Sepsis and septic shock in children in resource-abundant settings: Ongoing management after resuscitation

INTRODUCTION — 

The management of sepsis and septic shock in children in resource-abundant settings after the first hour of resuscitation is reviewed here.

The rapid recognition and initial resuscitation of pediatric patients with sepsis in resource-abundant and resource-limited settings and the definitions, epidemiology, and clinical manifestations of sepsis in children are discussed separately:

●(See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)".)

●(See "Shock in children in resource-limited settings: Recognition" and "Shock in children in resource-limited settings: Initial management".)

●(See "Sepsis in children: Definitions, clinical manifestations, and diagnosis".)

RESUSCITATION — 

The key interventions in the initial resuscitation of children from septic shock are discussed in detail separately (algorithm 1). (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)".)

INSTITUTIONAL PROTOCOL/GUIDELINE FOR STABILIZATION BEYOND THE FIRST HOUR — 

The Surviving Sepsis Campaign International Guidelines suggest that each pediatric institution should implement a protocol/guideline for the management of children with sepsis and septic shock or other sepsis-associated organ dysfunction [1,2]. Key aspects of the guideline should include:

●Fluid and vasoactive titration

●Infectious source control as needed after having started empiric broad-spectrum antibiotics

●Respiratory support and assessment for pediatric acute respiratory distress syndrome (PARDS)

●Multimodal monitoring to optimize therapies designed to achieve hemodynamic goals (table 1) while continuously reassessing the patient

ONGOING MANAGEMENT

Approach — Our approach to ongoing management of children with sepsis or septic shock is largely consistent with the 2020 Surviving Sepsis Campaign International Guidelines for the management of septic shock and sepsis-associated organ dysfunction in children [1,2]. Whenever possible, children requiring resuscitation should receive ongoing management by a pediatric critical care specialist or pediatrician with similar expertise in a pediatric intensive care unit.

Repeated, frequent assessment of the patient is essential to good outcomes. In children who have responded to initial resuscitation in the first hour with resolution of hypotension and improved perfusion, the care team must continue with ongoing monitoring, antimicrobial therapy, and optimization of respiratory support.

In patients with fluid-refractory hypotension or abnormal perfusion, aggressive resuscitation should be targeted to therapeutic endpoints (table 1). (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Approach'.)

Priorities for continued management of children with sepsis or septic shock include:

●Manage the infection by identifying the optimal choice of antimicrobial therapy based upon culture results and by ensuring that the source of infection is controlled. (See 'Eradicate infection' below.)

●Monitor respiratory status, assess for pediatric acute respiratory distress syndrome (PARDS), and provide optimal respiratory support. (See 'Continue respiratory support' below.)

●Monitor tissue perfusion (capillary refill time, heart rate, pulses, urine output, and mental status), blood pressure, and cardiac function.

●Avoid hypoglycemia and correct electrolyte and metabolic derangements (eg, hypocalcemia).

●Monitor blood lactate levels; patients with persistently elevated and/ or worsening blood lactate are at increased risk of mortality and may warrant escalation of support [3,4].

In the subpopulation of children with fluid-refractory septic shock requiring continued vasopressor support, additional priorities include:

●Place invasive monitoring devices (eg, central venous catheter, arterial line, bladder catheter) to accurately assess blood pressure and response to treatment as well as to deliver vasopressor infusions safely. (See 'Ongoing and invasive monitoring' below.)

●Continue fluid resuscitation and vasopressor delivery targeted to measured cardiac function, lactate, and central venous oxygen saturation (ScvO₂). (See 'Continue fluid administration' below.)

●Administer blood products, when needed, to treat severe anemia or bleeding. (See 'Blood transfusion' below and 'Treat disseminated intravascular coagulation' below.)

●Treat of adrenal insufficiency and evaluate other potential underlying causes (eg, hypothyroidism). (See 'Relative adrenal insufficiency' below and 'Treat reversible etiologies' below.)

●Provide advanced extracorporeal therapies in patients who do not respond to conventional therapy.

For children with evolving or existing sepsis and normal blood pressures, therapeutic endpoints based upon noninvasive indicators are reasonable targets but may be unreliable. (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Approach'.)

Eradicate infection — Prompt identification and treatment of the source of infection are essential to the successful management of sepsis and constitute critical interventions that can reverse septic shock [5-7]. Initial antimicrobial therapy should provide broad-spectrum coverage tailored to host factors, such as age and underlying medical conditions, and be administered as soon as possible after presentation at doses appropriate for patients with life-threatening infections. (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric antibiotic therapy'.)

Subsequent antimicrobial treatment should be optimized based upon results of culture and/or highly accurate means of pathogen detection (eg, polymerase chain reaction or other assays) in collaboration with an infectious disease specialist.

Whenever possible, undertake source control (physical measures undertaken to eradicate a focus of infection, to eliminate ongoing microbial contamination, and to render a site inhospitable to microbial growth and invasion) because localized foci of infection (ie, abscess) or an infected foreign body may not respond to antibiotics alone (table 2). Intervention should occur as soon possible after an infection amenable to a source-control procedure is identified [2]. As examples, remove potentially infected foreign bodies and abscesses, drain infected fluid collections, or debride infected tissues. If an indwelling intravascular access device is suspected or confirmed to be the source of sepsis or septic shock and the pathogen is unlikely to be effectively treated with antibiotics alone, then remove it once another vascular access has been established [2].

A careful history and physical examination often yield clues to the source of sepsis and help guide subsequent microbiologic evaluation (table 2). Gram stain of suspicious fluids may give early clues to the etiology of infection while cultures are incubating. In addition to cultures of specific sites, draw aerobic and anaerobic blood cultures. (See "Detection of bacteremia: Blood cultures and other diagnostic tests".)

Obtain additional investigations targeted to the suspected source(s) and based upon specific physical findings as soon as possible, ideally within the first 6 to 12 hours. Studies may include imaging (eg, computed tomography and/or ultrasonography) or sample acquisition (eg, bronchoalveolar lavage, aspirating fluid collections or joints, abscess drainage, or thoracentesis). In unstable patients, the benefit of interventional procedures must be balanced with potential risk for decompensation during the procedure.

