SEPSIS

S. Kache, MD, A. Schroeder, MD, P. Trinkus, MD

OVERVIEW
Sepsis is a common, life-threatening condition in the pediatric ICU. Severe sepsis and
septic shock occur in all settings and age groups though these children often have
associated co-morbidities such as prematurity or malignancy. Though in the community
at large recent epidemiologic data indicate that more than half the cases of severe
sepsis occur in children without a predisposing condition. Early recognition and
aggressive early intervention for severe sepsis and septic shock, however, are essential
in preventing a poor outcome.

Term Definition
SIRS: Systemic Presence of two or more of the following symptoms (see
Inflammatory Table 1): temperature instability (core temp > 38.5 / <36),
Response tachycardia / bradycardia, tachypnea or mechanical
Syndrome ventilation, leukocytosis/leucopenia.
Sepsis SIRS with infection
Severe Sepsis Sepsis with one other organ dysfunction (see Table 2):
cardiovascular dysfunction, ARDS/ALI, mechanical ventilation,
change in mental status, rising creatinine, rising hepatic
enzymes TBili or ALT
Septic Shock Fluid refractory hypotension: hypotension or hypoperfusion
despite fluid resuscitation
MODS / MOFS Multi-organ dysfunction syndrome / multi-organ failure
syndrome at least two organ system failures see table
below

SEPSIS EPIDEMIOLOGY
In children the vast majority (? millions of cases per year) with a SIRS type picture will
have minor infectious disease and be treated as outpatients. The second and third tears
of the pyramid will be much smaller.

Estimates of the incidence of severe sepsis in children suggest that there are
about 40,000 cases per year, some 10 15% of who develop septic shock
(4,000 6,000). Half of these cases occur in children with co-morbidities.
Co-morbidities conditions include prematurity, therapeutic immunosuppression
(e.g. transplant or cancer patients) along with patients with neurological, cardiac,
respiratory, GI, etc. diseases.
Neonates (under 30 days) account for about 1/3 of cases and infants under 1
year account for half.
The mortality rate for severe sepsis in children is estimated to be between 5 10
% regardless of age group. Patients with co-morbidities, in particular, those with

Sepsis 1
 neoplasms, immunodeficiency or severe cardiac disease have significantly higher
mortality rates (15%).

BACTERIOLOGY
The bacteriology varies by age, co-morbidity, and geography.
Coagulase negative staphylococcus, non group A or B strep, and fungus now
predominate in all age groups.
In neonates Group B strep and gram negative species including pseudomonas
account for about 10% of cases.
H. Flu and pneumococcus have become uncommon due to immunization but still
account for 2 7% of all severe sepsis cases in the US.
Meningococcus, the other classic pathogen, is also uncommon in the US
accounting for less than 2 % of severe sepsis cases overall and for less than
10% in the 1 10 year old group.
In previously healthy children the predominance of the classic bacterial
pathogens is approximately twice what it is overall. S. aureus and gram-negative
enterics are also significant contributors.

PATHOPHYSIOLOGY (See Figure 1)

The basic pathophysiology of severe sepsis and septic shock includes:
o Vasodilation
o Third spacing due to capillary leak
o Myocardial dysfunction.
Vascular endothelium is both a source and target of injury in SIRS / sepsis.
Injury may be due to toxins such as LPS (endotoxin) or from ischemia itself.
Tissue factor release leads to amplification of the inflammatory response and to
DIC via the thrombin pathway. Thrombin not only catalyzes fibrin formation but
also causes leukocyte adhesion which leads to further endothelial damage. As
DIC progresses, clotting factors are consumed and bleeding occurs.
Clotting factors, pro-fibrinolytic, and anti-thrombin factors are consumed leading
to loss of fibrinolysis & normal down-regulation of thrombin pathway. This
phenomenon is both pro-inflammatory and pro-thrombotic.
Protein C depletion has been associated with increased mortality. In
meningococcemia protein C depletion can be profound and is associated with
large vessel thromboses (purpura fulminans) as well as mortality. This has led to
a series of clinical trials utilizing protein C, activated protein C (APC),
antithrombin III (AT-III), and tissue factor pathway inhibitor to try and disrupt
this cycle. Activated protein C has in fact been shown to reduce mortality in
severe sepsis in adults. Bleeding problems seems to outweigh the benefits in
children.

