986 MINERVA ANESTESIOLOGICA October 2011

R E V I E W

Anno: 2011
Mese: October
Volume: 77
No: 10
Rivista: MINERVA ANESTESIOLOGICA
Cod Rivista: Minerva Anestesiol
Lavoro:
titolo breve: Diferences between adult and pediatric septic shock
primo autore: ANEJA
pagine: 986-92
A B S T R A CT
Sepsis is a signifcant public health problem that afects children and adults alike. Despite some similarities in
the approach to pediatric and adult septic shock, there are key diferences as it relates to pathophysiology, clinical
presentation, and therapeutic approaches. In this review article, we discuss these diferences under 4 headings: a)
Developmental diferences in the hemodynamic response, b) Activated Protein C, c) Trombocytopenia associated
multiple organ failure and d) Hemophagocytic Lymphohistiocytosis (HLH). (Minerva Anestesiol 2011;77:986-92)
Key words: Pediatrics - Sepsis - Shock, septic.
Similarities in pediatric and
adult septic shock
I
n daily practice, intensivists often extrapolate
the results of adult clinical research trials to
treat critically ill pediatric patients. Although,
this may be a useful therapeutic strategy for cer-
tain problems in clinical medicine, it has its pit-
falls when used for the treatment of septic shock.
In this article, we highlight the diferences be-
tween adult and pediatric septic shock as it re-
lates to pathophysiology, clinical presentation,
and therapeutic approaches. Before we empha-
size the diferences between adult and pediatric
septic shock, it is important to highlight the
similarities.
Outcome from septic shock is dependent on
time sensitive therapies whether it is a child or a
big kid (i.e., an adult). In pediatrics, every hour
that goes by without using PALS/APLS guide-
line is associated with a 40% increase in risk of
mortality. For this reason, shock in children is
defned by prolonged capillary refll time of >2
seconds or hypotension. Children who present
to the emergency room with either hypotension
(warm shock) or prolonged capillary refll (com-
pensated shock) experience a 5-7% mortality;
however, if both prolonged capillary refll and
hypotension (decompensated shock) are present,
the mortality drastically increases to 30%.
1
Re-
versal of these shock states in the emergency
room resulted in a two-fold reduction in mortal-
ity and near complete prevention of functional
morbidity. Te take-home message is early recog-
nition and rapid treatment. Sebat et al. reported
a similar experience in adult patients admitted
to community hospitals. Using a SHOCK pro-
tocol that empowered non-physicians to activate
shock protocols, they reported a reduction in
the time until receipt of fuid resuscitation and
antibiotics from greater than three hours to less
than ninety minutes.
2
Tis was associated with a
concomitant reduction in adult sepsis mortality
rates from 50% to 10% over the fve year imple-
mentation period.
Rivers et al. assigned adult emergency room
Diferences between adult
and pediatric septic shock
R. K. ANEJA, J. A. CARCILLO
Departments of Critical Care Medicine and Pediatrics
University of Pittsburgh School of Medicine and Childrens Hospital of Pittsburgh, Pittsburgh, PA, USA
MINERVA MEDICA COPYRIGHT
T
h
i
s

d
o
c
u
m
e
n
t

i
s

p
r
o
t
e
c
t
e
d

b
y

i
n
t
e
r
n
a
t
i
o
n
a
l

c
o
p
y
r
i
g
h
t

l
a
w
s
.

N
o

a
d
d
i
t
i
o
n
a
l

r
e
p
r
o
d
u
c
t
i
o
n

i
s

a
u
t
h
o
r
i
z
e
d
.

I
t

i
s

p
e
r
m
i
t
t
e
d

f
o
r

p
e
r
s
o
n
a
l

u
s
e

t
o

d
o
w
n
l
o
a
d

a
n
d

s
a
v
e

o
n
l
y

o
n
e

f
i
l
e

a
n
d

p
r
i
n
t

o
n
l
y

o
n
e

c
o
p
y

o
f

t
h
i
s

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

m
a
k
e

a
d
d
i
t
i
o
n
a
l

c
o
p
i
e
s

(
e
i
t
h
e
r

s
p
o
r
a
d
i
c
a
l
l
y

o
r

s
y
s
t
e
m
a
t
i
c
a
l
l
y
,

e
i
t
h
e
r

p
r
i
n
t
e
d

o
r

e
l
e
c
t
r
o
n
i
c
)

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

p
u
r
p
o
s
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

d
i
s
t
r
i
b
u
t
e

t
h
e

e
l
e
c
t
r
o
n
i
c

c
o
p
y

o
f

t
h
e

a
r
t
i
c
l
e

t
h
r
o
u
g
h

o
n
l
i
n
e

i
n
t
e
r
n
e
t

a
n
d
/
o
r

i
n
t
r
a
n
e
t

f
i
l
e

s
h
a
r
i
n
g

s
y
s
t
e
m
s
,

e
l
e
c
t
r
o
n
i
c

m
a
i
l
i
n
g

o
r

a
n
y

o
t
h
e
r

m
e
a
n
s

w
h
i
c
h

m
a
y

a
l
l
o
w

a
c
c
e
s
s

t
o

t
h
e

A
r
t
i
c
l
e
.

T
h
e

u
s
e

o
f

a
l
l

o
r

a
n
y

p
a
r
t

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

C
o
m
m
e
r
c
i
a
l

U
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

c
r
e
a
t
i
o
n

o
f

d
e
r
i
v
a
t
i
v
e

w
o
r
k
s

f
r
o
m

t
h
e

A
r
t
i
c
l
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

p
r
o
d
u
c
t
i
o
n

o
f

r
e
p
r
i
n
t
s

f
o
r

p
e
r
s
o
n
a
l

o
r

c
o
m
m
e
r
c
i
a
l

u
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

r
e
m
o
v
e
,

c
o
v
e
r
,

o
v
e
r
l
a
y
,

o
b
s
c
u
r
e
,

b
l
o
c
k
,

o
r

c
h
a
n
g
e

a
n
y

c
o
p
y
r
i
g
h
t

n
o
t
i
c
e
s

o
r

t
e
r
m
s

o
f

u
s
e

w
h
i
c
h

t
h
e

P
u
b
l
i
s
h
e
r

m
a
y

p
o
s
t

o
n

t
h
e

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

f
r
a
m
e

o
r

u
s
e

f
r
a
m
i
n
g

t
e
c
h
n
i
q
u
e
s

t
o

e
n
c
l
o
s
e

a
n
y

t
r
a
d
e
m
a
r
k
,

l
o
g
o
,

o
r

o
t
h
e
r

p
r
o
p
r
i
e
t
a
r
y

t
i
o
n

o
f

t
h
e

P
u
b
l
i
s
h
e
r
.
DIFFERENCES BETWEEN ADULT AND PEDIATRIC SEPTIC SHOCK ANEJA
Vol. 77 - No. 10 MINERVA ANESTESIOLOGICA 987
patients with severe sepsis or septic shock to
receive

either six hours of early goal-directed
therapy (central venous oxygen saturation >70%
and normal blood pressure) or standard