If invasive fungal infection is suspected, serologic assays for 1,3 beta-D-glucan and galactomannan testing or other nonculture methods (eg, in-house polymerase chain reaction testing), if available, may provide early evidence of fungal infections and support empiric antifungal therapy. These assays are discussed separately. However, appropriate cultures or biopsy of infected tissue are still necessary to confirm the presence of fungal infection. (See "Candidemia and invasive candidiasis in children: Clinical manifestations and diagnosis", section on 'Nonculture methods' and "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection' and "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)

Empiric antifungal coverage under the guidance of a pediatric infectious disease specialist is warranted in selected high-risk patients, such as children with immunosuppressive conditions or on parenteral nutrition.

Continue respiratory support — Monitor oxygenation using continuous pulse oximetry. Based upon trials of oxygen delivery in adults, children with septic shock and hypoxemia should be treated with supplemental oxygen, as needed, to maintain oxygen saturation (SpO₂) at 94 to 96 percent (see "Adverse effects of supplemental oxygen").

Otherwise, patients who can maintain pulse oximetry in this range in room air do not warrant supplemental oxygen unless they have severe anemia (eg, hemoglobin <7 gm/dL [hematocrit 21 percent]).

In patients with continued shock, worsening hypoxemia, or progression to PARDS, advanced airway support (ie, noninvasive or invasive ventilation) is frequently needed. A trial of noninvasive mechanical ventilation (over invasive mechanical ventilation) in children with hypoxemia and normal mentation/ability to protect their airway who do not have overt respiratory failure and who are responding to initial resuscitation is reasonable [1,2]. However, for children with high metabolic demand from refractory shock, typically indicated by progressive lactic acidemia and end-organ dysfunction, early intubation and mechanical ventilation prior to overt hypoxemic or hypercarbic respiratory failure can help to mitigate deficits in systemic oxygen delivery [1,2]. Mechanical ventilation should be performed with the following goals in mind [8,9]:

●Keep plateau pressure ≤30 cm H₂O.

●Keep tidal volume under 10 mL/kg ideal body weight. Tidal volume may need to be decreased as low as 4 to 6 mL/kg in patients with very low lung compliance using lung protective ventilation strategies to achieve a plateau pressure ≤30 cm H₂O [10].

●Maintain arterial pH ≥7.25.

●In patients with hypoxia who require a fraction of inspired oxygen (FiO₂) ≥50 percent, titrate FiO₂ and positive end-expiratory pressure to maintain arterial oxygen concentration (PaO₂) between 60 and 80 mmHg (8 to 10.7 kPa) or pulse oximetry 90 to 96 percent.

●Use positive end-expiratory pressure levels ≥10 to 15 cm H₂O for children with severe PARDS requiring FiO₂ >60 percent (with attention to potential adverse hemodynamic effects of reduced cardiac pre-load).

●For patients with severe PARDS, a trial of a short-course of neuromuscular blockade (for up to 24 to 48 hours after PARDS onset) is reasonable.

●For patients with severe PARDS, a trial of prone positioning for children is reasonable.

Ongoing and invasive monitoring — During ongoing management of sepsis or septic shock, monitoring of tissue perfusion using physiologic indicators and target goals continues (table 1).

Based upon limited observational evidence, serial cardiac ultrasound can also help to identify patients with persistent hypovolemia, myocardial dysfunction, and/or pericardial effusion that may be contributing to persistent shock. This is especially important for children who do not improve with initial fluid resuscitation or develop signs of fluid overload; in these patients, direct assessment of cardiac function can more accurately gauge physiologic derangements than physical examination alone [2]. As an example, in one case series of 48 children who remained in septic shock despite at least 40 mL/kg of fluid, 33 percent had persistent hypovolemia and 40 percent had myocardial dysfunction. Serial monitoring detected clinically important changes, including late development of myocardial dysfunction, that allowed for more refined titration of fluids, inotropes, and vasopressors over time [11].

In addition, the clinician should determine the need for invasive monitoring via intra-arterial and central venous cannulas:

●Intra-arterial cannula placement – Noninvasive blood pressure measurement is acceptable in patients who have markedly improved or had total reversal of septic shock. Efforts to obtain intra-arterial access should not interfere with the resuscitation of septic shock. However, automated blood pressures overestimate systolic blood pressure relative to intra-arterial or Doppler ultrasound measurements in hypotensive children and underestimate systolic blood pressure among hypertensive patients [12]. Thus, insertion of an intra-arterial catheter is suggested if blood pressure is labile or if restoration of arterial perfusion pressures is expected to be a protracted process. Procedures for obtaining intra-arterial access in children are discussed separately. (See "Arterial puncture and cannulation in children for pediatric emergency medicine and critical care", section on 'Arterial cannulation'.)

●Central venous access – Central venous access is indicated for patients with fluid-resistant septic shock because these patients frequently are dependent upon uninterrupted vasoactive medication administration to prevent further decompensation. If they also have poor perfusion, then they are at a greatly increased risk of extravasation and significant local tissue damage from peripherally administered vasoactive medications. Furthermore, central venous access permits monitoring of central venous pressures and ScvO₂ in these unstable patients, which helps guide ongoing therapy.

Central venous access is also appropriate in patients who have reversal of shock after initiation of vasoactive drugs, although patients who rapidly improve after receiving vasoactive medications and those in whom a rapid weaning of support is expected may not require central venous line placement.

In the absence of elevated intra-abdominal pressure, the correlation between femoral vein pressure and central venous pressure is good, though absolute values may differ slightly [13,14]. Changes in ScvO₂, which provide reliable information regarding tissue oxygenation, should also be frequently monitored [15]. If direct measure of ScvO₂ is not available, limited evidence suggests that a capillary refill time ≤2 seconds is associated with a ScvO₂ ≥70 percent. However, capillary refill time can be brisk despite significant myocardial dysfunction in children with septic shock. (See "Shock in children in resource-abundant settings: Initial management", section on 'Clinical and physiologic targets'.)

Continue fluid administration — The need for aggressive administration of fluids to optimize tissue perfusion and to achieve physiologic goals typically continues beyond the first hour of care in children with evolving or existing sepsis treated in resource-abundant settings. The volume per bolus and types of fluid are as for the resuscitation period. Fluid input and output should be carefully monitored on an hourly basis (algorithm 1). (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Fluid resuscitation'.)

