Current Management of Sepsis
According to the World Health Organization, sepsis is the leading cause of death in infants and children worldwide, with an annual mortality of 2.2 million.1 More than 42,000 cases of severe pediatric sepsis occur annually in the United States,2,3 and the majority of these patients are admitted through the emergency department (ED).4 As front-line medical providers, it is essential that emergency physicians be familiar with the recognition and treatment of the septic pediatric patient.
— Ann M. Dietrich, MD, Editor
Executive Summary
- Early-onset sepsis occurs within 72 hours of birth and is often related to maternal infection at the time of birth. Group B Streptococcus (GBS) disease remains the leading cause of morbidity and mortality in this young population; however, GBS sepsis has declined by 80% since the widespread adoption of universal screening for mothers at 35-37 weeks’ gestation and subsequent intrapartum antibiotic prophylaxis.
- Late-onset sepsis is defined as those occurring after 3-7 days of life, with the majority of these nosocomial infections by coagulase negative Staphylococcus, found primarily in hospitalized premature neonates with indwelling catheters and devices. In previously healthy infants, Escherichia coli is now the most common pathogen and a large percentage of these patients also have concurrent E. coli urinary tract infections.
- The patient may require more than 60 mL/kg of fluids in the first hour if tissue perfusion and oxygen delivery remains inadequate.
- Vasoactive agents are recommended for children who remain in shock despite 40-60 mL/kg isotonic fluid therapy.
Definitions
Infection. Infection is defined as a suspected or proven infection caused by a pathogen and diagnosed by culture, tissue stain, or polymerase chain reaction (PCR). A clinical picture demonstrating positive findings on physical examination, imaging, or laboratory tests can also lead to an empiric diagnosis of infection.5
Sepsis and SIRS. Sepsis is historically defined as documented or suspected infection in the presence of systemic inflammatory response syndrome (SIRS)6 (see Table 1). Several of these values pertain only to the adult population, and children are often prone to increased heart rates or respiratory rates for non-specific reasons such as pain, anxiety, dehydration, and agitation. This prompted the International Pediatric Sepsis Consensus Conference (IPSCC) to publish pediatric-specific SIRS criteria in 2005.5 These include age-appropriate values for normal vital signs and emphasis on temperature and leukocyte abnormalities. Pediatric SIRS is defined as meeting two of the four criteria listed in Table 2, one of which must fall into the categories of abnormal temperature or leukocyte count.5
Table 1. SIRS Criteria
SIRS criteria (presence of at least 2 out of 4) |
|
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Table 2. Pediatric SIRS Criteria
Pediatric SIRS criteria (presence of at least 2 out of 4, 1 must be abnormal temperature or leukocyte count) |
|
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Severe Sepsis. Severe sepsis is defined as sepsis in the presence of cardiovascular dysfunction, acute respiratory distress syndrome (ARDS), or dysfunction in more than two organs, including neurologic, renal, hematologic, or hepatic systems (see Table 3).5
Table 3. Criteria of Organ Dysfunction Qualifying for Severe Sepsis
Respiratory |
|
Neurologic |
|
Renal |
|
Hematologic |
|
Hepatic |
|
Cardiovascular |
See Table 4 |
Septic Shock. The definition for pediatric septic shock does not include distinct blood pressure parameters as compared to adults. Blood pressure in children with septic shock is often within the normal range in early stages. Hypotension is a sign of late decompensation, which often happens precipitously.7 Therefore, the IPSCC defines septic shock as sepsis with cardiovascular dysfunction despite intravenous (IV) fluid bolus of > 40 mL/kg in 1 hour and manifesting in at least one of the criteria as defined in Table 4.5
Table 4. Septic Shock Criteria
Cardiovascular Dysfunction (despite fluid bolus > 40 mL/kg in 1 hour) |
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|
|
Epidemiology and Etiology
Incidence of sepsis is 15% higher in males than females.2 Age is one of the most important risk factors, and neonates are the most vulnerable population. Of the estimated 42,000 cases of severe pediatric sepsis per year in the United States, infants (≤ 12 months of age) account for about half of the cases, and neonates with low or very-low birth weight account for half of the cases within this age group (~25% of total cases).3 Mortality is estimated to be 4-10%.2,4
Worldwide, infectious diseases account for more than 2.2 million deaths annually in children under the age of 5 years. The greatest mortality risk is in children living in developing nations, especially during the perinatal period.1 Promoting clean birth and postnatal practices in these countries can help to reduce the incidence of sepsis and the subsequent devastating child mortality.8,9
Early-onset sepsis occurs within 72 hours of birth and is often related to maternal infection at the time of birth. Group B Streptococcus (GBS) disease historically has been the leading cause of morbidity and mortality in this young population. Though it currently remains the predominant organism, GBS sepsis has declined by 80% since the widespread adoption of universal screening for mothers at 35-37 weeks’ gestation and subsequent intrapartum antibiotic prophylaxis.10 Infection in pregnant women with Listeria monocytogenes can cause spontaneous abortion and stillbirth as well as sepsis in the neonate. According to several large studies, pediatric incidence of this disease has also declined drastically.10-12 This may be due to increased regulation and monitoring of food manufacture, as well as public health campaigns educating pregnant women about processed meat consumption.11,13
Late-onset sepsis is defined as those occurring after 3-7 days of life, during which time neonates are rapidly colonized with bacteria that may cause infections. The majority of these are nosocomial infections by coagulase negative Staphylococcus, which are found primarily in hospitalized premature neonates with indwelling catheters and devices.14,15 In previously healthy infants, Escherichia coli is now the most common pathogen to cause bacteremia. A large percentage of these patients also have concurrent E. coli urinary tract infections (UTI).11,12 The second most common pathogen in infants is GBS, followed by Staphylococcus aureus. Other common pathogens include Streptococcus pneumoniae and Neisseria meningitidis. Herpes simplex virus (HSV) also can cause disseminated or central nervous system disease in neonates.