CLINICAL PRESENTATION / EVALUATION

The recognition of sepsis may be straightforward in the hospital setting where it is
common. In the office setting, identifying which of the many febrile children is actually
Sepsis 2
septic may be much more difficult. Severe sepsis should be suspected when there is
lethargy and flash capillary perfusion. The additional presence of a rash should alert
one to the possibility of meningococcemia.

Cardiovascular changes (see Table 1) are most significant physical findings in

patients with septic shock; changes of heart rate tachycardia / bradycardia, and
changes in perfusion are seen. Hypotension, when noted is a late finding and
suggests decompensated shock.
Warm / Early shock: presentation is a febrile, warm, pink, well-perfused child
with tachycardia and tachypnea. The initial release of inflammatory cytokines
causes a drop in systemic vascular resistance (SVR) which leads to low diastolic
blood pressures. On physical exam, this causes a widened pulse pressure and
bounding pulses.

Cold shock: describes a condition that resembles cardiogenic or severe

hypovolemic shock. Pulses are poor, extremities are cool, and perfusion is
severely diminished. The septic patient progresses to this state once the
compensatory mechanisms are exhausted. Myocardial function is depressed and
catecholamine response may be diminished due to relative cortisol and
vasopressin deficiency.

Respiratory: (see Table 1) Tachypnea is primarily due either to an inciting

respiratory process or metabolic acidosis. Patients often have a primary respiratory
alkalosis on presentation and develop hypoxemia and respiratory acidosis as the
sepsis progresses.

Neurologic: Patients may present with agitation, which often progresses, to

decreased mentation due to poor end organ perfusion.

Renal: Decreased urine output is noted for inpatients and elicited on history for
outpatients.

Skin: Palpable petechiae and purpura may be present if the patient presents in DIC.
Poor skin turgor and perfusion can also be noted.

Pediatric ICU patients often have significant co-morbidities leading to unusual

presentations:
Patients with pulmonary hypertension may develop a pulmonary hypertensive
crisis and severe RV failure
Single ventricle patients may develop profound hypoxemia from a decreased
Qp:Qs as blood is shunted into the vasodilated peripheral vascular bed
Transplant patients may manifest failure of the transplanted organ.

Table 1 Age Specific Vital and WBC

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Age Group Tachycardia Bradycardia Respiratory rate WBC X103/mm Systolic BP mm
Hg
0 days 1 wk > 180 < 100 > 50 > 34 <65
1 wk 1 mo > 180 < 100 > 40 >19.5 or <5 <75
1 mo 1 yr > 180 < 90 > 34 >17.5 or <5 <100
2-5 yrs > 140 NA > 22 >15.5 or <6 <94
6-12 yrs > 130 NA > 18 >13.5 or <4.5 <105
13 - <18 yrs > 110 NA > 14 >11 or <4.5 <117

Table 2 Organ dysfunction criteria

From: International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Goldstein,
Brahm MD; Giroir, Brett MD; Randolph, Adrienne MD; Members of the International Consensus Conference on Pediatric Sepsis.
Pediatric Critical Care Medicine: Volume 6(1) January 2005 pp 2-8

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TREATMENT
Between 1963 and 1993, with the advent of neonatal and pediatric intensive care units,
mortality from sepsis decreased from >95% to 10%. The basic tenets of treatment
developed over those three decades are: recognition, appropriate antibiotics,
fluid resuscitation and to a lesser extent other intensive care interventions such as
inotropes and mechanical ventilation. Despite a large number of clinical trials trying to
identify the magic bullet for the treatment of sepsis these interventions remain the
cornerstones of management.

An algorithm published by the society of critical care medicine for the treatment of
pediatric and adult severe sepsis follows. Essential elements in this algorithm are,
Recognition
Initial resuscitation
Diagnosis
Appropriate antibiotics
Source identification and control
Early access to critical care. Delays in access to a critical care bed should not
delay these interventions.
Institution of inotropic and vasopressor support
Management of metabolic derangements
Frequent, repeated assessment of the response to therapy
Institution of this type of protocol has been the basis for current reductions in mortality
in pediatric septic shock. Each of these topics is discussed in detail below.

Recognition: Flash capillary refill and altered mental status with a febrile illness are
the hallmarks. Rash in this setting should signal possible meningococcemia.
Increased suspicion is warranted in children with co-morbidities.

