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INTRODUCTION — The early recognition and initial management of severe sepsis and septic shock in children during the critical 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 in children: Ongoing management after resuscitation".)
DEFINITIONS — A child with two or more of the criteria for the systemic inflammatory response syndrome (table 1) who also has suspected or proven infection has sepsis.
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. The severity of illness for an individual patient is a continuum through which it may be clinically impossible to distinguish transitions from sepsis to severe sepsis and septic shock.
RAPID RECOGNITION — The goal of the initial phase of management for children with septic shock is to rapidly recognize those with infections who have severe sepsis (and are at risk for rapid progression to septic shock) as well as those with septic shock. Septic shock is associated with high morbidity and mortality. In addition, delayed recognition of septic shock has repeatedly been associated with worse clinical outcomes in adults and children. 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'.)
Institutional "bundle" for recognition of severe sepsis or septic shock — To minimize delays in recognition of severe sepsis and septic shock, each pediatric institution should develop a multidisciplinary approach to improve early identification of septic shock also called a septic shock "recognition bundle" .
The major components of the recognition bundle that are recommended by the American College of Critical Care Medicine (ACCM) are :
●Identification of severe sepsis or septic shock – Institutions should implement a septic shock identification/trigger tool that consists of combinations of clinical diagnoses and findings (eg, high-risk patient conditions, vital signs, and/or physical findings) which prompt further evaluation. The tool should be adapted to the setting and patient population where it will be used. Implementation through an electronic health record may facilitate clinician compliance. An example of an emergency department trigger tool designed for use by triage nurses and incorporating vital sign thresholds used in the Pediatric Advanced Life Support course is provided (algorithm 1). Some institutions may choose vital sign triggers initially proposed by the ACCM (table 1). Each institution should base their vital sign triggers on their best interpretation of the evidence and what will be most functional in their system.
●Rapid clinical assessment for patients with possible severe sepsis/septic shock – Once screening with the trigger tool indicates that a patient may have severe sepsis/septic shock, they should undergo rapid clinical assessment within 15 minutes by a physician, physician assistant, or advanced practice nurse to confirm findings of septic shock, implement additional monitoring, and determine the resuscitation plan.
●Rapid initiation of resuscitation – Resuscitation should be initiated within 15 minutes of confirming severe sepsis or septic shock. (See 'Resuscitation' below.)
Red flag findings — Red flag findings that should prompt rapid clinical assessment and resuscitation for severe sepsis or septic shock include :
●Presence of fever (core temperature >38.5°C [101°F] for patients 3 months of age and older or >38°C [100.5°F] for infants <3 months of age)
●Hypothermia (core temperature <36°C [97.5°F])
●Abnormal pulse (diminished, weak, or bounding)
●Abnormal capillary refill (central refill ≥3 seconds or flash refill [<1 second])
●Abnormal mental status:
•Inappropriate drowsiness (eg, excessive per caregiver)
•Not interacting with caregiver
•Difficult to arouse (lethargic or obtunded)
•Confused (not oriented to person, place, or time when developmentally appropriate to test)
Each institution should base their vital sign triggers for tachycardia, tachypnea, and hypotension upon their best interpretation of the evidence and what will be most functional in their system. Examples are provided in the table and algorithm (table 1 and algorithm 1).
Tachycardia and tachypnea are common and nonspecific findings in young pediatric patients and may be due to fever, anxiety, dehydration, pain/discomfort, anemia, or agitation. In febrile children, the heart rate may be adjusted by deducting approximately 10 beats/minute for every 1°C elevation in temperature. However, tachycardia should resolve when the temperature returns to normal; 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'.)
In a child with tachycardia and impaired perfusion, a rapid fluid bolus of 20 mL/kg is recommended unless there is evidence for cardiac dysfunction (eg, hepatomegaly, jugular venous distention, S3 gallop, and/or cardiomegaly) or impending respiratory failure from pulmonary edema for which fluid should be carefully titrated.