In children older than 1 year, the incidence of sepsis is dramatically decreased as compared to younger children.2 Common organisms in this age group are Streptococcus and Staphylococcus species, N. meningitidis, and fungi. The majority of children with sepsis in this age group have comorbidities that influence their susceptibility to infection. Mortality is greatest for patients with underlying neuromuscular, cardiovascular, and respiratory conditions, as well as HIV infection and neoplastic disorders.2,4 Case fatalities are highest for endocarditis and central nervous system infections.2 Meningococcemia infections (although rare) primarily affect previously healthy patients, while fungal infections are more common in those with comorbidities.2
Overall, the most commonly identified pathogen in severe sepsis is Staphylococcus.2,15 Lobar pneumonia and bacteremia are the most common presentations in children in the United States. More than half of the infants with S. aureus bacteremia also have evidence of skin and soft tissue infection.11 Yet for the vast majority of septic patients presenting to the ED, medical workup never reveals a distinct source of infection.15
Pathophysiology
In the normal host response to infection, when infectious organisms invade the body, innate immune cells like macrophages respond to the source location and initiate a signaling cascade. This activates proinflammatory cytokines and chemokines causing migration to the site of infection and aggregation of polymorphonuclear leukocytes.16 Here, neutrophils release inflammatory mediators, resulting in local vasodilation and increased microvascular permeability, which produces the clinical signs of infection including warmth, erythema, and edema. What follows is a complex process of both proinflammatory and anti-inflammatory mechanisms that promote the killing of bacteria and subsequent phagocytosis of debris from injured tissue. This process is closely regulated so as to sequester the local infection and restore homeostasis to the body.17
Sepsis results when these proinflammatory processes extend beyond the initial site of injury and induce a systemic response. If left unchecked, this systemic immune response eventually leads to organ dysfunction and death. Direct effects of the invading microorganisms and bacterial endotoxin production may further its progression.18
While the exact pathway of sepsis progression is poorly understood, the cellular mechanisms underlying many of its symptoms have been fairly well described. Circulating level of tumor necrosis factor-alpha (TNF-α) and other cytokines increases in response to bacterial endotoxin. This increased level causes fever, hypotension, and coagulation abnormalities associated with septic shock.19,20 The same bacterial endotoxin also initiates the production of vasodilators such as nitric oxide.21 This, in combination with increased vascular permeability and poor arterial vascular tone, further contributes to hypotension.22 Endothelial lesions and circulatory dysfunction lead to tissue ischemia.23 Direct cytotoxicity from mitochondrial injury,24 along with aberrations in the cellular apoptotic mechanisms are also thought to contribute to cell death.
On a macroscopic level, these cellular processes can lead to damage of multiple organ systems. In neonates and infants, septic shock is often characterized by reduced cardiac output and systemic perfusion, though it may present with a "normal" blood pressure because of increased systemic vascular resistance (SVR). Despite inadequate systemic blood flow, septic shock can be associated with a "normal" blood pressure.25 Dysfunctional vasoregulation affects circulation within the kidneys, causing acute renal failure. Changes in microvascular permeability damage lung tissue and lead to pulmonary edema and eventual ARDS.26 The gastrointestinal tract loses its normal barrier function, allowing bacteria and accompanying endotoxin to traverse into bloodstream via lymphatics. Ineffective bacterial clearing in the liver further contributes to systemic spread of infection.26 Finally, septic patients display central nervous system dysfunction and encephalopathy through direct cell injury and microvascular failure.
Clinical Manifestations
Currently there is no diagnostic tool with adequate sensitivity and specificity that allows for early recognition of sepsis. Therefore, treating physicians must rely on clinical suspicion in light of the presenting history, vital signs, and physical examination. It is particularly important to recognize that signs and symptoms of sepsis may be subtle in children, with potential for rapid deterioration if it is unrecognized and intervention is delayed.
