free of cost
to ICU), and received grant support from Royal Brisbane and Womens
Hospital Research Foundation. Dr. Paterson consulted for Merck, Astra-
Zeneca, and Pfizer; and lectured for AstraZeneca.
For information regarding this article, E-mail: j.paratz@uq.edu.au
Copyright 2014 by the Society of Critical Care Medicine and Lippincott
Williams & Wilkins
DOI: 10.1097/CCM.0000000000000400
Critical Care Medicine www.ccmjournal.org 2029
Patients: Fifty-four patients with burns to total body surface area
of greater than or equal to 15%, intubated with no previous car-
diovascular comorbidities, were enrolled.
Interventions: At admission, a FloTrac/Vigileo system was attached
and daily blood samples taken from the arterial catheter. Infection
surveillance was carried out daily with patients classified as septic/
nonseptic according to American Burns Consensus criteria.
Measurements and Main Results: N-terminal pro-B-type natri-
uretic peptide, procalcitonin, and waveform analysis of changes
in stroke volume index and systemic vascular resistance index
were measured within the first 24 hours after burn and daily
thereafter for the length of the ICU stay or until their first epi-
sode of sepsis. Prevalences of stroke volume variation less than
12% (normovolemia) with hypotension (systolic blood pressure
< 90mm Hg) were recorded. Patients with sepsis differed sig-
nificantly from no sepsis for N-terminal pro-B-type natriuretic
peptide, systemic vascular resistance index, and stroke volume
index on days 37. Procalcitonin did not differ between sepsis
and no sepsis except for day 3. Area under the receiver operat-
ing characteristic curves showed excellent discriminative power
for B-type natriuretic peptide (p = 0.001; 95% CI, 0.991.00),
systemic vascular resistance index (p < 0.001; 95% CI, 0.97
0.99), and stroke volume index (p < 0.01; 95% CI, 0.960.99) in
predicting sepsis but not for procalcitonin (not significant; 95%
CI, 0.290.46). A chi-square crosstab found that there was no
relationship between hypotension with normovolemia (stroke vol-
ume variation < 12%) and sepsis.
Conclusions: Serum N-terminal pro-B-type natriuretic peptide levels
and certain hemodynamic changes can be used as an early indicator
of sepsis in patients with burn injury. Procalcitonin did not assist in
the early diagnosis of sepsis. (Crit Care Med 2014; 42:20292036)
Key Words: burns; natriuretic peptide, brain; procalcitonin; sepsis
syndrome; systemic inflammatory response syndrome
D
espite an increased overall survival rate, severe infec-
tion remains the main cause of mortality in burn
injury (1, 2). Prompt antimicrobial therapy for septic
shock demonstrates a mortality benefit in general critical care
patients (3); hence, an early diagnosis is important. However,
diagnosing sepsis in burn patients has been associated with a
number of difficulties.
Paratz et al
The accepted methods to diagnose sepsis in general inten-
sive care patients (4) are insensitive and nonspecific in burn
patients due to the sustained systemic inflammatory state fol-
lowing a burn injury. In an attempt to improve accuracy of
diagnosis, a consensus conference was held by the American
Burns Association (ABA) in 2007 (5). Table 1 identifies both
the triggers to search for infection and confirmation of infec-
tion in burn subjects suggested by this conference (5). However,
there is inevitably a time delay as confirmation of results from
tissue and blood cultures can take 48 hours.
In a further attempt to find indicators of sepsis in burns,
inflammatory markers have been investigated. Evidence
for procalcitonin (PCT), erythrocyte sedimentation rate,
C-reactive protein, and interleukin-6 is conflicting (611),
with PCT the strongest contender (12). B-type natriuretic pep-
tide (BNP) has been shown to be elevated in sepsis in nonburn
patients independent of cardiac status (1315) but has not pre-
viously been researched specifically in burn patients.
Following increased use of hemodynamic monitoring arte-
rial pressurebased cardiac output (APCO) device (Vigileo,
FloTrac, Edwards Lifesciences, Irvine, CA) in our ICU, an