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 may be 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 and symptoms of infection — In addition to the red flag findings listed above, signs and symptoms of infection support the clinical suspicion of septic shock. Common clinical findings found in children with sepsis and septic shock include:
●Toxic or ill appearance
●Signs of dehydration (eg, dry mucus membranes, sunken eyes, decreased urine output, prolonged capillary refill time, decreased skin turgor, and, in infants, a sunken fontanelle) (table 2)
●Decreased tone in neonates and infants
●Respiratory depression or failure
●Pulmonary rales or decreased breath sounds caused by bronchopneumonia
●Distended, tender abdomen (eg, perforated viscus or intraabdominal abscess)
●Costovertebral angle tenderness (eg, pyelonephritis)
●Macular erythema (toxic shock syndrome)
●Skin cellulitis or abscess (picture 6)
●Warmth, swelling, and/or erythema of an extremity or joint suggestive of osteomyelitis and/or septic arthritis
●Peripheral edema caused by capillary leak
●Multiple nodules which can be seen with disseminated S. aureus or fungal infections (picture 7)
●Ecthyma associated with Pseudomonas infection (picture 8)
Institutional resuscitation "bundle" — Each pediatric institution should develop a multidisciplinary approach to the resuscitation of patients with severe sepsis or septic shock (ie, a resuscitation "bundle") that codifies the time-limited stabilization tasks recommended within the first hour of treatment as presented below and recommended by the American College of Critical Care Medicine (ACCM). This bundle should mobilize institutional resources such as electronic health record systems and quality improvement activities to meet those goals .
Institutional 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 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 intravenous (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.
Approach — The approach provided in this topic is largely consistent with rapid, goal-targeted therapy for pediatric and neonatal septic shock recommended by the American College of Critical Care Medicine (ACCM) and published in 2017 . Goal-targeted therapy for septic shock refers to an aggressive systematic approach to resuscitation aimed at improving physiologic indicators of perfusion and vital organ function within the first six hours of care.
In the first hour of resuscitation, the goals are to restore or maintain :
●Airway, oxygenation, and ventilation
●Threshold heart rate (ie, heart rate that is neither too low nor too high to ensure adequate cardiac output)
●Obtain vascular access (IV or intraosseous [IO]) within 5 minutes.
●Start appropriate fluid resuscitation within 30 minutes.
●Begin broad-spectrum antibiotics within 60 minutes.
●For patients with fluid-refractory shock, initiate peripheral or central ionotropic infusion within 60 minutes.
●These timelines are proposed as a goal because observational studies suggest that outcomes among children with septic shock are improved when these goals are met. However, these timeframes are not always achievable depending upon resources available. Furthermore, individual patients can have good outcomes despite these time limits not being met.
Restoration of tissue perfusion and reversal of shock is identified by the following therapeutic endpoints (goals below in parentheses) [3,6,7]:
●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/hour, up to 40 mL/hour, once effective circulating volume is restored).
●Blood pressure (systolic pressure at least fifth percentile for age):
•<1 month of age – 60 mmHg
•1 month to 10 years of age – 70 mmHg + [2 x age in years]
•10 years of age and older – 90 mmHg
However, blood pressure by itself is not a reliable end point for assessing the adequacy of resuscitation.
●Normal serum lactate (eg, <2 mmol/L).
●Central venous oxygen saturation (ScvO2) (≥70 percent), if available and appropriate (invasive monitoring may not be needed in patients who rapidly respond to initial resuscitation). This target is not applicable to children with congenital heart disease characterized by mixing lesions.
Heart rate is an important physiologic indicator of circulatory status that should also be monitored closely. 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 'Red flag findings' above.)
Blood lactate can be obtained by bedside testing. Limited evidence suggests that serum lactate that decreases with treatment is associated with better outcomes for children with sepsis. In our practice, our therapeutic target is <2 mmol/L. Small observational studies in children have demonstrated that lactate can correlate with severity of shock and prognosis in sepsis [8,9]. 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. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Initial investigations' and "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Laboratory'.)
Except in patients with congenital heart disease with mixing lesions, ScvO2 <70 percent may also indicate persistence of abnormal end-organ. However, a ScvO2 ≥70 percent can be falsely reassuring in sepsis due to hyperdynamic cardiac function, microcirculatory shunting, or mitochondrial dysfunction [10,11]. When measuring ScvO2 in pediatric patients, pulmonary artery catheters are rarely used. Instead, changes in ScvO2 are more commonly obtained from a catheter with its tip in the distal superior vena cava .
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 (SVR), 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 and 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'.)
All patients — All patients with suspected septic shock should receive continuous monitoring of heart rate, breathing, and pulse oximetry and frequent measurements of blood pressure; timely support of airway and breathing; and rapid fluid resuscitation . Further treatment is determined by the initial response to fluid resuscitation (algorithm 2).