Resuscitation: the ABCDs of sepsis

A Airway
B Breathing
C crystalloids, crystalloids, crystalloids, crystalloids, calcium
D Dextrose, Drugs = antibiotics, inotropes
s Steroids

Airway:
o Septic patients often have depressed mental status and may require
airway protection.

Breathing consider intubation in the following circumstances. Assure lung

protective strategies are instituted if the patient requires intubation (see chapter
13 ARDS).
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 o Hypoxemia: ALI / ARDS, pneumonia
o Metabolic acidosis
o Work of breathing accounts for up to 40% of cardiac output in children;
intubation may therefore improve end organ perfusion
o After 40ml/kg of fluid resuscitation
o Induction meds: Ketamine minimizes hypotension by maintaining systemic
vascular resistance + atropine to decrease secretions and a short acting
neuromuscular blocking agent

Circulation: Rapid fluid administration is the key.

o The first 20 ml/kg should be given in 5 10 minutes. Adequate IV
access should be established quickly to allow for rapid fluid administration.
If IV access cannot be rapidly accomplished, an IO should be placed (a
minimum of 4 potential IO sites exist).
o Fluids should be given in 20 ml/kg boluses and patients may require up to
200 ml/kg. Fluid resuscitation should occur until resolution of tachycardia,
improvement of end organ perfusion or the patient develops
hepatomegaly or rales. Note frequent patient reassessment is required.
o Those patients requiring > 40-60 ml/kg of volume should have a central
venous catheter placed and the CVP should be continuously measured.
Note however that continued fluid resuscitation should not be delayed for
a CVC placement.
o Adult studies have demonstrated that targeting a CVP of 8-12 (slightly
higher in mechanically ventilated patients to account for increased
intrathoracic pressure) and a MVO2 Sat > 70% increases survival.
o Concerns about worsening respiratory distress should not limit fluid
resuscitation unless the CVP is higher than the target range.
o Crystalloids are the choice of fluids for patients in septic shock since no
data exists to demonstrate improved outcomes with colloid solution.
Patients with severe malaria are the only group of patients in whom
decreased mortality has been noted with 5% albumin resuscitation. There
is a growing body of evidence for the use of hypertonic saline (3% to 7%
or more) as a resuscitation fluid.
o Data shows that early rapid fluid resuscitation in referring clinics /
emergency rooms without delay of initiation of treatment improves
mortality in pediatric septic patients. The most common cause of delay in
treatment is inability to establish vascular access. Therefore, an IO should
be considered if vascular access cannot be rapidly established in a patient
with septic shock.

Fluid refractory shock: Hypotension despite 40 60 ml/kg of fluid

Sepsis 6
 o Dopamine is initiated through a central venous catheter. If a CVC is not
available, inotropic support should not be delayed and should be initiated
through a PIV / IO as the CVC is being placed.
o Note that in adult sepsis guidelines, either norepinephrine or dopamine
can be the initial inotrope (and many pediatric intensivists may also
choose to start with norepinephrine.)
o An arterial line for continuous blood pressure monitoring is recommended
if prolonged or increasing doses of inotropes are required.

Dopamine refractory shock: Hypotension on 10 mcgs/kg/min of dopamine.

o Warm shock norepinephrine flash capillary refill, bounding pulses
o Cold shock epinephrine prolonged cap refill, thready pulses
o Once the blood pressure has normalized, if signs of poor perfusion persist,
dobutamine, milrinone, and/or vasodilators like nitroprusside may also be
considered.
o Other vasoconstrictors to be considered include vasopressin and
phenylephrine if hypotension persists despite optimal inotropic support.

Catecholamine refractory shock consider Steroid replacement:

o Consider if patient on steroids within last year or at high risk for being
steroid deficient
 Oncology
 Organ transplant
 Asthma
 Meningococcemia (Waterhouse-Friderichsen syndrome)
 Congenital adrenal hyperplasia
o Send spot cortisol level prior to administering steroids
o Hydrocortisone: 1 50 mg/kg/day can be administered until the reversal
of shock symptoms are noted.

Correct hypocalcemia and hypoglycemia

Note from the diagram below that the initial resuscitation of sepsis, ABCDs, all occur
within 60 minutes of diagnosing a patient with septic shock.

