Pathophysiology and Treatment Syok Septic in Pediatric

Pathophysiology and
Tre a t m e n t o f S e p t i c
Shock in Neonates
a, b
James L. Wynn, MD *, Hector R. Wong, MD
KEYWORDS
Neonate Sepsis Shock Treatment Pathophysiology
Sepsis or serious infection within the first 4 weeks of life kills more than 1 million
newborns globally every year.1 The attack rate for neonatal sepsis is variable (from
<1% to >35% of live births) based on gestational age and time of onset (early [<72
hours after birth] or late [>72 hours after birth]).2–5 Neonates with sepsis may present
in or progress to septic shock, exemplified initially by cardiovascular dysfunction
requiring fluid resuscitation or inotropic support.6 If the progression of infection cannot
be stopped, end-organ damage and death become much more likely. Although the
true incidence is not known, a recent retrospective cohort study of 3800 neonates
admitted to the neonatal intensive care unit (NICU) in a 6-year period reported septic
shock in 1.3% with an associated mortality peaking at 71% for extremely low birth
weight (ELBW) neonates less than 1000 g.7 There are few published data regarding
the pathophysiology of septic shock in neonates. Previous clinical investigations
into neonatal sepsis and shock have largely focused on diagnostic markers. Descrip-
tions of septic shock are predominantly case reports on very small numbers, mixed
populations with severe respiratory distress syndrome (RDS) and sepsis, or pediatric
studies that included neonates who were not evaluated as a separate group.8–24
DEFINITIONS OF THE SEPSIS CONTINUUM
In 2005, definitions for pediatric infection, systemic inflammatory response syndrome

(SIRS), sepsis, severe sepsis, septic shock, and organ dysfunction were suggested
that included term neonates (0–7 days), newborns (1 week to 1 month) and infants
(1 month to 1 year) (Tables 1 and 2).25 Working definitions for the sepsis continuum
specific for preterm neonates are needed to provide a uniform basis for clinicians
and researchers to study and diagnose severe sepsis in this particularly vulnerable
a
Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Duke University, 2424
Hock Plaza, Suite 504, DUMC Box 2739, Durham, NC 27710, USA
b
Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet
Avenue, Cincinnati, OH 45229, USA
* Corresponding author.
E-mail address: [email protected]
Clin Perinatol 37 (2010) 439–479

doi:10.1016/j.clp.2010.04.002 perinatology.theclinics.com
0095-5108/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
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Wynn & Wong
Table 1
Definition of systemic inflammatory response syndrome (SIRS), infection, sepsis, severe sepsis, and septic shock
Consensus Definitions Suggested Modifications for Premature Infants

SIRS SIRS
The presence of at least 2 of the following 4 criteria, 1 of which must be The presence of at least 2 of the following 4 criteria, 1 of which must be
abnormal temperature or leukocyte count: abnormal temperature or leukocyte count:
Corea temperature of >38.5 C or <36 C Core temperature of >38.0 Cb or <36 C
Tachycardia, defined as a mean heart rate >2SD more than normal Tachycardia, defined as a mean heart rate >2SD more than normal
for age in the absence of external stimulus, chronic drugs, or painful for age in the absence of external stimulus, chronic drugs, or painful
stimuli; or otherwise unexplained persistent increase in a 0.5- to 4-h stimuli; or otherwise unexplained persistent increase in a 0.5- to 4-h
time period OR for children <1 y old: bradycardia, defined as a mean time period OR bradycardia, defined as a mean heart rate <10th
heart rate <10th percentile for age in the absence of external vagal percentile for age in the absence of b-blocker drugs or congenital
stimulus, b-blocker drugs, or congenital heart disease; or otherwise heart diseasec; or otherwise unexplained persistent bradycardiad
unexplained persistent depression in a 0.5-h time period Mean respiratory rate >2SD more than normal for age or mechanical
Mean respiratory rate >2SD more than normal for age or mechanical ventilation for an acute process not related to underlying neuro-
ventilation for an acute process not related to underlying neuro- muscular disease or the receipt of general anesthesia
muscular disease or the receipt of general anesthesia Leukocyte count increased or decreased for age or >20% immature
Leukocyte count increased or decreased for age (not secondary to to total neutrophil ratioe or C-reactive protein >10 mg/dL
chemotherapy-induced leukopenia) or >10% immature neutrophils
Infection No change suggested
A suspected or proven (by positive culture, tissue stain, or polymerase
chain reaction test) infection caused by any pathogen OR a clinical
syndrome associated with a high probability of infection. Evidence of
infection includes positive findings on clinical examination, imaging,
or laboratory tests (eg, white blood cells in a normally sterile body
fluid, perforated viscus, chest radiograph consistent with pneumonia,
petechial or purpuric rash, or purpura fulminans)
Sepsis No change suggested
SIRS in the presence of or as a result of suspected or proven infection
Severe sepsis No change suggested
Sepsis plus 1 of the following: cardiovascular organ dysfunction OR ARDS
OR 2 or more other organ dysfunctions
Septic shock No change suggested
Sepsis and cardiovascular organ dysfunction
a
Core temperature must be measured by rectal, bladder, oral, or central catheter probe.
b
Neonatal fever is considered greater than 38 C.
c
External vagal stimulus use is uncommon in preterm infants.
d
Infrequent self-resolving bradycardic episodes can be common in premature neonates in the absence of sepsis.
e
More commonly accepted ratio is greater than 20% immature to total ratio and chemotherapy-induced leukopenia is uncommon in premature infants.
From Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr
Crit Care Med 2005;6(1):2–8; with permission.
Treatment of Septic Shock in Neonates

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Table 2
Definitions of organ dysfunction
Consensus Definitions of Organ Dysfunction25 Suggested Modifications for Premature Infants

Cardiovascular dysfunction Cardiovascular dysfunction
Despite administration of isotonic intravenous fluid bolus >40 Despite administration of isotonic intravenous fluid bolus >40 mL/kg in 1 h
mL/kg in 1 h (>10 ml/kg in infants <32 weeks)d
Decrease in BP (hypotension) <5th percentile for age or Decrease in BP (hypotension) <5th percentile for age or systolic BP
systolic BP >2SD less than normal for age >2SD less than normal for age or MAP <30 mm Hg with poor capillary
OR refill time (>4 s)e
Need for vasoactive drug to maintain BP in normal range OR
(dopamine >5 mg/kg/min or dobutamine, Need for vasoactive drug to maintain BP in normal range (dopamine
epinephrine, or norepinephrine at any dose) >5 mg/kg/min or dobutamine, or epinephrine at any dose)f
OR OR
Two of the following: Two of the following:
Unexplained metabolic acidosis: base deficit >5.0 mEq/L Unexplained metabolic acidosis: base deficit >5.0 mEq/L
Increased arterial lactate >2 times upper limit of normal Increased arterial lactate >2 times upper limit of normal
Oliguria: urine output <0.5 mL/kg/h Oliguria: urine output <0.5 mL/kg/h
Prolonged capillary refill >5 s Prolonged capillary refill >4 sg
Core to peripheral temperature gap >3 C Simultaneous measurement of core and peripheral temperature not
common in premature neonates
Pulmonarya Pulmonary
PaO2/FIO2 <300 in absence of cyanotic heart disease or Excessive oxygen should be limited to avoid complications including
preexisting lung disease retinopathy of prematurity
OR PaCO2 >65 torr or 20 mm Hg more than baseline PaCO2
PaCO2 >65 torr or 20 mm Hg more than baseline PaCO2 OR
OR Proven need for >50% FIO2 to maintain saturation >92% (88% for <32
Proven needb for >50% FIO2 to maintain saturation >92% weeks)
OR OR
Need for nonelective invasive or noninvasive mechanical Need for nonelective invasive or noninvasive mechanical ventilation
ventilationc
Neurologic Neurologic
Glasgow Coma Score >11 Acute change in mental statush
OR
Acute change in mental status with a decrease in
Glasgow Coma Score >3 points from abnormal baseline
Hematologic Hematologic
Platelet count <80,000/mm3 or a decline of 50% in platelet Platelet count <80,000/mm3 or a decline of 50% in platelet count from
count from highest value recorded in the past 3 days (for highest value recorded in the past 3 daysi
chronic hematology/oncology patients) OR
OR International normalized ratio >2
International normalized ratio >2
Renal Renal
Serum creatinine >2 times upper limit of normal for age or Serum creatinine >2 times upper limit of normal for age or 2-fold
2-fold increase in baseline creatinine increase in baseline creatinine
Hepatic Hepatic
Total bilirubin >4 mg/dL (not applicable for newborn) ALT 2 times upper limit of normal for agej or 50% increase over pa-
OR tient’s baselinek
ALT 2 times upper limit of normal for age