Initial symptoms of sepsis can be very nonspecific in young children, such as poor interaction with parents, irritability, crying, drowsiness, lethargy, and confusion. Neonates may present with poor feeding, poor tone, respiratory distress, tachypnea, and diarrhea. Maternal history of prolonged rupture of membranes or chorioamnionitis should increase the clinical suspicion of infection.25
Children with sepsis often present with vital sign abnormalities such as fever, tachycardia, tachypnea, or hypotension. The IPSCC guidelines enumerate age-specific vital signs that define SIRS, which help alert clinicians to the possibility of sepsis in children (See Table 5).5 Nevertheless, diagnosis of sepsis should not be made based on these physiologic and hemodynamic values alone.25
Table 5. Abnormal Age-specific Vital Signs
Age |
Heart Rate (Bradycardia or Tachycardia) |
Respiratory Rate, Breaths/Min |
Systolic Blood Pressure, mmHg |
0 days to 1 wk |
< 100 or > 180 |
> 50 |
< 65 |
1 wk to 1 mo |
< 100 or > 180 |
> 40 |
< 75 |
1 mo to 1 yr |
< 90 or > 180 |
> 34 |
< 100 |
2-5 yrs |
> 140 |
> 22 |
< 94 |
6-12 yrs |
> 130 |
> 18 |
< 105 |
13 to < 18 yrs |
> 110 |
> 14 |
< 117 |
Adapted from: Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2-8.
Unlike adult septic patients who typically present with low SVR and hypotension, children with septic shock may present with "warm" or "cold" shock. Children in "warm shock" have low SVR and present with warm and dry extremities, wide pulse pressure, bounding peripheral pulses and "flash" capillary refill. "Cold shock" is characterized by prolonged capillary refill, cyanosis, diminished pulses, and mottled cool extremities, and is the initial presentation in the majority of children with septic shock.25 The body compensates for decreased intravascular volume by increasing SVR and heart rate, and prioritizes blood flow to maintain central organ perfusion. Although myocardial depression is common and cardiac output is usually low, blood pressure may be normal or even elevated at this stage. These children may show signs of inadequate tissue perfusion including depressed mental status, decreased urine output, dry mucous membranes, lack of tears, and sunken eyes.7,25 As shock progresses, they may rapidly decompensate, resulting in hypotension, which is often a late finding (see Table 6).25
Table 6. Findings in Warm and Cold Shock
Warm Shock |
Cold Shock |
Warm, dry extremities |
Cool, cyanotic extremities |
Bounding peripheral pulses |
Diminished pulses |
"Flash" capillary refill |
Prolonged capillary refill > 2 sec |
Identifying the source of infection in a septic patient can be pivotal in ascertaining effective and appropriate treatment. Clinicians should search for cough, sputum production, pulmonary rales, hypoxemia, dyspnea, abdominal pain, and myalgia. Bone or joint pain may suggest osteomyelitis or septic joint, most often caused by Staphylococcal infections. Neck stiffness is associated with meningitis. Dysuria is concerning for urinary tract infection. Vomiting, diarrhea, and hematochezia suggest gastroenteritis. Presence of an in-dwelling catheter or history of an immunocompromised condition should raise the suspicion of bacterial or fungal infection.14,15,27 Skin ulcerations, cellulitis and abscesses can indicate Staphylococcus, Streptococcus, or Pseudomonas skin infections. A petechial rash deserves special attention from the examiner, especially if it starts to spread or becomes purpuric.28 These findings can indicate meningococcemia and bacterial meningitis, which have an extremely high morbidity and mortality.2
HSV infection in neonates can manifest as mucocutaneous disease, central nervous system (CNS) disease, or disseminated disease. Mucocutaneous disease account for approximately 45% of HSV infections in neonates.29 Typical findings are vesicular skin lesions, conjunctival erythema, and ulcerative lesions of the mouth and tongue.30 CNS disease accounts for about one-third of neonatal HSV infections. It typically presents with seizures, lethargy, tremors, and a full anterior fontanelle. Only 60-70% of these patients have evidence of vesicular lesions.29,31 Disseminated disease affects approximately one-fourth of the neonates with HSV. It occurs by direct hematogenous spread, causing infections in the liver, CNS, lungs, adrenals, and skin. More than 20% of those affected do not display skin vesicles, hence making it a challenge to diagnose.29 Respiratory failure and shock are common presentations.30
Diagnostic Approach
The diagnosis of sepsis is made primarily by clinical examination of the child or neonate, but can also be guided by laboratory testing. A bedside blood glucose test should be recorded on any child displaying altered mental status. Blood cultures are the best means to identify a particular bacteria in sepsis, and ideally should be obtained within 45 minutes in any patient with a suspicion for sepsis and before antibiotic administration.32 It is recommended that cultures be drawn from two separate sites and include both aerobic and anaerobic samples. If the child has an indwelling vascular catheter that was placed > 48 hours before presentation, then a culture should be taken from the device.32 Urinalysis and urine cultures should be part of the workup for neonates with late-onset sepsis as well as older infants and children. Routine urine culture is not needed for a workup of early onset sepsis (age < 72 hours), as early urinary tract infections are not accompanied by bacteremia.33 In low-resource settings where culture is unavailable, the presence of bacteriuria on Gram stain may be used to diagnose UTI in septic neonates.34 Scrapings or swabs from skin lesions should be sent for bacterial culture as well as viral culture if HSV is suspected.30 Cerebrospinal fluid (CSF) should be sent for cell count, glucose, protein, and culture if meningitis is a concern. CSF can also be sent for HSV PCR if suspicion is high.30,35 Respiratory secretions and other bodily fluid cultures can be drawn as necessary, but should not delay antibiotic administration. Molecular assay tests, such as PCR, are being investigated as an alternate means of rapid and efficient diagnosis of sepsis. Currently, they lack the appropriate sensitivity and specificity when compared to the gold standard of microbial cultures.36
White blood cell count is useful when applying the SIRS criteria (see Table 7).5 A complete metabolic panel further delineates specific organ dysfunction among the cardiovascular, renal, and hepatic systems.5 Abnormalities within coagulation panels heighten suspicion for hematologic disturbances and disseminated intravascular coagulation.