audit of retrospective data indicated that stroke volume index
Table 1. American Burn Association Criteria
for Sepsis
Sepsis should be considered when three or more of the
following criteria are met:
1. Temperature: > 39C or < 36.5C
2. Progressive tachycardia: > 110 beats/min
3. Progressive tachypnea:
a. > 25 breaths/min not ventilated
b. Minute ventilation > 12L/min ventilated
4. Thrombocytopenia (not applied until 3 d after initial
resuscitation): < 100,000/L
5. Hyperglycemia (in the absence of preexisting diabetes
mellitus)
a. Untreated plasma glucose > 200mg/dL or equivalent
mM/L
b. > 7U of insulin/hr IV drip
c. Significant resistance to insulin (> 25% increase in
insulin requirement over 24hr)
6. Inability to continue enteral feedings > 24 hr
a. Abdominal distension
b. High gastric residuals (residuals two times feeding rate)
c. Uncontrollable diarrhea (> 2,500mL/d)
Documented infection when any of these criteria are met:
1. Positive culture
2. Pathologic tissue source
3. Clinical response to antimicrobials
Reproduced with permission from Greenhalgh et al (5).
2030 www.ccmjournal.org September 2014 Volume 42 Number 9
(SVI) increased and systemic vascular resistance index (SVRI)
decreased above those figures expected for the flow stage of
the burn hemodynamic response during proven infection.
Because of the association of BNP with sepsis in general patients
mentioned previously, we instituted a prospective study aim-
ing to investigate the efficacy of serum BNP and PCT, changes
in predicted values of SVI and SVRI, and prevalences of stroke
volume variation (SVV) less than 12% (normovolemia) with
hypotension (systolic blood pressure < 90mm Hg) as criteria
for an accurate expedited marker of suspicion of sepsis in burns.
MATERIALS AND METHODS
This study was conducted in a quaternary-level university-
affiliated ICU. Approval was granted by both the Hospital and
University Human Medical Ethics Committees and consent was
obtained from the next of kin or legal guardian of every subject.
Subjects
Subjects to be included were those with greater than or equal
to 15% TBSA burns who were intubated, with an indwell-
ing arterial catheter, previous normal cardiac function, and
not expected to be extubated within 72 hours. Subjects were
excluded if they had toxic epidermal necrolysis, had a history
of cardiovascular disease including coronary artery disease, car-
diac failure, or congenital heart problems, had multiple trauma,
took longer than 8 hours to reach the tertiary center, or were
for compassionate care only. They were resuscitated using the
modified Parkland formula (including judicious use of colloid)
(16) aiming at the endpoints of urinary output 0.52mL/kg/hr
lean body mass, mean arterial pressure greater than 60mm Hg,
intra-abdominal pressure less than 25mm Hg, hemoglobin less
than 16mg/dL and more than 8mg/dL, and Na less than 155
mEq/L. Although a number of patients underwent part of their
resuscitation in a smaller hospital or in transit, personnel were
in contact with tertiary center staff regarding fluid resuscita-
tion. All fluids received were recorded, and it was stated Yes/No
whether patients had exceeded the Parkland formula.
All patients received the usual standard of care:
Mechanical ventilation initially using the modes of
synchronized intermittent mandatory ventilation or
BiLevel initially, followed by pressure support ventilation
with positive end-expiratory pressure or inspired oxygen
as the patients sedation requirements lessened.
Inhalation injury diagnosed by bronchoscopy for those
suspected of a lung injury.
Sedation and analgesia administered according to rou-
tine guidelines, including a mixture of fentanyl, k etamine,
morphine, and midazolam.
Escharotomies as required.
Early debridement and grafting with autografts, allografts,
or both as soon as initial resuscitation is complete.
Intensive care clinical staff were blinded to FloTrac results
(i.e., cardiac output, systemic vascular resistance, and SVV) but
accessed heart rate, arterial blood pressure, arterial blood gases,
urine output, fluid balance, electrolytes, lactate, and central

