Approach

Management of sepsis in children requires prompt recognition. Reviews of child deaths suggest that there is often a failure to recognize sepsis and septic shock, with consequent delayed or inappropriate treatment at first contact with healthcare services.[96][97] Education of parents and community healthcare professionals in recognizing early signs of sepsis is therefore of immense importance.

A standard ABC (airway, breathing, circulation) approach with particular emphasis on early administration of antibiotics and fluid resuscitation is key in the management of children with sepsis and septic shock.[58][94]

Pediatric Sepsis Six

Several studies have demonstrated the importance of protocolized care and care bundles in pediatric sepsis, particularly when designed and implemented with understanding of nuances of the local healthcare system.[6][98][99][100][101][102] The Pediatric Sepsis Six initiative is an example of a care bundle designed to facilitate prompt management of sepsis using 6 elements of care in a time-critical manner.

The following 6 interventions are recommended to be initiated within 1 hour of presentation of suspected sepsis:[103]

  • Experienced senior clinicians or specialists should be involved and consulted early.

  • Supplemental oxygen should be given if oxygen saturations are less than 92% or there is evidence of shock.

  • Intravenous or intraosseous (IO) access should be obtained within 5 minutes of presentation and blood tests ordered, including blood cultures, blood glucose (low blood glucose should be treated), and arterial, capillary, or venous blood gases. Complete blood count (CBC), serum lactate, and C-reactive protein (CRP) should also be ordered for baseline assessment.

  • Intravenous or IO antibiotics should be given with broad-spectrum cover as per local policies.

  • Fluid resuscitation should be considered. If lactate is >18 mg/dL (>2 mmol/L) give a fluid bolus of 10 mL/kg without delay and call the pediatric intensive care unit (PICU) if it is >36 mg/dL (>4 mmol/L). Caution should be taken to avoid fluid overload by examining the patient regularly (e.g., for pulmonary crepitations and hepatomegaly).

  • Vasoactive-inotropic support should be considered early if normal physiologic parameters are not restored after giving ≥20 mL/kg of fluids (or ≥10 mL/kg in neonates). Inform PICU or a regional center at this stage urgently.

Airway and respiratory support

Airway and breathing should be managed as per pediatric advanced life support and resuscitation algorithms.

The patient's airway should be maintained at all times; not all patients with sepsis or septic shock require intubation and ventilation. Intubation is recommended if respiratory support is required or for patients with a reduced level of consciousness. Mechanical ventilation reduces the cardiac workload in patients with cardiovascular compromise by reducing the effort of breathing and through positive effects on left ventricular function.[104] The clinician should be prepared for cardiovascular collapse and/or cardiac arrest on induction of anesthesia for intubation. Concomitant fluid resuscitation and inotrope use should be considered during anesthetic induction. Anesthetic agents with a relatively stable cardiovascular profile are recommended (e.g., ketamine with atropine).[94] Etomidate is not currently recommended for anesthesia in children with septic shock, due to concerns regarding adrenal suppression.[6]

Supplemental oxygen should be provided, initially at high concentration if there is cardiovascular instability or shock.[94] It should be delivered, preferably, via a mask with a reservoir bag or a headbox in neonates. Oxygen should then be titrated according to pulse oximetry, aiming for an oxygen saturation of >94% once the patient is hemodynamically stable. Caution should be exercised in premature neonates or neonates suspected of having congenital heart disease.

Initial fluid resuscitation

Profound fluid loss from the intravascular space occurs in sepsis due to capillary leakage and may persist for several days. Fluid resuscitation aims to restore the patient’s normal heart rate, blood pressure, and capillary refill time.[94]

The choice of fluid is a topic of debate, but is less important, provided the fluid is isotonic. The pediatric Surviving Sepsis Campaign guidelines recommend using balanced/buffered crystalloid solutions (Hartmann solution, or lactated Ringer solution), rather than normal saline or albumin for initial resuscitation. Although high quality pediatric data are lacking, evidence from observational and adult interventional studies favors use of balanced solutions due to the chloride content in normal saline inducing hyperchloremic metabolic acidosis when given in large amounts.[6]