In patients with persistent poor perfusion or hypotension, boluses of fluids should continue until hemodynamic improvement is noted or evidence of cardiac insufficiency/fluid overload (eg, pulmonary edema, hepatomegaly, enlarged heart, or gallop cardiac rhythm) occurs. Serial bedside cardiac ultrasound or echocardiography can also help to identify patients who remain hypovolemic.

Fluid overload — Fluid overload frequently occurs in children with sepsis or septic shock. Observational studies in critically ill children, including children with sepsis who received renal replacement therapies, indicate that more than 10 percent fluid overload is associated with mortality [16,17]. However, the evidence is not sufficient to determine whether or not fluid overload has an independent deleterious effect on survival. Non-survivors may have had more severe septic shock, and therefore required greater amount of fluid and were more likely to develop renal insufficiency.

Patients with sepsis or septic shock who have insufficient urine output and evidence of fluid overload despite fluid restriction and diuretic therapy may warrant renal replacement therapy (RRT; eg, continuous veno-venous hemofiltration or intermittent hemodialysis). The decision to initiate RRT should be made in collaboration with a pediatric nephrologist, whenever available. If RRT is used, the Surviving Sepsis Campaign suggests against high-volume hemofiltration over standard hemofiltration in children with septic shock or other sepsis-associated organ dysfunction. The indications and timing of RRT for fluid overload and modality choice in children are discussed separately [1,2]. (See "Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy", section on 'Kidney replacement therapy modalities: Overview' and "Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy", section on 'Fluid overload'.)

Interstitial edema is common in sepsis due to increased vascular permeability. Clinical findings of significant fluid overload consist of pitting edema, anasarca, or pulmonary edema. For patients with hypoxia and pulmonary edema, early initiation of diuretic therapy (eg, furosemide) may be appropriate after a period of 12 to 24 hours of sustained hemodynamic stability off vasoactive infusions.

Blood transfusion — Hemoglobin is the primary determinant of blood oxygen carrying capacity and, therefore, of tissue oxygen delivery. Thus, maintaining adequate hemoglobin levels is an important aspect of managing children with sepsis or septic shock. However, evidence is lacking regarding the appropriate hemoglobin target for all children. Thresholds vary by the hemodynamic condition of the patient:

●Hemodynamically unstable – In unstable patients with sepsis or septic shock (eg, hypotension, persistently elevated blood lactate, progressive/persistent end-organ dysfunction, and/or ScvO₂ <70 percent despite vasopressor support, or hypoxia), we suggest hemoglobin 9 to 10 g/dL as the threshold for blood transfusion until further data are available [15,18].

In hemodynamically unstable children with septic shock, the American College of Critical Care Medicine previously suggested a hemoglobin goal of 10 g/dL (equivalent to 30 percent hematocrit) as a target to maintain with blood transfusion for persistent malperfusion until further data are available [15]. This recommendation was based largely on a single trial from Brazil in which children with septic shock had better outcomes when transfused to a goal hemoglobin concentration of ≥10 g/dL as part of a protocol that included continuous ScvO₂ monitoring [18]. Evidence is lacking to support the safety of tolerating a lower hemoglobin in pediatric patients, though there is evidence in adult sepsis that a lower hemoglobin target may be safe. (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Intensive care unit'.)

●Hemodynamically stable – For children with sepsis or septic shock who are hemodynamically stable (defined as mean arterial blood pressure higher than two standard deviations below normal for age and no increase in vasoactive medications for at least two hours), we suggest a hemoglobin of 7 g/dL instead of 10 g/dL as the threshold for blood transfusion [1,2,19].

Limited evidence suggests that this lower hemoglobin threshold for blood transfusion is likely to be safe [20,21]. As an example, in a multicenter unblinded trial of 137 children with sepsis who were hemodynamically stable (mean systemic arterial pressure was not below two standard deviations of normal for age and cardiovascular support was not increased for at least two hours before enrollment) that compared restrictive transfusion (transfusion for hemoglobin <7.0 g/dL) with liberal transfusion (transfusion for hemoglobin <9.5 g/dL), no clinically significant differences were found for the occurrence of new or progressive multiple organ dysfunction syndrome (18.8 versus 19.1 percent), pediatric intensive care unit length of stay (13 days in both groups), or pediatric intensive care unit mortality (7 versus 3 percent, respectively) [20]. However, two additional patients died in the restrictive transfusion group after discharge from the pediatric intensive care unit.

Treat disseminated intravascular coagulation — Patients with sepsis or septic shock frequently have disseminated intravascular coagulopathy that may warrant treatment. Thus, baseline measures of clotting status are necessary in these patients. (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Obtain laboratory studies'.)

Platelets, fresh frozen plasma, and/or cryoprecipitate should be provided to patients with disseminated intravascular coagulopathy and significant bleeding. A reasonable guide for the judicious use of blood components in the setting of significant bleeding includes maintaining platelet counts >50,000 per mm³ and fibrinogen concentration >100 mg/dL (1 mol/L). Replacement therapy should not be used to normalize laboratory tests (which often is impossible) [1,2].

There have been no trials to study the efficacy of platelet, fresh frozen plasma, or cryoprecipitate transfusions in children with sepsis and disseminated intravascular coagulopathy. Nevertheless, the use of these agents seems rational in patients with significant bleeding (melena, or prolonged bleeding from venipuncture sites) due to thrombocytopenia and clotting factor consumption or significant risk of bleeding (eg, pre- or postoperative patients). (See "Disseminated intravascular coagulation in infants and children", section on 'Transfusion of platelets and/or plasma'.)

In the setting of bleeding or need for an invasive procedure, clotting factors can be replaced by either fresh frozen plasma or cryoprecipitate. Fresh frozen plasma provides both procoagulant and anticoagulant proteins and is administered every 12 to 24 hours at a dose of 10 to 15 mL/kg per infusion. Cryoprecipitate has higher concentrations of factor VIII and fibrinogen and can be used to correct hypofibrinogenemia. It is administered every six hours as needed at a dose of 10 mL/kg per infusion. (See "Disseminated intravascular coagulation in infants and children", section on 'Transfusion of platelets and/or plasma'.)

Activated protein C is used mainly in patients with severe congenital protein C deficiency and is not recommended as an adjunct treatment for children with sepsis at this time [22]. (See "Protein C deficiency" and "Treatment and prevention of meningococcal infection", section on 'Protein C concentrate'.)