Abbreviations: ALT, alanine transaminase; BP, blood pressure.
a
ARDS must include a PaO2/FIO2 ratio %200 mm Hg, bilateral infiltrates, acute onset, and no evidence of left heart failure. Acute lung
injury is defined identically except the PaO2/FIO2 ratio must be R300 mm Hg.
b
Proven need assumes oxygen requirement was tested by decreasing flow with subsequent increase in flow if required.
c
In postoperative patients, this requirement can be met if the patient has developed an acute inflammatory or infectious process in the
lungs that prevents them from being extubated.
d
Rapid large volume expansion can be associated with intraventricular hemorrhage.
e
30 mm Hg suggested as minimum MAP.
f
Norepinephrine not commonly used in premature neonates.
g
Greater than 4 s may reflect a low systemic blood flow.264
h
Glasgow Coma Score not applicable to term or preterm neonates.
i
Neonates not frequently chronic hematology-oncology patients.
j
Indirect hyperbilirubinemia is common in newborns.
k
Transaminases are commonly increased in preterm neonates on long-term intravenous hyperalimentation.
From Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics.
Pediatr Crit Care Med 2005;6(1):2–8; with permission.
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population. The authors have proposed modifications to the consensus definitions to

incorporate preterm infants that are also presented in Tables 1 and 2.
Why have definitions of sepsis and septic shock not been established for preterm
neonates? These patients present diagnostic challenges that are clouded by immatu-
rity of organ systems and transitional physiology. For example, normal blood pressure
values for gestational and postnatal age have not been established, particularly in
the very low birth weight neonate (VLBW, <1500 g), largely because blood pressure
alone cannot identify abnormal cardiac output, organ perfusion, and oxygen
delivery.26 In the absence of normative values, it is nearly impossible to establish
parameters that are associated with poor outcome. Perhaps the most obvious limita-
tion is the differences in monitoring capabilities between the preterm neonate and
older, physically larger patients. For example, pulmonary artery catheterization may
be used in children or adults to monitor the course of septic shock, but this is not
feasible in small neonates. For these reasons, the hemodynamic response to septic
shock and optimum clinical interventions in preterm neonates are not well understood.
RISK FACTORS FOR DEVELOPMENT OF NEONATAL SEPTIC SHOCK
Risk factors for a neonate developing sepsis have been well described. Although risk
factors for septic shock overlap those for sepsis, specific antenatal and postnatal risks
for the development of neonatal septic shock have not been described in detail.
Maternal factors contributing to the risk of neonatal sepsis are shown in Box 1 and
include prematurity, low birth weight, rectovaginal colonization with group B strepto-
coccus (GBS), prolonged rupture of membranes, maternal intrapartum fever, and cho-
rioamnionitis.2,3,27–33
Factors in the postnatal period associated with an increased risk of sepsis or septic
shock include male gender, birth weight less than 1000 g, hypogammaglobulinemia,
intravenous alimentation, central venous catheters, use of steroids or drugs that
decrease gastric acid acidity, and prolonged duration of mechanical ventilation. The
development of severe necrotizing enterocolitis (NEC) is also associated with severe
sepsis, shock, multi-organ system failure, and death.34,35 Genetic evaluations in chil-
dren and adults have identified several polymorphisms in cytokines and their recep-
tors as well as other host defense proteins that may either increase or decrease risk
for sepsis or poor outcome from sepsis.36–41 However, gene polymorphism studies
in neonates have not yielded consistent results because of relatively small sample
sizes and a general lack of formal prospective validation studies.42–56
MICROBIOLOGY OF SEPSIS AND SEPTIC SHOCK IN NEONATES
Several pathogens have been associated with sepsis in the neonatal period. The
predominant agents are bacterial, but viruses including herpes simplex and enterovi-
ruses have been associated with fulminant neonatal sepsis with high mortality.57–59 In
1 study, gram-negative infection accounted for 38% of cases of septic shock and
62.5% of sepsis mortality.7 These results are similar to those from a previous study
that showed gram-negative infection was associated with 69% of cases of fulminant
septic shock (death within 48 hours).60 Gram-positive causes of sepsis are dominated
by GBS and coagulase-negative staphylococcus (CoNS).3,61 Although lethality and
shock from GBS have been well described, mortality associated with CoNS is
extremely low3,4 and septic shock is rare.60 Fungi (primarily Candida albicans) may
also lead to fulminant neonatal sepsis and predominantly affect ELBW infants.3,62,63
Studies of neonatal sepsis are confounded by the limitations of sensitivity of the
current diagnostic gold standard blood culture. Sample volume constraints in
Treatment of Septic Shock in Neonates 445
Box 1
Risk factors for the development of neonatal sepsis and septic shock
Maternal factors
Maternal age (>30 years)
Lack of prenatal care
High gravidity
Premature or prolonged (>6 hours) rupture of membrane (PROM)
Meconium-stained amniotic fluid
Foul-smelling amniotic fluid
Premature labor
Chorioamnionitis
GBS rectovaginal colonization
Urinary tract infection
Intrapartum fever
Multiple courses of prenatal steroids or tocolytic agents
Prolonged duration of internal monitoring
Delivery room
Prematurity <37 weeks
Low birth weight %2500 g
5-minute Apgar score <5
Resuscitation in delivery room
Male gender
Neonatal
Vascular catheterization
Mechanical ventilation (continuous positive airway pressure or endotracheal tube)
Lack of enteral feeding
Gastrointestinal tract pathology
Medications (H2 blockers, proton pump inhibitors; postnatal steroids, cephalosporins)
Neutropenia
Decreased baseline serum IgG concentrations
Hyperalimentation
Prolonged hospital stay
Delay in time to regain birth weight
newborns may undermine the identification of organisms causing shock, particularly in

preterm infants.64 For this reason, many studies combine the entities culture-proven
sepsis and clinical sepsis (cultures negative but strong clinical suspicion leading to
long-term antibiotic treatment). Improved techniques such as molecular diagnostics,
see the article by Benitz elsewhere in this issue for further exploration of this topic, may
help to delineate which patients with clinical sepsis truly have sepsis versus other
causes of clinical deterioration.
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PATHOPHYSIOLOGY OF SEPSIS AND SHOCK: MOLECULAR AND CELLULAR EVENTS

