ARTICLE IN PRESS

Journal of Cardiothoracic and Vascular Anesthesia 000 (2019) 19

Contents lists available at ScienceDirect

Journal of Cardiothoracic and Vascular Anesthesia

journal homepage: www.jcvaonline.com

Review Article
Clinical Update in Pediatric Sepsis: Focus on Children
With Pre-Existing Heart Disease
Scott L. Weiss, MD, MSCE*,y,z,1, Susan C. Nicolson, MD*,x,
Maryam Y. Naim, MD*,x
*
Department of Anesthesiology and Critical Care, Children’s Hospital of Philadelphia, Perelman School of
Medicine at the University of Pennsylvania, Philadelphia, PA
y
Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Perelman School
of Medicine at the University of Pennsylvania, Philadelphia, PA
z
Pediatric Sepsis Program, Children’s Hospital of Philadelphia, Philadelphia, PA
x
Cardiac Center, Children’s Hospital of Philadelphia, Philadelphia, PA

SEPSIS REMAINS one of the most common causes of childhood morbidity, mortality, and higher healthcare costs, with over 75,000 hospital admissions
in the United States and an estimated 4 million cases worldwide per year. While standardized criteria to define sepsis are in flux, the general concept of
sepsis is a severe infection that results in organ dysfunction. Although sepsis can affect previously healthy children, those with certain pre-existing
comorbid conditions, including congenital and acquired heart disease, are at higher risk for both developing sepsis and having a poor outcome after sep-
sis. Multiple specialists including intensivists, cardiologists, surgeons, and anesthesiologists commonly contribute to the management and outcome of
sepsis in children. In this article, the authors examine the evolving epidemiology of pediatric sepsis, including the subset of patients with underlying heart
disease; contrast pediatric and adult sepsis; review the latest hemodynamic guidelines for management of pediatric septic shock and their application to
children with heart disease; discuss the role of mechanical circulatory support; and review key aspects of anesthetic management for children with sepsis.
Ó 2019 Elsevier Inc. All rights reserved.

Key Words: sepsis; septic shock; severe sepsis; critically ill children; congenital heart disease; acquired heart disease

Epidemiology of Pediatric Sepsis infection that can progress (sometimes rapidly) to cardiovascular
dysfunction (septic shock) or multiple organ dysfunction
Sepsis is the primary cause of death from infection, and remains syndrome (severe sepsis) (Table 1).3 Sepsis-3 recently updated the
one of the most common causes of pediatric mortality related to definitions and criteria for adult sepsis to exclude the need for
pneumonia, gastroenteritis, malaria, influenza (and other viral SIRS and removed the term “severe sepsis”4 with a similar frame-
infections), and varying invasive infectious diseases worldwide.1,2 work proposed, but not yet adapted, for pediatric sepsis.5
By nature of its severity, most patients with sepsis require inten- In the United States,4 there were an estimated 75,000 pediatric
sive care management. Current consensus guidelines for pediatric hospitalizations involving severe sepsis in 2005, which was up
sepsis designate a spectrum of illness severity ranging from a sys- from 42,000 in 1995, corresponding to an increase in prevalence
temic inflammatory response syndrome (SIRS) to an invasive from 0.56 to 0.89 cases per 1,000 pediatric-aged persons.6
The mortality rate for pediatric sepsis has declined dramatically in
Financial support was provided by the Department of Anesthesiology and the United States since the mid-1900s, with contemporary reports
Critical Care at the Children’s Hospital of Philadelphia. Dr Weiss is also sup- of the case fatality for pediatric sepsis ranging from 4% to 9%.68
ported by NIGMS K23-GM110496.
1 However, for critically ill children with severe sepsis who require
Address reprint requests to Scott L. Weiss, MD, MSCE, FCCM, Depart-
ment of Anesthesiology and Critical Care, The Children’s Hospital of Phila- treatment in a pediatric intensive care unit (PICU), hospital mortal-
delphia, Perelman School of Medicine at the University of Pennsylvania, 3401 ity rates often exceed 10%.913 The recent Sepsis PRevalence
Civic Center Blvd., 7 South Tower, Room 7C04, Philadelphia, PA 19104. OUtcomes Therapies (SPROUT) point prevalence study involving
E-mail address: WeissS@email.chop.edu (S.L. Weiss).

https://doi.org/10.1053/j.jvca.2019.10.029
1053-0770/Ó 2019 Elsevier Inc. All rights reserved.
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2 S.L. Weiss et al. / Journal of Cardiothoracic and Vascular Anesthesia 00 (2019) 19

