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INTRODUCTION — The early recognition and initial management of severe sepsis and septic shock in children during the first hour of resuscitation are reviewed here.
The definitions, epidemiology, and clinical manifestations of sepsis in children and ongoing management of children with septic shock are discussed separately. (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis" and "Septic shock: Ongoing management after resuscitation in children".)
DEFINITION — Septic shock refers to sepsis with cardiovascular dysfunction (ie, hypotension, reliance on vasoactive drug administration to maintain a normal blood pressure, or two of the following: prolonged capillary refill, oliguria, metabolic acidosis, or elevated arterial lactate) that persists despite the administration of ≥40 mL/kg of isotonic saline in one hour. Severe sepsis and septic shock are characterized by dysfunction of ≥2 organ systems and cardiovascular dysfunction, respectively . (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Severity'.)
Sepsis is a clinical syndrome complicating severe infection that is characterized by systemic inflammation, immune dysregulation, microcirculatory derangements, and end-organ dysfunction. There is a continuity of severity ranging from sepsis to severe sepsis and septic shock.
RAPID RECOGNITION — A clinical diagnosis of septic shock is made in children who have signs of inadequate tissue perfusion, two or more criteria for the systemic inflammatory response syndrome (table 1), and suspected or proven infection . Rapid recognition of hemodynamic abnormalities and early suspicion of infection are essential to achieve favorable outcomes. As an example, in a prospective cohort study of 91 infants and children presenting to community hospitals with septic shock (defined by hypotension or delayed capillary refill), each hour delay in initiation of appropriate resuscitation or persistence of hemodynamic abnormalities was associated with a clinically significant increased risk of death (odds ratio [OR] 1.5 and 2.3, respectively) . (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Definitions' and "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Severity'.)
With increased attention to rapid recognition, aggressive fluid administration, and early administration of vasoactive agents and antibiotics, pediatric mortality from severe sepsis and septic shock has markedly decreased [3-8].
Inadequate tissue perfusion — Seriously ill patients should undergo urgent evaluation for the following signs of impaired perfusion or shock [2,9]:
●Tachycardia or bradycardia
●Decreased peripheral pulses compared with central pulses
●Mottled or cool extremities
●"Flash" or >3 second capillary refill
●Dry mucus membranes, sunken eyes, and decreased urine output
●Tachypnea, bradypnea, or apnea
●Altered mental status (irritability, anxiety, confusion, lethargy, somnolence, apnea)
●Hypothermia (especially neonates)
Tachycardia and tachypnea are common and non-specific findings in young pediatric patients and may be due to fever, anxiety, dehydration, pain/discomfort, anemia, or agitation. Fever is common in children with a severe infection. In febrile children, the heart rate may be adjusted by deducting approximately 10 beats/minute for every 1°C elevation in temperature. However, persistent tachycardia is a sensitive indicator of circulatory dysfunction and should not be overlooked. (See "Approach to the child with tachycardia", section on 'Vital signs'.)
If a question exists as to whether tachycardia is due to circulatory impairment, a fluid bolus is recommended unless there is evidence for cardiac dysfunction (eg, hepatomegaly, jugular venous distention, S3 gallop, cardiomegaly).
Hypotension is a late sign of cardiovascular dysfunction and shock in pediatric patients and is not necessary to diagnose septic shock. Infants and children with sepsis often maintain blood pressure despite the presence of septic shock through an increase in heart rate, systemic vascular resistance, and venous tone but have a limited capacity to augment myocardial stroke volume. As a result, infants and children are also more likely to exhibit "cold" shock in sepsis compared to the classic presentation of "warm" (or hyperdynamic or vasodilated) shock in adults. (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Shock'.)
Signs of infection — Patients should be simultaneously evaluated for an infectious source to distinguish non-infectious from septic shock. Fever, cough or congestion, dyspnea, hypoxemia, rash, abdominal pain, myalgias, immunocompromising condition (eg, chemotherapy, sickle cell disease, or other known conditions associated with splenic dysfunction or primary immune deficiency), leukocytosis, or leukopenia with thrombocytopenia should raise suspicion for infection (table 2). Other factors concerning for specific infections, such as dysuria (urinary tract infection), hematochezia (gastroenteritis), headache and neck stiffness (meningitis), bone or joint inflammation (Staphylococcus aureus), conjunctival suffusion/injection (toxic shock syndrome), ecthyma (Pseudomonas species) and petechiae/purpura (meningococcemia), should also be quickly ascertained. (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Infection'.)
If an infection is suspected or a non-infectious etiology of shock is not clear, current guidelines recommend obtaining blood, urine, and, as indicated, other cultures and administering empiric broad-spectrum antibiotics within one hour of presentation . Antibiotic therapy should not be delayed beyond one hour in order to obtain cultures if there is a concern for severe sepsis or septic shock. Patients with a recent history of an immunocompromising condition (eg, neutropenia, chemotherapy, sickle cell disease, or primary immune deficiency) are at highest risk for sepsis and severe complications and their outcome is highly dependent on rapid antimicrobial treatment. (See 'Initial antimicrobial therapy' below.)