venous pressure (i.e., the usual variables to provide resuscita-
tion and management in burn patients). All usual demograph-
ics were recorded and are listed in Table1.
Hemodynamic Indices
An APCO device (Vigileo, FloTrac, Edwards Lifesciences) was
attached to an existing peripheral artery catheter to record
hemodynamic variables. This third-generation model of semi-
invasive machine has shown good correlation with more inva-
sive methods and is capable of tracking hemodynamic changes
and trends (19, 20). We considered utilization of the Vigileo
to be more acceptable from an ethical point of view than the
insertion of a pulmonary artery catheter.
SVI, SVRI, and SVV were downloaded continuously, together
with all other observations, that is, arterial blood pressure, heart
rate, respiratory rate, Spo2, and central venous pressure, to
the Integrated Clinical Information Program (ICIP) (Phillips
Healthcare, Andover, MA). A program using purpose-written
software automatically calculated the daily highest, lowest, mean,
and median for all these variables. The variables are described as
percentage of normal SI and SVRI for age, height and gender,
and prevalence of hypotension (systolic blood pressure < 90mm
Hg) with normovolemia (i.e., SVV < 12%). SVV% is a measure
that provides information on relative preload responsiveness.
SVV is calculated as percentage change between the maximal
and minimal stroke volumes divided by the average of the mini-
mum and maximum over a respiratory cycle or other period
of time. This measure can be useful in differentiating the cause
of hypotension between hypovolemia or a distributive cause
and was therefore included in the outcome measures. SVV was
recorded only when the subject was on full mechanical ventila-
tion with a tidal volume of greater than 8mL/kg and no arrhyth-
mias. The SVV at which the burn patient is fluid responsive has
been shown to be 13.6% (21); therefore, the figure of less than
12% was chosen to ensure normovolemia.
Blood Samples
Blood samples were taken once daily from indwelling arterial
catheters for measurements of PCT and BNP. They were then
centrifuged, separated, and plasma stored at 80C and ana-
lyzed in bulk at the end of the study. Serum levels of the inactive
cleavage product of BNP, N-terminal fragment (NT-proBNP),
were determined by electrochemiluminescence immunoas-
say (ECLIA) (Elecsys proBNP II Assay, Cobas, Henningsdorf,
Germany). The coefficient of variation was 2%, with a lower
limit of detection of 5 pg/mL. NT-proBNP was measured as it
has higher plasma levels and a longer half-life and, therefore,
slower fluctuations than BNP, but NT-proBNP will be referred
to by the term BNP throughout the remainder of the article.
PCT was measured by ECLIA (Elecsys BRAHMS PCT, Cobas),
with a coefficient of variation of 2% and a lower detection rate
of less than or equal to 0.02ng/mL.
Diagnosis of Sepsis
The following criteria by the research staff were independent
and additional to infection surveillance by the clinical staff. For
the purposes of diagnosis of sepsis in this study, all triggers
Critical Care Medicine www.ccmjournal.org 2031
Clinical Investigations
(heart rate, temperature, and respiratory rate [if not fully
sedated and fully ventilated], platelets, prevalence of feeding
intolerance, and insulin requirements) as per Table1 were con-
tinuously screened by the researchers.
If these variables indicated infection, tissue diagnosis and
blood cultures were requested if the clinical staff had not
already ordered these. Blood cultures consisted of three sepa-
rate sets from separate venipuncture sites with a minimum of
20-mL volume (22). To satisfy the criteria for sepsis, three or
more criteria were presented in Table1, with either a positive
tissue or blood culture diagnosis. We purposely did not use the
criteria of response to antimicrobial therapy in our diagnosis.
Additionally, the organ suspected of being the source of infec-
tion was required to satisfy the modified criteria for Centers
for Disease Control and Prevention as per the ABA (5). When
all results were available, the patients were scored as Yes/No
for the presence of sepsis for each day. Clinical staff had the
responsibility for prescription of antibiotics, based on their
clinical judgment of whether an infection was present.
Statistics
The analyses were performed using SPSS 19.0 software (SPSS,
Chicago, IL). Patients satisfied the criteria for sepsis on a Yes/
No basis, with this criteria applied every day. Overall values
for BNP, PCT, SVI, and SVRI were compared between patients
described as septic/nonseptic for each day using a one-way
analysis of variance for time. As group allocation, that is,
whether sepsis criteria were met, altered each day, a t test com-
pared factors between sepsis and nonsepsis for each day. A chi-
square crosstab investigated whether BNP levels were related to
exceeding the recommended Parkland formula. A chi-square
crosstab investigated whether significantly more patients with
SVV less than 12% and systolic arterial blood pressure less
than 90mm Hg satisfied the criteria for sepsis.
The sensitivity, specificity, and positive likelihood ratio for
BNP, PCT, SVI, and SVRI in diagnosing sepsis were calculated
at the best cutoff value (Table 2) To determine the predictive
ability of these four factors, receiver operating characteristic
(ROC) curves were constructed and the areas under the curve
were calculated with 95% CIs. Factors were then entered into
a binary logistic regression to detect which factors were inde-
pendent markers of sepsis (23). A p value of less than 0.05 was
considered to be statistically significant in all tests.
RESULTS
Fifty-four patients were included in the study, with clinical
characteristics included in Table 3. Figure1 indicates the flow
of patients and reasons for exclusion. Although it may appear
unusual that subjects with less than or equal to 20% burns were
admitted to intensive care, all these subjects had inhalation or
airway injuries, necessitating an endotracheal tube.
There were 23 of 54 patients with sepsis confirmed. Day refers
to the actual day post burn not the day of admission to the ter-
tiary burn unit. Only the first episode of sepsis for each patient
was recorded for the purposes of this study. Following resolution
of this first episode, no further pathology tests or hemodynamic
Paratz et al