Table 1 children with pre-existing cardiac disease compared with those

Definitions of the Spectrum of Pediatric Sepsis* without (odds ratio 1.49, 95% confidence interval 1.33-1.50).24
Condition Definition
Reported rates of healthcare-acquired infections for children after
cardiac surgery is between 3.3 and 8.9 per 1,000 patient-days, in
SIRS 2 abnormalities in temperature, heart rate, respiratory part related to indwelling catheters, the severity of the illness
rate, or white blood cell county prior to surgery, and surgical site infections.2527 A single-center
Sepsis SIRS plus suspected or proven invasive infection
Severe sepsis Sepsis plus either cardiovascular dysfunction, ARDS, or
study from Canada found that 19% of 502 patients
6 weeks of
MODS age developed sepsis after CPB over a 14-year period.28 Another
Septic shock Sepsis plus cardiovascular dysfunction study reported that 24% of children <1 year admitted to a single
MODS Presence of 2 concurrent organ system dysfunctions French cardiac intensive care unit (ICU) after CPB developed
Abbreviations: ARDS, acute respiratory distress syndrome; MODS, multiple
hospital-acquired infections.29 A report from a single United
organ dysfunction syndrome; SIRS, systemic inflammatory response syndrome. States center found that admissions for sepsis (16%) were more
* Adapted from Goldstein et al.3 common than suspected (11%) or confirmed (8%) rejection after
y
For pediatric SIRS, one of the 2 abnormalities must be either temperature heart transplant.30 In a prospective study at 10 pediatric hospitals
or white blood cell count. in Switzerland, cardiovascular and other surgical conditions only
trailed cancer as the most common comorbidities among children
128 PICUs across 26 countries reported 25% all-cause hospital with blood cultureproven bacterial sepsis.31
mortality and a 17% rate of new moderate functional disability in The most common sites of infection in children with
survivors.14 It has been estimated that more than one-third of chil- CHD and sepsis are respiratory, blood, urinary tract, gas-
dren who die in a tertiary care PICU in the United States have trointestinal, and surgical sites. However, the bacterial
severe sepsis.11,15 pathogens that cause severe sepsis vary by age, institution,
The overall prevalence of pediatric severe sepsis is increasing, and presence of additional risk factors, including an immu-
which is in large part driven by an increase in sepsis among pre- nocompromising condition, indwelling vascular catheters,
term neonates and infants, many of whom have congenital heart and immunization status. Gram-positive bacteria, mainly
disease (CHD).6,7,11,13,16 Patients with CHD are exposed to major Staphylococcus and Streptococcus, remain the most preva-
surgical procedures, cardiopulmonary bypass (CPB), extracorpo- lent organisms isolated.6,9,29 However, gram-negative
real membrane oxygenation (ECMO), invasive devices, prolonged organisms, including Escherichia coli, Klebsiella species,
central venous access, mechanical ventilation, and extended hospi- and Pseudomonas aeruginosa, are also frequently identi-
tal stays, all of which increase the likelihood of hospital-acquired fied, especially in neonates and patients with neutropenia
sepsis. CPB itself has a number of effects on the immune system, or hospital-acquired sepsis. 6,11,13,14,29 Fungal infections
including activation of the coagulation cascade, release of endo- account for 3% to 11% of cases of pediatric sepsis but por-
toxin and cytokines, and activation of leukocytes and the vascular tend a higher risk of mortality. 6,14,29,32
endothelium.17,18 Moreover, certain conditions, such as trisomy 21
and chromosome 22q11 deletion syndrome are associated with an
increased risk of CHD and defects in the immune response. The Pediatric Versus Adult Sepsis
subset of children with CHD or acquired heart disease who prog-
ress to heart or heart and lung transplantation require lifelong Several physiological features differentiate pediatric from
immunosuppression. Finally, growth of a vulnerable population adult sepsis, making direct application of adult studies to chil-
with additional noncardiac chronic comorbid conditions,19,20 dren, and particularly infants, challenging. First, pediatric
increasing rates of multidrug-resistant organisms and healthcare- patients with septic shock often present a more distinct hemo-
acquired infections,21 and a surge in sepsis surveillance22,23 are dynamic profile when compared with adults. By monitoring 50
also contributing to an increase in rates of sepsis. children with fluid-refractory septic shock using pulmonary
Although the specific incidence and outcomes of severe sepsis artery catheters, Ceneviva et al. found that the majority (58%)
in children with pre-existing heart disease have not been well had primary myocardial dysfunction with low cardiac index
studied, the presence of an underlying cardiac comorbid condi- and high systemic vascular resistance, referred to as “cold
tion is a consistent risk factor in epidemiologic studies, particu- shock,” while only 20% had the more classic findings of vas-
larly in younger patients.11,13 Hartman et al. found that cular dysfunction with high cardiac index and low systemic
approximately 15% of infants hospitalized in the United States vascular resistance, referred to as “warm shock.”33 These find-
with severe sepsis had CHD.6 In the SPROUT study, 24% of ings are in contrast to the hemodynamic profile of 53 adults
PICU patients being treated for severe sepsis had a pre-existing treated with septic shock in which the majority presented with
cardiovascular comorbidity, even after excluding patients who warm shock.34 Although decreased myocardial contractility is
had undergone recent CPB.14 In a retrospective study from the common in adults and children, the underlying pathobiological
Pediatric Health Information Services database of 49,153 PICU difference is that older patients have left ventricular dilation
patients with severe sepsis, the most common comorbidity was that preserves stroke volume under stress, while neonates and
cardiac (27%). Of the 7,074 sepsis deaths, 37% occurred in chil- infants possess a limited ability to increase stroke volume.
dren with heart disease. After controlling for other potential con- They instead rely on a limited increase in heart rate to augment
founders, the odds of mortality were significantly higher in cardiac output in sepsis.35
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Second, although both children and adults can develop acute peripheral pulses, and narrow pulse pressure), or hypotension.42