Airway and breathing — 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 3). Emergency endotracheal intubation in children and pediatric RSI are discussed in detail separately. (See "Emergency endotracheal intubation in children" and "Rapid sequence intubation (RSI) outside the operating room in children: Approach".)
When performing RSI in children with septic shock, key actions include :
●Patients with hemodynamic instability should receive appropriate support with fluid and/or catecholamines (see below) prior to or during intubation.
●Pretreatment with atropine is suggested in infants and younger children to counteract reflex bradycardia that may progress to progressive, unstable bradycardia during RSI. (See "Rapid sequence intubation (RSI) outside the operating room in children: Approach", section on 'Pretreatment'.)
●Ketamine, if available and not contraindicated (eg, patients younger than three months of age or with psychosis), is suggested for sedation prior to endotracheal intubation. (See "Rapid sequence intubation (RSI) outside of the operating room in children: Medications for sedation and paralysis", section on 'Ketamine'.)
●Etomidate inhibits cortisol formation and is not recommended unless ketamine is not available or is contraindicated by psychosis. Fentanyl in doses of 1 to 2 mcg/kg given slowly is suggested for infants younger than three months of age.
●Short-acting barbiturates and propofol are associated with hypotension and should be avoided in children with septic shock.
When performing RSI 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 [14,15]. In one case series of 31 children with meningococcal sepsis who required endotracheal intubation, of the eight children who died, seven received etomidate .
Rapid fluid resuscitation — Relative intravascular hypovolemia is common in septic shock (due to vasodilation and capillary leak) and may be severe. The major goal for the initial treatment of septic shock consists of rapid fluid resuscitation to restore tissue perfusion based upon clinical therapeutic endpoints (eg, improvement of quality of pulses, capillary refill time, mental status, urine output). The specific goals identified for each endpoint is discussed above (algorithm 2) [3,6,7]. (See 'Approach' above.)
Specific aspects of recommended fluid resuscitation include :
●Rapid 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 IO 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'.)
●Fluid resuscitation – Rapid fluid resuscitation is an essential treatment for septic shock. Fluid resuscitation begins with 20 mL/kg of normal saline or lactated Ringer solution. Infusion of this amount of fluid over five minutes can be achieved 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 and to identify any signs of fluid overload (eg, pulmonary rales or gallop rhythm). (See 'Red flag findings' above and "Initial management of shock in children", section on 'Risks'.)
The clinical and hemodynamic response and the presence or absence of volume overload must be assessed before and after each bolus. Experience suggests that patients with septic shock often require volumes of up to 60 mL/kg in the first hour and some receive 120 mL/kg or more during the first several hours of fluid administration . Use of a time clock has facilitated the timely administration of fluids in at least one setting . Fluid resuscitation should continue until tissue perfusion, oxygen delivery, and blood pressure are adequate, or signs of fluid overload (rales, gallop rhythm, enlarged liver) develop.
Ideally within the first hour of treatment, the physician should determine if the patient is responding to timely fluid administration or not. Patients who are fluid-refractory (ie, no improvement or worsening despite appropriate fluid resuscitation) should begin inotropic therapy tailored to blood pressure and whether cold or warm shock is present. (See 'Patients with fluid-refractory shock' below.)
Observational studies from tertiary care pediatric facilities have documented high compliance (95 to 100 percent) with a one-hour fluid administration target after implementation of institutional bundles for rapid recognition and treatment of septic shock [4,5,17]. Achievement of targets for timely fluid resuscitation and antibiotic administration has been associated with reduction in mortality without negative impact on resource utilization [5,17]. However, despite institution-wide focus on the treatment of septic shock in these studies, the fluid resuscitation goal is not always met, even in these highly-resourced settings. The feasibility of a one-hour target for fluid resuscitation has not been addressed outside of tertiary care pediatric institutions.
Increased attention to rapid recognition, aggressive fluid administration, and early administration of vasoactive agents and antibiotics has been associated with a significant decrease in pediatric mortality from severe sepsis and septic shock [2,3,18-22]. With best clinical practices, mortality from septic shock in resource-rich settings is 0 to 5 percent among previously healthy children and 10 percent in chronically ill children. In one observational study, mortality was 19 percent among children who had persistent shock at pediatric intensive care unit admission, 62 percent of whom did not receive fluid administration and initiation of vasoactive infusions according to guidelines  In another prospective observational study, mortality from septic shock was 1 percent among children who met goals for timely administration of fluids and antibiotics versus 4 percent for those who did not (adjusted odds of death 0.2, 95% CI 0.07 to 0.53) . (See 'Outcomes' below.)