There is currently insufficient evidence to make a recommendation for or against use of colloids in children.[105][106][107] [ Cochrane Clinical Answers logo ] [Evidence B] Starch-containing solutions (including hydroxyethyl starch - HES) should not be used in the management of sepsis as there is evidence to show that they increase the risk of kidney dysfunction and mortality.[110][111][112] In addition, in July 2021 the US Food and Drug Administration (FDA) issued safety labeling changes for solutions containing hydroxyethyl starch (HES) stating that HES products should not be used unless adequate alternative treatment is unavailable.[108]

In view of the serious risks posed to these patient populations, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency in February 2022 recommended suspending HES solutions for infusion in Europe.[109]​ The Surviving Sepsis Campaign advises against the use of starches for patients with sepsis and septic shock.[113]

Vasoactive-inotropic support should be considered early in fluid-refractory shock.

Initial fluid management according to setting

Guidance from the pediatric Surviving Sepsis Campaign on initial fluid resuscitation stratifies recommended fluid management according to whether or not the child is being treated at a center with critical care availability:[6]

  • If a critical care facility is present, administer up to 40-60 mL/kg in bolus fluid (given as individual boluses of 10-20 mL/kg at a time) over the first hour, titrated to clinical markers of cardiac output and discontinued if signs of fluid overload develop. If a child has evidence of abnormal perfusion after 40-60 mL/kg of fluids according to the Surviving Sepsis Campaign (or 20 mL/kg according to the Sepsis 6 Toolkit), or earlier if they develop fluid overload, treatment should be escalated to include initiation of inotropes/vasopressors, which would be typically given in a critical care environment.

  • If there is no critical care availability and the child is normotensive, maintenance fluids should be started without administration of bolus fluids. This recommendation is based on the FEAST trial, in which rapid bolus fluid in the first hour of resuscitation given in a resource-limited setting increased mortality compared with maintenance fluids only.[114][115]

  • If there is no critical care availability and the child is hypotensive, up to 40 mL/kg in bolus fluid is recommended over the first hour, given as individual boluses of 10–20 mL/kg at a time and titrated according to clinical markers of cardiac output. This should be discontinued if signs of fluid overload develop (i.e., increased work of breathing, pulmonary crepitations, hepatomegaly, gallop rhythm).

Patients may require large volumes of fluid to support their circulating volume

It would not be unusual for a child in septic shock to receive >100 mL/kg of fluid resuscitation within the first 24 hours of admission, due to fluid maldistribution. However, they should always be monitored closely for signs of fluid overload. Identifying fluid overload is especially difficult in young children, in whom crackles (rales) are often absent on respiratory examination even in the context of gross pulmonary edema. Worsening respiratory status, particularly increasing respiratory rate, radiologic evidence of pulmonary edema, or new or expanding hepatomegaly may be the only clues of evolving fluid overload.[6]

Maintenance fluid requirements

Vary depending on the clinical condition and should be assessed and tailored according to each child's needs. The following equation is used to calculate fluid requirements:

  • (4 mL/kg for the first 10 kg) + (2 mL/kg for each kg between 11-20) + (1 mL/kg for every kg >20) = hourly rate.

For example, to calculate the hourly maintenance fluid rate for a child weighing 23 kg:

  • (4 mL x 10 kg) + (2 mL x 10 kg) + (1 mL x 3 kg) = hourly rate

  • 40 mL + 20 mL + 3 mL = 63 mL/hour.

Fluid requirements assessed using this equation are often over-estimated. The usual advice is to restrict fluid to 60% to 80% of the estimated value based on the equation, as children with sepsis often have water retention due to the presence of syndrome of inappropriate antidiuretic hormone. In contrast, insensible losses of water may be increased if the child has significant fever.

It is important to review fluids alongside regular formal review of hydration status, fluid balance, renal function, and serum electrolyte levels.

In the UK, the National Institute for Health and Care Excellence (NICE) has published guidance on sepsis, as well as guidance on intravenous fluid administration in hospitalized children and infants.[50][116][Evidence B][Evidence C] The NICE guidelines on sepsis recommend that age, risk factor profile, and lactate measurement of a patient should guide fluid resuscitation.[50]

Further maintenance of fluid balance

In patients who cannot maintain an even fluid balance naturally following adequate fluid resuscitation, diuresis or renal replacement therapy (RRT) may be indicated.[6] 

Fluid overload is common in critically ill children with hemodynamic instability and acute kidney injury, and it is important to monitor for clinical signs (e.g., pulmonary crepitations on auscultation, hepatomegaly, >10% weight increase from baseline).