Table 7. Abnormal WBC Values
Age |
Leukocytes × 103/mm3 |
0 days to 1 wk |
> 34 |
1 wk to 1 mo |
> 19.5 or < 5 |
1 mo to 1 yr |
> 17.5 or < 5 |
2-5 yrs |
> 15.5 or < 6 |
6-12 yrs |
> 13.5 or < 4.5 |
13 to < 18 yrs |
> 11 or < 4.5 |
Adapted from: Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2-8
In the pediatric population, the utility of ED-drawn serum lactic acid level is controversial. A small study found that serum hyperlactatemia was predictive of sepsis mortality in the intensive care unit (ICU).37 Another study of pediatric patients with SIRS in the ED found that early hyperlactatemia (≥ 4.0 mmol/L) was significantly associated with increased risk of 24-hour organ dysfunction (sensitivity 31%, specificity 94%). Patients with hyperlactatemia were also at a significantly increased risk of receiving ≥ 40 mL/kg of IV fluid resuscitation and admission to the ICU.38 On the contrary, other studies have found that a lactic acid level drawn in the ED lacked utility in the initial diagnosis of sepsis and had little predictive value.15,39
Biomarkers that correlate with inflammatory states are the subjects of ongoing investigation and research. C-reactive protein (CRP), procalcitonin, and cardiac troponins have been identified as having some clinical value in the management and prognosis of a septic patient. Unfortunately, none of them has adequate sensitivity or specificity to qualify as a standalone test in the diagnosis of pediatric sepsis.
CRP is an acute phase reactant that has low sensitivity during early infection but improves with serial tests, peaking at 48 hours.40 An elevated CRP level of > 1 mg/dL at symptom onset has a sensitivity of 62% in diagnosing late-onset sepsis. However, when drawn the morning after presentation, sensitivity increases to 84%, which further increases to 98% two mornings after symptom onset. Specificity is 69% on initial workup, increasing to 75% then decreasing to 61% at day 2 and day 3, respectively.41 A CRP of < 1 mg/dL drawn at 24-48 hours after the start of antibiotic therapy has also been shown to have a negative predictive value of 99% in identifying neonates who are not infected.41,42 Hence, the utility of CRP lies primarily in monitoring a patient’s response to antibiotic treatment and ruling out infection. Its utility in the ED is quite limited.15,41
Procalcitonin is produced in the C-cells of the thyroid. Its level rises with systemic inflammatory states produced by bacterial endotoxin exposure, and tends to do so more rapidly than CRP. In a study of pediatric patients presenting to the ED with fever and requiring central venous catheters, a high level of procalcitonin was more predictive of positive blood cultures. An ED procalcitonin level of < 0.3 ng/mL also had a sensitivity of 93% and a specificity of 63% in predicting negative blood cultures.43 Nevertheless, a recent meta-analysis found that procalcitonin at presentation was only 81% sensitive and 79% specific in diagnosis of neonatal sepsis.44
Cardiac troponins have been shown to predict longer hospitalization and mechanical ventilation, but are not associated with increased mortality.45 Troponins may also be beneficial for screening children complaining of chest pain associated with electrocardiogram (EKG) abnormalities and fever.45
Plasma cytokines and pancreatic stone protein are additional biomarkers associated with inflammatory states. Current investigations into these markers may provide potential future benefit in diagnosis and management of sepsis.46-49
Imaging studies may also help identify the infectious source, but should only be pursued once the patient is stable after initial resuscitation and antibiotic therapy. A chest radiograph may reveal respiratory pathology, abdominal computed tomography (CT) or ultrasound can further delineate intra-abdominal etiologies, and brain imaging such as CT or magnetic resonance imaging (MRI) may show abnormalities in patients with CNS infections.31 Echocardiography may reveal a source of infection (e.g., bacterial endocarditis) or provide valuable information to help guide hemodynamic management of the patient.