Evidence regarding the outcomes of resuscitation of children with septic shock using normal saline or balanced crystalloid fluids (eg, lactated Ringer solution) is inconclusive and, until high-quality data is available, either crystalloid fluid is acceptable. In one retrospective study that using propensity-matched data from a national registry, exclusive resuscitation with balanced crystalloid fluids for the first 72 hours was associated with a shorter duration of vasoactive infusions, less acute kidney injury, and significantly lower mortality compared to normal saline . However, a second retrospective study that used data from insurance records and matched over 2000 children who received balanced crystalloid solution 1:1 with children who received normal saline found no difference in mortality, likelihood of acute kidney injury, or length of hospital or ICU stay .
In our practice, we generally use a crystalloid solution instead of albumin solution because of the lack of clear benefit and higher cost of albumin. In children, randomized trials comparing colloid with crystalloid for hypotensive newborns and for children with dengue shock syndrome have not demonstrated a difference between the solutions (see "Initial management of shock in children", section on 'Choice of fluid'). Among adults with sepsis, several randomized trials and meta-analyses have reported no difference in mortality when albumin was compared with crystalloids, although one meta-analysis suggested benefit in those with septic shock. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Choice of fluid'.)
However, some experts administer albumin as an additive or maintenance fluid as discussed below.
●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; replacement of measured or estimated fluid losses; serial blood lactate levels; and, if available and appropriate, measurement of radial arterial blood pressure, central venous pressure, and central venous oxygen saturation (ScvO2). (See "Septic shock in children: Ongoing management after resuscitation", 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, should be avoided because they 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. (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 (WHO) 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) [27,28]. 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 re-analysis 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 [29,30].
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 resource-limited settings. 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 lactated Ringer solution) guided by the degree and type of shock present as a key component of goal-targeted therapy. (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'.)
Obtain laboratory studies — Suggested laboratory studies for children with sepsis and septic shock should be obtained as vascular access is achieved 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 (ALT)
●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 abnormal laboratory findings are often reported in children with septic shock:
●Lactic acidosis indicated by metabolic acidosis on blood gases and elevation of arterial blood lactate (>2 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, INR, PT, or PTT) (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 ALT >2 times upper limit of normal for age
●Pyuria indicating an urinary tract infection
Additional discussion of the interpretation of laboratory findings in children with septic shock is provided separately. (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Laboratory studies'.)
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 IV access is obtained.
●Hypoglycemia – Hypoglycemia should be corrected by rapid IV infusion of dextrose as described in the rapid overview (table 4). 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 'Patients with catecholamine-resistant shock' below and "Septic shock in children: Ongoing management after resuscitation", 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 electrocardiogram, 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 IV or 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.
Calcium should be administered in a larger vein or, preferably, a central line. Sodium bicarbonate should not be introduced into an IV or IO 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.
Although definitive evidence to support improved clinical outcomes in humans receiving IV calcium for low ionized calcium levels is lacking , the 2014 ACCM guidelines recommend correcting ionized hypocalcemia in patients with septic shock even in the absence of clinical manifestations of hypocalcemia (eg, seizures, cardiac arrhythmias) .
Hypocalcemia is a common finding in critically ill children with sepsis likely due to changes in the hormonal milieu, though the exact pathophysiology remains unclear  (see "Etiology of hypocalcemia in adults", section on 'Sepsis or severe illness'). 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 [33,34].
Empiric antibiotic therapy — Prompt identification and treatment of the site(s) of infection is the primary therapeutic intervention for septic shock, with most other interventions being purely supportive.
Timing — Whenever possible, broad spectrum IV antibiotic therapy should begin within one hour of presentation, preferably after obtaining appropriate cultures. Effective delivery of antibiotics usually requires two ports or sites for IV access: one devoted to fluid resuscitation and one for antimicrobial delivery. Antibiotics should not be withheld for children in whom lumbar puncture cannot be performed safely due to hemodynamic instability or coagulopathy (algorithm 3). If obtaining blood cultures is difficult, it should not impede antibiotic initiation within the first hour. As discussed below, antifungal and antiviral agents should be included as part of the initial regimen for susceptible patients.