therapy
(as a control), prior to their admission to the
intensive care

unit. Te in-hospital mortality

in
the group assigned to early goal-directed

therapy
was 30.5%, as compared to 46.5% in the group
assigned

to standard therapy (P=0.009). Patients
randomized to the goal-directed therapy arm had
higher mean central venous oxygen saturations,
lower lactate concentrations and base defcit.
3
De
Oliveira et al. repeated this work in children and
evaluated the role of goal-directed therapy aimed
at maintaining central venous oxygen saturation
levels >70%. He found that goal-directed thera-
py over 72 hours, rather than 6 hours as noted in
the Rivers study, reduced mortality from 40% to
12%, with all of the benefts attained in children
who had oxygen saturations <70% at the time of
enrollment.
4
PALS/APLS/ACCM guidelines also recom-
mend administration of antibiotics in the frst
hour and subsequent removal of the nidus of in-
fection. In support of this approach, Kumar et
al. noted that initiation of antimicrobial therapy
within one hour of onset of hypotension in adult
septic shock leads to higher survival i.e., 79.9%
of patients survive hospitalization. Unfortu-
nately, the average time to receipt of antibiot-
ics in their cohort was 6 hours. Tey noted an
increase of 7.6% in absolute mortality for every
hour that went by without administration of an-
tibiotics. Tis explained the 50% mortality rate
in their North American study cohort.
5
Barie
et al. evaluated the activated protein C trial in
the adult surgical patient sub group. Tey found
that survival with complete removal of the nidus
of infection was 95% whereas survival without
removal of the nidus was only 4%, regardless of
which study arm the patients occupied.
6
Tus,
time sensitive recognition and therapies includ-
ing resuscitation, antibiotic administration, and
nidus removal are the keystones of successful
management for children and adults alike.
After initial resuscitation, both children and
adults develop post sepsis immune depression
syndromes that contribute to ongoing multiple
organ dysfunction syndromes. Sepsis is a com-
plex immune-pathological disease characterized
by an initial pro-infammatory response that
shifts toward an anti-infammatory immunosup-
pressive state.
7-9
Numerous trials using anti-in-
fammatory agents in sepsis have failed; this has
led many investigators to question if mortality in
sepsis is due to uncontrolled anti-infammation
rather than pro-infammation. Autopsy studies in
adult and pediatric patients who died with sepsis
and multi-organ failure demonstrate lymphoid
depletion due to apoptosis.
10, 11
Tis lymphoid
depletion sets the stage for anergy, a state of non-
responsiveness to antigen. Tis anti-infammato-
ry response, referred to as compensatory anti-
infammatory response syndrome (CARS), is an
adaptive immune response that dampens an ag-
gressive, infammatory process. It is also believed
to contribute to the increased susceptibility of
critically ill patients to secondary nosocomial in-
fections, due in part to sepsis-induced leukocyte
immunoparalysis. Terapies for immune de-
pression remain a subject of active investigation
in children and adults alike. Tese strategies in-
clude therapeutic immune suppressant tapering
during septic shock and multi-organ failure, an-
tibiotic/antifungal prophylaxis for lymphopenia,
IVIg for hypogammaglobulinemia, and low dose
GM-CSF for immune paralysis (T
H
2 monocyte/
macrophage).
12

Diferences in pediatric and
adult septic shock
Having mentioned the general similarities be-
tween adult and pediatric septic shock, we will
now highlight the key diferences. We categorize
them under 4 headings: a) developmental difer-
ences in the hemodynamic response, b) activated
Protein C, c) thrombocytopenia associated mul-
tiple organ failure and d) gemophagocytic Lym-
phohistiocytosis (HLH).
Developmental diferences in the hemodynamic re-
sponse to sepsis in children vs adults
Neonatal septic shock is often complicated by
lack of the physiologic transition from fetal to
neonatal circulation. In utero, 85% of fetal cir-
culation will bypass the lungs through the pat-
MINERVA MEDICA COPYRIGHT
T
h
i
s

d
o
c
u
m
e
n
t

i
s

p
r
o
t
e
c
t
e
d

b
y

i
n
t
e
r
n
a
t
i
o
n
a
l

c
o
p
y
r
i
g
h
t

l
a
w
s
.

N
o

a
d
d
i
t
i
o
n
a
l

r
e
p
r
o
d
u
c
t
i
o
n

i
s

a
u
t
h
o
r
i
z
e
d
.

I
t

i
s

p
e
r
m
i
t
t
e
d

f
o
r

p
e
r
s
o
n
a
l

u
s
e

t
o

d
o
w
n
l
o
a
d

a
n
d

s
a
v
e

o
n
l
y

o
n
e

f
i
l
e

a
n
d

p
r
i
n
t

o
n
l
y

o
n
e

c
o
p
y

o
f

t
h
i
s

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

m
a
k
e

a
d
d
i
t
i
o
n
a
l

c
o
p
i
e
s

(
e
i
t
h
e
r

s
p
o
r
a
d
i
c
a
l
l
y

o
r

s
y
s
t
e
m
a
t
i
c
a
l
l
y
,

e
i
t
h
e
r

p
r
i
n
t
e
d

o
r

e
l
e
c
t
r
o
n
i
c
)

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

p
u
r
p
o
s
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

d
i
s
t
r
i
b
u
t
e

t
h
e

e
l
e
c
t
r
o
n
i
c

c
o
p
y

o
f

t
h
e

a
r
t
i
c
l
e

t
h
r
o
u
g
h

o
n
l
i
n
e

i
n
t
e
r
n
e
t

a
n
d
/
o
r

i
n
t
r
a
n
e
t

f
i
l
e

s
h
a
r
i
n
g

s
y
s
t
e
m
s
,

e
l
e
c
t
r
o
n
i
c

m
a
i
l
i
n
g

o
r

a
n
y

o
t
h
e
r

m
e
a
n
s

w
h
i
c
h

m
a
y

a
l
l
o
w

a
c
c
e
s
s

t
o

t
h
e

A
r
t
i
c
l
e
.