Molecular Signaling: Pattern Recognition Receptors, Pathogen-associated Molecular
Patterns, and Damage- or Danger-associated Molecular Patterns
Pathogen recognition by local immune sentinel cells is the first step toward the devel-
opment of an immune response once local barrier function has been compromised
(Fig. 1). Recognition is initiated via the activation of pattern recognition receptors
(PRRs)65 including Toll-like receptors (TLRs). There are 10 known TLRs in humans,
and each receptor has a specific molecular activation trigger.66,67 TLRs, present on
and within multiple cell types, recognize extracellular and intracellular pathogens by
their signature microbial products known as pathogen-associated molecular patterns
(PAMPs). Lipopolysaccharide (LPS, endotoxin) on gram-negative bacteria is the
prototypic PAMP and a key mediator of systemic inflammation, septic shock, and
multi-organ failure and death.68 LPS signals primarily through TLR4 in conjunction
with the cell surface adaptor proteins CD14 and MD-2.65 Gram-positive bacterial
PAMPS such as lipoteichoic acid signal primarily through TLR2, whereas viral PAMPS
such as double-stranded RNA signal through TLR3. Microorganisms often stimulate
more than 1 TLR simultaneously allowing for initiation of a pathogen-specific host
response.67,69 Ligand-receptor binding results in downstream production of cytokines
and chemokines as well as activation of other antimicrobial effector mechanisms.66
Intracellular non-TLR PRRs include NOD-like receptors (NLRs) and RIG-like recep-
tors (RLRs). Nucleotide-binding oligomerization domain (an NLR) detects peptido-
glycan of gram-positive bacteria in the cytosol, and retinoic acid–inducible protein I
(RIG-I) detects viral double-stranded RNA and induces type I interferon production.67
Once engaged by pathogens, these PRRs initiate an immune response including the
production of proinflammatory cytokines via mitogen-activated protein kinase (MAPK)
and the transcription factor nuclear factor kB (NF-kB). To date, RLR and NLR function
have not been examined in neonates with sepsis.
Because TLRs play an essential role in recognition and response to pathogens,
alterations in their expression, structure, signaling pathways, and function can have
consequences to host defense. Polymorphisms or mutations in TLRs are associated
with increased risk for infection in adults70–73 and in children74–76 but are less well
characterized in neonates. Upregulation of TLR2 and TLR4 mRNA in leukocytes of
neonates occurs during gram-positive and gram-negative infection, respectively,
across gestational ages.77 Dysregulation or overexpression of TLR4 is involved in
the development of necrotizing enterocolitis in experimental animal models,78 demon-
strating the importance of TLRs in the initial immune response to pathogens and their
role in neonatal sepsis and septic shock. Mutations have been identified in NLRs that
are involved in the pathogenesis of neonatal-onset multisystem inflammatory disease
(cryopyrin).79 Investigation for mutations in specific domains of NLRs has been per-
formed to identify causes of abnormal inflammatory signaling leading to NEC, but
no associations have been identified.80 RLR mutations have been identified but are
of unknown clinical significance.81 The role that intracellular PRR play is of particular
interest with respect to defense against Listeria monocytogenes, a pathogen particu-
larly virulent in neonates, which can be recognized by NLRs.82
Mutations or decreased expression of costimulatory molecules necessary for TLR
activation are also associated with an increased risk for infection. For example, the
lipopolysaccharide (LPS, endotoxin) coreceptor CD14 and LPS-binding protein
(LBP, which binds intravascular LPS and facilitates its attachment to CD14) are
both increased during neonatal sepsis.83–85 Genetic variations in these proteins
have been associated with increased risk for sepsis in adults.47,49,50 Gene
Fig. 1. Activation of sentinel immune cells. Sentinel cells (e.g. monocyte, macrophage) sense pathogens via Pathogen-associated molecular patterns
(PAMPs) or damage-/danger-associated molecular patterns (DAMPs) binding to PRRs. PRRs include Toll-like receptors (TLRs), Rig-1-like receptors
(RLRs), and NOD-like receptors (NLRs). PAMPs include lipopolysaccharide (LPS), lipotechoic acid (LTA), DNA, and RNA. DAMPs can also be sensed
through TLRs and include uric acid (UA), heat shock proteins (Hsp), and HMGB-1. Signaling occurs through a series of second messengers and results
in transcription and translation of cytokines and chemokines that amplify the immune response.
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polymorphisms in myeloid differentiation-2 (MD-2), a small protein involved in LPS

signaling through TLR4, increase the risk for organ dysfunction and sepsis in adults86
but the significance in neonates is unknown. Polymorphisms in select cytokines (IL-6
and IL-10) or their receptors (IL-4ra53), and constituents of their signaling pathways,
may be associated with increased risk of infection,42,43,46,51 although there is not
complete agreement on these findings.44,52,54 Polymorphisms in post-TLR activation
intracellular signaling molecules including myeloid differentiation factor 88 (MyD88),87
IL-1 receptor–associated kinase 4 (IRAK-4),88 and NF-kB essential modulator
(NEMO)89 are associated with invasive bacterial infection in older populations. These
genetic factors predisposing to sepsis are likely just the tip of the iceberg because
evaluation of intracellular second messenger inflammatory signaling systems is a rela-
tively new and active area of research.
In addition to being activated by PAMPs, TLRs can be activated by damage- or
danger-associated molecular patterns (DAMPs), such as intracellular proteins or
mediators released by dying or damaged cells (see Fig. 1). High-mobility group
box-1 (HMGB-1), an important DAMP, is involved in the progression of sepsis to septic
shock.68,90 HMGB-1 is produced by macrophages or endothelial cells stimulated with
LPS or TNF-a and signals through TLR2, TLR4, and receptor for advanced glycation
end products (RAGE).91 Important actions of HMGB-1 include cytokine production,
activation of coagulation, and neutrophil recruitment.90,92 HMGB-1 mediates disrup-
tion of epithelial junctions within the gut via the induction of reactive nitrogen interme-
diates (RNI) leading to increased bacterial translocation.93 The role of HMGB-1 and
RAGE signaling in septic shock in human neonates has not been well studied, but
has been linked to the pathophysiology of NEC in a preclinical model.94
Other DAMPs including heat shock proteins (Hsps) and uric acid may also
contribute to the pathophysiology of septic shock. Hsps activate proinflammatory
signaling through TLRs, regulate neutrophil function, are immune adjuvants, and
are increased in adults and children with sepsis.95 Increased Hsp60 and Hsp70
measured within 24 hours of pediatric intensive care unit admission was associated
with pediatric septic shock and there was a strong trend toward a significant asso-
ciation with death.96,97 Hsp production in septic neonates has not been evaluated.
Uric acid can increase cytokine production, polymorphonuclear leukocyte (PMN)
recruitment, and dendritic cell stimulation,98 and may also serve as an antioxidant.99
Uric acid is reduced in the serum of septic neonates compared with control
neonates.100 The importance of DAMPs in neonatal sepsis and shock has yet to
be determined.
Cytokines, Chemokines, and Adhesion Molecules
Following PRR stimulation, production of cytokines and chemokines results in ampli-
fication of the innate response directed at the invading organisms (see Fig. 1).
Increases of proinflammatory cytokines during sepsis and septic shock have been
identified including interleukin (IL)-1b, IL-6, IL-8, IL-12, IL-18, interferon gamma
(IFN-g), and tumor necrosis factor-alpha (TNF-a).101 Compared with septic adults,
septic neonates produce less IL-1b, TNF-a, IFN-g, and IL-12.102–107 The decreased
cytokine production is due in part to decreased production of important intracellular
mediators of TLR signaling including myeloid differentiation factor 88 (MyD88), inter-
feron regulatory factor 5 (IRF5), and p38, which exhibit gestational age-specific dimi-
nution.108 In a recent comprehensive study (>140 analytes) of serum from neonates
evaluated for late-onset sepsis, IL-18 emerged as a predictive biomarker to differen-
tiate infected from noninfected neonates,109 similar to data from adults with sepsis.110
IL-18 reduces PMN apoptosis,111 potentiates IFN-g production,112 and induces
production of TNF-a, IL-1b, and IL-8.113 IL-18 primes PMNs for degranulation with
production of reactive oxygen intermediates (ROI) on subsequent stimulation.114 Dys-
regulation of many of these functions linked to IL-18 are seen in sepsis and septic
shock.
Proinflammatory cytokine production leads to activation of endothelial cells
including increased expression of cell adhesion molecules (CAMs) that facilitate leuko-
cyte recruitment and diapedesis (Fig. 2). Upregulation of CAMs (soluble ICAM, VCAM,
L-, P-, and E-selectins, and CD11b/CD18) during sepsis facilitates rolling and extra-
vascular migration of leukocytes.115–118 Decreased neonatal PMN and monocyte L-
selectin and MAC-1 expression impair accumulation at sites of inflammation.119,120
Chemokine gradients produced by endothelial cells and local macrophages are
necessary in addition to CAM interactions for effective and specific leukocyte attrac-
tion and accumulation. Without adequate leukocyte recruitment, there is increased
risk for propagation from a local to a systemic infection. Although poor cellular chemo-
taxis in the neonate has been observed, it is not likely a result of reduced serum
concentrations of chemokines.121 Suboptimal chemotaxis may be related to other
mechanisms such as poor complement receptor upregulation following stimula-
tion,122 deficiencies in another downstream signaling process,123 or inhibition by
bacterial products.124
A wide variety of chemokines are increased during sepsis including IP-10, CCL5
(RANTES), MCP-1, MIP-1, and IL-8.125 Other chemoattractive molecules are also
increased in sepsis including complement proteins C3a and C5a, host defense
proteins or peptides such as cathelicidins and defensins, and components of invading
bacteria themselves.101,109 The role of chemoattractive substances in the pathogen-
esis of severe sepsis is highlighted by recent studies showing IL-8 can be used as
a stratifying factor for survival in children126 and C5a is implicated in sepsis-associated
organ dysfunction in adults.68 Studies of chemokines in neonates with sepsis have
shown that IP-10 is a sensitive early marker of infection,125 and decreased levels of
CCL5 help predict development of disseminated intravascular coagulation (DIC).127
Antiinflammatory Response
If inflammatory homeostasis is not restored, the consequences can include SIRS,
which is associated with multi-organ failure and death (Fig. 3). The careful interplay
between anti- and proinflammatory stimuli serves to govern the immune response
to allow local pathogen containment but prevent systemic activation leading to
excessive inflammatory damage through SIRS.128 Near simultaneous increases in
antiinflammatory cytokine production occur during infection, with TGF-b, IL-4, IL-10,
IL-11, and IL-13 countering the actions of proinflammatory cytokines (see
Fig. 2).101,129,130 These mediators blunt the activation of phagocytic cells, block fever,
modify coagulation factor expression, and decrease production of ROI/RNI, NO, and
other vasoactive mediators.131–135 In addition to the antiinflammatory cytokines,
specific soluble cytokines and receptor antagonists produced during sepsis modulate
proinflammatory mediator action, including TNFR2 (which regulates the concentration
of TNF-a), sIL-6R, sIL2, and IL-1ra. Increases in these inhibitors have been docu-
mented in neonatal sepsis with resolution following effective treatment.130,136,137
The role of these regulatory cytokine inhibitors in the immune response to neonatal
sepsis and septic shock has been incompletely characterized. Soluble RAGE (sRAGE)
competes with cell-bound RAGE for the binding of HMGB-1 and other RAGE
ligands,138 reduces the intensity of the inflammatory response, and is increased in
adults during sepsis.139 In addition, administration of exogenous sRAGE improved
survival and reduced inflammation in infected adult rodents.140
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Fig. 2. Cellular recruitment and endothelial activation following pathogen detection. Pathogen-stimulated tissue/blood monocytes, dendritic cells (DC),
and macrophages release proinflammatory cytokines that activate the surrounding endothelium. Endothelial activation results in upregulation of CAM,
production of chemokines and vasoactive substances, activation of complement, and development of a procoagulant state. Recruitment of PMNs occurs
along the chemokine gradient surrounding the area of inflammation. Antiinflammatory cytokines counter the actions of proinflammatory cytokines to
prevent excessive cellular activation and recruitment that can result in tissue damage and systemic inflammation. Endothelium can be damaged when
PMNs release ROI. LTE, leukotriene; NO, nitric oxide; PMN, neutrophil.
Fig. 3. Pathophysiology of neonatal sepsis and septic shock. AEM, antimicrobial effector
mechanisms; CV, cardiovascular; DAMP, danger-/damage-associated molecular patterns;
DIC, disseminated intravascular coagulation; PRR, pattern recognition receptors; SIRS,
systemic inflammatory response syndrome.
Role of Complement in Host Defense and Sepsis Pathophysiology