Table 2. Sensitivity, Specificity, Positive Likelihood Ratios, Negative Likelihood Ratios,

and Diagnostic Odds Ratio for Each Factor as a Marker of SepsisFor the First Episode
of Sepsis
Systemic Vascular
Factor B-Type Natriuretic Peptide Procalcitonin Stroke Volume Index Resistance Index

Sensitivity 95.9% (86.299.1%) 20.2% (12.134.3%) 94.3% (84.298.4%) 86.2% (73.393.4%)

Specificity 99.4% (98.199.8%) 64.3% (59.169.2%) 94.2% (91.396.5%) 97.1% (94.698.2%)
Positive likelihood ratios 165.5 (41.5659.7) 0.57 (0.3211.01) 14.68 (9.4722.1) 24.6 (13.9743.47)
Negative likelihood ratios 40.04 (0.010.16) 1.24 (1.061.46) 0.07 (0.020.19) 0.15 (0.080.29)
Diagnostic odds ratio 4030.1 (554.529293.3) 0.53 (0.231.22) 0.46 (0.220.94 166.5 (62.1445.2)
Cutoff values are taken as B-type natriuretic peptide > 1,200 (pg/mL); procalcitonin 1.4 (ng/mL); stroke volume index 160% of predicted for age, height, and
gender; systemic vascular resistance index 50% of predicted for age, height, and gender.

Table 3. Demographics and Patient Details for Patients Both With and Without Sepsis
Factor Sepsis (n = 23) No Sepsis (n = 31) All Subjects (n = 54)

Age (yr)a 42.65 (12.8) 37.68 (10.4) 40.16 (1860)