Suggestive laboratory findings — Suggested laboratory studies for children with sepsis and septic shock are discussed in detail separately and include (see "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Laboratory studies'):
●Rapid blood glucose
●Arterial or venous blood gas
●Complete blood count with differential
●Blood urea nitrogen and serum creatinine
●Ionized blood calcium
●Serum total bilirubin and alanine aminotransferase
●Prothrombin and partial thromboplastin times (PT and PTT)
●International normalized ratio (INR)
●Fibrinogen and D-dimer
●Other cultures as indicated by clinical findings
●Diagnostic serologic testing as indicated to identify suspected sources of infection
●Inflammatory biomarkers (eg, C-reactive protein, procalcitonin) in selected cases
The following laboratory findings support the diagnosis of septic shock:
●Lactic acidosis indicated by metabolic acidosis on blood gases and elevation of arterial blood lactate (>3.5 mmol/L) (see "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Laboratory studies')
●Age-specific leukocytosis or leukopenia (table 1)
●Platelet count <80,000/microL or a decline of 50 percent from highest value recorded over the past three days
●Disseminated intravascular coagulopathy (decreased fibrinogen with increased D-dimer, international normalized ratio, prothrombin time, or partial thromboplastin time) (see "Disseminated intravascular coagulation in infants and children", section on 'Diagnosis')
●Renal insufficiency suggested by a serum creatinine ≥2 times upper limit of normal for age or twofold increase in baseline creatinine
●Liver dysfunction implied by a total bilirubin ≥4 mg/dL (not applicable to newborn) or alanine aminotransferase (ALT) >2 times upper limit of normal for age
●Pyuria indicating an urinary tract infection
PHYSIOLOGIC INDICATORS AND TARGET GOALS — Restoration of tissue perfusion, such as reversal of shock, should be targeted to the following therapeutic endpoints (goals in parentheses) (algorithm 1) [2,9,10]:
●Quality of central and peripheral pulses (strong, distal pulses equal to central pulses)
●Skin perfusion (warm, with capillary refill <2 seconds)
●Mental status (normal mental status)
●Urine output (≥1 mL/kg per hour, up to 40 mL per hour, once effective circulating volume is restored)
●Blood pressure (systolic pressure at least fifth percentile for age: 60 mmHg <1 month of age, 70 mmHg + [2 x age in years] in children 1 month to 10 years of age, 90 mmHg in children 10 years of age or older); however, blood pressure by itself is not a reliable end point for assessing the adequacy of resuscitation
●Lactate (<4 mmol/L or ≥10 percent decrease per every one to two hours until normal)
●Central venous oxygen saturation (ScvO2), (≥70 percent), if available
Heart rate is an important physiologic indicator of circulatory status that should also be monitored closely (table 3). However, many other factors (ie, fever, drugs, anxiety) influence heart rate. Although trends in response to treatment should be carefully monitored, specific target goals for heart rate are difficult to define and may not be useful. Children with persistently elevated heart rate unresponsive to repeated fluid boluses should be evaluated for cardiac dysfunction. (See 'Inadequate tissue perfusion' above.)
Blood lactate can be obtained by bedside testing. Small observational studies in adults and children have demonstrated that lactate can correlate with severity of shock and prognosis in sepsis [11-14]. In one observational study of septic shock in children, normalization of lactate (lactate level <2 mmol/L) within four hours was associated with reduced organ dysfunction but lactate clearance (reduction ≥10 percent decrease in lactate level) was not . In adults, normalization of lactate and lactate clearance have been associated with decreased mortality [12,13].
ScvO2 <70 percent may also indicate persistence of abnormal end-organ perfusion. However, an ScvO2 ≥70 percent can be falsely reassuring in sepsis due to hyperdynamic cardiac function, microcirculatory shunting, or mitochondrial dysfunction [15,16]. When measuring ScvO2 in pediatric patients, pulmonary artery catheters are rarely used. Instead, changes in central venous oxygen saturation (ScvO2) are more commonly obtained from a catheter with its tip in the distal superior vena cava (ScvO2) .
Identifying physiologic indicators to monitor the effectiveness of resuscitation for children with septic shock is challenging. Noninvasive ultrasonic determination of cardiac index, cardiac output, systemic vascular resistance, and stroke volume is feasible in healthy children, and age-based normative values have been published. Although not widely available, bedside Doppler ultrasound shows promise as a noninvasive method to guide vasoactive therapy by calculating cardiac output (CO) and systemic vascular resistance (SVR) from measurements of blood flow over the pulmonary artery or aorta. (See "Initial management of shock in children", section on 'Physiologic indicators and target goals'.)
Regardless of the method used to measure vascular pressures, clinical signs of end organ perfusion must also be monitored in order to accurately determine the severity of shock and response to treatment. These indicators can be readily monitored noninvasively during the initial management of shock and, since many children in shock respond well, invasive monitoring can often be avoided. Mean arterial pressure can be measured with a blood pressure cuff. Clinical experience suggests that quality of central and peripheral pulses, skin perfusion, mental status, and urine output are useful signs for assessing response to therapy. Limited observational evidence suggests that capillary refill time may correlate with ScvO2. (See "Initial management of shock in children", section on 'Physiologic indicators and target goals'.)
Early goal-directed therapy — Goal-directed therapy for septic shock refers to an aggressive systematic approach to resuscitation targeted to improvements in physiologic indicators of perfusion and vital organ function within the first six hours. Effective treatment of septic shock requires rapid correction of circulatory dysfunction with continuous monitoring and re-evaluation at frequent intervals and early administration of empiric broad-spectrum antimicrobial therapy .
We suggest that children with septic shock receive treatment according to the 2007 American College of Critical Care Medicine (ACCM) guidelines with emphasis on early goal-directed therapy (algorithm 1) . These guidelines are also largely compatible with the algorithm for pediatric septic shock promoted in the Pediatric Advanced Life Support (PALS) course (algorithm 2). However, the ACCM guidelines provide a tighter time frame for optimal delivery of initial intravenous fluid boluses. The timing of therapeutic actions in the ACCM guidelines should be viewed as best practices for resuscitation of a child with septic shock. However, meeting the time targets may not always be possible within the first hour of illness depending upon patient factors and available pediatric expertise.