Manage glucose abnormalities — Hypoglycemia remains a concern during the initial management phase of septic shock. Children have limited glycogen stores and may develop profound hypoglycemia during periods of stress. Thus, blood glucose should be monitored frequently upon admission and at least every six hours while the patient is unstable. Management of hypoglycemia is provided in the rapid overview (table 3). (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Treat hypoglycemia'.)

Once tissue perfusion is restored and shock is resolved, children should receive intravenous (IV) fluid that contains dextrose sufficient to avoid hypoglycemia [15]. This therapy typically consists of 5 to 10 percent dextrose in electrolyte solution appropriate to the patient's ongoing sodium and potassium requirements. (See "Maintenance intravenous fluid therapy in children", section on 'Dextrose'.)

Hyperglycemia is commonly present in children with septic shock. Insulin therapy is reasonable to maintain a glucose concentration between 140 and 180 mg/dL (7.8 and 10 mmol/L) given the lack of harm demonstrated in three pediatric trials, which included children with septic shock or other sepsis-associated organ dysfunction treated with IV insulin with a goal upper blood glucose target of 180 mg/dL (10 mmol/L) [23-25]. When insulin is started, careful monitoring with at least hourly measures of point-of-care glucose must be continued to avoid hypoglycemia [26,27]. We do not advocate tight glycemic control to maintain glucose target at or below 140 mg/dL (7.8 mmol/L) based on negative results from three trials that included children with sepsis and septic shock [23-25].

Glycemic control in children with critical illness is discussed separately. (See "Glycemic control in critically ill adult and pediatric patients".)

Avoid hypocalcemia — Adequate calcium stores are essential for maintaining myocardial contractility, although definitive evidence that maintaining normal blood calcium levels improves outcomes in children with sepsis or septic shock is lacking.

Our practice is to monitor ionized blood calcium levels every one to two hours during initial management of sepsis or septic shock, and, for patients with persistent shock and an ionized calcium <1.1 mmol/L (4.8 mg/dL) or those with symptomatic hypocalcemia (eg, positive Chvostek or Trousseau signs, seizures, prolonged QT interval on electrocardiogram, or cardiac arrhythmias) in association with an ionized calcium <1.1 mmol/L (4.8 mg/dL), we typically treat with calcium gluconate 10 percent solution in a dose of 50 mg/kg (0.5 mL/kg), maximum dose 2 g (20 mL) by slow IV or intraosseous (IO) 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. This practice is consistent with that of other experts involved in drafting the pediatric Surviving Sepsis Campaign guidelines [1,2]. (See "Primary drugs in pediatric resuscitation", section on 'Calcium'.)

Calcium should be administered in a larger vein or, preferably, a central line. Sodium bicarbonate should not be introduced into the IV or IO 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 (except during impending or actual cardiac arrest). Patients receiving a calcium infusion warrant continuous cardiac monitoring.

Known adrenal insufficiency or hypothyroidism — Patients with septic shock who are receiving replacement therapy for adrenal insufficiency should receive stress doses of glucocorticoids. (See "Treatment of adrenal insufficiency in children", section on 'Stress conditions'.)

Similarly, children with septic shock and hypothyroidism should continue to receive thyroid replacement with levothyroxine [15]. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Levothyroxine dose' and "Treatment and prognosis of congenital hypothyroidism", section on 'Treatment'.)

Nutrition — For children with sepsis or septic shock who become hemodynamically stable, including those patients who are receiving vasoactive infusions who no longer require escalating doses or are weaning the medication, we suggest initiation of early enteral feeding rather than parenteral feeding during the first seven days of care [1,2]. However, enteral feeding should be done cautiously or withheld altogether for patients treated with "high doses" of vasoactive medications, although the cut-point to define "high dose" is not clear. We also suggest that feeding be delivered via a gastric tube rather than a post-pyloric feeding tube as long as gastric feeds are tolerated, and the risk of aspiration is low. Either early hypocaloric/trophic feeding with slow increase to full feeding or early full feeding are acceptable approaches. We avoid the routine use of prokinetic agents during enteral feeding. (See "Overview of enteral nutrition in infants and children".)

For hemodynamically stable patients, evidence is lacking to support the routine use of the following nutrients or supplements [1,2]:

●Selenium

●Glutamine

●Arginine

●Zinc

●Ascorbic acid (vitamin C)

●Thiamine

REFRACTORY (CATECHOLAMINE-RESISTANT) SEPTIC SHOCK — 

The initial treatment of evolving or existing sepsis, including management recommendations for fluid-refractory septic shock, are described in detail separately (algorithm 1). (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)".)

Catecholamine-resistant shock is generally defined as cardiovascular dysfunction despite at least 40 to 60 mL/kg of fluid resuscitation and escalating doses of epinephrine, norepinephrine, or dopamine, or patients who have received adequate fluid resuscitation but remain on high doses of vasoactive medications that cannot be weaned. Principles of management for children with refractory septic shock include treatment of reversible etiologies, stress-dose glucocorticoid therapy for patients with known or possible absolute or relative adrenal insufficiency, and combination vasoactive drug therapy targeted to maintaining central venous oxygen saturation (ScvO₂) ≥70 percent and normalizing blood lactate levels.

If cardiac index is measured, the target range is 3.3 to 6 L/minute/m². Cardiac index may be measured by use of femoral artery thermodilution or pulse index contour. In larger children, it can also be measured using Doppler ultrasound of the proximal aorta. In the past, pulmonary artery catheters were placed for the measurement of cardiac index. However, given the complications associated with placement and maintenance of pulmonary artery catheters, their use for this purpose alone is discouraged. (See "Novel tools for hemodynamic monitoring in critically ill patients with shock" and "Pulmonary artery catheterization: Indications, contraindications, and complications in adults", section on 'Complications'.)

Treat reversible etiologies — The clinician should evaluate for and correct reversible etiologies in children with refractory septic shock:

●Mechanical obstruction of cardiovascular function – Pneumothorax, pericardial tamponade, and intra-abdominal hypertension (eg, peritonitis or ascites) comprise mechanical causes of shock that can be reversed by chest tube thoracostomy, pericardiocentesis, and paracentesis or abdominal decompression surgery, respectively. (See "Emergency pericardiocentesis", section on 'Technique overview' and "Thoracostomy tubes and catheters: Placement techniques and complications", section on 'Techniques'.)