lung injury from sepsis, children are especially vulnerable to The utility of other biomarkers, such as lactate and procalcitonin,
respiratory failure during critical illness owing to several unique can further aid in the diagnosis of sepsis, although data in pediatric
anatomic and physiological features. Young children have fewer patients remains limited.43,44 In children with CHD, the utility of
alveoli, immature inter-alveoli channels, and a more compliant procalcitonin and other plasma cytokines is further challenged by
chest wall that increases the risk for atelectasis. The rib cage is the sterile inflammatory response after CBP, though maintenance
also more horizontal compared with adults, which diminishes of an elevated procalcitonin level beyond 4 days or a second
the ability for young children to generate negative intra-thoracic increase have been associated with postoperative infections.45,46
pressures in the presence of poor lung compliance.36 The point The difficulty in distinguishing early signs of sepsis in chil-
of maximal airway resistance is also more distal, leaving young dren with CHD likely impacts timing of antibiotic administra-
children more vulnerable to airway edema from capillary leak, tion and may delay efforts to reverse septic shock. Longer time
left ventricular dysfunction, and inflammation. to antibiotic initiation is associated with increased mortality in
Third, several pathobiologic phenotypes have been described young infants with culture-proven sepsis, including those with
in children with sepsis.37 Similar to adults, some children with CHD.47 Moreover, while many children with CHD have pre-
sepsis evolve toward an immune-suppressed phenotype with served myocardial function or are dependent upon adequate pre-
increased vulnerability to secondary infections. However, a sub- load (eg, those with a total cavopulmonary anastomosis),
set of children also develop a sustained hyperinflammatory clinicians can be reluctant to administer fluid resuscitation for
response with high blood ferritin, cytopenias, hypofibrinogene- fear of “fluid overload,” start vasopressors for fear of increasing
mia, and hyperbilirubinemia that mimics secondary hemopha- afterload, or administer supplemental oxygen for fear of wors-
gocytic lymphohistiocytosis/macrophage activation syndrome. ening left-to-right shunt. Although the impact of variability in
These children may benefit from immunosuppressive therapy, resuscitation on patient outcomes is difficult to fully assess,
including anakinra, methylprednisolone, or intravenous immu- such factors may contribute to the higher risk of adverse out-
noglobulin.38,39 Another phenotype described in pediatric sepsis comes among children with CHD who develop sepsis. Until fur-
is thrombocytopenia-associated multiple organ failure ther data are available, it is the authors’ opinion that sepsis
(TAMOF), which is a microangiopathy caused by depletion of resuscitation for children with heart disease should follow the
ADAMTS-13 leading to accumulation of ultra-large von Wille- general recommendations for children without heart disease
brand factor multimers that cause microvascular obstruction. (see Table 2) with the addition of early consultation with a pedi-
Children with TAMOF may benefit from daily plasma atric cardiologist or cardiac intensivist.
exchange.40
Hemodynamic Management of Pediatric Sepsis
Recognizing Sepsis in Children with Heart Disease
The ACCM published its most recent update of hemody-
The systemic inflammatory response to cardiac surgery— namic management guidelines for neonatal and pediatric septic
CPB, in particular—overlaps with the SIRS response in sepsis, shock in 2017.42 The cornerstones of management include (1)
with fever, tachycardia, tachypnea, and leukocytosis common in early recognition of abnormal tissue perfusion with restoration
both scenarios. This overlap poses a challenge to both early of cardiovascular function using intravenous fluids and vasoac-
diagnosis and accurate epidemiologic estimates of pediatric sep- tive medications to optimize oxygen delivery to vital organs;
sis in cardiac intensive care. Moreover, the application of (2) infectious source control through prompt administration of
consensus definitions for cardiovascular and respiratory dys- empirical, broad-spectrum antibiotics and removal of infec-
function is problematic for neonates and infants with a signifi- tious foci not amenable to antimicrobial therapy alone; and (3)
cant cardiac shunt who may have baseline low blood pressure intensive supportive care of organ dysfunction. Current pediat-
(particular diastolic hypotension) owing to “steal” through an ric sepsis management bundles are largely applicable to chil-
open ductus arteriosus, hypoxia from pulmonary overcircula- dren with pre-existing congenital and acquired heart disease,
tion, or cyanosis from right-to-left shunt. A recent multicenter with some special considerations (Tables 2 and 3).
study of 2,594 children treated for infection in mixed pediatric/ Fluid resuscitation is generally the preferred initial interven-
cardiac ICU demonstrated that a pediatric Sequential Organ tion to restore perfusion, with crystalloid fluid boluses of
Failure Assessment and the Pediatric Logistic Organ Dysfunc- 20 mL/kg being administered rapidly. However, the ACCM
tion score-2 predicted mortality with higher discrimination com- guidelines acknowledge that subgroups of children with septic
pared with consensus SIRS criteria,41 but these findings need to shock may require a differential approach to fluid resuscita-
be validated in a dedicated pediatric cardiac population. tion.42 In particular, children with evidence of pre-existing
The American College of Critical Care Medicine (ACCM) myocardial dysfunction or newly acquired sepsis-induced car-
guidelines emphasize that septic shock should be diagnosed by diomyopathy may benefit from early initiation of inotropic
clinical signs, including abnormal temperature, tachycardia, medications over high-volume fluid resuscitation.42 Still, early
altered mental status, peripheral vasodilation (warm shock as indi- fluid administration can be beneficial in patients with myocar-
cated by “flash” capillary refill, bounding pulses, or diastolic dial dysfunction because these patients can benefit from an ini-
hypotension with wide pulse pressure) or vasoconstriction (cold tial increase in intravascular volume to optimize preload. For
shock as indicated by delayed capillary refill >3 seconds, weak example, although a more conservative strategy of fluid
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Table 2
Pediatric Sepsis Management Bundles With Special Considerations for Children With Congenital or Acquired Heart Disease