Complement is an extraordinarily important component of early innate immunity that
facilitates killing of bacteria through opsonization and direct microbicidal activity.
Complement components also possess chemotactic or anaphylactic activity that
increases leukocyte aggregation and local vascular permeability at the site of invasion.
In addition, complement components reciprocally activate several other important
processes such as coagulation, proinflammatory cytokine production, and leukocyte
activation (see Fig. 3).68 Dysregulation of complement activation may participate in the
untoward effects seen in neonates with severe sepsis or septic shock. Neonates, partic-
ularly the very premature, exhibit decreased basal levels of complement proteins and
function for the alternative and classic pathways.141,142 In addition, complement-medi-
ated opsonization is poor in premature neonates and limited in term neonates.143,144
Complement-mediated activation of leukocytes during sepsis occurs via up-regulated
cell surface receptors (CR1 [CD35], CR3 [Mac-1, CD11b/CD18]).145,146 For example,
stimulation of CR1 and C5aR, the receptors for C3b and C5a, respectively, facilitate
opsonization (CR1-C3b), redistribution of blood flow, increased inflammation, platelet
aggregation, and release of ROI (C5a-C5aR).147,148 In addition, activation of the multi-
functional CR3 facilitates leukocyte adhesion, phagocytosis, migration and activation,
as well as recognition of a broad range of microbial products.149 Upregulation of CR3
on neutrophils following stimulation is blunted in neonates compared with adults and is
believed to play a significant role in diminished chemotaxis and transmigration.122 Similar
to the effects of TLR stimulation, C5a-mediated local leukocyte activation also results in
increased cytokine production with subsequent upregulation of adhesion molecules on
452 Wynn & Wong
vascular endothelium allowing for increased cell recruitment to the site of infection.150
Deficiencies in C5aR found in term neonates compared with adults may limit the ability
to respond to C5a and therefore increase the likelihood of infection.151 The expression
of C5aR on neutrophils of preterm infants has not been quantified.
Complement regulatory proteins modify the effects of complement and prevent potential
damage caused by over activation. In particular, CD59 blocks formation of C9 polymeriza-
tion and target lysis, CD55 destabilizes CR1 and C3 and C5 convertases, and CD35 (CR1)
accelerates the deactivation of C3b.152 The role of these regulators in the neonatal
response to sepsis and septic shock is presently unknown. Dysregulation of complement
activation can lead to a vicious activation cycle that results in excessive cellular stimulation,
cytokine production, endothelial cell activation, and local tissue damage. Dysregulation
likely contributes to the development of SIRS and shock (see Fig. 3).153
Data in adults link increased C5a levels with multiple facets of sepsis-associated
pathology such as the development of DIC via increased tissue factor expression,
cardiomyopathy, increased proinflammatory cytokine levels and the development of
SIRS, adrenal insufficiency, and neutrophil dysfunction.68 Whether or not C5a or other
complement proteins play a role in the development of these phenomena in septic
neonates remains to be determined.
Other Host Defense Proteins, Acute Phase Reactants, and Opsonins

In addition to the initial inflammatory response and complement activation following path-
ogen recognition, the presence of microbes result in increases in other innate proteins
that possess valuable immune function.154 These components serve to reduce bacterial
load and include collectins (eg, surfactant proteins A and D), lactoferrin, cathelicidins,
bacteriocidal permeability increasing protein (BPI), and phospholipase A2.155 Acute
phase reactant proteins such as CRP (opsonin), haptoglobin and lactoferrin (reduce avail-
able iron/antimicrobial peptide-lactoferricin), serum amyloid A (cellular recruitment), pro-
calcitonin (unknown function), and others increase during sepsis and provide useful
ancillary immune functions.101 Neutrophils from term neonates are deficient in BPI,
potentially contributing to the increased risk for infection.156 Polymorphisms in BPI
increase the risk for gram-negative sepsis in children,157 although the effect of these poly-
morphisms in neonates is unknown. Sepsis results in an increase in other serum compo-
nents with opsoninic function including fibronectin and natural antibodies (predominantly
IgM) produced by circulating B1 lymphocytes.158–160 Despite these increases, neonatal
plasma has significantly impaired opsonizing activity compared with adults that
increases the likelihood of progression to systemic infection.161
Role of Dysregulated Coagulation in Severe Sepsis

Development of a procoagulant state in the microvasculature surrounding a focal site
of infection is a natural host defense mechanism, trapping invading pathogens and
preventing further dissemination (see Fig. 2). However, like the inflammatory
response, if the procoagulant response to infection escalates unchecked, it can
lead to DIC resulting in severe tissue and organ damage (see Fig. 3).162 Neonates
with early increased ratios of serum inflammatory to antiinflammatory cytokines during
sepsis have an increased risk of developing DIC.127 This finding is consistent with the
increased serum levels of IL-659 and high frequency of DIC seen with disseminated
HSV infection.163
Initiation of coagulation cascades during infection may begin with activated
neutrophils, monocytes, or endothelium, which express increased tissue factor
apoprotein.164,165Activation of tissue factor leads to increased clotting proteins
including thrombin-antithrombin complex (TAT), plasminogen activator inhibitor
(PAI), and plasmin-a2-antiplasmin complex.166 There is also a shift toward inactivation

of protein S and depletion of anticoagulant proteins including antithrombin III (ATIII)
and protein C.167,168 A small study reported that low protein C levels in preterm
neonates with sepsis predicted death.169 In DIC, platelets are consumed in micro-
thrombi creating a state of thrombocytopenia; a common finding in infected
neonates.170 The longest duration and lowest initial and nadir platelet levels have
been noted during neonatal gram-negative and fungal infections,171 and this thrombo-
cytopenia may or may not be associated with DIC. Decreased platelet function in
preterm neonates with sepsis further increases the risk for bleeding.172 In ELBW
infants, platelets are hyporeactive for the first few days after birth, complicating the
ability of the immune system to contain a microbiological threat and increasing the
risk for hemorrhage.173
Role of the Neutrophil in Septic Shock