Sepsis 7
Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American
College of Critical Care Medicine. Brierley J, Carcillo JA, Choong K, Cornell T, Decaen A, Deymann A, Doctor A, Davis A, Duff J,
Dugas MA, Duncan A, Evans B, Feldman J, Felmet K, Fisher G, Frankel L, Jeffries H, Greenwald B, Gutierrez J, Hall M, Han YY,
Hanson J, Hazelzet J, Hernan L, Kache S, Kiff J, Kissoon N, Kon A, Irazusta J, Lin J, Lorts A, Mariscalco M, Mehta R, Nadel S,
Nguyen T, Nicholson C, Peters M, Okhuysen-Cawley R, Poulton T, Relves M, Rodriguez A, Rozenfeld R, Schnitzler E, Shanley T,
Skippen P, Torres A, von Dessauer B, Weingarten J, Yeh T, Zaritsky A, Stojadinovic B, Zimmerman J, Zuckerberg A.
Crit Care Med. 2009 Feb;37(2):666-88.

Sepsis 8

Diagnosis: Lab studies:
Chemistries:
o Evaluate the degree of acidosis
o Evaluate for possible end organ dysfunction liver, kidney
CBC:
o Often an elevated WBC count is noted, but a low WBC with immature
neutrophils is a strong indicator of severe sepsis as well.
o Low Hct and platelet count can be seen in patients with DIC
Coag panel:
o Elevated Pt, PTT, INR, d-dimer and decreased fibrinogen levels can be
seen in patients with DIC
Appropriate cultures
o Blood & urine culture in all patients prior to antibiotics if feasible.
o An LP should be considered in patients with signs of meningitis.
o Indwelling catheters, drains, etc. should be cultured
o ETT culture and gram stain in intubated patients.
Acute phase reactants: CRP, fibrinogen, platelets, ESR, will be elevated
Lactate: Multiple studies in adults and children have shown that elevated lactate
levels are predictive of early mortality in sepsis.
o May be elevated in warm shock due to poor oxygen extraction and micro
shunts in the capillary beds that may be the cause of flash capillary filling.
o Elevated in cold shock due to poor tissue perfusion.
Consider further radiologic studies based on patients presenting symptoms
e.g. CXR if respiratory symptoms, abdominal CT if abdominal pain, etc.

Antibiotic selection:
Data shows that incorrect empiric antibiotic coverage increases morbidity and
mortality. Therefore, broad-spectrum coverage is initiated and then narrowed as
the organism and resistance pattern are identified.
Empiric antibiotic therapy should be based on the clinical scenario. Table 3
below provides guidelines for empiric antibiotic selection.
For nosocomial infections, institutional antibiotic resistance patterns and prior
antibiotic exposure in the child become important factors.
When Staphylococcus aureus is suspected vancomycin should be used because
of the rising incidence of MRSA.
If a source of infection is identified (i.e. positive blood culture or urine culture),
antimicrobials should be tailored appropriately.

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Table 3 Empiric antibiotic coverage
CLINICAL ANTIMICROBIAL RATIONALE
SCENARIO
Meningitis GPC Vanco + 3rd gen Cover for resistant S. pneumo
on gram stain cephalosporin
Meningitis gram 3rd gen cephalosporin Likely N. meningitides
neg diplococci
Neutropenia Vanco + Double- Pts are susceptible to
coverage for GNR Pseudomonas and other
SPACE organisms
Toxic shock Clinda + Vanco Cover for MRSA/Strep
Indwelling central Vanco + 3rd gen Vanco is needed for Gram +
venous catheters cephalosporin organisms, most notably S.
epi.
Deterioration Antifungals; also Loss of normal bacterial flora
despite broad- consider what possible increases susceptibility to
spectrum resistant organisms fungus, particularly in patients
antibiotics may be involved on steroids, with
hyperglycemia, or who are
immunosuppressed.

Source Control:
Consider if a specific anatomic site of infection can be identified e.g.
necrotizing fasciitis, diffuse peritonitis
If focus of infection can be treated by surgical intervention, e.g. abscess
drainage, it should implemented as quickly as possible

Supportive Therapy:

Glucose control: Much recent ICU literature has been devoted to the association
noted between high blood sugar levels and short term increases in morbidity and
mortality. RCTs in adults have demonstrated that maintaining euglycemia (blood
sugars 80-110) with insulin significantly improves morbidity and mortality in
critically ill surgical patients. In medical patients, improvements are noted in
patients that have a 3-day or longer ICU stay. Though data in children is
lacking, consensus supports treatment of hyperglycemia in critically ill children.
Given that children are more susceptible to hypoglycemia, the targeted range is
usually higher than in adults, 100-150 mg/dL. The risk of hypoglycemia was
highlighted in a recent adult trial (Brunkhorst et al, NEJM, 2008) where severe
hypoglycemia was 4x higher in the intensive insulin group. Mortality outcomes
did not differ between groups in this study.