The rationale for the one-hour target for antimicrobial administration comes from observational studies that show poor outcomes with delays in antibiotic therapy, even beyond one hour. In one pediatric series of 130 patients with severe sepsis or septic shock, delays greater than three hours were associated with significantly increased odds of mortality (OR 4.0 [95% CI 1.3-12.1]) . In another prospective observational study, mortality from septic shock was 1 percent among children who met goals for timely administration of fluids within one hour and antibiotics within three hours versus 4 percent for those who did not (adjusted odds of death 0.2, 95% CI 0.07 to 0.53) . Each hour delay in antibiotic administration has been associated with an approximately 8 percent increase in mortality in adults. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Timing'.)
Observational studies from tertiary care pediatric facilities have documented high compliance (95 to 100 percent) with a one-hour antibiotic administration target after implementation of institutional bundles for rapid recognition and treatment of septic shock [4,5]. Achievement of targets for timely antibiotic administration and rapid fluid administration has been associated with reduction in mortality without negative impact on resource utilization . However, despite institution-wide focus on the treatment of septic shock in these studies, the goal of administering antibiotic therapy within one hour is not always met, even in these highly-resourced settings. The feasibility of a one-hour target for empiric antibiotic therapy has not been addressed outside of tertiary care pediatric institutions.
Empiric regimens — 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 severe sepsis or septic shock include the following:
●Most 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, neutropenic patient).
●Listeria monocytogenes and herpes simplex virus (HSV) are important pathogens in infants ≤28 days of age.
●When treating empirically, antibiotics which can be given by rapid IV 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)
•Consider combination therapy (using at least two antibiotics of different antimicrobial classes) aimed at covering resistant organisms, if prevalent or patient at risk, in presence of septic shock [6,36]
●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 cefepime (50 mg/kg, maximum 2 g, for the initial dose) OR ceftazidime (50 mg/kg, maximum 2 g, for the initial dose) OR carbapenem (eg, imipenem, meropenem) in settings where bacterial organisms with extended-spectrum beta-lactamase (ESBL) resistance are prevalent or for patients who have been recently (within two weeks) treated with broad-spectrum antibiotics (eg, third-generation cephalosporin, or fluoroquinolone)
●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 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 5). (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations'.)
Patients with 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 and are indicated in patients with fluid-refractory septic shock .
The American College of Critical Care Medicine recommends that the need for vasoactive medications be identified and administration begins within 60 minutes of presentation. Although meeting this goal is technically feasible based upon one observational study performed in a tertiary care pediatric institution , the feasibility of this goal outside of pediatric tertiary care institutions has not been studied.
Central venous access is preferred for vasopressor administration (eg, epinephrine, norepinephrine, dopamine, or dobutamine). However, peripheral IV access or IO cannula is acceptable while central venous access is being obtained. Initial therapy with low-dose epinephrine is suggested with further tailoring of the agent and dose according to the type of septic shock [3,38]. (See 'Cold shock' below and 'Warm shock' below.)
Cold shock — The approach to cold shock manifested by weak peripheral pulses, cold distal extremities, and prolonged capillary refill time 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/minute, titrate to response up to 1.5 mcg/kg/minute) rather than dopamine (algorithm 2) . Examples of how to prepare an epinephrine infusion for a 10 kg or 20 kg child are provided in the tables (table 6 and table 7). 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/minute.
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/minute, then a second agent, such as epinephrine, should be added.
•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 PICU (88 percent with cold shock), patients who received infusions of dopamine rather than epinephrine had significantly higher mortality (21 versus 7 percent) and more health care-associated infections (29 versus 2 percent) . This study compared a titration of dopamine of 5 to 7.5 to 10 mcg/kg/minute with a titration of epinephrine of 0.1 to 0.2 to 0.3 mcg/kg/minute. 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/minute or epinephrine 0.1 to 0.3 mcg/kg/minute, patients who received epinephrine were significantly more likely to have resolution of shock within the first hour than those who received dopamine (12 out of 29 versus 4 out of 31 patients; OR 4.8, 95% CI 1.3 to 17.2) . Patients who received epinephrine also had significantly better organ function on day 3 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 suggest that patients with persistent signs of cold shock but normal blood pressure after initial fluid resuscitation receive low-dose epinephrine infusions (eg, 0.03 to 0.05 mcg/kg/minute) (Grade 2C). These patients should also continue to receive fluid resuscitation unless signs of volume overload are present. If patients do not respond to fluid resuscitation augmented by low-dose epinephrine infusion, then vasodilatory agents (eg, dobutamine or milrinone) are typically employed. Close monitoring of clinical and laboratory parameters (ie, lactate, urine output, and heart rate) with frequent patient reassessment are needed to guide the need for escalation of therapies (algorithm 2). 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 .