Differential Diagnosis
It is important to consider alternate, non-infectious diagnoses when evaluating a septic-appearing child. Congenital heart diseases dependent on blood flow through a patent ductus arteriosus typically present in the first days to weeks after birth. Patients may present with dyspnea, hypoxemia, mottled or cyanotic skin color, and lethargy. Administration of prostaglandin E1 (PGE1) can keep the ductus open and temporarily stabilize the patient. An undiagnosed cardiac arrhythmia such as supraventricular tachycardia may also present with similar symptoms. Adrenal crisis often presents with vomiting, diarrhea, and hypotension. Lab abnormalities of hypoglycemia, hyponatremia, and hyperkalemia can be clues to this diagnosis, which most often is due to congenital adrenal hyperplasia in the neonate. In this case, a stress dose of hydrocortisone will be life saving. Diabetic ketoacidosis, hypothyroidism, inborn errors of metabolism, seizures, and hyperbilirubin encephalopathy should also be included in the differential diagnosis. Intra-abdominal pathology, such as midgut volvulus, intussusception, and necrotizing enterocolitis, can present with vomiting and symptoms suggestive of sepsis. Non-accidental injury causing increased intracranial pressure can cause an infant to display lethargy, poor feeding, altered mental status, and at times vital sign instability. Environmental toxic exposures, hyperthermia, and accidental water intoxication are additional causes of poor mentation and SIRS.
Treatment/Management
Active and early use of the Pediatric Advance Life Support (PALS) algorithm has been shown to reduce mortality and morbidity in these patients.50,51 In a retrospective study following children and infants diagnosed with septic shock in community hospitals, it was found that each hour delay of shock reversal was associated with a more than two-fold increase in the odds of mortality.50
In light of these results, the American College of Critical Care Medicine (ACCM) has developed guidelines and an algorithm (see Figure 1 and Table 8) for a timed systematic approach to treating the septic child, which includes antibiotic administration within the first hour. These treatment goals are also emphasized in the 2012 Surviving Sepsis Campaign.25,32
Table 8. PICU Septic Shock Management
Attain normal MAP, CVP, and ScvO2 > 70%
Cold Shock with Normal Blood Pressure |
Cold Shock with Low Blood Pressure |
Warm Shock with Low Blood Pressure |
Titrate fluid and epinephrine, |
Titrate fluid and epinephrine, |
Titrate fluid and norepinephrine, |
If still hypotensive, consider norepinephrine. |
If still hypotensive, consider vasopressin, terlipressin or angiotensin. |
Adapted 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;37:666-688.
The goal of resuscitation is to restore tissue perfusion rapidly. The physiologic targets include normal mental status, warm extremities, capillary refill ≤ 2 seconds, strong peripheral and central pulses, urine output > 1 mL/kg/hr, and age-appropriate vital sign thresholds (see Table 9).7,25,32 Implementation of an ED pediatric sepsis protocol has been shown to help facilitate timely resuscitation in these patients.52,53
Table 9. ACCM Age-specific Vital Signs Indicating Adequate Resuscitation
Age |
Goal Heart Rate |
Goal Mean Arterial Pressure |
Term newborn |
120-180 |
55 |
Up to 1 year |
120-180 |
60 |
1-2 years |
102-160 |
65 |
2-7 years |
100-140 |
65 |
7-15 years |
90-140 |
65 |
Early goal-directed therapy (EGDT) of septic shock involves intensive hemodynamic monitoring and aggressive resuscitation to achieve end-organ perfusion and cardiovascular stability within the first 6 hours of patient presentation and diagnosis. In a single, prospective, randomized trial, EGDT has been shown to reduce mortality and organ dysfunction in pediatric septic shock patients.54 It is currently part of the recommended ICU shock management algorithm in the 2012 Surviving Sepsis guidelines.
Airway, Breathing, Circulation. After evaluation of the airway, floridly septic patients should be placed on high-flow, humidified oxygen by face mask, nasal cannula, or a positive airway pressure device if needed.25 Breathing can be optimized by placing the child in a sniffing position.7 In a child requiring airway protection or assistance in ventilation and oxygenation, endotracheal intubation should be performed using rapid sequence intubation techniques. Ketamine is the preferred induction agent due to its neutral effect on the adrenal axis and maintenance of cardiovascular stability. Etomidate is not recommended in children with septic shock because of concerns for potential adrenal suppression and subsequent increase in mortality.25 Succinylcholine or rocuronium can be used as a paralytic agent in pediatric patients as long as airway patency is maintained. Tidal volume should be set at 6 mL/kg (ideal body weight) for mechanical ventilation, with low positive end-expiratory pressure, and plateau pressures < 30 cm H2O.32
Intravenous Fluid Therapy. Preferably two large bore IV access should be established within 5 minutes. If unsuccessful, an intraosseous line is recommended.25 Pediatric patients in septic shock are often hypovolemic and require rapid restoration of intravascular volume. Begin with an IV fluid bolus of 20 mL/kg of isotonic crystalloid infused as rapidly as possible. This can be done by pressure bag or even push doses divided up into aliquots. Reassess the child and repeat boluses as needed as long as the child does not have signs of fluid overload, such as hepatomegaly or rales on lung exam. The patient may require more than 60 mL/kg of fluids in the first hour if tissue perfusion and oxygen delivery remains inadequate.25 There is currently no consensus on the treatment of septic children with colloids such as albumin.