Early diuretics and continuous RRT should be considered if fluid overload occurs. In the context of acute kidney injury and fluid overload, there is increasing evidence that early use of RRT and active management of fluid balance confers survival benefit.[117][118] 

Venoarterial extracorporeal membrane oxygenation (ECMO) may be used as a rescue therapy in children with septic shock only if refractory to all other treatments.[6]

Antibiotic therapy

Early administration of antibiotics saves lives. Initiating antibiotics within one hour of recognition of suspected sepsis is one of the interventions recommended under the Paediatric Sepsis Six care protocol.[58] The pediatric Surviving Sepsis Campaign guidelines strongly recommend that antibiotics should be given as soon as possible, and always within 1 hour of sepsis recognition if there are signs of septic shock.[6]

In adults, a study found that for every hour of delay in starting antibiotics in septic shock, there is an associated 7.6% increase in mortality.[119] There are only a few similar studies in children; however, there is compelling evidence that early antibiotic administration saves lives in unwell children as well. In a retrospective study of 80 children with "severe sepsis"/septic shock, those who received antibiotics within 1 hour of admission were observed to have significantly lower levels of serum lactate and C-reactive protein within the first 24 hours of admission.[120] Another retrospective study of 130 children with "severe sepsis" or septic shock reported an increase in the odds ratio (3.92) for mortality in the pediatric intensive care unit in children who receive antibiotics more than 3 hours from recognition of sepsis (or 4.84 after adjusting for severity of illness).[121]

The choice of antibiotic is complex and should be based on the clinical syndrome, underlying disease, drug allergies or intolerances, and local pathogen susceptibility. Treatment should be initiated with a broad-spectrum antibiotic to cover the appropriate prevalent organisms for each age group and geographic area. This should be changed to an appropriate narrow-spectrum antibiotic regimen once a causative pathogen has been identified.[6]

It is good practice to review antibiotic therapy on a daily basis for clinical effect and de-escalate when appropriate. A 5- to 7-day course of intravenous antibiotics would suffice in most uncomplicated infections. In deep-seated or disseminated infections, or infections in immunocompromised patients, prolonged courses of antimicrobials may be required.

Antibiotics for early-onset neonatal sepsis

Early-onset neonatal sepsis (EOS) is defined as neonatal sepsis occurring in the first 72 hours of life.[9]

The antibiotic regimen should cover group B streptococci (GBS) and gram-negative bacilli. The American Academy of Pediatrics recommends ampicillin plus gentamicin as first-line empirical therapy for early-onset neonatal infection.[9][93] There is insufficient evidence to support any antibiotic regimen for early-onset neonatal sepsis being superior to another. Large randomized controlled trials are needed.[122]

Antibiotics for late-onset neonatal sepsis

Late-onset neonatal sepsis (LOS) is defined as neonatal sepsis occurring after the first 72 hours to 1 month of life.[10]

Causative organisms differ from EOS and vary widely among units. In developed countries, coagulase-negative staphylococci is the leading cause, followed by GBS and gram-negative bacteria.

Treatment options for causative organisms include:

  • Coagulase-negative staphylococci: vancomycin

  • GBS, Escherichia coli, enterococci: cefotaxime or piperacillin/tazobactam

  • Gram-negative bacteria (e.g., Klebsiella): gentamicin

  • Pseudomonas: ceftazidime or piperacillin/tazobactam

  • Listeria monocytogenes: ampicillin

  • Anaerobic bacteria (e.g., in necrotizing enterocolitis): metronidazole or clindamycin

There is insufficient evidence to support any antibiotic regimen for late-onset neonatal sepsis being superior to another. Large randomized controlled trials are needed.[123] Examples of suitable empiric antibiotic regimens include ampicillin plus gentamicin or cefotaxime, or vancomycin plus gentamicin or cefotaxime. Ceftazidime or piperacillin/tazobactam may be added to the empiric regimen if Pseudomonas is suspected. Metronidazole or clindamycin may be added to the empiric regimen to cover for anaerobes/necrotizing enterocolitis.