This recommendation is supported by one trial and observational studies that show a marked reduction in mortality among children with severe sepsis after wide dissemination of the 2002 ACCM guidelines on which the 2007 guidelines are based as follows:
●In a trial of goal-directed therapy in 102 children with severe sepsis or fluid-refractory septic shock treated in two pediatric intensive care units, 28-day mortality was lower in patients who received goal-directed therapy versus therapy guided by blood pressure (12 versus 39 percent, respectively) primarily due to the marked benefit of goal-directed therapy among the children with central venous oxygen saturation (ScvO2) <70 percent . Patients managed according to goal-directed therapy received a clinically significantly greater volume of crystalloid, more blood transfusions, and more vasoactive drug therapy. Although patients with ScvO2 >70 who received goal-directed therapy also had lower mortality than controls (12 versus 22 percent), this difference was not statistically significant.
●Institution of timely goal directed interventions by a mobile intensive care team compatible with the ACCM 2002 guidelines, including early and aggressive bolus colloid administration, endotracheal intubation and mechanical ventilation, and vasoactive therapy in conjunction with regionalization of care for 331 children with meningococcemia in the United Kingdom was associated with a decrease in the case fatality rate from 23 to 2 percent over five years (annual reduction in the odds of death 0.41, 95% CI: 0.27-0.62) .
●Analysis of the case fatality rate among children treated for sepsis and purpura (primarily caused by Neisseria meningitidis, serogroup C) over 20 years in a children's hospital demonstrated a drop in annual mortality from approximately 20 to 1 percent with no deaths after 2002, corresponding to release of the ACCM guidelines and a nation-wide meningococcal C vaccination campaign .
●In the United States, the annual death rate from severe sepsis was estimated as 4 percent (2 percent in healthy children and 8 percent in children with prior chronic illness) in 2003 compared with 9 percent in 1999 [4,5].
Airway and breathing — All patients with septic shock should initially receive 100 percent supplemental oxygen to optimize blood oxygen content and, thus, oxygen delivery to tissues. Oxygenation should be monitored using continuous pulse oximetry (SpO2). Once adequate perfusion has been restored, supplemental oxygen should be titrated to avoid SpO2 >97 percent to prevent the adverse effects (eg, lung injury and microcirculatory vasoconstriction) associated with hyperoxia and free radical generation . (See "Continuous oxygen delivery systems for infants, children, and adults" and "Basic airway management in children".)
Endotracheal intubation using rapid sequence intubation (RSI) is frequently necessary in children with septic shock to protect the airway, assist with ventilation, and/or promote oxygenation. In addition, endotracheal intubation and sedation reduces the work of breathing which may avoid diversion of cardiac output to the muscles of respiration and may improve perfusion to other organs. A rapid overview of RSI in children is provided in the table (table 4). Emergent endotracheal intubation in children and pediatric rapid sequence intubation (RSI) are discussed in detail separately. (See "Emergency endotracheal intubation in children" and "Rapid sequence intubation (RSI) in children".)
Key actions when performing RSI in children with septic shock include:
●Patients with hemodynamic instability should receive appropriate support with fluid and/or catecholamines (see below) prior to or during intubation.
●Ketamine, if available and not contraindicated, is preferable for sedation prior to endotracheal intubation. (See "Induction agents for rapid sequence intubation outside the operating room in adults", section on 'Ketamine'.)
●Etomidate inhibits cortisol formation and should not be used routinely. If etomidate is used, we suggest the following:
•It is important to evaluate for signs of adrenal insufficiency sometimes evidenced by refractory shock [22,23]. (See "Septic shock: Ongoing management after resuscitation in children", section on 'Address adrenal insufficiency' and "Rapid sequence intubation (RSI) in children".)
•Emergency clinicians should inform the physicians assuming care for the patient in the intensive care unit when etomidate has been used for induction.
•Etomidate should not be used as an infusion or in repeated bolus doses for maintenance of sedation after intubation.
●Short-acting barbiturates and propofol are associated with hypotension and should be avoided in children with septic shock.
When performing rapid sequence intubation in a child with septic shock, it is important to choose agents that do not worsen cardiovascular status. Previously, etomidate was a common choice because it typically does not compromise hemodynamic stability. However, small observational studies in children with sepsis and septic shock undergoing intubation with or without etomidate indicate that one dose of etomidate is associated with lower levels of serum cortisol, cortisol to 11-deoxycortisol ratios, and higher adrenocortical hormone levels for up to 24 hours [22,24]. In one case series of 31 children with meningococcal sepsis who required endotracheal intubation, of the eight children who died, seven received etomidate .
The 2007 update to the Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock from the American College of Critical Care Medicine states that etomidate is no longer recommended to sedate children with septic shock . The 2010 advanced life support recommendations provided by the American Heart Association and the International Liaison Committee on Resuscitation on which the Pediatric Advanced Life Support course is based also suggest that etomidate not be used routinely in children with septic shock .
Treat hypoglycemia and hypocalcemia — Children with septic shock are at risk for hypoglycemia and hypocalcemia Rapid blood glucose and ionized calcium should be measured as intravenous access is obtained.
●Hypoglycemia – Hypoglycemia should be corrected by rapid intravenous infusion of dextrose as described in the rapid overview (table 5). After initial hypoglycemia is reversed, the clinician should provide a continuous infusion of dextrose to maintain blood glucose in a safe range (70 to 150 mg/dL [3.89 to 8.33 mmol/L]) for children whose condition does not permit oral intake. Hypoglycemia may also be an indicator of adrenal insufficiency in predisposed children and those with refractory septic shock. (See 'Corticosteroids' below and "Septic shock: Ongoing management after resuscitation in children", section on 'Address adrenal insufficiency'.)
In normoglycemic young children, a continuous maintenance infusion of dextrose 10 percent is a reasonable option to prevent the occurrence of hypoglycemia and is suggested by the American College of Critical Care Medicine . Hyperglycemia should be avoided.