●Anaphylaxis – In rare instances, persistent shock may reflect anaphylaxis to administered antibiotic agents. These patients may have a rash consistent with a drug reaction and warrant treatment with antihistamines, epinephrine, and glucocorticoids; and removal of the inciting agent. (See "Anaphylaxis: Emergency treatment", section on 'Immediate management'.)

●Hemorrhage – Uncontrolled hemorrhage, typically caused by spontaneous bleeding secondary to disseminated intravascular coagulopathy, warrants timely administration of blood and blood products. (See 'Treat disseminated intravascular coagulation' above and 'Blood transfusion' above.)

●Reevaluate source control – Drainage or debridement of infection sites (eg, necrotizing fasciitis) or broadening of antimicrobial coverage are additional actions that may be warranted. (See 'Eradicate infection' above and "Necrotizing soft tissue infections", section on 'Treatment'.)

●Neutropenia – Children with neutropenia and septic shock may benefit from administration of granulocyte-colony stimulating factor under the guidance of a pediatric hematologist or oncologist. (See "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'Granulocyte colony-stimulating factor' and "Fever in children with chemotherapy-induced neutropenia", section on 'Colony stimulating factors'.)

●Patients on immunosuppression therapy – Patients who are status post-bone marrow or solid organ transplant typically warrant weaning of their immunosuppression therapy to a safe and tolerable extent as determined by their oncologist or transplant surgeon.

Obtain cardiac evaluation — Patients with refractory septic shock warrant an electrocardiogram to assess for signs of myocardial ischemia or infarction and heart failure. Pediatric cardiology consultation and echocardiography is also advised to assess for signs of depressed cardiac function, myocarditis or, especially in neonates and young infants, signs of congenital heart disease [2]. Bedside cardiac ultrasound is increasingly available for use by trained and experienced pediatric critical care specialists to assess for hypovolemia, myocardial dysfunction, and pericardial effusion [28-30]. Expert cardiology and echocardiographic consultation is warranted to confirm initial abnormal findings or assess for signs of myocarditis, valvular disease, or structural heart disease. Serial bedside echocardiography is also a component of advanced multimodal monitoring of fluid and cardiac function in children with sepsis who require vasoactive therapy to help guide management decisions. (See 'Vasoactive drug therapy' below.)

Patients with myocarditis diagnosed by endomyocardial biopsy may benefit from intravenous (IV) gamma globulin, although evidence is very limited. Glucocorticoids or other immunosuppressive agents may be appropriate for patients with myocarditis caused by systemic autoimmune disease in addition to infection. (See "Treatment and prognosis of myocarditis in children", section on 'Immunomodulatory therapy'.)

Relative adrenal insufficiency — Children with septic shock unresponsive to fluid and vasopressor therapy may have relative adrenal insufficiency [15,31,32]. For these children, we typically administer stress-dose glucocorticoids (eg, hydrocortisone) as described below. However, because of their known adverse effects and questionable benefit, some experts do not [1,2,33]. For children with septic shock in whom adequate fluid resuscitation and vasoactive-inotropic therapy are able to restore hemodynamic stability, presumptive treatment of relative adrenal insufficiency is not required unless the patient also has one of the following [1,2]:

●Acute or chronic corticosteroid exposure

●Hypothalamic-pituitary-adrenal axis disorders

●Congenital adrenal hyperplasia or other corticosteroid-related endocrinopathies

●Recent treatment with ketoconazole or etomidate

The role of specific testing for adrenal insufficiency to guide corticosteroid therapy is debated, and evidence is lacking. Relative adrenal insufficiency can exist in critically ill children with a relatively high random cortisol level, and it can resolve without specific treatment [34]. These findings have led some experts to treat children with fluid-refractory, catecholamine-resistant septic shock without specific testing. For those who favor testing, experts debate whether to use baseline cortisol measurements or adrenocorticotropin stimulation testing (rapid IV ACTH test) as indicators of adrenal insufficiency (table 4). Testing of adrenocortical function is discussed separately. (See "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Initial evaluation'.)

If given, appropriate stress-dose regimens consist of hydrocortisone with dosing determined by body surface area (BSA), weight, or age [1,35]:

●BSA-based hydrocortisone dose: Initial IV dose 50 to 100 mg/m² (preferred if the BSA can be promptly calculated from the patient’s height and weight (calculator 1))

●Weight-based hydrocortisone dose: Initial IV dose 1 to 2 mg/kg (maximum single dose 100 mg)

●Age-based hydrocortisone dose:

•Infants and toddlers (<3 years old): Initial IV dose 25 mg

•Children (3 to 12 years old): Initial IV dose 50 mg

•Children and adolescents (12 years and older): Initial IV dose 100 mg

After the initial bolus IV dose, glucocorticoid administration consists of the same stress dose given daily either as a continuous IV infusion or divided and given every four to six hours. Children with sepsis or septic shock and receiving stress-dose corticosteroids warrant stress ulcer prophylaxis. (See "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention".)

Glucocorticoid therapy should be discontinued when the patient becomes hemodynamically stable and no longer requires vasoactive medication administration. Practice varies regarding whether glucocorticoids are abruptly discontinued or tapered in children with septic shock. Adult guidelines suggest tapering of glucocorticoids, but there are insufficient data in children. However, tapering is suggested if duration of glucocorticoid use is long enough to potentially have caused adrenal suppression, or it is identified by provocative testing. (See "Corticosteroid therapy for refractory septic shock in adults", section on 'Administration'.)

In a meta-analysis of 16 trials that included children with systemic inflammatory response syndrome, sepsis, or septic shock, children who were assigned to corticosteroid treatment had lower mortality (13 studies, RR 0.65, 95% CI 0.50 to 0.85) and a shorter duration of shock (3 studies, 2.3 fewer days) than those who were not [36]. The incidence of gastrointestinal bleeding was higher in patients in the corticosteroid treatment group; secondary infections were similar in both groups. The quality of the evidence was considered low to very low. Further limitations of this meta-analysis include wide variation in the corticosteroid dose and duration of therapy in the included studies. In addition, many patients in these studies did not have catecholamine-resistant shock.

More evidence is anticipated from an ongoing trial that is examining the potential risks and benefits of adjunctive hydrocortisone for fluid and vasoactive-inotropic recalcitrant septic shock in children [37].