The most important means of early innate cellular defense against bacterial invasion in
neonates is the neutrophil or PMN. Neonatal PMNs exhibit quantitative and qualitative
deficits compared with adult cells.174,175 A complete discussion of these deficits is
presented elsewhere in this issue. Three aspects of PMN function with particular rele-
vance to neonatal severe sepsis and septic shock deserve brief mention: neutropenia,
decreased deformability, and delayed apoptosis.
Rapid depletion of neonatal marrow PMN reserves during infection176 can lead to
neutropenia with consequent impaired antimicrobial defenses and significantly
increased risk for death.177 Neutropenia is particularly common in gram-negative
sepsis in neonates.178 Release of immature neutrophil forms (bands), which have
even greater dysfunction than mature neonatal neutrophils,179 can further predispose
to adverse outcomes. PMN respiratory burst activity is also suppressed during sepsis
and may contribute to poor microbicidal activity.180–182
PMNs of neonates have reduced deformability compared with PMNs of adults,
which, combined with the low blood pressure/flow state associated with septic shock,
increases the risk of microvascular occlusion.174,183 Irreversible aggregation of
newborn PMNs in the vascular space leads to decreased diapedesis, rapid depletion
of bone marrow reserves, vascular crowding,183 and increased likelihood of compro-
mised tissue perfusion184 leading to organ dysfunction.
Neutrophils, although essential for combating pathogens, can also cause significant
tissue damage and thus play a role in progression from sepsis to multi-organ system
dysfunction. Reactive oxygen and nitrogen intermediates and proteolytic enzymes
produced by PMNs can be released extracellularly, via activation of membrane-asso-
ciated NADPH oxidase. Extracellular release of these reactive intermediates and
enzymes can lead to destruction of nonphagocytized bacteria but can also cause local
tissue destruction.185 Increased levels of neutrophil elastase as well as the neutrophil
activators urokinase plasminogen activator, and urokinase plasminogen activator
receptor have been described in infected neonates.109 Compared with adult PMNs,
neonatal PMNs exhibit delayed apoptosis186,187 as well as sustained capacity for acti-
vation (CD11b upregulation) and cytotoxic function (ROI production) that contributes
to tissue damage.188 Neutrophil-mediated damage may include endothelial and lung
injury (including surfactant inactivation189) (see Fig. 2) in addition to other organ
dysfunction (see Fig. 3).
Other Innate Cellular Contributions to Sepsis

Many other cells besides neutrophils are involved in the development of an immune
response to infection, but the role that these cells play in the development of neonatal
454 Wynn & Wong
septic shock is incompletely characterized. Monocytes, macrophages, and dendritic

cells amplify cellular recruitment through production of inflammatory mediators,
phagocytosis and killing of pathogens, and antigen presentation to cells of the adap-
tive immune system. Important substances produced by stimulated monocytes that
may contribute to septic shock include complement components, cytokines (pro-
and antiinflammatory), coagulation factors, and extracellular matrix proteins (see
Fig. 1).190 The role of NK cells in neonatal bacterial sepsis is incompletely defined.
Despite activation,191 NK cytotoxicity is deficient in sepsis and recurrent infec-
tions.192,193 Circulating NK cells are decreased with neonatal shock.194 Further studies
are necessary to more clearly define the role of NK cells in neonatal sepsis and shock.
Mast cells play a role in the response to pathogen invasion via production of hista-
mines (which promote vasodilation and upregulation of P-selectin) and cytokines
(TNF-a, IL-1a/b), and by promoting neutrophil recruitment, direct bacterial phagocy-
tosis, and antigen presentation.195 The production of histamine by mast cells likely
contributes to the vasodilation associated with septic shock. Like eosinophils and
PMNs, mast cells of adults are also capable of bacterial killing via generation of extra-
cellular traps, like the neutrophil extracellular traps described previously.196 This
means of immune protection has not been investigated in neonates. Mast cells may
also alter adaptive immune function by patterning the TH2 immunosuppressive pheno-
type seen in the neonate and therefore contribute to the increased risk of infection.
Immature dendritic cells exposed to histamine and LPS during maturation exhibit
altered T-cell polarizing activity with predominance of TH2 phenotype via increased
production of IL-10 and decreased production of IL-12.197 Furthermore, compared
with mast cells of adults198 stimulated mast cells from neonates secrete significantly
more histamine, which may contribute to vasodilation and the development of
shock.199
Role of the Endothelium and Vasoactive Mediators in Septic Shock

Vascular endothelium has not historically been considered part of the innate cellular
defenses, but recent studies have shown the importance of these sentinel cells in
the early recognition and containment of microbial invasion. The endothelium can
be a 2-edged sword, however, as excessive activation can lead to vascular dilation
and leak, which are a driving forces behind the severe consequences of septic shock
(see Fig. 3).124,200
Expression of TLRs allows endothelium to become activated in the presence of
microbial components, leading to production of cytokines, chemokines, and adhesion
molecules that attract circulating leukocytes and facilitate adherence.124 Vasoactive
substances released from activated leukocytes, platelets, and endothelial cells are
shown in Fig. 2 and include platelet-activating factor (PAF), thromboxane (TBX), leuko-
trienes (LTE), nitric oxide (NO), histamine, bradykinin, and prostaglandins (PGE).201,202
Activated PMNs produce phospholipase A2 (PLA2), which is increased in the serum of
neonates with sepsis203 and leads to generation of vasoactive substances including
PGE and LTE. Thromboxane produced by activated platelets and endothelin
produced by activated endothelium204 are potent vasoconstrictors that participate
in the development of pulmonary hypertension (PPHN).205–208 Systemic overproduc-
tion of cytokines and vasoactive substances is associated with circulatory alterations
and organ failure seen in severe sepsis and septic shock (see Fig. 3).25,209–212 For
example, the balance of NO and endothelin-1 (ET-1) may be disrupted with endothelial
damage, favoring the constrictive effects of ET-1 leading to ischemia and injury. This
may explain in part why NO inhibitors increased mortality in adults with septic
shock.213
Activated or damaged endothelium establishes a prothrombotic environment that

can result in local microvascular occlusion165 or progress to DIC.214 Endothelial cell
apoptosis, detachment from the lamina, and alterations in vascular tone combine to
promote capillary leak of proteins and fluid leading to hypovolemia and shock.215
The role of endothelial activation during sepsis and septic shock in neonates, partic-
ularly in the premature infant, has not been thoroughly investigated. Adhesion mole-
cules E- and P-selectin, expressed and secreted by activated endothelium, are
increased in the serum of septic neonates109 and likely reflect significant endothelial
activation. Toxins from GBS have been shown to damage pulmonary endothelium216
and likely participate in pulmonary complications associated with GBS pneumonia
such as acute respiratory distress syndrome (ARDS) and PPHN.217 Using transgenic
mice, it was recently shown that pulmonary endothelial cells sense blood-borne
bacteria and their products,124 whereas alveolar macrophages patrol the airspaces
for pathogens.218 These data help to explain in part the occurrence of ARDS and
PPHN associated with severe sepsis in the absence of a primary pulmonary infectious
focus.
PATHOPHYSIOLOGY OF SEPTIC SHOCK: CARDIOVASCULAR AND OTHER