●Hypocalcemia – Children with persistent shock in association with an ionized calcium <1.1 mmol/L (4.8 mg/dL) or symptomatic hypocalcemia (eg, positive Chvostek or Trousseau signs, seizures, prolonged QT interval on EKG, or cardiac arrhythmias) should undergo correction with calcium gluconate 10 percent solution in a dose of 50 to 100 mg/kg (0.5 to 1 mL/kg), up to 2 g (20 mL) by slow intravenous or intraosseous infusion over five minutes. This suggested dose is equivalent to elemental calcium 5 mg/kg (0.15 mmol/kg), up to 180 mg elemental (4.5 mmol) per single dose.
Calcium should be administered in a larger vein or, preferably, a central line. Sodium bicarbonate should not be introduced into an intravenous or intraosseous cannula without flushing before and after administration because of potential precipitation.
Calcium chloride 10 percent in a dose of 10 to 20 mg/kg (0.1 to 0.2 mL/kg), maximum dose 1 g (10 mL) provides an equivalent dose but should only be administered through a central line. Patients receiving a calcium infusion warrant continuous cardiac monitoring.
Hypocalcemia is a common finding in critically ill patients with sepsis likely due to changes in the hormonal milieu, though the exact pathophysiology remains unclear [25-27]. Intracellular calcium is necessary for cardiac and smooth muscle contraction. Infants under 12 months of age may rely more heavily on extracellular calcium to maintain adequate cardiac contractility than older patients. Animal models and observational studies have suggested improved physiologic outcomes when hypocalcemia is treated [28,29]. Although definitive evidence to support improved clinical outcomes in humans receiving intravenous calcium for low ionized calcium levels is lacking , current guidelines recommend correcting ionized hypocalcemia in patients with septic shock even in the absence of clinical manifestations of hypocalcemia (eg, seizures, cardiac arrhythmias) .
Intravenous fluid therapy — Relative intravascular hypovolemia is common in septic shock (due to vasodilation and capillary leak) and may be severe. Observational evidence suggests that vigorous fluid resuscitation may have a major role in preventing end-organ damage and improving survival. (See "Initial management of shock in children", section on 'Early goal-directed therapy'.)
●Rapid intravenous (IV) access – IV access (preferably two sites and of the largest caliber that can be reliably inserted) should be established within five minutes. If a peripheral IV cannot be obtained in this time, guidelines advise placement of an intraosseous needle. (See "Vascular (venous) access for pediatric resuscitation and other pediatric emergencies", section on 'Peripheral access' and "Intraosseous infusion", section on 'Indications' and "Intraosseous infusion", section on 'Fluid and drug administration'.)
●Initial IV fluid bolus – In resource-rich settings and when not contraindicated by comorbidities (eg, severe anemia, diabetic ketoacidosis, heart failure, severe malnutrition), initial therapy should begin with a bolus of 20 mL/kg of isotonic crystalloid solution (ie, 0.9 percent normal saline or lactated Ringer solution) infused over five minutes or as rapidly as possible, preferably with a manual "push-pull" technique or rapid infuser. After the initial infusion, the child should be quickly reassessed for signs of inadequate end-organ perfusion to determine if additional fluid is needed. (See 'Inadequate tissue perfusion' above and "Initial management of shock in children", section on 'Risks'.)
●Repeated IV fluid bolus – Repeated 20 mL/kg fluid boluses should be given until tissue perfusion, oxygen delivery, and blood pressure are adequate, or signs of fluid overload (rales, gallop rhythm, enlarged liver) develop. Experience suggests that patients may require volumes of 60 mL/kg or more in the first hour and up to 120 mL/kg or more during the first several hours of fluid administration .
●Establish ongoing monitoring of tissue perfusion – Once effective circulating volume has been restored, ongoing fluid requirements are guided by monitoring of tissue perfusion, including capillary refill time; urine output; serial blood lactate levels; and, if available and appropriate, measurement of radial arterial blood pressure, central venous pressure, and central venous oxygen saturation. (See "Septic shock: Ongoing management after resuscitation in children", section on 'Ongoing and invasive monitoring'.)
●Other fluids – The use of colloid for fluid resuscitation for children with septic shock is controversial. Nevertheless, colloid infusion with albumin 5 percent is a reasonable option for children who have not improved following >60 mL/kg of crystalloid fluid, have hypoalbuminemia (albumin <3 g/dL), or who develop a hyperchloremic metabolic acidosis. Although the findings are not consistent and multiple preparations are available, synthetic colloids, such as hydroxyethyl starch solutions, have been shown to increase the risk of acute kidney injury, coagulopathy, and death in adults with severe sepsis or septic shock, especially with administered volumes >15 mL/kg and should be avoided. (See "Treatment of hypovolemia (dehydration) in children", section on 'Crystalloid versus colloid' and "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Intravenous fluids (first three hours)'.)
Preliminary evidence in one small pediatric trial suggests that administration of hypertonic saline may achieve hemodynamic stability with a lower volume of fluid, but its impact on other outcomes relative to normal saline are uncertain ; thus, we do not advocate use of hypertonic saline outside of an experimental protocol.
Resource-limited settings — In resource-limited settings, fluid resuscitation according to emergency triage assessment and treatment guidelines developed by the World Health organization is suggested for children with signs of shock. (See "Initial management of shock in children", section on 'Resource-limited settings'.)
In resource-limited settings that cannot provide advanced airway and circulatory support, children with signs of compensated shock and severe febrile illness but without dehydration or hemorrhage who receive rapid bolus administration of albumin or normal saline may have increased mortality. Thus, rapid fluid infusion according to the American College of Critical Care Medicine as described above should be avoided in this special population of patients. (See "Initial management of shock in children", section on 'Risks'.)