Warm shock — For patients with warm shock (eg, bounding pulses, pink extremities, and "flash" capillary refill), we suggest norepinephrine infusion starting at 0.03 to 0.05 mcg/kg/minute as the first-line drug . If the patient remains hypotensive, then further treatment consists of adding an additional vasopressor guided by the cardiac index (algorithm 2). (See "Septic shock in children: Ongoing management after resuscitation", section on 'Combination vasoactive drug therapy'.)
Norepinephrine (Levophed) acts on both alpha-1 and beta-1 adrenergic receptors, thus producing potent vasoconstriction as well as a modest increase in cardiac output. This physiologic effect counteracts the toxin-induced vasodilation frequently seen in patients with septic shock. Based upon one small observational study of children with septic shock, norepinephrine therapy is associated with improved cardiac index . However, patients in this study frequently required additional vasoactive agents (eg, epinephrine) to maintain a normal cardiac index.
Patients with catecholamine-resistant shock — Patients at risk for absolute adrenal insufficiency due to purpura fulminans, recent or chronic treatment with corticosteroids, hypothalamic or pituitary abnormalities, or other causes of congenital or acquired adrenal insufficiency should be treated with stress-dose hydrocortisone early in the course of resuscitation.
We suggest that other patients who persist with shock in spite of rapid fluid administration and vasoactive infusion receive hydrocortisone in stress doses (50 to 100 mg/m2/day or approximately 2 to 4 mg/kg/day, intermittent or continuous infusion, maximum dose 200 mg/day) (table 8 and algorithm 2) . Such patients may have relative adrenal insufficiency, more recently termed critical illness-related corticosteroid insufficiency.
Evidence is lacking regarding the best method to identify adrenal insufficiency in children with refractory septic shock, and no recommendation can be made about whether it is beneficial or not to assess adrenal status (either baseline serum cortisol or adrenocorticotropin hormone stimulation testing) prior to corticosteroid administration. (See "Septic shock in children: Ongoing management after resuscitation", section on 'Address adrenal insufficiency'.)
Patients with catecholamine-resistant shock also warrant evaluation for unrecognized morbidities. Etiologies to evaluate during initial management include pneumothorax, pericardial effusion, intraabdominal hypertension, and ongoing blood loss. Bedside ultrasound of the lungs, heart, and abdomen by a properly trained and experienced provider may supplement more definitive imaging . (See "Septic shock in children: Ongoing management after resuscitation", section on 'Treat reversible etiologies'.)
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'.)
OUTCOMES — Increased attention to rapid recognition, aggressive fluid administration, and early administration of vasoactive agents and antibiotics has been associated with a significant decrease in pediatric mortality from severe sepsis and septic shock [2,3,18-22]. With best clinical practices, mortality from septic shock in resource-rich settings is 0 to 5 percent among previously healthy children and 10 percent in chronically ill children as demonstrated in the following single institution and population-based studies:
●In a trial of goal-targeted therapy in 102 children with severe sepsis or fluid-refractory septic shock treated in two pediatric intensive care units (PICUs), 28-day mortality was lower in patients who received goal-targeted therapy versus therapy guided by blood pressure (12 versus 39 percent, respectively) primarily due to the marked benefit of goal-targeted therapy among the children with central venous oxygen saturation (ScvO2) <70 percent . Patients managed according to goal-targeted 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-targeted 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 American College of Critical Care Medicine (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) .
●In an observational study of 136 children with septic shock, mortality was 6 percent (3 of 53 patients) in those who were not in shock on admission to a PICU versus 19 percent (21 of 83 patients) in those with shock on arrival who did not have shock reversed during emergency department care or transport (p = 0.02) . Mean transfer time ranged from 6 to 14 hours and was not different between the two groups. Fluid and vasopressor management followed the 2002 ACCM/Pediatric Advanced Life Support consensus guidelines in only 38 percent of these children with persistent shock.
●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 nationwide 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 [18,47]. In a more recent study, the case-fatality rate for pediatric sepsis decreased from 10.3 percent in 1995 to 8.9 percent in 2005 with improvements in every age group except for newborns in whom mortality increased slightly over time . Underlying comorbidities remained a risk factor for mortality in this second study.