T
h
e

u
s
e

o
f

a
l
l

o
r

a
n
y

p
a
r
t

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

C
o
m
m
e
r
c
i
a
l

U
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

c
r
e
a
t
i
o
n

o
f

d
e
r
i
v
a
t
i
v
e

w
o
r
k
s

f
r
o
m

t
h
e

A
r
t
i
c
l
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

p
r
o
d
u
c
t
i
o
n

o
f

r
e
p
r
i
n
t
s

f
o
r

p
e
r
s
o
n
a
l

o
r

c
o
m
m
e
r
c
i
a
l

u
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

r
e
m
o
v
e
,

c
o
v
e
r
,

o
v
e
r
l
a
y
,

o
b
s
c
u
r
e
,

b
l
o
c
k
,

o
r

c
h
a
n
g
e

a
n
y

c
o
p
y
r
i
g
h
t

n
o
t
i
c
e
s

o
r

t
e
r
m
s

o
f

u
s
e

w
h
i
c
h

t
h
e

P
u
b
l
i
s
h
e
r

m
a
y

p
o
s
t

o
n

t
h
e

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

f
r
a
m
e

o
r

u
s
e

f
r
a
m
i
n
g

t
e
c
h
n
i
q
u
e
s

t
o

e
n
c
l
o
s
e

a
n
y

t
r
a
d
e
m
a
r
k
,

l
o
g
o
,

o
r

o
t
h
e
r

p
r
o
p
r
i
e
t
a
r
y

t
i
o
n

o
f

t
h
e

P
u
b
l
i
s
h
e
r
.
ANEJA DIFFERENCES BETWEEN ADULT AND PEDIATRIC SEPTIC SHOCK
988 MINERVA ANESTESIOLOGICA October 2011
ent ductus arteriosus and foramen ovale into the
aorta. Prenatally, this fow pattern is maintained
by suprasystemic pulmonary artery pressures, but
at birth inhalation of oxygen triggers a cascade of
biochemical events resulting in reduction of pul-
monary artery pressure. Te closure of the pat-
ent ductus arteriosus and foramen ovale results
in blood fow being directed to the pulmonary
circulation, thereby completing the transition
from fetal to neonatal circulation. Sepsis-induced
acidosis and hypoxia increase pulmonary vascular
resistance and pulmonary artery pressures leading
to patent ductus arteriosus, persistent pulmonary
hypertension (PPHN) and persistent fetal circula-
tion (PFC) in the newborn. Neonatal septic shock
with PPHN is associated with increased right ven-
tricle afterload, cardiac failure, tricuspid regurgi-
tation and hepatomegaly. Due to supra-systemic
pulmonary artery pressures, therapies that are di-
rected at reduction of pulmonary artery pressure
are likely to beneft the critically ill neonate. Ex-
amples of such therapies that are potentially life-
saving in newborns, infants, and children include
inhaled nitric oxide, oxygen, phosphodiesterase
III inhibitors i.e. milrinone. In contrast, adult sep-
tic shock has been associated with increased pro-
duction of nitric oxide leading to hypotension,
and development of multiple organ failure.
13, 14
Te presentation of septic shock is diferent in
adults as compared to children. Almost 90% of
the adult patients present with a hyperdynamic
shock syndrome or warm shock. Te hemody-
namic response includes low systemic vascular
resistance (SVR), hypotension, normal or in-
creased cardiac output, tachycardia and elevat-
ed oxygen concentrations in pulmonary-artery
blood.
15
Despite the hyperdynamic state, these
patients exhibit myocardial depression charac-
terized by decreased ejection fraction, ventricular
dilatation, and a fattening of the Frank-Starling
curve after fuid resuscitation.
16, 17
Tachycar-
dia and reduction in SVR is the primary com-
pensation mechanism for the declining cardiac
output. Patients whose SVR is not amenable to
manipulation with vasopressor agents is at high
risk of death. In comparison, the hemodynamic
response to sepsis is remarkably diferent in ne-
onates and older children. Severe hypovolemia is
a hallmark of pediatric septic shock; therefore,
children frequently respond well to aggressive
volume resuscitation. Almost 50% of children
with septic shock present with cold clamped
down extremities, low CO and elevated SVR,
often referred to as Cold Shock.
Children have limited cardiac reserve as com-
pared to adults. Te adult resting heart rate is 70;
therefore, a twofold increase in heart rate from 70
to 140 beats per minute can be easily tolerated and
used to maintain cardiac output when stroke vol-
ume is decreased. Similar mechanisms are not pos-
sible in babies and infants. A resting heart rate of
140 beats per minute cannot be doubled to 280
beats per minute because there is not enough time
for diastolic flling. Terefore, the predominant re-
sponse to a decreasing cardiac output in children
is vasoconstriction. Tis continued increase in va-
soconstriction is detrimental, as it further impairs
cardiac output leading to cardiac failure and death.
Tis elevated systemic vascular resistance makes
hypotension a late sign of shock.
18
Children com-
monly require inotropes, vasodilators and at times
ECMO to support cardiac function.
In summary, the transition of fetal to neonatal
physiology ofers a distinct challenge for physi-
cians treating neonatal sepsis. Te presentation of
septic shock in children is diferent as compared
to adult patients and presents the bedside clini-
cian with a diagnostic and therapeutic challenge.
We recommend that the reader review the algo-
rithms for hemodynamic support of newborn and
children with septic shock in reference 19 Clini-
cal practice parameters for hemodynamic support
of pediatric and neonatal septic shock: 2007 up-
date from the American College of Critical Care
Medicine.
19
Te major change highlighted in
the 2007 update is the recommendation to use
peripheral intravenous epinephrine and not wait
for central venous access. While central vascular
access is being obtained, alternate options include
intraosseous access for children, and umbilical ve-
nous access for newborns.
Activated protein C in adult vs. pediatric septic
shock
Te normal microvascular milieu is in a prof-
brinolytic and anticoagulant state and is convert-
ed to a procoagulant and antifbrinolytic state by
MINERVA MEDICA COPYRIGHT
T
h
i
s

d
o
c
u
m
e
n
t

i
s

p
r
o
t
e
c
t
e
d

b
y

i
n
t
e
r
n
a
t
i
o
n
a
l

c
o
p
y
r
i
g
h
t

l
a
w
s
.

N
o

a
d
d
i
t
i
o
n
a
l

r
e
p
r
o
d
u
c
t
i
o
n

i
s

a
u
t
h
o
r
i
z
e
d
.

I
t

i
s

p
e
r
m
i
t
t
e
d

f
o
r

p
e
r
s
o
n
a
l

u
s
e

t
o

d
o
w
n
l
o
a
d

a
n
d

s
a
v
e

o
n
l
y

o
n
e

f
i
l
e

a
n
d

p
r
i
n
t

o
n
l
y

o
n
e

c
o
p
y

o
f

t
h
i
s

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

m
a
k
e

a
d
d
i
t
i
o
n
a
l

c
o
p
i
e
s

(
e
i
t
h
e
r

s
p
o
r
a
d
i
c
a
l
l
y

o
r

s
y
s
t
e
m
a
t
i
c
a
l
l
y
,

e
i
t
h
e
r

p
r
i
n
t
e
d

o
r

e
l
e
c
t
r
o
n
i
c
)

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

p
u
r
p
o
s
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

d
i
s
t
r
i
b
u
t
e

t
h
e

e
l
e
c
t
r
o
n
i
c

c
o
p
y

o
f

t
h
e

a
r
t
i
c
l
e

t
h
r
o
u
g
h

o
n
l
i
n
e

i
n
t
e
r
n
e
t

a
n
d
/
o
r

i
n
t
r
a
n
e
t

f
i
l
e

s
h
a
r
i
n
g

s
y
s
t
e
m
s
,

e
l
e
c
t
r
o
n
i
c

m
a
i
l
i
n
g

o
r

a
n
y

o
t
h
e
r

m
e
a
n
s

w
h
i
c
h

m
a
y

a
l
l
o
w

a
c
c
e
s
s

t
o

t
h
e

A
r
t
i
c
l
e
.