The fluid expansion as support therapy (FEAST) trial, a randomized trial of 3141 children between 60 days and 12 years of age with severe febrile illness (altered mental status, respiratory distress, or both) and impaired perfusion (eg, delayed capillary refill time ≥3 seconds, weak pulses, or severe tachycardia) and treated in six district hospitals in sub-Saharan Africa found that 48-hour mortality was significantly higher among those who received boluses of albumin or normal saline when compared to controls who did not receive fluid boluses (10.6, 10.5, and 7.3 percent, respectively) [33,34]. These children had a high frequency of malaria parasitemia (57 percent) and severe anemia (hemoglobin <5 g/dL, 32 percent) although preplanned subgroup analyses did not find a difference in mortality based upon these characteristics. More children in the no fluid bolus group received blood transfusions in the first hour than in the fluid bolus groups (22 versus 2 to 4 percent). However, the overall amount of blood delivered after eight hours was not significantly different among the groups. A subsequent reanalysis of this study found that cardiovascular collapse from cardiotoxicity or ischemia-reperfusion injury in patients receiving fluids accounted for the excess mortality rather than fluid overload [35,36].
Of note, none of the patients in this trial had hypovolemic dehydration or trauma as the primary cause of their illness, and patients with severe hypotension received 40 mL/kg of normal saline or albumin. Such patients still warrant fluid resuscitation according to the WHO guidelines. (See "Initial management of shock in children", section on 'Resource-limited settings'.)
Although the FEAST trial is the only randomized trial of fluid therapy in children with compensated septic shock, it indicates a potential for significant harm if fluid therapy is used indiscriminately among children with severe febrile illness in developing nations. There is no evidence that these findings can be generalized to resource-rich settings where intensive monitoring, mechanical ventilation, and vasopressor support are routinely available and the baseline characteristics of the patients are significantly different. In clinical facilities with these capabilities, observational evidence supports early isotonic fluid resuscitation (eg, normal saline or Ringer’s lactate) guided by the degree and type of shock present as a key component of goal-directed therapy (algorithm 3). (See "Initial management of shock in children", section on 'Fluid administration' and "Initial management of shock in children", section on 'Early goal-directed therapy' and "Initial management of shock in children", section on 'Resource-limited settings'.)
Initial antimicrobial therapy — Intravenous antimicrobial therapy should be initiated immediately after obtaining appropriate cultures with the goal of completing administration within one hour of presentation. Each hour delay in antibiotic administration has been associated with an approximately 8 percent increase in mortality in adults . In one pediatric series, delays greater than three hours were associated with significantly increased odds of mortality (OR 4.0 [95% CI 1.3-12.1]) increased odds of mortality . In patients in septic shock, effective delivery of antimicrobials usually requires two ports or sites for intravenous access: one devoted to fluid resuscitation and one for antimicrobial delivery. Antimicrobials should not be withheld for children in whom lumbar puncture cannot be performed safely due to hemodynamic instability or coagulopathy (algorithm 4).
The choice of antimicrobials can be complex and should consider the child's age, history, comorbidities, clinical syndrome, Gram stain data, and local resistance patterns. Consultation with an expert in pediatric infectious disease is strongly encouraged for all children with septic shock.
General principles for initial antimicrobial coverage for children who are critically ill with sepsis include the following:
●All children with septic shock should receive coverage for methicillin-resistant Staphylococcus aureus (MRSA).
●Coverage for enteric organisms should be added whenever clinical features suggest genitourinary (GU) and/or gastrointestinal (GI) sources (eg, perforated appendicitis or bacterial overgrowth in a child with short gut syndrome).
●Treatment for Pseudomonas species should be included for children who are immunosuppressed or at risk for infection with these organisms (ie, those with cystic fibrosis).
●Listeria monocytogenes and herpes simplex virus are important pathogens in infants ≤28 days of age.
●When treating empirically, antibiotics which can be given by rapid intravenous bolus (eg, beta-lactam agents or cephalosporins) should be administered first followed by infusions of antibiotics, such as vancomycin, that must be delivered more slowly.
●Ongoing antimicrobial therapy should be modified based upon culture results, including antimicrobial susceptibility and the patient's clinical course.
Suggested initial empiric antimicrobial regimens based upon patient age, level of immunocompetence, and previous antibiotic administration include:
●Children >28 days of age who are normal hosts:
•Vancomycin (15 mg/kg, maximum 1 to 2 g, for the initial dose)
●Children >28 days who are immunosuppressed or at risk for infection with Pseudomonas species:
•Vancomycin (15 mg/kg, maximum 1 to 2 g, for the initial dose)
•PLUS an aminoglycoside (eg, gentamicin, amikacin) or carbapenem (eg, imipenem, meropenem) in settings where bacterial organisms with extended-spectrum beta-lactamase (ESBL) resistance are prevalent. For patients who have been recently (within two weeks) treated broad-spectrum antibiotics (eg, third-generation cephalosporin, aminoglycoside, or fluoroquinolone), the addition of a carbapenem is favored over an aminoglycoside.
●Children who cannot receive penicillin or who have recently received broad-spectrum antibiotics:
•Vancomycin (age appropriate dose)
•PLUS Meropenem (<3 months: 20 mg/kg for the initial dose, ≥3 months: 20 mg/kg, maximum 2 g, for the initial dose)
●Patients at increased risk of fungal infection (eg, identified fungal source, immunocompromised with persistent fever on broad spectrum antibiotics)
●Patients with risk factors for rickettsial infection (eg, travel to or reside in an endemic region):
●Infants 0 to 28 days of age:
•Vancomycin (15 mg/kg for the initial dose)
•PLUS cefotaxime (50 mg/kg for the initial dose)
•PLUS gentamicin (2.5 mg/kg for the initial dose)
•PLUS ampicillin (50 mg/kg for the initial dose)
•Add acyclovir (20 mg/kg per dose) for suspicion of HSV infection
For neonates with clinical features concerning for herpes simplex virus (HSV) infection who may receive acyclovir, viral cultures of vesicles if present, cerebrospinal fluid and surface (mouth, nasopharynx, eye, and anus can be obtained from one swab ending with the anal swab) and polymerase chain reaction testing (from cerebrospinal fluid and blood) for HSV should be obtained whenever possible. Concerning clinical features include family members with HSV infection, respiratory collapse, elevated transaminases, thrombocytopenia, and/or abnormal cerebrospinal fluid suggestive of HSV infection (table 6). (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations'.)