Recommended Management in Pediatric Septic Shock* Special Considerations for Children With Heart Disease

Recognition Bundle
Screen patient for septic shock using a trigger tool Unique baseline physiology with deviations in resting vital signs from age-
based norms in children with heart disease may diminish utility of some
trigger tools
Clinician assessment within 15 min for a positive sepsis screen No change
Initiate Resuscitation Bundle within 15 min of clinician confirmation of No change
suspected septic shock
Resuscitation Bundle
Attain IV/IO access within 5 min No change, though peripheral IV access may be especially challenging
Fluid resuscitation within 30 min Smaller fluid boluses (eg, 5-10 mL/kg) with frequent reassessment are prudent
in children with suspected myocardial dysfunction, valvular insufficiency,
obstructive lesions, or other risks for pulmonary edema. However, early fluid
administration can be beneficial in patients with heart disease because many
of these patients will benefit from increased intravascular volume to
optimize preload
Initiation of broad-spectrum empiric antibiotics within 60 min No change, other than to consider increased risk for hospital-acquired and
multidrug-resistant pathogens and potential for surgical site infections and
endocarditis
Begin peripheral or central inotrope infusion for fluid-refractory shock Early echocardiographic evaluation for impaired contractility, cardiac shunt,
within 60 min valvular insufficiency, arrhythmias, pulmonary hypertension, pericardial
effusion, and anatomic obstruction can help to guide management
Stabilization Bundle
Use multimodal monitoring to optimize and obtain hemodynamic goals Unique goals (eg, lower SpO2 and higher hemoglobin) may need to be
established. Nonsinus tachyarrhythmias are more common in children with
heart disease and should be considered in the evaluation for sustained
tachycardia and altered perfusion.
Confirm administration of appropriate antimicrobial therapy and source Attention to increased risk for hospital-acquired and multidrug-resistant
control pathogens and potential, possible surgical site infections and endocarditis,
and potential infection of foreign material (eg, prosthetic heart valves and
patch materials)