Vasoactive drug therapy — Epinephrine or norepinephrine is recommended as a first-line vasoactive agent for fluid-refractory pediatric septic shock over dopamine; epinephrine is preferred if there is evidence of myocardial dysfunction. Vasoactive drug therapy should be initiated after 40 to 60 mL/kg of fluid resuscitation if the patient continues to have evidence of abnormal perfusion. Additional fluid resuscitation may be concurrently administered if physiologic improvement is evident following each fluid bolus without signs of fluid overload (algorithm 1) [1,2]. (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Patients with fluid-refractory shock'.)

After initiation, the ongoing management of vasoactive drug therapy in children with septic shock should be performed by clinicians with pediatric critical care expertise whenever possible. The approach provided here is for patients with septic shock who have already received crystalloid fluid and initial infusions of epinephrine or norepinephrine. The regimen is determined by whether myocardial dysfunction or low systemic vascular resistance is the predominant physiologic finding.

●Patients with myocardial dysfunction – Epinephrine is the preferred inotrope for patients with sepsis-induced myocardial dysfunction. Although dopamine may be substituted if epinephrine is not available, two randomized controlled trials in children with fluid-refractory septic shock demonstrated improved survival with initiation and titration of epinephrine compared with dopamine [38,39].

If abnormal perfusion, poor myocardial contractility, or hypotension persist despite escalating doses of epinephrine, options include:

•Systemic vascular resistance is normal or low – Addition of norepinephrine is suggested to provide additional vasoconstriction.

•High systemic vascular resistance – If there is evidence of high systemic vascular resistance (either by clinical exam findings or direct hemodynamic measures), then dobutamine or milrinone is suggested because of their inotropic properties and afterload reduction. However, because hypotension could be exacerbated by addition of inodilators, including dobutamine and milrinone, these agents should be titrated carefully with close attention to hemodynamic changes.

Careful titration is of utmost importance when administering milrinone because it has a relatively long half-life (even longer with kidney dysfunction) and may take hours to see a full effect or reverse adverse effects (hypotension). Vasodilators should be discontinued if hypotension worsens. In a small trial of 12 children with refractory catecholamine-resistant shock, administration of milrinone was associated with improved cardiac index and increased oxygen delivery although survival was not different [34]. Milrinone is a phosphodiesterase inhibitor that provides both increased cardiac contractility and vasodilation with afterload reduction. However, long-term use of milrinone is associated with an increased frequency of ventricular arrhythmias, including torsade de pointes. Patients receiving milrinone warrant close monitoring for hypotension, given its long half-life.

●Patients with low systemic vascular resistance (vasodilation) – Norepinephrine is preferred for children with low systemic vascular resistance or vasodilation who do not respond to fluid resuscitation [1,2]. Epinephrine, which at higher doses provides potent vasopressor effect, is a reasonable alternative, especially if myocardial dysfunction is concurrently present. In particular, one must be cognizant that addition of a vasopressor agent, such as norepinephrine, may "unmask" sepsis-induced myocardial dysfunction that may not have been evident when systemic vascular resistance was low. Serial assessment with cardiac ultrasound or echocardiography can be helpful to evaluate for evolution of cardiovascular physiology over time, especially as vasoactive medications are titrated.

Patients who do not respond to norepinephrine infusion and are euvolemic may benefit from treatment with epinephrine or dopamine if inotropic support is necessary for documented or suspected myocardial dysfunction (which may be unmasked in the setting of norepinephrine-induced vasoconstriction). For persistent vasomotor dilation despite adequate fluid resuscitation, vasopressin or its long-acting formulation, terlipressin, if available, may also provide additional vasopressor effect through a noncatecholamine pathway, although use of these agents is controversial [1,2].

Case reports, case series, and one trial indicate that administration of either vasopressin or terlipressin is associated with an increase in mean arterial blood pressure and urine output in children with fluid-refractory, catecholamine-resistant septic shock [40-42]. However, in a multicenter trial of 65 children with vasodilatory shock, low-dose vasopressin did not decrease the time to hemodynamic stability off vasopressor agents versus placebo (49.7 versus 47.1 hours) [43]. Patients receiving low-dose vasopressin had higher mortality (30 versus 16 percent) although this difference was not statistically significant.

Previous guidelines [15] recommended using bedside clinical signs to categorize septic shock in children as "warm" (presumably indicating high cardiac output and low systemic vascular resistance) or "cold" (presumably indicating low cardiac output and high systemic vascular resistance) to guide ongoing management of vasoactive infusions. However, the 2020 Surviving Sepsis Campaign suggests against using bedside clinical signs in isolation for this purpose and instead prefers the use of advanced hemodynamic variables (eg, direct measures of cardiac output/cardiac index, systemic vascular resistance, and ScvO₂) in addition to physical examination to guide the ongoing resuscitation of children with septic shock or other sepsis-associated organ dysfunction.

This change in approach is based on a number of observational studies that demonstrated very poor correlation of bedside clinical signs with more direct measures of myocardial dysfunction, cardiac index, and systemic vascular resistance as measured by advanced monitoring, including echocardiography [11,28,44-47]. For example, in a study of 48 children who remained in septic shock despite at least 40 mL/kg fluid, 14 (67 percent) of 21 with "cold shock" on clinical examination had vasodilation evident once invasive blood pressure monitoring was available [11]. Similarly, many children with "warm shock" had evidence of myocardial dysfunction on echocardiography. Overall, echocardiography and invasive blood pressure monitoring enabled more precise titration of fluid and vasoactive medications than clinical examination alone in 88 percent of patients. In another study of 50 children with septic shock and pulmonary artery catheterization, 88 percent had a change in therapy once direct hemodynamic measurements were available to augment bedside clinical signs [48].

Extracorporeal membrane oxygenation — We suggest that children with persistent catecholamine-resistant shock in whom physiologic targets (eg, ScvO₂ ≥70 percent, decreasing lactate) cannot be attained with fluid repletion, vasoactive infusion, and hormonal therapy; who do not have an immediately reversible cause, such as myocarditis, pneumothorax, or pericardial effusion; and who have a high likelihood of mortality be evaluated for extracorporeal membrane oxygenation (ECMO) support, if available [9]. If ECMO is not available at the facility in which the child is receiving care, then the potential benefits of ECMO must be weighed against the likelihood that the patient can tolerate transfer.