Gender, male:female b
16:7 29:2 45:9
TBSA %a 46.2 (15.3) 42.0 (16.7) 44.1 (16.0)
Total body surface area full thickness %b 21.8 (11.0) 20.8 (7.4) 20.86(9.2)
Baux indexa 96.1 (18.6) 89.8 (18.5) 93.0 (18.5)
Inhalation injurya 17 (74%) 7 (23%) 24 (44%)
Admission Sequential Organ Failure 9 (711) 9 (811) 9 (711)
Assessment (17)c
Admission shock index (18)c 1.1 (0.91.5) 1.1 (0.851.5) 1.1 (0.851.5)
Severity of burn injury injury 3 (16) 3 (16) 3 (16)
(Belgian Outcome in Burn Injury) (24)c
LOS (ICU) (d)a 21.2 (4.6) 17.0 (5.4) 19.1 (5.0)
LOS (hospital) (d) a
42.9 (7.6) 37.7 (9.4) 40.8 (8.5)
Mortality 1 0 1
Comorbidities
Depression 5 2 7
Asthma 3 2 5
Hepatitis C 2 2 4
Total volume (024hr) (mL/kg/%TBSA) 9.65 (3.2) 9.88 (3.7) 9.77 (3.5)
Total % of ICU stay on vasoactive drugs b
22% 15% 17.5%
Abdominal hypertension 2 1 3
Escharotomy/fasciotomy 4 5 9
No. of grafting procedures/patient 6.5 (3.2) 5.1 (2.9) 5.5 (3.0)
Time to first excision (d) 1.9 (0.8) 1.8 (0.7) 1.85 (0.7)
TBSA = total body surface area, LOS = length of stay.
a
The subjects who developed sepsis were significantly different at the p < 0.01 level.
b
The subjects who developed sepsis were significantly different at the p < 0.05 level.
c
Median (range).
Values are mean and sd or number and percentage unless otherwise specified.

2032 www.ccmjournal.org September 2014 Volume 42 Number 9

 Clinical Investigations

(p < 0.001) and SVI significantly lower (p < 0.001) in the first 2
days post burn compared to days 37. However, those patients
who reached the criteria for sepsis had a significantly lower
SVRI (p < 0.001) and higher SVI (p < 0.001) on days 35 than
patients who did not reach the criteria. BNP was significantly
lower on days 1 and 2 (p < 0.001) compared with days 37 in
all patients. However, in those who reached the sepsis criteria,
BNP was significantly higher from days 3 to 7. There was no
correlation between levels of BNP and exceeding the recom-
mended Parkland formula in the first 48 hours.
A chi-square crosstab indicated that there was no relation-
ship between hypotension with normovolemia (SVV < 12%)
and prevalence of sepsis. The overall sensitivity and specific-
ity for each factor are described in Table2. Optimum cutoff
values are listed in Table2. A receiver operating characteristic
(ROC) curve was constructed for the factors and is illustrated
in Figure4. Logistic regression models were constructed to
investigate the association between the potential markers and
Figure 1. Flowchart of patients through the study.
sepsis. First, we investigated each factor individually and then
included all significant factors (BNP, SVRI, and SVI) in a mul-
tivariable model with adjustment for severity of burn (24).
These factors were entered into a binary logistic regression
using the backward conditional method, with sepsis (Yes = 1,
No = 0) as the dependent variable. The overall model was sig-
nificant at the p less than 0.001 level according to the model c2
statistic (Table2). The model predicted 99.2% of the responses
correctly. The overall result was that BNP was an independent
marker of sepsis (Table 5).
Figure 2. Source of infection for the septic episode.
DISCUSSION
Early, accurate diagnosis of sepsis is vital in thermal injury
Most Commonly Isolated Bacterial
Table 4.
both for a mortality advantage potentially achieved by timely
Pathogens initiation of empiric antibiotics and to decrease inappropriate
No. of Pathogens Isolated antibiotic use increasing the risk of antimicrobial resistance.
From Positive Blood This study found a high degree of both positive and negative
Bacteria Cultures or Tissue Culture predictive ability for BNP and the hemodynamic values of
Gram negative 21 stroke volume index (SI) and SVRI but not for PCT or hypo-
tension with normovolemia.
Pseudomonas aeruginosa
 8 BNP is a well-known biomarker of cardiac failure (25). High
Klebsiella species
 6 levels have been well documented and accepted to differentiate
dyspnea in the emergency setting, specify levels of severity, and
Acinetobacter baumannii
 2
provide prognosis in cardiac failure (26, 27). However, increases
Serratia marcescens
 1 in BNP have been well documented in other clinical conditions
Escherichia coli
 2 including sepsis (14, 28, 29). At first, this was attributed to cardiac
failure in conjunction with sepsis (29) and then later to the accom-
Gram positive 3 panying myocardial depression that occurs in 50% of patients
Enterococcus species
 1 with septic shock (29) considered to be functional rather than
Staphylococcus aureus
 2
structural (3032) with adequate perfusion of coronary arteries.
More recently, investigators (33) have claimed that high lev-
els in sepsis are related to an alteration in the BNP clearance
data were recorded for the study. However, outcome data, for pathway specifically the neutral endopeptidase 24.11 with a
example, length of stay and mortality, were recorded. Figure2 parallel increase in BNP. It is being increasingly recognized that
indicates sites of infection and Table 4 organisms identified. elevated levels of BNP are present in subjects without myocar-
The mean level for each day for patients with episodes of sep- dial dysfunction including marathon runners at the comple-
sis and no sepsis is illustrated for BNP (Fig. 3A), PCT (Fig.3B), tion of a race (34) and healthy volunteers given an infusion of
SVRI (Fig. 3C), and SVI (Fig. 3D). SVRI was significantly higher LPS to induce sepsis (35).