T
h
e

u
s
e

o
f

a
l
l

o
r

a
n
y

p
a
r
t

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

C
o
m
m
e
r
c
i
a
l

U
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

c
r
e
a
t
i
o
n

o
f

d
e
r
i
v
a
t
i
v
e

w
o
r
k
s

f
r
o
m

t
h
e

A
r
t
i
c
l
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

p
r
o
d
u
c
t
i
o
n

o
f

r
e
p
r
i
n
t
s

f
o
r

p
e
r
s
o
n
a
l

o
r

c
o
m
m
e
r
c
i
a
l

u
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

r
e
m
o
v
e
,

c
o
v
e
r
,

o
v
e
r
l
a
y
,

o
b
s
c
u
r
e
,

b
l
o
c
k
,

o
r

c
h
a
n
g
e

a
n
y

c
o
p
y
r
i
g
h
t

n
o
t
i
c
e
s

o
r

t
e
r
m
s

o
f

u
s
e

w
h
i
c
h

t
h
e

P
u
b
l
i
s
h
e
r

m
a
y

p
o
s
t

o
n

t
h
e

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

f
r
a
m
e

o
r

u
s
e

f
r
a
m
i
n
g

t
e
c
h
n
i
q
u
e
s

t
o

e
n
c
l
o
s
e

a
n
y

t
r
a
d
e
m
a
r
k
,

l
o
g
o
,

o
r

o
t
h
e
r

p
r
o
p
r
i
e
t
a
r
y

t
i
o
n

o
f

t
h
e

P
u
b
l
i
s
h
e
r
.
DIFFERENCES BETWEEN ADULT AND PEDIATRIC SEPTIC SHOCK ANEJA
Vol. 77 - No. 10 MINERVA ANESTESIOLOGICA 989
the secondary endpoints were 28-day mortality,
major amputations, and safety. Children that re-
ceived DrotAA when compared to the placebo
group did not demonstrate any signifcant dif-
ference in either CTCOFR score or mortality.
However, in comparison to patients that received
placebo, DrotAA patients had more episodes of
central nervous system (CNS) bleeding during
the infusion and 28-day study period. Te risk
of bleeding was higher in patients who were less
than 60 days old and weighed less than 4 kg.
24

As a result, of the adverse risk to beneft ratio,
the use of DrotAA is not recommended in chil-
dren with sepsis (Table I).
Trombocytopenia-associated multiple organ fail-
ure
Trombocytopenia-associated multiple organ
failure (TAMOF) is a thrombotic microangio-
pathic syndrome and is defned by a spectrum of
pathology that includes thrombotic thrombocy-
topenic purpura (TTP), secondary thrombotic
microangiopathy (TMA), and disseminated in-
travascular coagulation (DIC).
25
A discussion
of the entire spectrum of thrombotic microan-
giopathy syndromes is beyond the scope of this
manuscript; therefore, we will mainly discuss
TMA. Non-consumptive TMA is characterized
by thrombocytopenia associated multiple organ
failure, elevated prothrombin time (PT)/acti-
vated partial thromboplastin time (aPTT) and
little evidence of hemolysis on peripheral smear.
Unlike DIC, plasma concentrations of factors
V, VIII, and X and fbrinogen are normal or
increased. Nguyen et al. demonstrated the role
of disintegrin and metalloprotease with throm-
bospondin motifs (ADAMTS)-13, also known as
von Willebrand factor (VWF) cleaving-protease,
in the pathophysiology of secondary thrombotic
microangiopathy syndromes in pediatric sepsis.
ADAMTS-13 is a zinc-containing metallopro-
tease enzyme that cleaves the large thrombogenic
von Willebrand factor (VWF) multimers. Sepsis
is characterized by a decline in ADAMTS-13
activity (defned as <57% of control plasma)
leading to the formation of ultra-large VWF
multimers. Tese multimers attract platelets and
fbrin leading to microthrombi, organ dysfunc-
infammatory mediators and microbial prod-
ucts. Protein C is a soluble, vitamin K-depend-
ent, plasma serine protease that plays a central
role in endogenous anticoagulation. Its activated
form is a potent anticoagulant enzyme and is ca-
pable of inactivating clotting co-factors Va and
VIIIa and plasminogen-activator inhibitor 1.
20

Reduced circulating concentrations of protein
C and its activated form, activated protein C,
are associated with an increased risk for death in
patients with sepsis.
21
In the landmark Recom-
binant Human Activated Protein C Worldwide
Evaluation in Severe Sepsis (PROWESS) study,
patients with severe sepsis were randomized to
receive an intravenous infusion of either placebo
or drotrecogin alfa (recombinant human acti-
vated protein C) (DrotAA) for 96 hours. Te
mortality rate was 30.8% in the placebo group
and 24.7% in the DrotAA group (P=0.005).
22

Te Surviving Sepsis Campaigns international
guidelines for management of severe sepsis and
septic shock suggest that adult patients with
sepsis-induced organ dysfunction and at a high
risk of death (APACHE II 25 or multiple organ
failure) should receive DrotAA.
23

Another global open-label phase 2 trial in adult
and pediatric severe sepsis patients (Extended
Evaluation of Recombinant Activated Protein C,
or ENHANCE) was also completed gathering ad-
ditional mortality and safety data. Secondary anal-
ysis (in press: Dalton et al. Pediatr Critical Care
Med) found that children in the ENHANCE
placebo group experienced increased activated
protein C activity over time, whereas adults in
the PROWESS placebo group did not. It is not
known whether this is because of age specifc dif-
ferences in coagulation, or because of diferences
in therapy. For example, fresh, frozen plasma has
protein C activity, and it is administered more
commonly in children than in adults.
Te RESOLVE (Researching severe Sepsis
and Organ dysfunction in children: a gLobal
perspectiVE) trial assessed the use of DrotAA in
children with sepsis.
24
In this double-blinded,
international trial, children were randomized to
receive a 4-day course of DrotAA or placebo (in-
travenous saline). Te primary endpoint was a
pre-defned Composite Time to Complete Or-
gan Failure Resolution (CTCOFR) score and
MINERVA MEDICA COPYRIGHT
T
h
i
s

d
o
c
u
m
e
n
t

i
s

p
r
o
t
e
c
t
e
d

b
y

i
n
t
e
r
n
a
t
i
o
n
a
l

c
o
p
y
r
i
g
h
t

l
a
w
s
.

N
o

a
d
d
i
t
i
o
n
a
l

r
e
p
r
o
d
u
c
t
i
o
n

i
s

a
u
t
h
o
r
i
z
e
d
.

I
t

i
s

p
e
r
m
i
t
t
e
d

f
o
r

p
e
r
s
o
n
a
l

u
s
e

t
o

d
o
w
n
l
o
a
d

a
n
d

s
a
v
e

o
n
l
y

o
n
e

f
i
l
e

a
n
d

p
r
i
n
t

o
n
l
y

o
n
e

c
o
p
y

o
f

t
h
i
s

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

m
a
k
e

a
d
d
i
t
i
o
n
a
l

c
o
p
i
e
s

(
e
i
t
h
e
r

s
p
o
r
a
d
i
c
a
l
l
y

o
r

s
y
s
t
e
m
a
t
i
c
a
l
l
y
,

e
i
t
h
e
r

p
r
i
n
t
e
d

o
r

e
l
e
c
t
r
o
n
i
c
)

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

p
u
r
p
o
s
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

d
i
s
t
r
i
b
u
t
e

t
h
e

e
l
e
c
t
r
o
n
i
c

c
o
p
y

o
f

t
h
e

a
r
t
i
c
l
e

t
h
r
o
u
g
h

o
n
l
i
n
e

i
n
t
e
r
n
e
t

a
n
d
/
o
r

i
n
t
r
a
n
e
t

f
i
l
e

s
h
a
r
i
n
g

s
y
s
t
e
m
s
,

e
l
e
c
t
r
o
n
i
c

m
a
i
l
i
n
g

o
r

a
n
y

o
t
h
e
r

m
e
a
n
s

w
h
i
c
h

m
a
y

a
l
l
o
w

a
c
c
e
s
s

t
o

t
h
e

A
r
t
i
c
l
e
.