ORGAN EFFECTS
Cardiovascular Effects
The hemodynamic response to sepsis has been less well characterized in premature
and term neonates compared with children and adults, and the hemodynamic abnor-
malities are significantly more variable.219 Factors contributing to developmental
differences in hemodynamic responses include altered structure and function of car-
diomyocytes, limited ability to increase stroke volume and contractility, and contribu-
tions of the transition from fetal to neonatal circulation.220 A patent ductus arteriosus
(PDA) and the presence of PPHN are significant modifying factors for the manage-
ment of hypotension and hypoxia. In preterm infants with a PDA, aggressive volume
administration to treat low blood pressure may lead to fluid overload, pulmonary
edema, or heart failure. In the term infant with severe PPHN, on the other hand,
aggressive volume and vasoactive medication administration to maintain a normal
blood pressure may be beneficial by reducing right to left shunting and improving
oxygenation. Although cardiomyopathy and heart failure may occasionally compli-
cate sepsis in neonates, underlying coronary artery disease or other chronic cardiac
conditions often present in septic adults do not complicate septic shock in the
neonate.
In adults, septic shock is most commonly characterized by reduced systemic
vascular resistance and increased cardiac index.221 In children, a nonhyperdynamic
state with reduced cardiac output and increased systemic vascular resistance is
most common.219,222–224 The hemodynamic presentation in neonates is much more
variable219 and complicated by an unclear association between a normal blood pres-
sure and adequate systemic blood flow.225,226 Abnormal peripheral vasoregulation
with or with out myocardial dysfunction are the primary mechanisms for the hypoten-
sion accompanying septic shock in the neonate.227 Neonates with sepsis may present
with tachycardia, poor perfusion and normal blood pressure (high systemic vascular
resistance) or with hypotension and either adequate perfusion (warm shock, vasodila-
tion) or inadequate perfusion (cold shock, vasoconstriction). These distinctions may
be important for directing appropriate therapy to restore tissue perfusion, as dis-
cussed later.
456 Wynn & Wong
Multi-organ Dysfunction Syndrome

Septic shock that leads to multi-organ failure or MODS carries a dismal prognosis.
Poor cardiac output and microcirculatory failure, sometimes combined with forma-
tion of microthrombi and DIC, can lead to compromised perfusion to the
kidney,228,229 liver,230 gut,231 and central nervous system232 (see
Fig. 3).59,210,233,234 Recent studies suggest that the mechanism of organ failure in
sepsis may relate to decreased oxygen use associated with mitochondrial dysfunc-
tion rather than or in addition to poor oxygen delivery to tissues.235,236 Many other
organ systems can be compromised in the setting of septic shock. Pulmonary
complications include ARDS,237 secondary surfactant deficiency,238 pulmonary
edema, pneumonia,23 and PPHN.220,237 Endocrine abnormalities may include
adrenal insufficiency associated with refractory hypotension239 and altered thyroid
function.240 Lymphocyte loss secondary to thymic involution and splenocyte
apoptosis may also be present and may lead to a state of immune compromise
following the acute phase of sepsis.241–246 The importance of this finding has been
shown in infected adults,247–249 but the effect in neonates in whom adaptive immune
function is immature is unknown. In a transgenic mouse model, neonatal animals
lacking an adaptive immune system showed no difference in survival with polymicro-
bial sepsis compared with wild-type controls. This is in stark contrast to findings in
adult mice.250 Hematologic findings during severe sepsis may include thrombocyto-
penia,170 neutropenia,177 and coagulation abnormalities including DIC.162 Sepsis can
lead to metabolic and nutritional consequences. Increased energy expenditure and
oxygen consumption251 and decreased mitochondrial oxidative function precipitated
by hypoxia and the presence of damaging free radicals may lead to impaired growth
and energy failure.252,253 The importance of providing optimum nutritional support in
septic adults and children is increasingly recognized and should also be considered
in septic neonates.
TREATMENT OF SEPSIS AND SEPTIC SHOCK

Initial Resuscitation
Treatment guidelines for the management of severe sepsis and septic shock have
been established for adults,254 children, and term neonates,255 but no such consensus
guidelines exist for preterm neonates. The authors have attempted to incorporate the
special circumstances related to premature physiology into the framework of treat-
ment guidelines for term infants (Fig. 4). Development, testing, and acceptance of
consensus guidelines for classification and management of preterm neonates with
sepsis and septic shock are urgently needed to more systematically assess, diagnose,
and treat these conditions.
As with all emergencies in neonatology, management of septic shock begins with
airway, breathing, and circulation. Septic neonates often present with apnea or
severe respiratory distress and may require intubation.3,4 Following establishment
of a secure airway and maintenance of lung volume for adequate gas exchange,
administration of antibiotics and continuing assessment for cardiovascular dysfunc-
tion is critical. Shortly after birth, an umbilical vein catheter can be used for resus-
citation but beyond this time, other peripheral or central venous access is
essential for volume resuscitation, antibiotic administration, and pressor therapy.
Timely therapy, including rapid restoration of adequate tissue perfusion, has been
shown to improve outcomes in adults and children with sepsis, and should be the
goal in neonates.
Fig. 4. American College of Critical Care Medicine consensus guidelines for treatment of shock in term infants and suggested modifications for preterm
infants. CI, cardiac index; CVP, central venous pressure; MAP, mean arterial pressure; NRP, Neonatal Resuscitation Program; PDA, patent ductus arterio-
sus; PPHN, persistent pulmonary hypertension of the newborn; RDS, respiratory distress syndrome; ScvO2, central venous oxygen saturation; SVC, supe-
rior vena cava; VLBW, very low birth weight. (From Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support of
pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009 Feb;37:666–88; with
permission.)
457
458 Wynn & Wong
Therapeutic Endpoints
In the absence of widely available or well-tested methods for quantifying hemody-
namic compromise in septic shock in neonates, clinicians generally rely on vital
signs and physical examination for decisions about therapy. Although mean arterial
pressure (MAP) may not reflect systemic blood flow, monitoring blood pressure and
other measures such as capillary refill time and urine output provide indirect infor-
mation on the adequacy of organ blood flow. Suggestions for cardiovascular thera-
peutic end points in term neonates include a capillary refill time of less than 2
seconds, normal pulses without differential between peripheral and central pulses,
warm extremities, urine output greater than 1 ml/kg/h, low serum lactate, and mixed
venous saturation of more than 70%.256 Therapeutic end points in premature
neonates have not been established but the goals for term infants seem reasonable.
ELBW infants present the greatest challenge for determination of therapeutic end
points in septic shock. Assessment of MAP, urine output, and capillary refill may
not be particularly useful determinates of systemic blood flow in ELBW infants,
particularly in the first 72 hours of life.257 In addition, the contribution of fetal hemo-
globin may complicate accurate determination of central venous oxygen saturation
(ScvO2) in neonates. ScvO2 obtained using hemoglobin A calibration is 4% to 7%
higher compared with ScvO2 that accounts for fetal hemoglobin258 implying that
perhaps the goal ScvO2 should be different in neonates than in older patients for
optimum tissue oxygen delivery.
In the future, monitoring techniques such as functional echocardiography (FE) and
near-infrared spectroscopy (NIRS) may provide physiologic data to optimize manage-
ment of septic shock. FE provides a bedside means to assess cardiac output, periph-
eral vascular resistance, and organ blood flow in response to volume, colloid, and
vasoactive medications.259,260 FE can also be used to assess superior vena cava
(SVC) flow, which has been suggested as a surrogate marker for cerebral blood
flow261 and should be maintained at 40 ml/kg/min or higher.262 Prolonged decreases
in SVC flow are associated with impaired neurodevelopmental outcome in very
preterm neonates.263 In the absence of FE to monitor SVC flow, a capillary refill
time of more than 4 seconds combined with a serum lactate concentration of more
than 4 mmol/L had a specificity of 97% for identifying VLBW infants with a low SVC
flow state on the first day of life.264 NIRS can be used to monitor end-organ perfusion
noninvasively265 and is used often in neonates with congenital heart disease.266 A
combination of FE and NIRS, in conjunction with traditional measures (MAP, SpO2,
capillary refill, urine output) as well as intermittent laboratory evaluations of tissue
perfusion such as pH, mixed venous saturation, lactate, and base deficit would be
ideal for monitoring severity of septic shock and response to therapy.
Management of Hypotension and Cardiovascular Support
An algorithm for time-sensitive, goal-directed stepwise management of hemodynamic
support for the term newborn with septic shock has been established and should be
followed.255 Preterm neonates require specific caveats to this algorithm because of
their unique physiology and risk for complications (see Fig. 4).
In contrast to term neonates, the definition of hypotension and shock in preterm
neonates is less clear, particularly in the immediate newborn period.26 Blood pres-
sure may be a poor indicator of systemic blood flow in preterm neonates,225 yet
objective measures of adequacy of tissue perfusion and oxygenation delivery are
lacking. Another confounding variable in the management of neonatal shock is that
inotrope use (dopamine, dobutamine) in hypotensive preterm neonates has not
been shown to significantly improve short- or long-term outcomes.227,267,268 These
considerations notwithstanding, and in absence of evidence of harm, some neonatol-