Fluid-refractory shock — Vasoactive agents are frequently necessary in the initial resuscitation of children with septic shock to sustain perfusion pressure while hypovolemia is corrected. Based upon expert opinion, the American College of Critical Care Medicine guidelines suggest the initiation of vasoactive therapy in children with septic shock who have not improved after initial fluid resuscitation with 40 to 60 mL/kg of isotonic crystalloid (eg, normal saline or Ringer’s lactate) along with continued fluid administration . Although central venous access is preferred for vasopressor administration (eg, epinephrine, norepinephrine, dopamine, or dobutamine), peripheral intravenous (IV) access or intraosseous needle is acceptable while central venous access is being obtained. The initial choice of vasoactive agents is guided by physical findings [2,40].
Cold shock — The approach to cold shock differs according to the severity of shock as follows:
●Fluid-refractory hypotensive shock – We suggest that infants and children with fluid-refractory, hypotensive, cold septic shock receive epinephrine infusions (initial starting dose 0.05 to 0.1 mcg/kg/min, titrate to response up to 1.5 mcg/kg/min) rather than dopamine . Examples of how to prepare an epinephrine infusion for a 10 kg or 20 kg child are provided in the tables (table 7 and table 8). At doses exceeding 0.1 mcg/kg/minute (and possibly lower in some patients), alpha-adrenergic effects of epinephrine are more pronounced, and systemic vasoconstriction may be more evident. We typically add a second vasopressor if patients have not responded to an epinephrine dose of 1.5 mcg/kg/min.
However, we regard dopamine as an acceptable alternative to epinephrine. If dopamine is given first but does not reverse shock after titration to 10 mcg/kg/min, then a second agent, such as epinephrine, should be added.
This weak recommendation for epinephrine differs from the 2009 American College of Critical Care Medicine (ACCM) sepsis guidelines which recommend dopamine as the first-line agent for fluid-refractory cold shock (algorithm 1) . The 2009 sepsis guidelines are undergoing review. The use of epinephrine instead of dopamine for fluid-refractory shock is supported by the following studies:
•In a single-center, blinded trial of 120 infants and children (1 month to 15 years of age) treated for fluid-refractory septic shock in a pediatric intensive care unit (88 percent with cold shock), patients who received infusions of dopamine rather than epinephrine had significantly higher mortality (21 versus 7 percent) and more healthcare-associated infections (29 versus 2 percent) . This study compared a titration of dopamine of 5 to 7.5 to 10 mcg/kg/min with a titration of epinephrine of 0.1 to 0.2 to 0.3 mcg/kg/min. Thus, the dopamine titration was less potent than the epinephrine titration which may, in part, explain the differences in outcome. This trial was also stopped early for potential harm.
•In a blinded trial of 60 infants and children (3 months to 12 years of age) with fluid-refractory septic shock who received dopamine at doses of 10 to 20 mcg/kg/min or epinephrine 0.1 to 0.3 mcg/kg/min, patients who received epinephrine were significantly more likely to have resolution of shock within the first hour than those who received dopamine (12/29 versus 4/31 patients; OR 4.8, 95% CI 1.3 to 17.2) . Patients who received epinephrine also had significantly better organ function on day three of treatment and more organ failure-free days. Overall mortality was 42 percent and did not significantly differ between the groups.
Based upon the results of two single center studies, epinephrine appears to be a better first-line agent for fluid-refractory hypotensive shock than dopamine. However, a larger, multicenter trial that compares equipotent dosing of both agents is necessary to confirm these findings .
●Fluid-refractory shock with normal blood pressure – Evidence is lacking to provide clear guidance for the management of infants and children with fluid-refractory cold shock and a normal blood pressure. We and the ACCM suggest that these patients receive judicious fluid resuscitation. Some may also benefit from addition of low-dose epinephrine infusions (eg, 0.03 to 0.05 mcg/kg/min). In addition, vasodilatory agents (eg, dobutamine or milrinone) may be helpful for specific patients. As always, close monitoring of clinical and laboratory parameters (ie, lactate, urine output, heart rate) with frequent patient reassessment are needed to guide the need for escalation of therapies.(algorithm 1) .
Warm shock — For patients with warm shock (eg, bounding pulses, pink extremities, and "flash" capillary refill) we and the 2009 ACCM guidelines suggest norepinephrine infusion starting at 0.03 to 0.05 mcg/kg/minute as the first-line drug (algorithm 1) .
Corticosteroids — Patients who persist with shock in spite of rapid fluid administration and continuous infusions of epinephrine or norepinephrine may have adrenal insufficiency. Risk factors include purpura fulminans, recent or chronic treatment with corticosteroids, hypothalamic or pituitary abnormalities, or adrenal insufficiency (congenital or acquired). When adrenal insufficiency is suspected, administration of hydrocortisone in stress doses (50 mg/m2/day or 2 mg/kg/day, intermittent or continuous infusion, maximum dose 50 mg/kg per day) is suggested . Although evidence is lacking regarding the best method to identify adrenal insufficiency in children with refractory septic shock, assessment of adrenal status (either baseline serum cortisol or adrenocorticotropin hormone stimulation testing) is advised prior to corticosteroid administration. (See "Septic shock: Ongoing management after resuscitation in children", section on 'Address adrenal insufficiency'.)
Transfer to definitive care — After resuscitation, children with septic shock should be managed by clinicians with pediatric critical care expertise in a setting that has the necessary resources to provide pediatric intensive care. Children with septic shock who present to facilities without the necessary clinical expertise or resources should undergo timely transfer to an appropriate facility. Use of a pediatric specialized team is associated with improved patient survival and fewer adverse effects during transport. Thus, the use of pediatric specialized teams for transport of children with septic shock is recommended whenever it is available. (See "Prehospital pediatrics and emergency medical services (EMS)", section on 'Inter-facility transport'.)