Sepsis and septic shock were previously considered to be contraindications to ECMO [15]. However, more recent data suggest that, for patients who receive ECMO, survival to hospital discharge approaches 50 percent in pediatric refractory septic shock and 80 percent for neonatal refractory septic shock. As an example, in a small case series of 23 children with refractory septic shock in which central cannulation was used to achieve higher blood flow rates, 18 (78 percent) patients survived to be decannulated off ECMO, and 17 (74 percent) children survived to hospital discharge [49]. Our experience suggests that the chances of survival in such patients with conventional therapy alone are otherwise very remote.

Additional advanced therapies

Therapeutic plasma exchange or plasmapheresis — Therapeutic plasma exchange has been proposed for patients with sepsis and multiorgan failure, but its role for optimal use has not been established, and its use is not routine. The practical limitations of inserting a large catheter for plasma exchange in young children (often with disseminated intravascular coagulopathy and increased risk of bleeding), the intensive resources necessary to perform plasma exchange or plasmapheresis, a lack of definitive benefit in children [50], and the potential to worsen hypotension in hemodynamically unstable patients have limited this therapy in pediatric sepsis. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'ASFA therapeutic categories'.)

However, case series and small trials have reported a survival benefit in selected pediatric patients with thrombocytopenia-associated multiple organ failure (TAMOF) [15]. TAMOF is a clinical phenotype of sepsis associated with thrombotic microangiopathy that includes cardiovascular dysfunction, hemolysis, and multiple organ dysfunction syndrome. TAMOF is defined as new-onset thrombocytopenia (platelet count ≤100,000/microliter or 50 percent decline if baseline thrombocytopenia is present along with at least three organ system dysfunctions [including shock and, usually, acute kidney injury]). One small trial of 10 children demonstrated a survival benefit in patients with the clinical phenotype of TAMOF receiving plasmapheresis versus standard therapy (five of five versus one of five surviving) [51]. In this study, low levels of the von Willebrand factor cleaving protease, ADAMTS-13, activity were reversed with daily plasma exchange, which the authors suggested as the potential benefit of this therapy. In an observational study of 81 children with sepsis-induced TAMOF, use of plasma exchange was associated with faster recovery from organ dysfunction and a lower adjusted risk of 28-day mortality [52]. However, additional high-quality data are needed to definitively ascertain the benefits of plasma exchange, including timing and duration, in children with sepsis-induced TAMOF and decreased ADAMTS-13 activity before it can be routinely suggested [1,2]. Decisions regarding the use of therapeutic plasma exchange in children with septic shock should be made in collaboration with a pediatric hematologist or transfusion medicine specialist. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'ASFA therapeutic categories'.)

Intravenous immune globulin — For patients with toxic shock syndrome, intravenous immune globulin (IVIG) may have clinical utility. IVIG for this indication is discussed separately. (See "Staphylococcal toxic shock syndrome", section on 'Intravenous immune globulin'.)

Adjuvant therapy with IVIG may also benefit selected patients with refractory septic shock and humoral immunodeficiencies with low immunoglobulin levels.

However, evidence for broad benefit in children with septic shock is unclear, and routine use is not suggested [1,2]. For example, a small trial of polyclonal IVIG in 100 children with pediatric sepsis syndrome showed a significant reduction in mortality (28 versus 44 percent), length of stay (six versus nine days), and less progression to complications (8 versus 32 percent) [53]. However, a more recent and larger multicenter trial of polyclonal IVIG in almost 3500 neonates receiving antibiotics for suspected or proven serious infection found no significant difference in the rate of the primary outcome of death or major disability at the age of two years (relative risk [RR] 1.00, 95% CI, 0.9-1.1) [54]. Evidence in adult patients with septic shock suggests that IVIG has no benefit in this population. (See "Investigational and ineffective pharmacologic therapies for sepsis", section on 'Intravenous immune globulin'.)

Other therapies — A variety of therapies have been investigated or are being evaluated to improve clinical outcomes in sepsis. Those therapies that appear promising as well as ones that have been proven to be ineffective are discussed in detail separately. (See "Investigational and ineffective pharmacologic therapies for sepsis".)

PROGNOSIS — 

The international Society of Critical Care Medicine Pediatric Sepsis Definition Task Force has published the International Consensus Criteria for Pediatric Sepsis and Septic Shock that define life-threatening sepsis as a clinical syndrome in children that complicates severe infection and causes end-organ dysfunction. Mechanisms contributing to organ dysfunction include systemic inflammation, immune dysregulation, and microcirculatory derangements [55].

Severity of illness, host factors, site of infection, microbiology, and organ dysfunction remote from the site of primary infection impact prognosis:

●Severity of illness – The development of multiple organ dysfunction indicates an increased severity of illness in patients with sepsis and is associated with a higher mortality. The Phoenix Sepsis Score (PSS) uses a four-organ system model that provides quantification of this risk (table 5). During validation of the PSS, the risk of mortality by setting was as follows [56]:

•Sepsis (infection and PSS ≥2 points):

-Resource abundant settings – 7.1 percent

-Resource limited settings – 28.5 percent

•Septic shock (sepsis and ≥1 cardiovascular point) in the first 24 hours:

-Resource abundant settings – 10.8 percent

-Resource limited settings – 33.5 percent

Mortality also increased in a dose-response fashion as the PSS increased; the in-hospital mortality was approximately 40 percent in patients with a PSS score of 8 in resource-abundant settings and in patients with a PSS score of 4 in resource-limited settings. Quantification of respiratory and neurologic system status was not always available in resource-limited settings.

●Host factors – Case fatality rates in children with severe sepsis by the 2005 International Pediatric Consensus Conference definition [57] are highest for infants 1 to 12 months of age (approximately 11 percent) and are higher across all age groups for children with comorbidities, especially in children with cancer or human immunodeficiency virus infection (12 to 16 percent) [58,59].

●Site of infection – Children with endocarditis, central nervous system infection, and primary bacteremia have high case fatality rates (15 to 20 percent) [58]. The case fatality rate is lowest for genitourinary tract infections (approximately 4 percent).