Abbreviations: IO, intraosseous; IV, intravenous; SpO2, oxygen saturation measured by pulse oximetry.
* Adapted from Davis et al.42

administration is commonly used for adults with known sensitive than fractional shortening or ejection fraction in detecting
congestive heart failure during septic shock, these patients impaired ventricular contractility.51,52 Moreover, in patients with
appeared to benefit from rapid fluid administration.48 pre-existing cardiac disease, evaluation for impaired contractility,
Ideally, resuscitation should be directed to measurable hemody- cardiac shunt, valvular insufficiency, arrhythmias, pulmonary
namic targets, with limits to further fluid administration if pulmo- hypertension, pericardial effusion, and anatomic obstruction should
nary rales or hepatomegaly develop. The ACCM recommends a be conducted as early as possible. Abnormal electrolyte values,
goal cardiac output of 3.3-6.0 L/min/m2 and age-appropriate perfu- especially hypoglycemia and hypocalcemia, and hypoxemia should
sion pressure (mean arterial pressure minus central venous pressure also be corrected as part of the initial resuscitation.42
[CVP] target of 55 + 1.5 £ age in years to maximum of 65 One major change from the 200753 to the 2017 ACCM guide-
mmHg).42 However, these parameters may not be routinely mea- lines42 is the general preference for epinephrine versus dopa-
sured, especially early in the course of resuscitation. CVP is contro- mine as the first-line vasoactive agent. Cold shock is more
versial and often not present early in the course of resuscitation, but common in pediatric sepsis because young children have a lim-
can also be used to identify patients unlikely to benefit from further ited capacity to augment stroke volume through acute dilation
fluid administration if CVP rises in the absence of a simultaneous of the left ventricle as observed in adult sepsis,33 and epineph-
improvement in peripheral perfusion or perfusion pressure. Notably, rine provides potent inotropy and chronotropy. Recently, 2
for those children who have undergone a cavopulmonary anastomo- small randomized clinical trials have demonstrated improved
sis, CVP more likely reflects transpulmonary (eg, Glenn or Fontan) mortality with initial titration of epinephrine over dopamine for
pressures rather than venous pressure, and thus should be inter- children with fluid-refractory septic shock.54,55 Dopamine also
preted with even greater caution. Early application of bedside ultra- has several potential adverse immunologic and endocrine
sound or echocardiography can be used to more precisely titrate effects, as well as an increased risk for supraventricular arrhyth-
fluid and vasoactive management compared with clinical signs mias in adults.56 Although cardiac rhythm disturbances are less
alone because direct assessments of volume status and myocardial common in children overall, those with pre-existing cardiovas-
contractility can be made serially and noninvasively.49,50 In particu- cular disease should be considered a higher-risk group, although
lar, incorporation of strain echocardiography appears to be more no data are available about the relative potential of dopamine
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Table 3
Special Considerations in the Recognition, Initial Resuscitation, and Stabilization of Children With Sepsis by Type of Congenital or Acquired Heart Condition

Condition Recognition Resuscitation Stabilization

Left-to-right cardiac shunt (eg, VSD, Usual age-based values to indicate Consider small fluid boluses Targets for heart rate and blood
PDA) SIRS and hypotension may be (eg, 5-10 mL/kg) with frequent pressure may need to be modified
unreliable owing to baseline, reassessment; perform early from usual age-based normal
tachycardia, tachypnea and echocardiography values
diastolic hypotension
Cyanotic CHD with single-ventricle Baseline cyanosis may be Cautious administration of Targets for hemoglobin, SpO2, and
before cavopulmonary anastomosis exaggerated in presence of fever supplemental oxygen; consider ScvO2 may need to modified from
(eg, HLHS with Blalock-Tausig and SIRS small fluid boluses (eg, 5-10 usual age-based normal values;
Shunt) mL/kg) with frequent Attention to possible surgical site
reassessment; perform early infections including potential
echocardiography infection of foreign material
CHD with single-ventricle after Baseline cyanosis may be Fluid boluses to restore euvolemia as CVP may be measuring Glenn or
cavopulmonary anastomosis (eg, exaggerated in presence of fever hypovolemia will reduce passive Fontan pressures rather than
HLHS with Glenn or Fontan) and SIRS pulmonary blood flow and increase venous pressure
cyanosis
Left or right ventricular outflow tract Hypotension may be present early in Consider small fluid boluses Attention to possible surgical site
obstruction sepsis (eg, 5-10 mL/kg) with frequent infections including potential
reassessment; perform early infection of foreign material
echocardiography
Valvular stenosis Hypotension may be present early in Consider small fluid boluses Consider at increased risk for
sepsis (eg, 5-10 mL/kg) with frequent endocarditis
reassessment; perform early
echocardiography
Valvular regurgitation Hypotension may be present early Consider small fluid boluses Consider at increased risk for
and wide pulse pressure may be (eg, 5-10 mL/kg) with frequent endocarditis
evident despite normal to high reassessment; perform early
SVR echocardiography
Arrhythmia Usual age-based values to indicate Cautious use of catecholamine Nonsinus tachyarrhythmias are more
SIRS may be unreliable owing to vasoactive infusions, as these may common in children with heart
increased or decreased heart rate exacerbate arrhythmias (especially disease and should be considered
and/or abnormal rhythm dopamine); aggressive in the evaluation for sustained
normalization of electrolytes; seek tachycardia and altered perfusion
early cardiology expertise