In a recent randomized, control trial of 3141 critically ill septic children treated in African hospitals without ICU capabilities, those who received 20-40 mL/kg IV fluid bolus were found to have significantly increased 48-hour mortality.55 In a follow-up to the original trial, it was concluded that mortality was largely due to cardiovascular collapse, with very few events related to overt fluid overload.56 The authors speculated that rapid fluid boluses in the absence of inotropic and pressor support might lead to adverse effects on vascular hemodynamics and myocardial performance. While controversial, it may be advisable to withhold large fluid boluses in children living in low-resource settings who demonstrate febrile illness and signs of shock, without gastroenteritis or transfusion-requiring anemia. This is particularly applicable to children with chronic malnutrition and those suffering from malaria.55,57
Vasoactive Therapy. Vasoactive agents are recommended for children who remain in shock despite 40-60 mL/kg isotonic fluid therapy. These medications can be administered initially through a peripheral or intraosseous line before central access is available, as delays in initiating therapy are associated with an increased mortality risk. For children with the clinical manifestations of "cold shock," such as diminished pulses and cool extremities, dopamine is recommended as the initial agent. The starting dose is usually
5 mcg/kg/min, but it can be titrated up to 10 mcg/kg/min. Infants
< 1 year old may be less responsive to dopamine, due to incompletely developed sympathetic innervation via which dopamine initiates the release of endogenic norepinephrine.25 Epinephrine and norepinephrine should be considered in these cases. If cold shock is resistant to dopamine infusion at 10 mcg/kg/min, the ACCM/Surviving Sepsis guidelines recommend starting epinephrine infusion at a rate between 0.05-0.3 mcg/kg/min. For patients with clinical manifestations of "warm shock" including warm extremities, "flash" capillary refill, and bounding pulses, norepinephrine is the primary agent of choice. Infusion doses starting at 0.03-0.05 mcg/kg/min are recommended.25
Antibiotics. Empiric broad-spectrum intravenous antibiotic therapy should be started within 1 hour of onset of septic shock. If possible, cultures should be obtained before initiation of antimicrobial therapy. Yet antibiotics should never be delayed for this reason.25,32 Antibiotic selection depends on many factors including the patient’s age, comorbidities, clinical presentation, and local disease prevalence patterns. Consultation with a pediatric infectious disease specialist is recommended when making these decisions.
In general, broad-based antibiotic coverage usually includes a third- or fourth-generation cephalosporin in combination with additional antibiotics. Vancomycin provides coverage for methicillin-resistant S. aureus, as it is one of the most common pathogens implicated in severe sepsis.2,15 Pseudomonas coverage with a beta-lactam and aminoglycoside is necessary for children who are immunosuppressed or have high-risk medical conditions.15 If infection from the genitourinary system or the gastrointestinal system is suspected, appropriate coverage for enteric organisms is indicated. When selecting antibiotics for neonates < 28 days old, it is important to consider ampicillin for L. monocytogenes coverage and acyclovir for herpes simplex virus. Multiple antibiotics are often necessary, especially when the source of the infection is unknown. In those patients whom bacterial meningitis infection is suspected, cefotaxime is recommended for patients younger than 30 days and ceftriaxone (given at meningitic dose) for those older than 30 days. Vancomycin should be considered to cover resistant strains of S. pneumoniae. Antimicrobial therapy should be modified according to culture results and changes in the patient’s clinical course.
Therapeutic Adjuncts. Patients who demonstrate continued manifestations of shock despite adequate fluid and vasopressor therapy may have adrenal insufficiency. History of chronic or recent steroid use, a diagnosis of congenital adrenal hyperplasia, hypothalamic or pituitary abnormalities, or evidence of purpura fulminans should heighten clinical suspicion. Stress dose hydrocortisone is recommended in these specific cases, starting at 2 mg/kg/day and titrated up to 50 mg/kg/day for reversal of shock.25 Cortisol stimulation test may help clarify the diagnosis in case of uncertainty, but is generally not feasible in the ED. Congenital heart disease should always be considered in a neonate with sepsis-like presentation and it may be beneficial to administer PGE1 until heart defect is ruled out. For continued refractory septic shock, extracorporeal membrane oxygenation (ECMO) should be considered. Survival for neonates placed on ECMO for septic shock is 80%, while infants and older children have a survival rate of 50%.25
Other therapeutic adjuncts that have shown promise in treatment of septic shock include lactoferrin, pentoxifylline, and granulocyte colony-stimulating factor.58-62 Plasma exchange may also lead to improved outcomes.63 Recombinant activated protein C has not been shown to be effective in the treatment of pediatric sepsis. The drug is no longer on the market and is not recommended for use.64,65
Summary
Early recognition and resuscitation of pediatric septic shock is one of the most challenging and important aspects of emergency care. Rapid fluid boluses of up to and over 60 mL/kg within the first hour is recommended, followed by early addition of pressors and inotropes and possibly corticosteroids for resistant cases. Antibiotics should be initiated in the ED on a timely basis, ideally within 1 hour. Effective management of shock directly affects mortality and functional outcomes in septic pediatric patients.
References
- World Health Organization. Levels and Trends in Child Mortality 2013. Available at: www.who.int/maternal_child_adolescent/documents/levels_trends_child_mortality_2013/en/index.html. Accessed March 4, 2014.