However, for critically ill children requiring admission to an ICU who develop multiple organ dysfunction syndrome, mortality rates between 10 to 25 percent have been reported [48-50]. Notably, in a single-center study of 321 children treated for septic shock admitted to a PICU, the administration of rapid IV fluids, antibiotics, and vasoactive infusions within the first hour of shock recognition was associated with a nonsignificant trend toward lower mortality (3.4 versus 6.4 percent, p = 0.31) and less new or progressive multiple organ dysfunction syndrome (7.7 versus 12.3 percent, p = 0.26) .
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 severe sepsis or septic shock is made in children who have signs of inadequate tissue perfusion, two or more criteria for the systemic inflammatory response syndrome (SIRS) (table 1), and suspected or proven infection. (See 'Rapid recognition' above and 'Red flag findings' above and 'Signs and symptoms of infection' above.)
●The essential components for initial resuscitation of severe sepsis or septic shock is provided in the algorithm and emphasizes the following actions and time goals (algorithm 2) (see 'Approach' above):
•Obtain vascular access (intravenous [IV] or intraosseous [IO]), ideally within 5 minutes.
•Start appropriate fluid resuscitation, ideally within 30 minutes.
•Begin broad-spectrum antibiotics, ideally within 60 minutes.
•For patients with fluid-refractory shock, initiate peripheral or central ionotropic infusion, ideally within 60 minutes.
Although not always achievable depending upon available resources, meeting these time goals is associated with improved outcomes.
●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 >97 percent. (See 'Airway and breathing' above.)
●Endotracheal intubation using rapid sequence intubation (RSI) is frequently necessary in children with septic shock. When performing RSI in children with septic shock, ketamine, if available and not contraindicated, is suggested for sedation prior to endotracheal intubation. Etomidate should not be used routinely in patients with septic shock. (See 'Airway and breathing' above.)
●In children with septic shock, we suggest infusion of a balanced crystalloid solution (eg, normal saline or lactated Ringer solution) instead of albumin solution because of the lack of clear benefit and higher cost of albumin (Grade 2C). Fluid resuscitation begins with 20 mL/kg of crystalloid solution. Infusion of this amount of fluid over five minutes can be achieved with a manual "push-pull" technique or rapid infuser. The initial volume and pace of infusion should be modified for patients with signs of heart failure (eg, 10 mL/kg over 15 minutes).
●After the initial infusion, the child should be quickly reassessed for signs of inadequate end-organ perfusion to determine if additional fluid is needed and to identify any signs of fluid overload. 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. (See 'Rapid fluid resuscitation' above.)
●Effective delivery of broad spectrum antibiotics usually requires two ports or sites for IV access: one devoted to fluid resuscitation and one for antimicrobial delivery. Antifungal and antiviral agents should be included as part of the initial regimen for susceptible patients. (See 'Empiric antibiotic therapy' above.)
●The physician should determine if the patient is responding to fluid administration or not in a timely fashion, ideally within the first hour of treatment. Patients who are fluid-refractory should begin vasoactive therapy tailored to blood pressure and manifestations of septic shock. Initial therapy with low-dose epinephrine is suggested with further tailoring of the agent and dose according to the type of septic shock as follows (see 'Patients with fluid-refractory shock' above):
•Hypotensive cold shock – We suggest that infants and children with fluid-refractory cold shock (weak peripheral pulses, cold distal extremities, and prolonged capillary refill time) receive epinephrine infusions (initial starting dose 0.05 to 0.1 mcg/kg/minute, titrate to response up to 1.5 mcg/kg/minute) rather than dopamine (Grade 2C). (See 'Cold shock' above.)
•Normotensive cold shock – We suggest that patients with persistent signs of cold shock but normal blood pressure after initial fluid resuscitation receive low-dose epinephrine infusions (eg, 0.03 to 0.05 mcg/kg/minute) (Grade 2C). These patients should also continue to receive fluid resuscitation unless signs of volume overload are present. If patients do not respond to fluid resuscitation augmented by low-dose epinephrine infusion, then vasodilatory agents (eg, dobutamine or milrinone) are typically employed. 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 suggest that infants and children with fluid-refractory, hypotensive warm shock (bounding pulses, pink extremities, and "flash" capillary refill) receive norepinephrine infusions starting at 0.03 to 0.05 mcg/kg/minute as the first-line drug (Grade 2C). (See 'Warm shock' above.)