GUIDELINE ADHERENCE — Implementation of a bundled approach to resuscitation with transparent goals can improve adherence to guidelines, decrease time to therapy, and improve outcomes in pediatric septic shock. As an example, in an observational study in one pediatric emergency department that compared outcomes before and after implementation of a sepsis resuscitation protocol, time from triage to receipt of the first fluid bolus decreased from a median of 56 to 22 minutes (p<0.001) and from triage to the first antibiotic from a median of 130 to 30 minutes (p<0.001) . In another study that evaluated the impact of specific quality improvement interventions in a pediatric emergency department, adherence to the following metrics as a bundle increased from 19 to 78 percent (p<0.001): timely (1) recognition of septic shock, (2) vascular access, (3) administration of IV fluid, (4) antibiotics, and (5) vasoactive agents, all within 60 minutes . This improved adherence was associated with a decrease in mortality from 5 to 2 percent.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sepsis in children and adults".)
SUMMARY AND RECOMMENDATIONS
●A clinical diagnosis of septic shock is made in children who have signs of inadequate tissue perfusion, two or more criteria for the systemic inflammatory response syndrome (table 1), and suspected or proven infection. (See 'Rapid recognition' above and "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)
●All patients with septic shock should initially receive 100 percent supplemental oxygen to optimize blood oxygen content and, thus, oxygen delivery to tissues. Once adequate perfusion has been restored, supplemental oxygen should be titrated to avoid oxygen saturation by pulse oximetry of greater than 97 percent to prevent the adverse effects associated with hyperoxia and free radical generation (eg, lung injury and microcirculatory vasoconstriction). (See 'Airway and breathing' above.)
●Endotracheal intubation using rapid sequence intubation (RSI) is frequently necessary in children with septic shock to protect the airway, assist with ventilation, and/or promote oxygenation. When performing RSI in children with septic shock, ketamine, if available and not contraindicated, is preferable for sedation prior to endotracheal intubation. Etomidate should not be used routinely in patients with septic shock. A rapid overview of RSI in children is provided in the table (table 4). (See 'Airway and breathing' above.)
●We suggest that children with septic shock receive initial treatment according to the 2009 American College of Critical Care Medicine (ACCM) guidelines including goal-directed therapy which provides a systematic approach to resuscitation of septic shock targeted to specific improvements in physiologic indicators of perfusion and vital organ function (algorithm 1) (Grade 2C). For children in resource-rich settings, rapid infusion of isotonic fluid (eg, normal saline or Ringer’s lactate) and early administration of empiric broad-spectrum antimicrobial therapy are essential actions. (See 'Early goal-directed therapy' above and 'Physiologic indicators and target goals' above and 'Resuscitation' above.)
●The 2009 ACCM guidelines suggest the initiation of vasoactive therapy in children with septic shock who have not improved after 40 to 60 mL/kg of isotonic crystalloid (eg, normal saline or Ringer’s lactate) along with continued fluid administration based upon the type of shock (see 'Fluid-refractory shock' above):
•Hypotensive cold shock – We suggest that infants and children with fluid-refractory cold shock receive epinephrine infusions (initial starting dose 0.05 to 0.1 mcg/kg/min, titrate to response up to 1.5 mcg/kg/min) rather than dopamine (Grade 2C). This recommendation differs from the 2009 guidelines, which are undergoing review. (See 'Cold shock' above.)
•Normotensive cold shock – We and the ACCM suggest that these patients receive judicious fluid resuscitation (Grade 2C). Some may also benefit from addition of low-dose epinephrine infusions (eg, 0.03 to 0.05 mcg/kg/min). In addition, vasodilatory agents (eg, dobutamine or milrinone) may be helpful for specific patients. Close monitoring of clinical and laboratory parameters (ie, lactate, urine output, heart rate) with frequent patient reassessment are needed to guide the need for escalation of therapies. (See 'Cold shock' above.)
•Hypotensive warm shock – We and the 2009 ACCM guidelines suggests that infants and children with fluid-refractory, hypotensive warm shock receive norepinephrine infusions starting at 0.03 to 0.05 mcg/kg/minute as the first-line drug (Grade 2C). (See 'Warm shock' above.)
●Patients who persist with shock in spite of rapid fluid administration and continuous infusions of epinephrine or norepinephrine may have adrenal insufficiency. When adrenal insufficiency is suspected, administration of hydrocortisone in stress doses (50 to 100 mg/m2/day or 1 to 2 mg/kg per day, intermittent or continuous infusion, maximum dose 50 mg/kg per day) is suggested . Assessment of adrenal status (either baseline serum cortisol or adrenocorticotropin hormone stimulation testing) is advised prior to corticosteroid administration. (See 'Corticosteroids' above.)
●After initial resuscitation, ongoing aggressive management of septic shock should continue according to the principles of goal-directed therapy for children in whom adequate circulation has not been restored (algorithm 1). This care should be provided by clinicians with pediatric critical care expertise in a setting that has the necessary resources to provide pediatric intensive care. (See 'Transfer to definitive care' above and "Septic shock: Ongoing management after resuscitation in children".)
●Establishment of a bundled approach to recognition and resuscitation can improve timely therapies and outcomes for children with septic shock. (See 'Guideline adherence' above.)
- 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.
- 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.
- 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.
- Odetola FO, Gebremariam A, Freed GL. Patient and hospital correlates of clinical outcomes and resource utilization in severe pediatric sepsis. Pediatrics 2007; 119:487.
- 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.
- Weiss SL, Parker B, Bullock ME, et al. Defining pediatric sepsis by different criteria: discrepancies in populations and implications for clinical practice. Pediatr Crit Care Med 2012; 13:e219.