Critical Care Medicine www.ccmjournal.org 2033

Paratz et al

Figure 3. N-terminal pro-B-type natriuretic peptide (NT-proBNP) % of predicted for days 17 (a), procalcitonin (PCT) over days 17 (b), systemic vascular
resistance index (SVRI) % of predicted for days 17 (c), and stroke volume index (SVI) % of predicted for days 17 (d). Number of patients with sepsis (S)
and those not reaching the criteria for sepsis (NS) differed each day, apart from days 1 and 2 on which no subjects had sepsis. Number of patients was as
follows: day 1 (NS) n = 54, day 2 (NS) n = 54, day 3 (S) n = 4 and (NS) n = 50, day 4 (S) n = 11 and (NS) n = 43, day 5 (S) n=16 and (NS) n = 37, day
6 (S) n = 12 and (NS) n = 31, and day 7 (S) n = 5 and (NS) n = 28. * indicates that on that particular day patients reaching sepsis criteria were significantly
different from those not reaching sepsis criteria: *p < 0.05, ** p < 0.01.

Figure 4. a, Area under the curve for B-type natriuretic peptide (BNP), procalcitonin, and stroke index (SI). b, Area under the curve for systemic vascular
resistance index (SVRI). This is shown separately in (a) as values become more negative with sepsis. ROC = receiver operating characteristic.

Irrespective of whether sepsis was present or not, there were 2days when the left ventricle was depressed and very large quan-
interesting results for BNP over the course of the burn. We had tities of fluid were administered. However, BNP values were very
predicted that we would see high values of BNP on the first low (66.257.6/mL) at this time, and BNP rose when the heart