T
h
e

u
s
e

o
f

a
l
l

o
r

a
n
y

p
a
r
t

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

C
o
m
m
e
r
c
i
a
l

U
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

c
r
e
a
t
i
o
n

o
f

d
e
r
i
v
a
t
i
v
e

w
o
r
k
s

f
r
o
m

t
h
e

A
r
t
i
c
l
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

p
r
o
d
u
c
t
i
o
n

o
f

r
e
p
r
i
n
t
s

f
o
r

p
e
r
s
o
n
a
l

o
r

c
o
m
m
e
r
c
i
a
l

u
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

r
e
m
o
v
e
,

c
o
v
e
r
,

o
v
e
r
l
a
y
,

o
b
s
c
u
r
e
,

b
l
o
c
k
,

o
r

c
h
a
n
g
e

a
n
y

c
o
p
y
r
i
g
h
t

n
o
t
i
c
e
s

o
r

t
e
r
m
s

o
f

u
s
e

w
h
i
c
h

t
h
e

P
u
b
l
i
s
h
e
r

m
a
y

p
o
s
t

o
n

t
h
e

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

f
r
a
m
e

o
r

u
s
e

f
r
a
m
i
n
g

t
e
c
h
n
i
q
u
e
s

t
o

e
n
c
l
o
s
e

a
n
y

t
r
a
d
e
m
a
r
k
,

l
o
g
o
,

o
r

o
t
h
e
r

p
r
o
p
r
i
e
t
a
r
y

t
i
o
n

o
f

t
h
e

P
u
b
l
i
s
h
e
r
.
ANEJA DIFFERENCES BETWEEN ADULT AND PEDIATRIC SEPTIC SHOCK
990 MINERVA ANESTESIOLOGICA October 2011
Tere are numerous case reports that discuss
the benefts of plasma exchange in adult and
pediatric septic shock. Despite the similarity in
patho-physiology and treatment options, plasma
exchange in patients with TAMOF is more preva-
lent in the pediatric community as compared to
the adult patients. A possible explanation for this
would be the limitation of resources in perform-
ing plasma exchange in adults. For example, a
single volume exchange in a 10 kg child would re-
quire 600 cc of plasma. Now, compare this to a 70
kg adult who would need approximately 4-5 liters
of plasma. At present, activated protein C is more
commonly used in adults, and plasma exchange
in children with sepsis-induced TAMOF.
Hemophagocytic lymphohistiocytosis a new dis-
ease
Hemophagocytic lymphohistiocytosis (HLH)
is a non-malignant, infammatory disorder re-
sulting from persistent and excessive activation
of antigen-presenting cells (histiocytes) and T
tion and multiple organ failure.
26
In addition,
autopsies from children who died with TAMOF
and decreased ADAMTS-13 activity, showed
VWF-rich thrombi in the microvasculature of
brain, lung, and kidney. Similar fndings were
recently reported in children with meningococ-
cemia.
27
Plasma exchange removes ultra large
VWF multimers and replenishes ADAMTS-13
activity in these children.
A similar mechanism may be operational
in adult patients with sepsis. In a single center
adult intensive care unit, ADAMTS-13 levels
were examined in patients with organ failure due
to severe sepsis and compared to organ failures
unrelated to sepsis and controls. ADAMTS-13
activity was decreased in patients with severe
sepsis as compared to patients with organ failure
unrelated to sepsis and controls.
28, 29
Busund et
al. and Darmon et al. demonstrated reduction in
mortality in two separate randomized trials com-
paring plasma exchange to plasma infusion for
septic shock/severe sepsis and thrombotic mic-
orangiopathy respectively.
28, 30
Table I.Compares therapies used in adults and children with septic shock.
Terapy Children Adults
Volume Usually need more fuid: may need up to
and over 60 cc/kg
Fluid resuscitation till CVP 12 cm H
2
O
Antibiotics Early initiation of appropriate antibiotics
recommended within 1 h
Early initiation of appropriate antibiotics
recommended within 2 h
Inotropes and vasopressors First line peripheral Epinephrine for cold
shock
Transition to central when able
Central norepinephrine for warm shock
First line Norepinephrine dobutamine
Vasopressin for warm shock
Vasodilators Used for pulmonary hypertension;
Low cardiac output high SVR shock
No role
Tight glycemic control Unresolved Harmful
ECMO Survival 80% in neonates and 50% in
children
Evolving - H1N1 is popularizing its use
Inhaled NO Neonates with right ventricle failure No role for NO
Plasma exchange Used for patients with TAMOF including
DIC/purpura fulminans
Efective in adults but rarely used
Activated Protein C Not recommended Recommended
Hydrocortisone Absolute Adrenal Insufciency only
Post ACTH cortisol level <18 g/dl or ba-
seline <5 g/dL
Use if continue to be on vasopressors regar-
dless of adrenal status
Primary HLH protocol - Etoposide/cyclo-
sporine A, dexamethasone, chemotherapy
Used for primary HLH with familial hi-
story, consanguineous parents, or perforin
mutations
Not indicated
MINERVA MEDICA COPYRIGHT
T
h
i
s

d
o
c
u
m
e
n
t

i
s

p
r
o
t
e
c
t
e
d

b
y

i
n
t
e
r
n
a
t
i
o
n
a
l

c
o
p
y
r
i
g
h
t

l
a
w
s
.

N
o

a
d
d
i
t
i
o
n
a
l

r
e
p
r
o
d
u
c
t
i
o
n

i
s

a
u
t
h
o
r
i
z
e
d
.

I
t

i
s

p
e
r
m
i
t
t
e
d

f
o
r

p
e
r
s
o
n
a
l

u
s
e

t
o

d
o
w
n
l
o
a
d

a
n
d

s
a
v
e

o
n
l
y

o
n
e

f
i
l
e

a
n
d

p
r
i
n
t

o
n
l
y

o
n
e

c
o
p
y

o
f

t
h
i
s

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

m
a
k
e

a
d
d
i
t
i
o
n
a
l

c
o
p
i
e
s

(
e
i
t
h
e
r

s
p
o
r
a
d
i
c
a
l
l
y

o
r

s
y
s
t
e
m
a
t
i
c
a
l
l
y
,

e
i
t
h
e
r

p
r
i
n
t
e
d

o
r

e
l
e
c
t
r
o
n
i
c
)

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

p
u
r
p
o
s
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

d
i
s
t
r
i
b
u
t
e

t
h
e

e
l
e
c
t
r
o
n
i
c

c
o
p
y

o
f

t
h
e

a
r
t
i
c
l
e

t
h
r
o
u
g
h

o
n
l
i
n
e

i
n
t
e
r
n
e
t

a
n
d
/
o
r

i
n
t
r
a
n
e
t

f
i
l
e

s
h
a
r
i
n
g

s
y
s
t
e
m
s
,

e
l
e
c
t
r
o
n
i
c

m
a
i
l
i
n
g

o
r

a
n
y

o
t
h
e
r

m
e
a
n
s

w
h
i
c
h

m
a
y

a
l
l
o
w

a
c
c
e
s
s

t
o

t
h
e

A
r
t
i
c
l
e
.