- Jaramillo-Bustamante JC, Marín-Agudelo A, Fernández-Laverde M, Bareño-Silva J. Epidemiology of sepsis in pediatric intensive care units: first Colombian multicenter study. Pediatr Crit Care Med 2012; 13:501.
- Kutko MC, Glick RD, Butler LM, et al. Histone deacetylase inhibitors induce growth suppression and cell death in human rhabdomyosarcoma in vitro. Clin Cancer Res 2003; 9:5749.
- Kleinman ME, de Caen AR, Chameides L, et al. Pediatric basic and advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Pediatrics 2010; 126:e1261.
- Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017; 43:304.
- Dugas MA, Proulx F, de Jaeger A, et al. Markers of tissue hypoperfusion in pediatric septic shock. Intensive Care Med 2000; 26:75.
- Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004; 32:1637.
- Arnold RC, Shapiro NI, Jones AE, et al. Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock 2009; 32:35.
- Scott HF, Brou L, Deakyne SJ, et al. Lactate Clearance and Normalization and Prolonged Organ Dysfunction in Pediatric Sepsis. J Pediatr 2016; 170:149.
- Velissaris D, Pierrakos C, Scolletta S, et al. High mixed venous oxygen saturation levels do not exclude fluid responsiveness in critically ill septic patients. Crit Care 2011; 15:R177.
- Fink MP. Bench-to-bedside review: Cytopathic hypoxia. Crit Care 2002; 6:491.
- Dueck MH, Klimek M, Appenrodt S, et al. Trends but not individual values of central venous oxygen saturation agree with mixed venous oxygen saturation during varying hemodynamic conditions. Anesthesiology 2005; 103:249.
- 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.
- Booy R, Habibi P, Nadel S, et al. Reduction in case fatality rate from meningococcal disease associated with improved healthcare delivery. Arch Dis Child 2001; 85:386.
- Maat M, Buysse CM, Emonts M, et al. Improved survival of children with sepsis and purpura: effects of age, gender, and era. Crit Care 2007; 11:R112.
- Asfar P, Calzia E, Huber-Lang M, et al. Hyperoxia during septic shock--Dr. Jekyll or Mr. Hyde? Shock 2012; 37:122.
- den Brinker M, Joosten KF, Liem O, et al. Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. J Clin Endocrinol Metab 2005; 90:5110.
- Menon K, Ward RE, Lawson ML, et al. A prospective multicenter study of adrenal function in critically ill children. Am J Respir Crit Care Med 2010; 182:246.
- den Brinker M, Hokken-Koelega AC, Hazelzet JA, et al. One single dose of etomidate negatively influences adrenocortical performance for at least 24h in children with meningococcal sepsis. Intensive Care Med 2008; 34:163.
- Sanchez GJ, Venkataraman PS, Pryor RW, et al. Hypercalcitoninemia and hypocalcemia in acutely ill children: studies in serum calcium, blood ionized calcium, and calcium-regulating hormones. J Pediatr 1989; 114:952.
- Zaloga GP, Chernow B. The multifactorial basis for hypocalcemia during sepsis. Studies of the parathyroid hormone-vitamin D axis. Ann Intern Med 1987; 107:36.
- Müller B, Becker KL, Kränzlin M, et al. Disordered calcium homeostasis of sepsis: association with calcitonin precursors. Eur J Clin Invest 2000; 30:823.
- Kovacs A, Courtois MR, Barzilai B, et al. Reversal of hypocalcemia and decreased afterload in sepsis. Effect on myocardial systolic and diastolic function. Am J Respir Crit Care Med 1998; 158:1990.
- Porcelli PJ Jr, Oh W. Effects of single dose calcium gluconate infusion in hypocalcemic preterm infants. Am J Perinatol 1995; 12:18.
- Forsythe RM, Wessel CB, Billiar TR, et al. Parenteral calcium for intensive care unit patients. Cochrane Database Syst Rev 2008; :CD006163.
- Carcillo JA, Davis AL, Zaritsky A. Role of early fluid resuscitation in pediatric septic shock. JAMA 1991; 266:1242.
- Chopra A, Kumar V, Dutta A. Hypertonic versus normal saline as initial fluid bolus in pediatric septic shock. Indian J Pediatr 2011; 78:833.
- 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.
- Myburgh JA. Fluid resuscitation in acute illness--time to reappraise the basics. N Engl J Med 2011; 364:2543.
- 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.
- Myburgh J, Finfer S. Causes of death after fluid bolus resuscitation: new insights from FEAST. BMC Med 2013; 11:67.
- Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589.
- Weiss SL, Fitzgerald JC, Balamuth F, et al. Delayed antimicrobial therapy increases mortality and organ dysfunction duration in pediatric sepsis. Crit Care Med 2014; 42:2409.
- Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:503.
- Pediatric Advanced Life Support Provider Manual, Chameides L, Samson RA, Schexnayder SM, Hazinski MF (Eds), American Heart Association, Dallas 2012.
- Ventura AM, Shieh HH, Bousso A, et al. Double-Blind Prospective Randomized Controlled Trial of Dopamine Versus Epinephrine as First-Line Vasoactive Drugs in Pediatric Septic Shock. Crit Care Med 2015; 43:2292.
- Ramaswamy KN, Singhi S, Jayashree M, et al. Double-Blind Randomized Clinical Trial Comparing Dopamine and Epinephrine in Pediatric Fluid-Refractory Hypotensive Septic Shock. Pediatr Crit Care Med 2016; 17:e502.
- Branco RG. Dopamine in Sepsis-Beginning of the End? Pediatr Crit Care Med 2016; 17:1099.
- 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.
- Paul R, Melendez E, Stack A, et al. Improving adherence to PALS septic shock guidelines. Pediatrics 2014; 133:e1358.