Sepsis 10
 Nutrition and gastric acid suppression: Sepsis is not a contraindication to enteral
nutrition. TPN should be avoided if possible as risk of secondary infections
increases. Patients may have poor gastric motility and benefit from trans-pyloric
feeding. Shock and intestinal hypoperfusion, however, require more caution,
especially in patients with even moderate vasoconstrictor requirements. These
patients are generally kept NPO. Nutrition, whether enteral or parenteral, should
not be neglected given the high metabolic demands of the septic patient. Stress
ulceration and GI bleed is a serious concern and although no hard evidence
exists for the use of acid-blockade, most septic ICU patients are placed on an
H2-blocker or proton pump inhibitor, especially when NPO.

Transfusion: Blood products have risks and therefore should be used with
caution and appropriate justification. PRBC transfusion to a Hct > 30% should
be considered in the following circumstances:
o Signs of shock hypotension, acidosis, mixed venous O2 saturation <
70% despite adequate fluid resuscitation and inotropic support
o Ongoing blood loss exsanguination or DIC
o Cyanotic heart disease
o Myocardial ischemia

NOVEL THERAPIES

ECMO is an important though infrequent tool. It should be considered in patients
with refractory shock despite maximal medical treatment, multi-system organ
dysfunction and patients with severe respiratory failure.

CVVH has become an important tool for patients developing renal failure and fluid
overload. The cytokine removal properties of CVVH are discussed extensively and
remain investigational.

Plasma exchange will remove cytokines, large von Willebrand multimers and other
toxic substances. It is used increasingly to manage patients with severe shock
though this indication is also still investigational.

Vasopressin is being increasingly used for sepsis but pediatric studies are limited. It
should be considered for cases of catecholamine-refractory vasodilatory shock.
Patients with sepsis have a relative vasopressin deficiency state and it may therefore
be very effective in increasing SVR. Vasopressin stimulates vascular smooth muscle
V1 receptors (i.e. not alpha receptors) and increases MAP. Pediatric dosing begins
at 0.01 unit/kg/hr and can be titrated up to 0.04 units/min.

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NEONATAL SEPTIC SHOCK
The management of neonatal septic shock deserves some special comments.

Traditional view: Historically, the regulation of cardiac output in neonates was

thought to be insensitive to both fluid loading and inotropes. Recent studies have
however documented that both these strategies can be effective and should be
used.

Intracranial hemorrhage: Concerns over precipitation of an intracranial hemorrhage

with rapid swings in intravascular volume, particularly in premature infants, has led
to a tempered use of volume resuscitation. New evidence, however, implicates
persistent under perfusion as perhaps a more significant cause of injury than ICH
alone. Therefore, overly cautious resuscitation in premature infants may be more of
a problem than vigorous resuscitation.

Pulmonary hypertension in the newborn (PHN): Neonates with acidosis,

hypercarbia, and temperature instability are at risk for the development of PHN. This
will lead to RV decompensation and can be addressed with a number of strategies
including alkalinization, ventilation, intravenous drug therapy with inodilators (drugs
that are both inotropes and vasodilators such as dobutamine and milrinone), inhaled
nitric oxide, and ultimately ECMO.

Metabolic considerations: deficiencies in glycogen, thyroid hormone, parathyroid

hormone, the adrenocortical axis may exist and need to be addressed with
appropriate replacement therapy.

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FIGURE 1
Initial Insult / Infection

Local inflammatory cytokine release

Systemic inflammatory cytokine release

Vascular Endothelial Injury Tissue Factor Release

Thrombin
WBC & Platelet pathway DIC
- Increased microvascular adhesion
Permeability
- Vasodilation Consumption of
Sludging & Coagulation Factors
Micro-thrombi
Third Spacing
Bleeding / Red cell hemolysis

Decreased preload Decreased O2 carrying capacity

Poor end-organ perfusion

Septic
Shock
Sepsis 13