T
h
e

u
s
e

o
f

a
l
l

o
r

a
n
y

p
a
r
t

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

C
o
m
m
e
r
c
i
a
l

U
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

c
r
e
a
t
i
o
n

o
f

d
e
r
i
v
a
t
i
v
e

w
o
r
k
s

f
r
o
m

t
h
e

A
r
t
i
c
l
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

p
r
o
d
u
c
t
i
o
n

o
f

r
e
p
r
i
n
t
s

f
o
r

p
e
r
s
o
n
a
l

o
r

c
o
m
m
e
r
c
i
a
l

u
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

r
e
m
o
v
e
,

c
o
v
e
r
,

o
v
e
r
l
a
y
,

o
b
s
c
u
r
e
,

b
l
o
c
k
,

o
r

c
h
a
n
g
e

a
n
y

c
o
p
y
r
i
g
h
t

n
o
t
i
c
e
s

o
r

t
e
r
m
s

o
f

u
s
e

w
h
i
c
h

t
h
e

P
u
b
l
i
s
h
e
r

m
a
y

p
o
s
t

o
n

t
h
e

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

f
r
a
m
e

o
r

u
s
e

f
r
a
m
i
n
g

t
e
c
h
n
i
q
u
e
s

t
o

e
n
c
l
o
s
e

a
n
y

t
r
a
d
e
m
a
r
k
,

l
o
g
o
,

o
r

o
t
h
e
r

p
r
o
p
r
i
e
t
a
r
y

t
i
o
n

o
f

t
h
e

P
u
b
l
i
s
h
e
r
.
DIFFERENCES BETWEEN ADULT AND PEDIATRIC SEPTIC SHOCK ANEJA
Vol. 77 - No. 10 MINERVA ANESTESIOLOGICA 991
eral and might lead to over diagnosis of SHLH.
Terefore, the bedside clinician should be ex-
tremely cautious when considering the diagnosis
of SHLH in a child, as the currently available
therapies are radically diferent.
Classically, HLH is predominantly thought to
be a disease of children, but lately case reports
describing HLH in adults have been published.
43

Majority of these patients had Epstein-Barr vi-
rus and presented with signs and symptoms
suggestive of lympho-proliferative disease and
multi-organ failure. At this time, many ques-
tions remain unanswered about the diagnosis
and therapeutic options available to treat HLH
in children. We need to understand the presenta-
tion and pathophysiology of the disease, before
we can ofer alternative therapies compared to
the chemotherapeutic regimen being used at the
present time. In summary, we have highlighted
the diferences between adult and pediatric sep-
tic shock. Tese diferences seek to reinforce the
notion that children are not little adults, and
attention should be paid to the treatment strat-
egy adopted while treating septic shock in both
adults and children.
References
1. Carcillo JA, Kuch BA, Han YY et al. Mortality and func-
tional morbidity after use of PALS/APLS by community
physicians. Pediatrics 2009;124:500-8.
2. Sebat F, Musthafa AA, Johnson D et al. Efect of a rapid re-
sponse system for patients in shock on time to treatment and
mortality during 5 years. Crit Care Med 2007;35:2568-75.
3. Rivers E, Nguyen B, Havstad S et al. Early goal-directed
therapy in the treatment of severe sepsis and septic shock.
N Engl J Med 2001;345:1368-77.
4. de Oliveira CF, de Oliveira DS, Gottschald AF et al.
ACCM/PALS haemodynamic support guidelines for paedi-
atric septic shock: an outcomes comparison with and with-
out monitoring central venous oxygen saturation. Intensive
Care Med 2008;34:1065-75.
5. Kumar A, Roberts D, Wood KE et al. Duration of hypoten-
sion before initiation of efective antimicrobial therapy is
the critical determinant of survival in human septic shock.
Critical Care Med 2006;34:1589-96.
6. Barie PS, Williams MD, McCollam JS et al. Beneft/risk
profle of drotrecogin alfa (activated) in surgical patients
with severe sepsis. Am J Surg 2004;188:212-20.
7. Hotchkiss RS, Karl IE. Te pathophysiology and treatment
of sepsis. N Engl J Med 2003;348:138-50.
8. Lederer JA, Rodrick ML, Mannick JA. Te efects of injury
on the adaptive immune response. Shock 1999;11:153-9.
9. Payen D, Faivre V, Lukaszewicz AC et al. Expression of
monocyte human leukocyte antigen-DR in relation with
sepsis severity and plasma mediators. Minerva Anestesiol
2009;75:484-93.
10. Felmet KA, Hall MW, Clark RSB et al. Prolonged Lym-
lymphocytes. HLH is classifed into two distinct
forms, familial and secondary HLH. Familial
HLH (FHLH) is a genetic disorder primarily
occurring in infancy and early childhood. Con-
versely, secondary HLH (SHLH) has been de-
scribed in association with bacterial and viral
infections.
31-39
Histopathologically, lymphohis-
tiocytic infltrates with evidence of hemophago-
cytosis by activated macrophages are present in
multiple organs e.g., bone marrow, spleen, liver,
lymph nodes and the central nervous system.
40,
41
Te prolonged and excessive activation of

an-
tigen-presenting cells (macrophages, histiocytes)
and CD8
+
T cells leads to signifcantly elevated
serum levels of pro-infammatory cytokines IL-
1, tumor necrosis factor

(TNF), IL-6 and IL-8.
Tis state of persistent hypercytokinemia leads
to progressive organ dysfunction and death in
patients with HLH.
41
Te 2007 guidelines no longer diferentiate
between FHLH and SHLH and use the follow-
ing criteria.
42
To diagnose HLH fve of the fol-
lowing eight diagnostic criteria need to be met:
1) fever; 2) cytopenia afecting 2 of 3 lineages
in the peripheral blood; 3) hypertriglyceridemia
and/or hypofbrinogenemia; 4) hyperferritine-
mia (>500 g/L); 5) hemophagocytosis; 6) el-
evated soluble interleukin-2 receptor (CD25);
7) decreased natural killer cell (NKC) activity;
and 8) splenomegaly. In addition, molecular di-
agnosis of HLH can be made if there are genetic
defects involving the perforin gene on chromo-
some 9q21, the MUNC134 gene on chromo-
some 17q25, and mutations in syntaxin 11 gene
6q24, or a suggestive family history.
42
According
to the International Histiocyte Society guide-
lines, the treatment for HLH involves initial
8 weeks of chemotherapy (etoposide, and cy-
closporine A) and steroids. Children with recur-
rent or persistent SHLH might need additional
chemotherapy and/or hematopoietic bone mar-
row transplantation. Conversely, the standard
of care for severe sepsis includes antibiotics and
supportive therapy.
Te clinical and laboratory criteria used for
the diagnosis of HLH can be met by patients
with severe sepsis/septic shock and MODS. An
in-depth examination of these criteria leads us
to conclude that the proposed criteria are gen-
MINERVA MEDICA COPYRIGHT
T
h
i
s

d
o
c
u
m
e
n
t

i
s

p
r
o
t
e
c
t
e
d

b
y

i
n
t
e
r
n
a
t
i
o
n
a
l

c
o
p
y
r
i
g
h
t

l
a
w
s
.

N
o

a
d
d
i
t
i
o
n
a
l

r
e
p
r
o
d
u
c
t
i
o
n

i
s

a
u
t
h
o
r
i
z
e
d
.