●Microbiology – Case fatality is increased in children with pneumococcal and fungal infections (15 and 13 percent, respectively) [58]. Infection with organisms resistant to antibiotics (eg, methicillin-resistant Staphylococcus aureus [MRSA] or vancomycin-resistant Enterococcus species) is also associated with a marked increased mortality in patients with sepsis. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Type of infection'.)

●Organ dysfunction remote from the site of primary infection – In the validation study for the PSS, children with sepsis and remote organ dysfunction accounted for 85 percent of the children with sepsis or septic shock. These patients also had higher mortality compared with children with sepsis and no remote organ dysfunction [56]:

•Remote organ dysfunction:

-Resource abundant settings – 8.0 percent

-Resource limited settings – 32.3 percent

•No remote organ dysfunction:

-Resource abundant settings – 1.7 percent

-Resource limited settings – 6.1 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" and "Society guideline links: Shock in children" and "Society guideline links: Gastrointestinal stress ulcer prophylaxis".)

SUMMARY AND RECOMMENDATIONS

●Approach – Our approach to the ongoing management of children with sepsis or septic shock in resource-abundant settings is largely consistent with the 2020 Surviving Sepsis Campaign International Guidelines. Whenever possible, these children should receive ongoing management by a pediatric critical care specialist or pediatrician with similar expertise in a pediatric intensive care unit. (See 'Approach' above.)

●Ongoing resuscitation – Ongoing aggressive resuscitation should continue after the first hour for children with sepsis or septic shock and be targeted to specific physiologic endpoints. Important actions include:

•Continue respiratory support (see 'Continue respiratory support' above)

•Monitor tissue perfusion using physiologic indicators and target goals (table 1) (see 'Ongoing and invasive monitoring' above)

•Judiciously administer fluids with attention to avoid fluid overload (see 'Continue fluid administration' above)

•Titrate vasoactive infusions (see 'Vasoactive drug therapy' above)

●Eradicate infection – In collaboration with an infectious disease specialist, antimicrobial treatment should be optimized based upon results of culture and/or other highly accurate means of pathogen detection (eg, polymerase chain reaction). Because localized foci of infection (ie, abscess) may not respond to antibiotics alone, undertake source control whenever possible. (See 'Eradicate infection' above.)

●Blood transfusion – For hemodynamically unstable children with septic shock (eg, hypotensive catecholamine-resistant shock) who have ongoing evidence of tissue hypoxia, such as persistently elevated lactate or central venous oxygen saturation (ScvO₂) <70 percent, the optimal hemoglobin level is unclear. However, it is reasonable to transfuse red blood cells to a hemoglobin target near 9 to 10 g/dL (equivalent to 30 percent hematocrit) during resuscitation and ongoing management. (See 'Blood transfusion' above.)

In stable patients (eg, resolution of shock and mean arterial blood pressure >2 standard deviations below normal for age without increases in vasoactive medications for at least two hours), we suggest a lower hemoglobin threshold of 7 g/dL (equivalent to 21 percent hematocrit) for blood transfusion (Grade 2C). (See 'Blood transfusion' above.)

●Treat disseminated intravascular coagulopathy (DIC) – Provide platelets, fresh frozen plasma, and/or to patients with DIC and significant bleeding. A reasonable guide for the judicious use of blood components in the setting of significant bleeding includes maintaining platelet counts >50,000/ mm³ and fibrinogen concentration >100 mg/dL (1 mol/L). Do not use replacement therapy solely to normalize laboratory tests (which often is impossible). (See 'Treat disseminated intravascular coagulation' above.)

●Other interventions – Other important interventions include:

•Manage glucose abnormalities (see 'Manage glucose abnormalities' above)

•Treat symptomatic hypocalcemia (see 'Avoid hypocalcemia' above)

•Provide replacement therapy for patients with known adrenal insufficiency or hypothyroidism (see 'Known adrenal insufficiency or hypothyroidism' above)

●Nutrition – For children with sepsis or septic shock who become hemodynamically stable, including those patients who are receiving vasoactive infusions and who no longer require escalating doses or who are weaning the medication, we suggest initiation of early enteral feeding rather than parenteral feeding during the first seven days of care (Grade 2C). We also suggest that feeding be delivered via a gastric tube rather than a post-pyloric feeding tube as long as gastric feeds are tolerated and the risk of aspiration is low (Grade 2C). Either early hypocaloric/trophic feeding with slow increase to full feeding or early full feeding are acceptable approaches. We avoid the use of prokinetic agents during enteral feeding. (See 'Nutrition' above and "Overview of enteral nutrition in infants and children".)

●Refractory (catecholamine-resistant) septic shock – Important actions for children with refractory septic shock include (See 'Refractory (catecholamine-resistant) septic shock' above.):

•Reversible causes – Identify and treat reversible causes (eg, pneumothorax, pericardial tamponade, hemorrhage). (See 'Treat reversible etiologies' above and 'Obtain cardiac evaluation' above.)

•Treat relative adrenal insufficiency – For children with fluid-refractory, catecholamine-resistant septic shock, we typically administer stress-dose glucocorticoids (eg, hydrocortisone) to address physiologic adrenal insufficiency. However, because of the known adverse effects and questionable benefit, some experts do not routinely give glucocorticoids to these patients. For patients receiving glucocorticoids, whether to use baseline cortisol measurements, adrenocorticotropin stimulation testing, or persistent hemodynamic instability alone as indicators for continued therapy is debated, and evidence for the best approach in children is lacking. If used, glucocorticoid therapy should be discontinued when the patient becomes hemodynamically stable. (See 'Relative adrenal insufficiency' above.)

•Maximize vasoactive drug therapy – Combination vasoactive therapy should target cardiac function, lactate, ScvO₂, and other measures of tissue perfusion (eg, capillary refill time, urine output, mental status, and serum lactate levels). (See 'Vasoactive drug therapy' above.)

●Extracorporeal membrane oxygenation (ECMO) – For children with persistent catecholamine-resistant shock in whom physiologic targets (eg, ScvO₂ ≥70 percent) cannot be attained despite maximal medical therapy; who do not have a reversible cause, such as myocarditis, pneumothorax, or pericardial effusion; and who have a high likelihood of mortality, we suggest evaluation for ECMO, if available. If the patient is an ECMO candidate and ECMO is not available at the facility in which the child is receiving care, then the potential benefits of ECMO must be weighed against the likelihood that the patient can tolerate transfer. (See 'Extracorporeal membrane oxygenation' above.)