ogists advocate treating hypotension in preterm neonates to achieve a MAP of
greater than or equal to 30 mm Hg. This goal MAP is based in part on a small study
showing improved cerebral blood flow autoregulation above this threshold.269
However, a gestational age-based cutoff for normal blood pressure (goal MAP >
GA) is used at many tertiary centers, especially in the first 3 days after birth. Clearly,
more studies are required to determine whether targeting a specific blood pressure
improves outcomes in preterm infants.
Once a decision is made to treat hypotension with or without shock in a neonate, the
recommended initial step is a fluid bolus (crystalloid). Although there is less data in
neonates to support this intervention, it remains the accepted clinical practice to treat
and monitor closely for signs of intravascular volume depletion.227 In term infants or
older preterm infants, aggressive volume expansion (20–40 mL/kg) should be consid-
ered. In contrast to outcomes with early aggressive fluid resuscitation in older popu-
lations,270 there is insufficient evidence to support early volume expansion in very
preterm neonates,271 and there is a significant risk of intracranial hemorrhage associ-
ated with rapid volume expansion in the first few days after birth.272 In hypotensive
preterm neonates, it is recommended that a single bolus of saline (10–20 ml/kg over
30–60 minutes) be given and if further intervention is necessary to begin vasoactive
medications.268 In cases of obvious acute volume loss in preterm infants, more volume
may be needed.
Dopamine is generally the first-line vasoactive drug, with a starting dose of 5 to 10
mg/kg/min227 and dose escalation as needed. For neonates with shock, which is unre-
solved with volume resuscitation and dopamine, several possibilities exist for addi-
tional therapy, including glucocorticoids (see later discussion), other
catecholamines, and inotropes/vasodilators. Epinephrine or norepinephrine infusions
for refractory shock in neonates have been studied to a limited extent. Neonates with
vasodilatory shock may have a positive response to the a-adrenergic vasoconstrictive
effect of these agents. A recent report in term neonates showed the addition of
noradrenaline to existing therapy (after fluid loading and dopamine or dobutamine
infusion) resulted in increased blood pressure and decreased tissue lactate.18 In
another study, low-dose epinephrine was found to be as effective as low-/
moderate-dose dopamine for increasing blood pressure, cerebral blood volume,
and cerebral oxygen delivery in VLBW infants.273 Patients with depressed myocardial
function may benefit from infusion of dobutamine for inotropy and vasodilation. In
a study of 42 preterm neonates with low systemic blood flow (as determined by low
SVC flow262) in the first 24 hours after birth, dobutamine treatment improved and
maintained systemic blood flow better than dopamine.274,275 As a caution, dobut-
amine, particularly in high doses, can increase myocardial oxygen demand caused
by b1 adrenergic stimulation. Dobutamine also has chronotropic actions and severe
tachycardia may lead to decreased cardiac output that may be corrected by
decreasing the dose. Milrinone, a phosphodiesterase inhibitor and inodilator, has
not been studied in neonatal septic shock but has been used in pediatric patients
with septic shock.276,277 In a study of patients aged 9 months to 15 years with
volume-resuscitated catecholamine-resistant nonhyperdynamic septic shock, milri-
none increased cardiac index, stroke volume, and oxygen delivery, and decreased
systemic vascular resistance without increasing heart rate or blood pressure.276
Another alternative agent for treating septic shock is the vasoconstrictor arginine-
vasopressin (AVP) or its longer half-life analogue terlipressin.278 In a report of 6
ELBW infants, AVP improved MAP and urine output in patients with septic shock
but not in those with nonseptic shock.279
460 Wynn & Wong
Hydrocortisone Treatment in Neonatal Septic Shock

Induced by proinflammatory cytokines, endogenous cortisol attenuates the intensity
of the systemic inflammatory response associated with severe sepsis and septic
shock.280 Studies in adults have shown that high-dose glucocorticoid therapy does
not affect sepsis mortality although low-dose therapy may be beneficial.254 In 1
randomized clinical trial, low-dose cortisol treatment in conjunction with standard of
care measures was associated with a reduction in mortality in adults with septic shock
and adrenal insufficiency.281 In another study in adults, cortisol treatment sped the
reversal of septic shock but had no effect on mortality.282
Cortisol production in the neonate is significantly increased early in septic shock.283
However, very preterm neonates can have relative adrenal insufficiency that may
contribute to hemodynamic instability and hypotension. In many clinical practices,
hydrocortisone is the third-line agent in treatment of neonatal shock after volume
resuscitation and dopamine.227,268,284 In addition to its cytokine-suppressing effects,
hydrocortisone has been shown to increase the sensitivity of the cardiovascular
system to endogenous or exogenous catecholamines, resulting in improvements in
myocardial contractility, stroke volume, effective circulating blood volume, systemic
vascular resistance, and urine output. Hydrocortisone has not been evaluated in
prospective randomized clinical trials for the treatment of septic shock in the neonate,
but it has been shown to increase blood pressure, decrease heart rate, and decrease
vasoactive medication requirements in preterm and term neonates.284,285 If hydrocor-
tisone treatment is considered, obtaining a pretreatment serum cortisol level is
prudent to differentiate contributing causes of hypotension. The reader is referred to
a recent review on the diagnosis and treatment of adrenal insufficiency in the prema-
ture neonate.286
Pulmonary Support
Increased inspired oxygen may be necessary in the setting of neonatal septic shock to
maximize tissue oxygen delivery. Decreased pulmonary function (RDS) and/or respi-
ratory failure (apnea) in conjunction with increased tissue demand (increased respira-
tory and metabolic activity associated with acidosis) contribute to tissue hypoxia.
Mechanical ventilation can improve gas exchange through maintenance of lung
volume and decreased work of breathing. Administration of exogenous surfactant
to neonates with severe pneumonia has been shown to improve oxygenation and
gas exchange and reduce the need for extracorporeal membrane oxygenation
(ECMO).238In extremely sick neonates, consideration should be given to maintaining
a normal or near-normal pH and oxygen saturations in the 90s rather than allowing
permissive hypercapnia and lower saturations, which is standard practice in healthy
preterm neonates. Normalizing pH and arterial oxygen content may improve cardiac
contractility and improve tissue oxygen content, thus decreasing the risk of multi-
organ dysfunction and the risk of pulmonary hypertension. Infants with sepsis and
PPHN may require inhaled nitric oxide (iNO) in addition to optimized ventilation strat-
egies such as high frequency oscillatory ventilation.287 If oxygenation or tissue perfu-
sion remain severely compromised despite optimal medical management, ECMO
should be considered in neonates greater than 2 kg without contraindications such
as the presence of or high risk for acute hemorrhage.288,289
OTHER SUPPORTIVE CARE OF NEONATES WITH SEPTIC SHOCK
Avoidance of hypothermia and hypoglycemia is important in neonates with septic

shock. With the exception of patients with acute perinatal hypoxic ischemic
encephalopathy,290 normothermia should be maintained on a radiant warmer. Use of

a 10% glucose solution delivering 4 to 6 mg/kg/min of glucose combined with frequent
monitoring to ensure normoglycemia is recommended. Correction of a significant coa-
gulopathy and anemia (hemoglobin %10 g/dL) through the transfusion of fresh frozen
plasma or packed red blood cells may also serve to improve blood pressure291 and
oxygen delivery. The importance of providing adequate protein and calories to the
infant with sepsis and septic shock cannot be overstated. Increased energy demands
promote catabolism if adequate nutrition is not provided. Premature neonates have
decreased muscles mass and energy reserves as well as higher baseline nutritional
requirements compared with term neonates.292 Increase in serum triglyceride levels
during sepsis293 and increased serum oxygen-derived free radicals associated with
infusions of lipid have prompted some clinicians to withhold or decrease intralipid infu-
sions. A recent study showed concurrent administration of intralipids in neonates with
infection is not associated with hypertriglyceridemia in the absence of liver dysfunction
or fetal growth restriction.294 It is suggested that intralipid infusions during sepsis or
septic shock in neonates be accompanied by careful monitoring of serum triglycerides
to avoid hypertriglyceridemia. Maintenance of a carbohydrate to lipid ratio of w3:1
increases fat use and decreases production of oxygen-derived free radicals to levels
seen with fat exclusion.295 Protein intakes of 2 to 3 g/kg/d are generally not associated
with azotemia, hyperammonemia, or metabolic acidosis296 in the setting of sepsis, but
monitoring of blood urea nitrogen is recommended. Monitoring liver and renal function
is important for assessing the effectiveness of therapies to improve tissue perfusion and
for making decisions about dosing medications that require modification for
elimination.
ALTERNATIVE IMMUNOLOGIC AND PHARMACOTHERAPIES FOR NEONATAL