- Watson RS, Carcillo JA, Linde-Zwirble WT, et al. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med 2003;167:695-701.
- Watson RS, Carcillo JA. Scope and epidemiology of pediatric sepsis. Pediatr Crit Care Med 2005;6(3 Suppl):S3-S5.
- Odetola FO, Gebremariam A, Freed GL. Patient and hospital correlates of clinical outcomes and resource utilization in severe pediatric sepsis. Pediatrics 2007;119:487-494.
- Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2-8.
- Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644-1655.
- Kleinman ME, Chameides L, Schexnayder SM, et al. Part 14: Pediatric Advanced Life Support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122(18 Suppl 3):S876-S908.
- Blencowe H, Cousens S, Mullany LC, et al. Clean birth and postnatal care practices to reduce neonatal deaths from sepsis and tetanus: A systematic review and Delphi estimation ofmortality effect. BMC Public Health 2011;11(Suppl 3):S11.
- Imdad A, Bautista RM, Senen KA, et al. Umbilical cord antiseptics for preventing sepsis and death among newborns. Cochrane Database Syst Rev 2013;(5):CD008635.
- Verani JR, McGee L, Schrag SJ, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B streptococcal disease—revised guidelines from CDC, 2010. MMWR Recomm Rep 2010;59(RR-10):1-36.
- Biondi E, Evans R, Mischler M, et al. Epidemiology of bacteremia in febrile infants in the United States. Pediatrics 2013;132:990-996.
- Greenhow TL, Hung YY, Herz AM. Changing epidemiology of bacteremia in infants aged 1 week to 3 months. Pediatrics 2012;129:e590-e596.
- Bennion JR, Sorvillo F, Wise ME, et al. Decreasing listeriosis mortality in the United States, 1990-2005. Clin Infect Dis 2008;47:867-874.
- Marchant EA, Boyce GK, Sadarangani M, et al. Neonatal sepsis due to coagulase-negative Staphylococci. Clin Dev Immunol 2013;2013:586076.
- Gaines NN, Patel B, Williams EA, et al. Etiologies of septic shock in a pediatric emergency department population. Pediatr Infect Dis J 2012;31:1203-1205.
- Movat HZ, Cybulsky MI, Colditz IG, et al. Acute inflammation in gram-negative infection: Endotoxin, interleukin 1, tumor necrosis factor, and neutrophils. Fed Proc 1987;46:97-104.
- Bone RC. Immunologic dissonance: A continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 1996;125:680-687.
- Suffredini AF, Fromm RE, Parker MM, et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989;321:280-287.
- Tracey KJ, Beutler B, Lowry SF, et al. Shock and tissue injury induced by recombinant human cachectin. Science 1986;234:470-474.
- Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985;229:869-871.
- Vincent JL, Zhang H, Szabo C, et al. Effects of nitric oxide in septic shock. Am J Respir Crit Care Med 2000;161:1781-1785.
- De Backer D, Creteur J, Preiser JC, et al. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002;166:98-104.
- Piagnerelli M, Boudjeltia KZ, Vanhaeverbeek M, et al. Red blood cell rheology in sepsis. Intensive Care Med 2003;29:1052-1061.
- Harrois A, Huet O, Duranteau J. Alterations of mitochondrial function in sepsis and critical illness. Curr Opin Anaesthesiol 2009;22:143-149.
- 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;37:666-688.
- Luce JM. Pathogenesis and management of septic shock. Chest 1987;91:883-888.
- Zaoutis TE, Prasad PA, Localio AR, et al. Risk factors and predictors for candidemia in pediatric intensive care unit patients: Implications for prevention. Clin Infect Dis 2010;51:e38-45.
- National Institute for Health and Care Excellence. Bacterial meningitis and meningococcal septicaemia. CG102. London: National Institute for Health and Care Excellence. Available at: http://guidance.nice.org.uk/CG102. Accessed May 27, 2014.
- Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol 2007;31:19-25.
- Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol Rev 2004;17:1-13.
- Toth C, Harder S, Yager J. Neonatal herpes encephalitis: A case series and review of clinical presentation. Can J Neurol Sci 2003;30:36-40.
- Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: International guidelines for management of severe sepsis. Crit Care Med 2013;41:580-637.
- Riskin A, Toropine A, Bader D, et al. Is it justified to include urine cultures in early (< 72 hrs) neonatal sepsis evaluations of term and late preterm infants? Am J Perinatol 2013;30:499-504.
- Samayam P, Ravi Chander B. Study of urinary tract infection and bacteriuria in neonatal sepsis. Indian J Pediatr 2012;79:1033-1036.
- Cantey JB, Mejias A, Wallihan R, et al. Use of blood polymerase chain reaction testing for diagnosis of herpes simplex virus infection. J Pediatr 2012;161:357-361.
- Pammi M, Flores A, Leeflang M, et al. Molecular assays in the diagnosis of neonatal sepsis: A systematic review and meta-analysis. Pediatrics 2011;128:e973-e985.