Abbreviations: CHD, congenital heart disease; CVP, central venous pressure; HLHS, hypoplastic left heart syndrome; PDA, patent ductus arteriosus; ScvO2,
central venous oxygen saturation; SIRS, systemic inflammatory response syndrome; SpO2, oxygen saturation measured by pulse oximetry; SVR, systemic vascular
resistance; VSD, ventricular septal defect.

versus other vasoactive agents to induce arrhythmias in pediat- dysfunction can be unmasked. The addition of inotropic sup-
ric sepsis. Warm shock is more common in hospital-acquired port, such as epinephrine, dobutamine, or milrinone, may be
sepsis, particularly in older children and adolescents with beneficial in this scenario. Moreover, Ranjit et al. showed that
indwelling central venous catheters.57 For this subset of patients, some children with cold septic shock had relative vasodilation
norepinephrine as a vasopressor is the preferred first-line vaso- responsive to the addition of vasopressors such as norepineph-
active agent.42 Other vasopressor options include higher doses rine in addition to inotropes.49
of epinephrine and dopamine. Although it can augment blood For patients with impaired perfusion despite fluid resuscitation
pressure in children with vasodilatory shock after cardiac sur- and vasoactive titration, additional rescue therapies include red
gery,58 vasopressin should be considered only after a failed blood cell (RBC) transfusion, corticosteroids, and ECMO. The
response to catecholamines because it has not yet demonstrated role for ECMO will be discussed later in the section titled
benefit in pediatric sepsis.59 Mechanical Circulatory Support. The intended benefit for RBC
Although the 2017 ACCM guidelines continue to dichoto- transfusion is to augment the oxygen-carrying capacity of blood
mize cold versus warm shock based on clinical signs, recent when cardiac output is limited. Although clearly beneficial in
studies using multimodal monitoring have demonstrated that hemorrhagic shock, the optimal use of RBC transfusion in septic
some patients with clinical signs of warm shock may have shock is not clear. After publication of the landmark Early Goal-
underlying myocardial dysfunction during sepsis.49 Often this Directed Therapy study by Rivers et al. in 2001, a hemoglobin
pathophysiology is manifested first when vasopressors such as threshold of 10 g/dL was commonly adopted for adult septic
norepinephrine are initiated to increase a presumably low sys- shock.60 In pediatric septic shock, de Oliveira et al. demonstrated
temic vascular resistance in children with warm extremities, a similar benefit in children without CHD.61 More recent studies,
bounding pulses, “flash” capillary refill, and low diastolic however, support the safety and efficacy of a lower hemoglobin
blood pressure. Once vascular tone is increased, myocardial threshold closer to 7 to 7.5 g/dL for acyanotic, nonbleeding
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patients.62,63 Children with cyanotic CHD may benefit from decreased after VV-ECMO initiation, hemodynamics often
transfusion to a hemoglobin closer to their baseline, though improve. Data from 4,332 pediatric ECMO runs for sepsis in
recent guidelines recommend using degree of cardiopulmonary the Extracorporeal Life Support Organization registry between
reserve and end-organ function rather than solely relying on a 1990 and 2008 found that overall survival was higher in VV-
predetermined hemoglobin level to guide transfusion.64 ECMO (79%) compared to VA-ECMO (64%, p < 0.001) in
Although RBC transfusion can increase blood oxygen content, patients without CHD. The increased risk of mortality in VA-
adverse effects can occur (eg, transfusion-related acute lung ECMO persisted after controlling for age, use of vasoactive
injury, immune suppression, or circulatory overload). Current agents, and advanced respiratory support (adjusted odds ratio
guidelines recommend RBC transfusion for children with septic 2.06, 95% confidence interval 1.74-2.44).73
shock and hemoglobin <10 g/dL with evidence of impaired oxy- The optimal timing, site of cannulation, and flow rate for ECMO
gen delivery (eg, mixed venous oxygen saturation <70% or in pediatric septic shock remains unclear. Some have suggested
hyperlactatemia) despite optimal fluid and vasoactive titration.42 that early initiation of VA-ECMO with supra-physiological flow
In hemodynamically stable children, however, RBC transfusion rates obtained through central transthoracic cannulation may be
is not recommended if hemoglobin concentration is 7 mg/dL.64 superior to lower flow rates generally obtained though peripheral
Hydrocortisone is indicated for children in septic shock with cannulation sites. For example, a single-center study from Australia
absolute adrenal insufficiency, including those with congenital reported 74% survival using central transthoracic VA-ECMO.74