I
t

i
s

p
e
r
m
i
t
t
e
d

f
o
r

p
e
r
s
o
n
a
l

u
s
e

t
o

d
o
w
n
l
o
a
d

a
n
d

s
a
v
e

o
n
l
y

o
n
e

f
i
l
e

a
n
d

p
r
i
n
t

o
n
l
y

o
n
e

c
o
p
y

o
f

t
h
i
s

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

m
a
k
e

a
d
d
i
t
i
o
n
a
l

c
o
p
i
e
s

(
e
i
t
h
e
r

s
p
o
r
a
d
i
c
a
l
l
y

o
r

s
y
s
t
e
m
a
t
i
c
a
l
l
y
,

e
i
t
h
e
r

p
r
i
n
t
e
d

o
r

e
l
e
c
t
r
o
n
i
c
)

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

p
u
r
p
o
s
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

d
i
s
t
r
i
b
u
t
e

t
h
e

e
l
e
c
t
r
o
n
i
c

c
o
p
y

o
f

t
h
e

a
r
t
i
c
l
e

t
h
r
o
u
g
h

o
n
l
i
n
e

i
n
t
e
r
n
e
t

a
n
d
/
o
r

i
n
t
r
a
n
e
t

f
i
l
e

s
h
a
r
i
n
g

s
y
s
t
e
m
s
,

e
l
e
c
t
r
o
n
i
c

m
a
i
l
i
n
g

o
r

a
n
y

o
t
h
e
r

m
e
a
n
s

w
h
i
c
h

m
a
y

a
l
l
o
w

a
c
c
e
s
s

t
o

t
h
e

A
r
t
i
c
l
e
.

T
h
e

u
s
e

o
f

a
l
l

o
r

a
n
y

p
a
r
t

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

C
o
m
m
e
r
c
i
a
l

U
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

c
r
e
a
t
i
o
n

o
f

d
e
r
i
v
a
t
i
v
e

w
o
r
k
s

f
r
o
m

t
h
e

A
r
t
i
c
l
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

p
r
o
d
u
c
t
i
o
n

o
f

r
e
p
r
i
n
t
s

f
o
r

p
e
r
s
o
n
a
l

o
r

c
o
m
m
e
r
c
i
a
l

u
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

r
e
m
o
v
e
,

c
o
v
e
r
,

o
v
e
r
l
a
y
,

o
b
s
c
u
r
e
,

b
l
o
c
k
,

o
r

c
h
a
n
g
e

a
n
y

c
o
p
y
r
i
g
h
t

n
o
t
i
c
e
s

o
r

t
e
r
m
s

o
f

u
s
e

w
h
i
c
h

t
h
e

P
u
b
l
i
s
h
e
r

m
a
y

p
o
s
t

o
n

t
h
e

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

f
r
a
m
e

o
r

u
s
e

f
r
a
m
i
n
g

t
e
c
h
n
i
q
u
e
s

t
o

e
n
c
l
o
s
e

a
n
y

t
r
a
d
e
m
a
r
k
,

l
o
g
o
,

o
r

o
t
h
e
r

p
r
o
p
r
i
e
t
a
r
y

t
i
o
n

o
f

t
h
e

P
u
b
l
i
s
h
e
r
.
ANEJA DIFFERENCES BETWEEN ADULT AND PEDIATRIC SEPTIC SHOCK
992 MINERVA ANESTESIOLOGICA October 2011
associated with severity and outcome. Tromb Haemost
2003;103:1181-7.
28. Busund R, Koukline V, Utrobin U et al. Plasmapheresis in
severe sepsis and septic shock: a prospective, randomised,
controlled trial. Intensive Care Med 2002;28:1434-9.
29. Martin K, Borgel D, Lerolle N et al. Decreased AD-
AMTS-13 (A disintegrin-like and metalloprotease with
thrombospondin type 1 repeats) is associated with a poor
prognosis in sepsis-induced organ failure. Crit Care Med
2007;35:2375-82.
30. Darmon M, Azoulay E, Tiery G et al. Time course of or-
gan dysfunction in thrombotic microanguiopathy patients
receiveign either plasma perfusion or plasm exchange. Crit
Care Med 2006;34:2127-33.
31. Aleem A, Al Amoudi S, Al-Mashhadani S et al. Haemo-
phagocytic syndrome associated with hepatitis-B virus
infection responding to etoposide. Clin Lab Haematol
2005;27:395-8.
32. Hsieh SM, Chang SC. Insufcient perforin expression in
CD8+ T cells in response to hemagglutinin from avian in-
fuenza (H5N1) virus. 2006. J Immunol 176:4530-4533.
33. Imashuku, S. Clinical features and treatment strategies of
Epstein-Barr virus-associated hemophagocytic lymphohis-
tiocytosis. Crit Rev Oncol Hematol 2002;44:259-72.
34. Sato S, Kawashima H, Oshiro H et al. Virological and im-
munological characteristics of a 19-year-old Japanese female
with fatal outcome with Epstein-Barr virus-associated he-
mophagocytic syndrome. J Clin Virol 2004;31:235-238.
35. Akamatsu N, Sugawara Y, Tamura S et al. Hemophagocytic
syndrome after adult-to-adult living donor liver transplan-
tation. Transplant Proc 2006;38:1425-8.
36. El Khoury N, Lassoued K, Pelle G et al. [Hemophagocyto-
sis associated with an Escherichia coli sepsis: a case report].
La Revue de medecine interne 2003;24:688-91.
37. Ito S, Takada N, Ozasa A et al. Secondary hemophagocytic
syndrome in a patient with methicillin-sensitive Staphy-
lococcus Aureus bacteremia due to severe decubitus ulcer.
Intern Med 2006;45:303-7.
38. Sun HY, Chen MY, Fang CT, et al. Hemophagocytic lym-
phohistiocytosis: an unusual initial presentation of acute
HIV infection. 2004. J Acquired Immunedefciency Syn-
dromes 1999;37:1539-40.
39. Castillo L, Carcillo J. Secondary hemophagocytic lympho-
histiocytosis and severe sepsis/ systemic infammatory re-
sponse syndrome/multiorgan dysfunction syndrome/mac-
rophage activation syndrome share common intermediate
phenotypes on a spectrum of infammation. Pediatr Crit
Care Med 2009;10:387-92.
40. Arico M, Janka G, Fischer A et al. Hemophagocytic lym-
phohistiocytosis. Report of 122 children from the Interna-
tional Registry. FHL Study Group of the Histiocyte Society.
Leukemia 1996;10:197-203.
41. Filipovich A, McClain K, Grom A. Histiocytic Disorders:
Recent Insights into Pathophysiology and Practical Guide-
lines. Biol Blood Marrow Transplant 2009;16:S82-S89.
42. Henter JI, Horne A, Arico M et al. HLH-2004: Diagnostic
and therapeutic guidelines for hemophagocytic lymphohis-
tiocytosis. Pediatric Blood Cancer 2007;48:124-31.
43. Elazary AS, Wolf DG, Amir G et al. Severe Epstein-Barr
virus-associated hemophagocytic syndrome in six adult
patients.J Clin Virol 2007;40:156-9.
phopenia, Lymphoid Depletion, and Hypoprolactinemia
in Children with Nosocomial Sepsis and Multiple Organ
Failure. J Immunol 2005;174:3765-72.
11. Hotchkiss RS, Swanson PE, Freeman BD et al. Apoptotic
cell death in patients with sepsis, shock, and multiple organ
dysfunction. Critical Care Med 1999;27:1230-51.
12. Meisel C, Schefold JC, Pschowski R et al. Granulocyte-
macrophage colony-stimulating factor to reverse sepsis-as-
sociated immunosuppression: a double-blind, randomized,
placebo-controlled multicenter trial. Am J Respir Crit Care
Med 2009;180:640-8.
13. Brady AJ, Poole-Wilson PA. Circulatory failure in septic
shock. Nitric oxide: too much of a good thing? Br Heart J
1993;70:103-5.
14. Schuerholz T, Marx G. Management of sepsis. Minerva
Anestesiol 2008;74:181-95.
15. Parker MM, Shelhamer JH, Natanson C et al. Serial cardio-
vascular variables in survivors and nonsurvivors of human
septic shock: heart rate as an early predictor of prognosis.
Crit Care Med 1987;15:923-9.
16. Munt B, Jue J, Gin K et al. Diastolic flling in human se-
vere sepsis: an echocardiographic study. Crit Care Med
1998;26:1829-33.
17. Court O, Kumar A, Parrillo JE et al. Clinical review: Myo-
cardial depression in sepsis and septic shock. Crit Care
2002;6:500-8.
18. Ceneviva G, Paschall JA, Mafei F et al. Hemodynamic
Support in Fluid-refractory Pediatric Septic Shock. Pediat-
rics 1998;102:e19.
19. Brierley J, Carcillo JA, Choong K et al. Clinical practice
parameters for hemodynamic support of pediatric and neo-
natal septic shock: 2007 update from the American College
of Critical Care Medicine. Crit Care Med 2009;37:666-8.
20. Toussaint S, Gerlach H. Activated Protein C for Sepsis. N
Engl J Med 2009;361:2646-52.
21. Fourrier F, Chopin C, Goudemand J et al. Septic shock,
multiple organ failure, and disseminated intravascular co-
agulation. Compared patterns of antithrombin III, protein
C, and protein S defciencies. Chest 1992;101:816-23.
22. Bernard GR, Vincent JL, Laterre PF et al. Efcacy and
safety of recombinant human activated protein C for severe
sepsis. N Engl J Med 2001;344:699-709.
23. Dellinger RP, Levy MM, Carlet JM et al. Surviving Sep-
sis Campaign: international guidelines for management
of severe sepsis and septic shock: 2008. Crit Care med
2008;36:296-327.
24. Nadel S, Goldstein B, Williams MD et al. Drotrecogin
alfa (activated) in children with severe sepsis: a multicen-
tre phase III randomised controlled trial. Lancet 2007;
369:836-43.
25. Nguyen T, Carcillo J. Bench-to-bedside review: Trom-
bocytopenia-associated multiple organ failure - a newly
appreciated syndrome in the critically ill. Crit Care 2006;
10:235.
26. Nguyen TC, Han YY, Kiss JE et al. Intensive plasma ex-
change increases a disintegrin and metalloprotease with
thrombospondin motifs-13 activity and reverses organ
dysfunction in children with thrombocytopenia-associated
multiple organ failure. Crit Care Med 2008;36:2878-87.
27. Bongers TN, Emonts M, de Maat MP et al. Reduced AD-
AMTS13 in children with severe meningococcal sepsis is
Received on June 29, 2010 - Accepted for publication on January 31, 2011.
Corresponding author: R. K. Aneja, MD, Department of Critical Care Medicine, Childrens Hospital of Pittsburgh, Childrens Hospital
Drive, 4401 Penn Ave, Faculty Pavilion, Suite 2000, Pittsburgh, PA 15224, USA. E-mail: anejar@upmc.edu
MINERVA MEDICA COPYRIGHT
T
h
i
s