●We suggest that previously healthy patients who persist with shock in spite of rapid fluid administration and vasoactive infusion receive hydrocortisone in stress doses (50 to 100 mg/m2/day or approximately 2 to 4 mg/kg/day, intermittent or continuous infusion, maximum dose 200 mg/day) (table 8) (Grade 2C). Patients at risk for absolute adrenal insufficiency due to purpura fulminans, recent or chronic treatment with corticosteroids, hypothalamic or pituitary abnormalities, or other causes of congenital or acquired adrenal insufficiency should be treated with stress-dose hydrocortisone early in the course of resuscitation. (See 'Patients with catecholamine-resistant shock' above.)
●Patients with catecholamine-resistant shock also warrant evaluation for unrecognized morbidities. Etiologies to evaluate during initial management include pneumothorax, pericardial effusion, intraabdominal hypertension, and ongoing blood loss.
●After initial resuscitation, ongoing aggressive management of septic shock should continue according to the principles of goal-targeted therapy for children in whom adequate circulation has not been restored (algorithm 2). 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 in children: Ongoing management after resuscitation".)
●Each pediatric institution should develop a multidisciplinary approach to early identification of septic shock, also called a "recognition bundle" consisting of a septic shock screening tool (algorithm 1) and timely clinical assessment and initiation of resuscitation in children with suspected septic shock. (See 'Institutional "bundle" for recognition of severe sepsis or septic shock' above.)
●Each pediatric institution should develop a multidisciplinary approach to the resuscitation of children with septic shock (ie, a resuscitation "bundle") that codifies the time-limited stabilization tasks recommended within the first hour of treatment as described above and mobilizes institutional resources such as electronic health record systems and quality improvement activities to meet those goals. (See 'Institutional resuscitation "bundle"' 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.
- 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.
- Davis AL, Carcillo JA, Aneja RK, et al. American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock. Crit Care Med 2017; 45:1061.
- 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.
- 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.
- 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.
- Dugas MA, Proulx F, de Jaeger A, et al. Markers of tissue hypoperfusion in pediatric septic shock. Intensive Care Med 2000; 26:75.
- 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.
- 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.
- 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.
- Carcillo JA, Davis AL, Zaritsky A. Role of early fluid resuscitation in pediatric septic shock. JAMA 1991; 266:1242.
- Lane RD, Funai T, Reeder R, Larsen GY. High Reliability Pediatric Septic Shock Quality Improvement Initiative and Decreasing Mortality. Pediatrics 2016; 138.
- 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.
- Inwald DP, Tasker RC, Peters MJ, et al. Emergency management of children with severe sepsis in the United Kingdom: the results of the Paediatric Intensive Care Society sepsis audit. Arch Dis Child 2009; 94:348.
- Emrath ET, Fortenberry JD, Travers C, et al. Resuscitation With Balanced Fluids Is Associated With Improved Survival in Pediatric Severe Sepsis. Crit Care Med 2017; 45:1177.
- Weiss SL, Keele L, Balamuth F, et al. Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study. J Pediatr 2017; 182:304.
- 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.
- Forsythe RM, Wessel CB, Billiar TR, et al. Parenteral calcium for intensive care unit patients. Cochrane Database Syst Rev 2008; :CD006163.
- 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.
- 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.
- 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.
- Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med 2017; 45:486.
- 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.
- Deep A, Goonasekera CD, Wang Y, Brierley J. Evolution of haemodynamics and outcome of fluid-refractory septic shock in children. Intensive Care Med 2013; 39:1602.
- Ranjit S, Aram G, Kissoon N, et al. Multimodal monitoring for hemodynamic categorization and management of pediatric septic shock: a pilot observational study*. Pediatr Crit Care Med 2014; 15:e17.
- 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.
- Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemiology of pediatric severe sepsis*. Pediatr Crit Care Med 2013; 14:686.
- Weiss SL, Fitzgerald JC, Pappachan J, et al. Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med 2015; 191:1147.
- Schlapbach LJ, Straney L, Alexander J, et al. Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002-13: a multicentre retrospective cohort study. Lancet Infect Dis 2015; 15:46.
- Kutko MC, Calarco MP, Flaherty MB, et al. Mortality rates in pediatric septic shock with and without multiple organ system failure. Pediatr Crit Care Med 2003; 4:333.
- Workman JK, Ames SG, Reeder RW, et al. Treatment of Pediatric Septic Shock With the Surviving Sepsis Campaign Guidelines and PICU Patient Outcomes. Pediatr Crit Care Med 2016; 17:e451.