adrenal hypoplasia, recent exposure to exogenous corticoste- Other types of mechanical support, including ventricular assist
roids, and meningococcemia. However, treatment with hydro- devices, are generally not recommended for acute sepsis, though
cortisone in other patients, who may have relative adrenal these may have a role for children who develop severe, persistent
insufficiency or critical illness-induced relative corticosteroid myocardial dysfunction after clearance of the inciting infection.
insufficiency, remains controversial.65 Observational studies
have demonstrated either no benefit66,67 or an association of
worse outcomes with hydrocortisone in pediatric septic Anesthetic Management of Children with Sepsis
shock.14,68 In adults, 2 large randomized studies of corticoste-
roid therapy were recently published. In the Activated Protein C Some children with sepsis require urgent or emergent sur-
and Corticosteroids for Human Septic Shock (APROCCHSS) gery, most commonly as part of infectious source control, under
trial, 90-day mortality was lower in adults with vasopressor- the care of an anesthesiologist. An anesthesiologist is trained to
dependent shock who received hydrocortisone plus fludrocorti- rapidly manage critical situations. Experience with monitoring
sone,69 although in the Adjunctive Corticosteroid Treatment in and resuscitation and an understanding of the impact of sepsis
Critically Ill Patients with Septic Shock (ADRENAL) trial, on both the pathophysiology of various organ systems and drug
there was no change in 90-day mortality with treatment with effects make the anesthesiologist ideally suited to meet the mul-
hydrocortisone alone.70 However, in the ADRENAL study, the tifaceted challenges present in children with sepsis who require
group randomized to hydrocortisone achieved faster time to surgery. The anesthesiologist’s priority should be to achieve
shock resolution and shorter ICU length of stay. There are no short-term survival while enabling the patient to get maximum
large randomized trials of corticosteroids in pediatric septic benefit from the procedure. The outcome from the procedure is
shock, though a small pilot study did suggest feasibility71 and a improved if the child’s condition is optimized preoperatively
multicenter pediatric trial will begin soon (Table 3). Until fur- using the guidelines discussed above.
ther data are available, guidelines recommend hydrocortisone, For children who present to the operating room with a natural
100 mg/m2/d for children with septic shock, including those airway, it is critical to ensure adequate monitoring, vascular
with pre-existing heart disease that is unresponsive to fluid and access, and volume resuscitation prior to induction of anesthe-
initial catecholamine therapy.42,65 sia. Sedation, analgesia, and institution of positive pressure ven-
tilation may cause a profound reduction in preload in a
Mechanical Circulatory Support hypovolemic patient and result in hemodynamic instability with
intubation. Isotonic crystalloid and vasoactive infusions need to
Mechanical circulatory support with venoarterial (VA)- be ready for immediate use. Induction with ketamine, which
ECMO is recommended for fluid-refractory, catecholamine- maintains relative cardiovascular stability, is preferred.42 How-
resistant pediatric septic shock. A recent report from the Pedi- ever, some patients with profound shock who are
atric Health Information Services database found that 9.8% of “catechoamine depleted” are at risk for ketamine-induced car-
children with severe sepsis were treated with extracorporeal diovascular collapse. Etomidate maintains cardiovascular stabil-
therapies, including ECMO, with a trend toward increased uti- ity but carries significant risk of inhibiting cortisol formation
lization over time (6.9% in 2004 to 10.3% in 2012). Overall and precipitating adrenal insufficiency,75 and observational
mortality for sepsis patients treated with ECMO was 47.8%, studies have raised concern that a single dose of etomidate for
but increased to 58% for those treated with ECMO and renal intubation may be associated with worse outcomes.76,77 There-
replacement therapies.72 fore, current recommendations discourage use of etomidate for
Venovenous (VV)-ECMO also can be effective in a subset intubation of children with sepsis.42 Induction with high-dose
of patients in whom the use of high mean airway pressures is benzodiazepines, barbiturates, and propofol can result in hypo-
driving hemodynamic compromise. Once ventilator support is tension and should also be avoided.
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Table 4
Current Clinical Trials Involving Children With Sepsis

Study Name Clinicaltrials.gov Reference No. Intervention CHD Included?