SEPSIS/SHOCK
There have been many attempts directed at improving outcomes of sepsis and septic
shock in neonates via immunomodulation. A complete review of adjunct immunologic
therapies in neonatal sepsis, see the article by Tarnow-Mordi and colleagues else-
where in this issue for further exploration of this topic.
OUTCOMES WITH SEPSIS AND SEPTIC SHOCK
The outcome of septic shock in the neonate is dismal. One study reported death or
severe sequelae in 52% of infants, with only 28% of infants less than 1000 g alive
and free of disability at 18 months of age.7 Variables predictive of mortality include
cardiac dysfunction manifested as refractory shock, acute renal failure, neutropenia,
increased prothrombin time, excessive bleeding, metabolic acidosis, and
hypothermia.231,297
Neurodevelopmental outcomes following neonatal sepsis, without stratification for
shock, have been studied in some detail and demonstrate significant risk for impair-
ment, particularly in the most premature neonates.298 VLBW infants with sepsis,
compared with those without, have been reported to have significantly increased
mortality (21% vs 9%), longer hospital stay (98 vs 58 days), and a higher risk of chronic
lung disease.31 ELBW infants are at especially high risk for sepsis-associated adverse
neurodevelopmental outcomes, including deafness, cerebral palsy, lower mental and
psychomotor development scores, and vision impairment.299,300 In a study of preterm
infants, white matter abnormality on magnetic resonance imaging at term corrected
age-predicted neurodevelopmental impairment in those with sepsis compared with
those without.301 Surgical NEC, which is often accompanied by SIRS or shock, has
462 Wynn & Wong
been associated with significant growth delay and adverse neurodevelopmental

outcomes at 18 to 22 months.302 A study of ELBW infants with systemic candidiasis
found that 73% died or developed a neurodevelopmental impairment63 including reti-
nopathy.303 These data show that the toll of neonatal sepsis and septic shock reaches
far beyond the acute complications of organ dysfunction and mortality.
FUTURE CONSIDERATIONS
Neonatal sepsis requires translational and clinical research. Definitions for the sepsis
continuum and treatment algorithms specific for preterm infants should be developed
to improve the quality of clinical trials and facilitate meta-analyses of prophylactic and
therapeutic interventions. Systems biology and genomic and proteomic studies have
yielded important data on septic shock in older populations304–312 and the use of these
modern techniques in the study of neonatal inflammation and response to pathogen
challenge has begun.109,138,313 With further research, real-time sampling using only
microliters of blood will allow rapid identification of highest-risk patients, pathogen-
specific responses, and sepsis-staging biomarkers.314 Immaturities of immune
function and physiology in the neonate necessitate developmental stage-specific
evaluations of sepsis pathophysiology and treatment. Exploration of adjuvant treat-
ments including LPS-binding proteins (rBPI,315 sCD14, or anti-CD14316), antiinflam-
matory therapies (pentoxifylline,317 nicotinic stimulation,318 statins319), synthetic
host defense peptides (rhSP-D,320 lactoferrin321,322), combination therapies323 (ie,
IVIg and colony-stimulating factor), and innate immune priming using TLR agonists250
may yield improved outcomes. Advances in these areas are urgently needed and are
likely to substantially improve long-term outcomes.
SUMMARY
Neonatal septic shock is a devastating condition associated with high morbidity and
mortality, Definitions for the sepsis continuum and treatment algorithms specific for
premature neonates are needed to improve studies of septic shock and assess benefit
from clinical interventions. Unique features of the immature immune system and path-
ophysiologic responses to sepsis, particularly those of extremely preterm infants,
necessitate that clinical trials consider them as a separate group. Keen clinical suspi-
cion and knowledge of risk factors will help to identify those neonates at greatest risk
for development of septic shock. Genomic and proteomic approaches, particularly
those that use very small sample volumes, will increase our understanding of the path-
ophysiology and direct the development of novel agents for prevention and treatment
of severe sepsis and shock in the neonate. Although at present antimicrobial therapy
and supportive care remain the foundation of treatment, in the future immunomodula-
tory agents are likely to improve outcomes for this vulnerable population.
ACKNOWLEDGMENTS
The authors thank Associate Professor C. Michael Cotten, MD, MHS for his review
of this manuscript.
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Pathophysiology and Treatment Syok Septic in Pediatric

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Pathophysiology and

DEFINITIONS OF THE SEPSIS CONTINUUM

In 2005, definitions for pediatric infection, systemic inflammatory response syndrome

Clin Perinatol 37 (2010) 439–479

Consensus Definitions Suggested Modifications for Premature Infants

Treatment of Septic Shock in Neonates

Consensus Definitions of Organ Dysfunction25 Suggested Modifications for Premature Infants

Treatment of Septic Shock in Neonates

population. The authors have proposed modifications to the consensus definitions to

RISK FACTORS FOR DEVELOPMENT OF NEONATAL SEPTIC SHOCK

MICROBIOLOGY OF SEPSIS AND SEPTIC SHOCK IN NEONATES

newborns may undermine the identification of organisms causing shock, particularly in

PATHOPHYSIOLOGY OF SEPSIS AND SHOCK: MOLECULAR AND CELLULAR EVENTS

polymorphisms in myeloid differentiation-2 (MD-2), a small protein involved in LPS

Role of Complement in Host Defense and Sepsis Pathophysiology

Other Host Defense Proteins, Acute Phase Reactants, and Opsonins

Role of Dysregulated Coagulation in Severe Sepsis

(PAI), and plasmin-a2-antiplasmin complex.166 There is also a shift toward inactivation

Role of the Neutrophil in Septic Shock

Other Innate Cellular Contributions to Sepsis

septic shock is incompletely characterized. Monocytes, macrophages, and dendritic

Role of the Endothelium and Vasoactive Mediators in Septic Shock

Activated or damaged endothelium establishes a prothrombotic environment that

PATHOPHYSIOLOGY OF SEPTIC SHOCK: CARDIOVASCULAR AND OTHER

Multi-organ Dysfunction Syndrome

TREATMENT OF SEPSIS AND SEPTIC SHOCK

considerations notwithstanding, and in absence of evidence of harm, some neonatol-

Hydrocortisone Treatment in Neonatal Septic Shock

OTHER SUPPORTIVE CARE OF NEONATES WITH SEPTIC SHOCK

Avoidance of hypothermia and hypoglycemia is important in neonates with septic

encephalopathy,290 normothermia should be maintained on a radiant warmer. Use of

ALTERNATIVE IMMUNOLOGIC AND PHARMACOTHERAPIES FOR NEONATAL

OUTCOMES WITH SEPSIS AND SEPTIC SHOCK

been associated with significant growth delay and adverse neurodevelopmental

79. Goldbach-Mansky R, Dailey NJ, Canna SW, et al. Neonatal-onset multisystem

116. Turunen R, Andersson S, Nupponen I, et al. Increased CD11b-density on circu-

176. Christensen RD, Rothstein G. Exhaustion of mature marrow neutrophils in

196. von Kockritz-Blickwede M, Goldmann O, Thulin P, et al. Phagocytosis-indepen-

216. Gibson RL, Nizet V, Rubens CE. Group B streptococcal beta-hemolysin

238. Engle WA. Surfactant-replacement therapy for respiratory distress in the

258. Shiao SY. Effects of fetal hemoglobin on accurate measurements of oxygen

277. Paradisis M, Evans N, Kluckow M, et al. Randomized trial of milrinone versus

permeability-increasing protein on growth and tumor necrosis factor-inducing

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