- Duke TD, Butt W, South M. Predictors of mortality and multiple organ failure in children with sepsis. Intensive Care Med 1997;23:684-692.
- Scott HF, Donoghue AJ, Gaieski DF, et al. The utility of early lactate testing in undifferentiated pediatric systemic inflammatory response syndrome. Acad Emerg Med 2012;19:1276-1280.
- Reed L, Carroll J, Cummings A, et al. Serum lactate as a screening tool and predictor of outcome in pediatric patients presenting to the emergency department with suspected infection. Pediatr Emerg Care 2013;29:787-791.
- Hofer N, Zacharias E, Müller W, et al. An update on the use of C-reactive protein in early-onset neonatal sepsis: Current insights and new tasks. Neonatology 2012;102:25-36.
- Benitz WE, Han MY, Madan A, et al. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998;102:E41.
- Ehl S, Gering B, Bartmann P, et al. C-reactive protein is a useful marker for guiding duration of antibiotic therapy in suspected neonatal bacterial infection. Pediatrics 1997;99:216-221.
- Kasem AJ, Bulloch B, Henry M, et al. Procalcitonin as a marker of bacteremia in children with fever and a central venous catheter presenting to the emergency department. Pediatr Emerg Care 2012;28:1017-1021.
- Vouloumanou EK, Plessa E, Karageorgopoulos DE, et al. Serum procalcitonin as a diagnostic marker for neonatal sepsis: A systematic review and meta-analysis. Intensive Care Med 2011;37:747-762.
- Liesemer K, Casper TC, Korgenski K, et al. Use and misuse of serum troponin assays in pediatric practice. Am J Cardiol 2012;110:284-289.
- Raynor LL, Saucerman JJ, Akinola MO, et al. Cytokine screening identifies NICU patients with Gram-negative bacteremia. Pediatr Res 2012;71:261-266.
- Boeck L, Graf R, Eggimann P, et al. Pancreatic stone protein: A marker of organ failure and outcome in ventilator-associated pneumonia. Chest 2011;140:925-932.
- Keel M, Härter L, Reding T, et al. Pancreatic stone protein is highly increased during posttraumatic sepsis and activates neutrophil granulocytes. Crit Care Med 2009;37:1642-1648.
- Schlapbach LJ, Graf R, Woerner A, et al. Pancreatic stone protein as a novel marker for neonatal sepsis. Intensive Care Med 2013;39:754-763.
- Han YY, Carcillo JA, Dragotta MA, et al. Early reversal of pediatric-neonatal septic shock by community physicians is associated with improved outcome. Pediatrics 2003;112:793-799.
- Carcillo JA, Kuch BA, Han YY, et al. Mortality and functional morbidity after use of PALS/APLS by community physicians. Pediatrics 2009;124:500-508.
- Cruz AT, Perry AM, Williams EA, et al. Implementation of goal-directed therapy for children with suspected sepsis in the emergency department. Pediatrics 2011;127:e758-e66.
- Larsen GY, Mecham N, Greenberg R. An emergency department septic shock protocol and care guideline for children initiated at triage. Pediatrics 2011;127:e1585-e1592.
- de Oliveira CF, de Oliveira DS, Gottschald AF, et al. ACCM/PALS haemodynamic support guidelines for paediatric septic shock: An outcomes comparison with and without monitoring central venous oxygen saturation. Intensive Care Med 2008;34:1065-1075.
- Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364:2483-2495.
- Maitland K, George EC, Evans JA, et al. Exploring mechanisms of excess mortality with early fluid resuscitation: Insights from the FEAST trial. BMC Med 2013;11:68.
- Ford N, Hargreaves S, Shanks L. Mortality after fluid bolus in children with shock due to sepsis or severe infection: A systematic review and meta-analysis. PLoS One 2012;7:e43953.
- Valenti P, Antonini G. Lactoferrin: An important host defence against microbial and viral attack. Cell Mol Life Sci 2005;62:2576-2587.
- Pammi M, Abrams SA. Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst Rev 2011;CD007138.
- Manzoni P, Stolfi I, Messner H, et al. Bovine lactoferrin prevents invasive fungal infections in very low birth weight infants: A randomized controlled trial. Pediatrics 2012;129:116-123.
- Haque KN, Pammi M. Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst Rev 2011;CD004205.
- El-Ganzoury MM, El-Farrash RA, Saad AA, et al. In vivo effect of recombinant human granulocyte colony-stimulating factor on neutrophilic expression of CD11b in septic neonates: A randomized controlled trial. Pediatr Hematol Oncol 2012;29:272-284.
- Qu L, Kiss JE, Dargo G, et al. Outcomes of previously healthy pediatric patients with fulminant sepsis-induced multisystem organ failure receiving therapeutic plasma exchange. J Clin Apher 2011;26:208-213.
- Zeerleder S, Stephan F, Emonts M, et al. Circulating nucleosomes and severity of illness in children suffering from meningococcal sepsis treated with protein C. Crit Care Med 2012;40:3224-3229.
- Kylat RI, Ohlsson A. Recombinant human activated protein C for severe sepsis in neonates. Cochrane Database Syst Rev 2012;CD005385.
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