d
o
c
u
m
e
n
t

i
s

p
r
o
t
e
c
t
e
d

b
y

i
n
t
e
r
n
a
t
i
o
n
a
l

c
o
p
y
r
i
g
h
t

l
a
w
s
.

N
o

a
d
d
i
t
i
o
n
a
l

r
e
p
r
o
d
u
c
t
i
o
n

i
s

a
u
t
h
o
r
i
z
e
d
.

I
t

i
s

p
e
r
m
i
t
t
e
d

f
o
r

p
e
r
s
o
n
a
l

u
s
e

t
o

d
o
w
n
l
o
a
d

a
n
d

s
a
v
e

o
n
l
y

o
n
e

f
i
l
e

a
n
d

p
r
i
n
t

o
n
l
y

o
n
e

c
o
p
y

o
f

t
h
i
s

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

m
a
k
e

a
d
d
i
t
i
o
n
a
l

c
o
p
i
e
s

(
e
i
t
h
e
r

s
p
o
r
a
d
i
c
a
l
l
y

o
r

s
y
s
t
e
m
a
t
i
c
a
l
l
y
,

e
i
t
h
e
r

p
r
i
n
t
e
d

o
r

e
l
e
c
t
r
o
n
i
c
)

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

p
u
r
p
o
s
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

d
i
s
t
r
i
b
u
t
e

t
h
e

e
l
e
c
t
r
o
n
i
c

c
o
p
y

o
f

t
h
e

a
r
t
i
c
l
e

t
h
r
o
u
g
h

o
n
l
i
n
e

i
n
t
e
r
n
e
t

a
n
d
/
o
r

i
n
t
r
a
n
e
t

f
i
l
e

s
h
a
r
i
n
g

s
y
s
t
e
m
s
,

e
l
e
c
t
r
o
n
i
c

m
a
i
l
i
n
g

o
r

a
n
y

o
t
h
e
r

m
e
a
n
s

w
h
i
c
h

m
a
y

a
l
l
o
w

a
c
c
e
s
s

t
o

t
h
e

A
r
t
i
c
l
e
.

T
h
e

u
s
e

o
f

a
l
l

o
r

a
n
y

p
a
r
t

o
f

t
h
e

A
r
t
i
c
l
e

f
o
r

a
n
y

C
o
m
m
e
r
c
i
a
l

U
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

c
r
e
a
t
i
o
n

o
f

d
e
r
i
v
a
t
i
v
e

w
o
r
k
s

f
r
o
m

t
h
e

A
r
t
i
c
l
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

T
h
e

p
r
o
d
u
c
t
i
o
n

o
f

r
e
p
r
i
n
t
s

f
o
r

p
e
r
s
o
n
a
l

o
r

c
o
m
m
e
r
c
i
a
l

u
s
e

i
s

n
o
t

p
e
r
m
i
t
t
e
d
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

r
e
m
o
v
e
,

c
o
v
e
r
,

o
v
e
r
l
a
y
,

o
b
s
c
u
r
e
,

b
l
o
c
k
,

o
r

c
h
a
n
g
e

a
n
y

c
o
p
y
r
i
g
h
t

n
o
t
i
c
e
s

o
r

t
e
r
m
s

o
f

u
s
e

w
h
i
c
h

t
h
e

P
u
b
l
i
s
h
e
r

m
a
y

p
o
s
t

o
n

t
h
e

A
r
t
i
c
l
e
.

I
t

i
s

n
o
t

p
e
r
m
i
t
t
e
d

t
o

f
r
a
m
e

o
r

u
s
e

f
r
a
m
i
n
g

t
e
c
h
n
i
q
u
e
s

t
o

e
n
c
l
o
s
e

a
n
y

t
r
a
d
e
m
a
r
k
,

l
o
g
o
,

o
r

o
t
h
e
r

p
r
o
p
r
i
e
t
a
r
y

t
i
o
n

o
f

t
h
e

P
u
b
l
i
s
h
e
r
.