SQUEEZE NCT03080038 Fluid-sparing resuscitation versus usual care Yes

Stress Hydrocortisone In Pediatric Septic Shock NCT03401398 Adjunctive hydrocortisone versus placebo for fluid Yes
(SHIPSS) and vasoactive refractory septic shock
Age of Blood in Children in Pediatric Intensive Care NCT01977547 Transfusion of RBCs stored
7 d versus standard Yes
Units (ABC-PICU) issue RBCs
Life After Pediatric Sepsis Evaluation (LAPSE) NCT01415180 Measurement of health-related quality of life after Yes
sepsis
GM-CSF for Reversal of immunopAralysis in NCT03769844 Open label administration of GM-CSF in children Yes
pediatriC sEpsis-induced MODS Study (GRACE) with sepsis and immunoparalysis

Abbreviations: CHD, congenital heart disease; GM-CSF, granulocyte-macrophage colony stimulating factor; MODS, multiple organ dysfunction syndrome; RBC,
red blood cell.

Given these considerations, the preferred approach is to use markers of early infection that distinguish evolving sepsis
either ketamine or fentanyl as the primary induction agent for from a sterile SIRS response after surgery, especially CPB.
anesthesia in children with sepsis with and without heart dis- This may include how best to incorporate procalcitonin or
ease. Careful titration starting with a low dose and then other biomarkers to stratify children by risk of infection. Sec-
increasing based on the patient’s response is essential. How- ond, the most advantageous approach to fluid, vasoactive, and
ever, there are no data to show that one anesthetic agent or hydrocortisone therapy remains unclear. It is likely that chil-
combination of agents makes a difference in the outcome of dren with congenital or acquired heart disease may require a
the child with or without CHD. more tailored approach to resuscitation compared with chil-
Intraoperative management requires vigilant monitoring dren without heart disease who have a lower risk of arrhyth-
coupled with ongoing volume resuscitation, titration of vaso- mia, valvular disease, myocardial dysfunction, pulmonary
active agents, respiratory support, and correction of electro- hypertension, and anatomic obstruction. Third, the optimal
lytes and coagulation profile abnormalities. Attention must RBC transfusion practice needs refinement. For example,
be paid to the possibility of sepsis-associated myocardial although there is evidence that a restrictive transfusion practice
dysfunction that may be superimposed on the physiological for children without CHD is safe,79 the timing of packed red
derangements of any pre-existing cardiac abnormalities, blood cell transfusion for those with cyanotic CHD who
both of which are impacted by anesthesia and surgery, develop sepsis requires specific attention.64 Lastly, a better
including blood loss and hypothermia. On completion of the understanding of the impact of sepsis on long-term neurocog-
surgical procedure, the septic child should be stabilized in nitive outcomes for children with CHD who are already at-risk
the operating suite and then transitioned to care in a pediatric for impaired development is needed.
or cardiac ICU with a thorough handoff of the child’s current
status and response to intra-operative pharmacologic and
Conclusions
surgical interventions.
Children with pre-existing congenital or acquired heart dis-
Sepsis remains an important public health problem in children,
ease are at higher risk of risk of anesthetic complications, par-
especially in those with congenital or acquired heart disease who
ticularly those infants with a single functional ventricle and
have a higher baseline risk of developing sepsis and worse out-
patients with severe pulmonary hypertension, left ventricular
comes after sepsis arises. Although the management of severe
outflow tract obstruction, or dilated cardiomyopathy. Specific
sepsis and septic shock in children with heart disease should
considerations for such patients who require noncardiac sur-
account for known impairments in contractility, cardiac shunt,
gery have been reviewed previously.78 For children with heart
valvular insufficiency, arrhythmias, pulmonary hypertension,
disease who require surgery during sepsis, early involvement
pericardial effusion, anatomic obstruction, the basic principles of
of experts in pediatric cardiac anesthesiology and pediatric
therapyearly recognition, restoration of circulating blood vol-
cardiology should be sought when possible.
ume, eradication of the inciting infection, and supportive care of
organ dysfunctionare generally the same as for children without
heart disease. When children with sepsis require surgery, the
Research Priorities for Children with CHD and Sepsis
anesthesiologist must pay close attention to the acute manage-
ment of shock, altered pharmacology, and ongoing resuscitative
There are many research priorities for children with CHD
and supportive care.
and sepsis. Some of these questions are currently being
addressed in ongoing clinical trials that include children with
CHD (Table 4), but there are no dedicated interventional trials Conflict of Interest
in children with sepsis who have pre-existing heart disease.
First, there is a need to identify more sensitive and specific The authors declare no conflicts of interest.
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