2034 www.ccmjournal.org September 2014 Volume 42 Number 9


Table 5. Backward Conditional Binary Logistic Regression for Independent Factors to
Predict Sepsis (Dependent Variable = SEPSIS)
Factor Ba
B-Type natriuretic peptide 0.005
Systemic vascular resistance index 0.29
Stroke volume index 0.11
Model 2c 194.42
OR = odds ratio, Exp = predicted change in odds for unit increase in predictor.
a
B = regression coefficient.
b
This statistic tests the unique contribution of each predictor and eliminates overlap between predictors.
c
Model 2 = how well the model predicts the outcome variable.
became hyperdynamic, that is, at 72 hours, fluid resuscitation
was completed, and a diuresis was occurring. Papp et al (36)
investigated BNP during fluid resuscitation in burns and found
similar results. They claimed that the cessation of capillary leak-
age and increasing filling pressures lead to atrial and ventricular
dilatation, showing an improved response to fluid therapy.
PCT is a peptide precursor of the hormone calcitonin and
rises in a response to a proinflammatory stimulus, especially of
bacterial origin. In cases of general sepsis, it has high predictive
ability (37). We did not find PCT useful as a marker of sepsis.
High levels were related to the day of burnthe levels of PCT
were significantly higher (Fig. 3b) on the first 2 days postburn
and then decreased. Previous studies investigating PCT as a
marker of sepsis in burn patients have had conflicting results
(811, 38) but can be criticized in terms of utilization of the
American College of Chest Physicians/Society of Critical Care
Medicine guidelines, which was intended for a general ICU
population (12). Only two studies (8, 38) have previously used
the ABA Consensus Criteria guidelines (5). Reynolds et al (39)
have recently reported that in general intensive care patients,
PCT is high in the first few days after admission and has a
strong association with shock independent of the presence of
infection. This was similarly found in our study.
A high sensitivity and specificity was also shown by SVRI. It
has been shown (40) that the normal hemodynamic response
in burns consists of high SVRI, that is, vasoconstriction and
low SVI during the first 4872 hours during active fluid resus-
citation followed by a dramatic alteration with low SVRI, that
is, vasodilatation and a high SVI. Our results illustrated this
ebb and flow response (Fig.3, c and d).
In cases of proven sepsis on days 37, SVRI was significantly
lower than in cases without sepsis. As low SVRI is a feature
of sepsis, it is hypothesized that this further decrease in SVRI
was due to a synergistic effect with potentially increased lev-
els of BNP exerting a vasodilatory effect via nitric oxide (NO)
production. An increased NO production in sepsis can have
both beneficial and deleterious effects. Interestingly, SVRI was
an item in the Baltimore Sepsis scale (41), a scoring system for
sepsis in burns, which is now rarely used.
SVV less than 12% with hypotension did not demonstrate
adequate sensitivity or specificity for sepsis. Hypotension
can be due to many circumstances in the burn patient, and
Critical Care Medicine www.ccmjournal.org 2035
Clinical Investigations
Wald 2b Significance OR (Exp ) 95% CI for Exp
9.86 p = 0.002 0.99 0.9920.998
3.46 p = 0.063 1.34 0.981.80
2.47 p = 0.12 1.12 0.971.28
distributive shock may have been due, on occasions, to medi-
cation as well as sepsis.
On a number of occasions (n = 8) when the results of tis-
sue diagnosis or blood cultures became available, according
to our criteria infection was not present, yet antibiotics had
been prescribed by the clinical staff. Conversely, there were also
occasions when a tissue diagnosis or blood culture was posi-
tive yet that patient had not received antibiotics (n = 4). For
this reason, the response to antibiotics was not recorded as a
component of the diagnostic criteria of sepsis.
The ABA consensus criteria (5) were used for diagnosis in
this study. A recent article (42) has further investigated the
validity for this scoring system against bacteremia. It was found
that the triggers of heart rate, maximum temperature, throm-
bocytopenia, hyperglycemia, and feed intolerance were all sig-
nificant in multivariate analysis. The article recommended that
the search for further biomarkers be continued.
The prospective markers that we have identified, that is,
NT-proBNP, SVI, and SVRI, are easy to apply and occur early in
the course of infection. BNP can be measured by point-of-care
devices (43). Likewise, APCO devices are noninvasive and form
part of routine care in most critical care units (44). However, it
is important to have an appreciation of normal values at vari-
ous stages for SVRI and SVI in burn patients in order to avoid
an over diagnosis of sepsis. Limitations of this study included
the fact that only the first episode of sepsis and the early stage
of intensive care admission were recorded. Further work is
required to elucidate normal values for BNP and hemodynam-
ics for the entire duration of the intensive care stay.
CONCLUSIONS
Diagnosing sepsis in patients post burn injury remains a major
problem in critical care units. This study indicated that the
variables of NT-proBNP and the hemodynamic values of SVRI
and SVI may assist in providing a high suspicion of sepsis prior
to results of the blood culture. Further work is required to con-
firm these findings.
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