Antibiotics for infants and young children

Empiric antibiotic regimens should cover the most common prevailing organisms (e.g.,  Staphylococcus, Streptococcus, Neisseria meningitides, and Haemophilus influenzae). For community-acquired infection, a third-generation cephalosporin (e.g., cefotaxime, ceftriaxone) is a suitable first-line option. For hospital-acquired infection, an extended-spectrum penicillin (e.g., piperacillin/tazobactam) or a carbapenem (e.g., meropenem) may be used. Additional broadening of this cover (e.g., with gentamicin or vancomycin) may be considered depending on case-specific factors.[124] However, in children without immune compromise and without high risk for multidrug-resistant pathogens, routine use of multiple empiric antimicrobials directed against the same pathogen is not recommended.[6]

Meropenem provides broad-spectrum cover against both gram-positive and gram-negative bacteria, including Pseudomonas. Piperacillin/tazobactam and ciprofloxacin also cover gram-negative bacteria.[124] Vancomycin is recommended to cover vascular catheter-associated coagulase-negative staphylococci and/or MRSA. It is also recommended in patients with neutropenia to treat line sepsis.[125] Teicoplanin may also be used for this indication; however, it is currently only available on a compassionate-use basis in the US. Clindamycin should be used for toxin-induced toxic shock syndromes with refractory hypotension.[6]

In neutropenic patients, piperacillin/tazobactam or meropenem are considered first-line agents.

Fluoroquinolone antibiotics should be avoided if alternatives are available

When effective and appropriate alternatives are available and can be given promptly, fluoroquinolone antibiotics should be avoided. In November 2018, the European Medicines Agency (EMA) completed a review of serious, disabling, and potentially irreversible adverse effects associated with systemic and inhaled fluoroquinolone antibiotics. These adverse effects include tendonitis, tendon rupture, arthralgia, neuropathies, and other musculoskeletal or nervous system effects. As a consequence of this review, the EMA now recommends that fluoroquinolone antibiotics be restricted for use in serious, life-threatening bacterial infections only. Patients who are older, have renal impairment, or have had a solid organ transplant, and those being treated with a corticosteroid are at a higher risk of tendon damage. Co-administration of a fluoroquinolone and a corticosteroid should be avoided.[126] The UK-based Medicines and Healthcare products Regulatory Agency (MHRA) supports these recommendations.[127] The Food and Drug Administration (FDA) issued a similar safety communication in 2016, restricting the use of fluoroquinolones in acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections.[128] In addition to these restrictions, the FDA has issued warnings about the increased risk of aortic dissection, significant hypoglycemia, and mental health adverse effects in patients taking fluoroquinolones.[129][130]

Early specialist consultation

Experienced senior clinicians or specialists should be involved and consulted early. A review of child deaths in the UK suggested that the most significant recurrent avoidable factor was a failure to recognize and/or failure to appreciate the history or clinical signs pointing to the severity of illness.[96][97] This most often occurred at the point of first contact between the sick (and often febrile) child and healthcare services. In many cases this leads to a critical delay in referral or treatment.

Vasoactive therapy

If cardiovascular instability persists despite fluid resuscitation, then vasoactive therapy (vasopressors and/or inotropes) should be considered. The early use of vasoactive medications in fluid-refractory shock has been shown to improve outcomes.[94][131] 

The pediatric Surviving Sepsis Campaign guidelines recommend either epinephrine (adrenaline) or norepinephrine (noradrenaline) as the preferred first line vasoactive agent. Dopamine may be substituted if epinephrine or norepinephrine are not readily available.[6]

In order not to delay treatment, dilute-strength vasoactive medications can be run through peripheral intravenous access prior to central line insertion. Intraosseous access is an alternative if intravenous access is not available.[94]

If advanced hemodynamic monitoring is available, distinguishing vasoconstrictive ("cold") shock and vasodilatory ("warm") shock may be helpful to guide therapy. This distinction should not be made on the basis of clinical signs alone.[6] In vasoconstrictive shock, defined as low cardiac output with high systemic vascular resistance or low cardiac output with low systemic vascular resistance, inotropes (including milrinone, dobutamine, or levosimendan) should be given in addition to fluid titration and an initial vasoactive agent (epinephrine, norepinephrine or dopamine). In vasodilatory shock, defined as a high cardiac output with low systemic vascular resistance, vasopressin-receptor agonists (vasopressin) should be given in addition to fluid titration and an initial vasoactive agent (epinephrine, norepinephrine or dopamine).[6][94] Cardiac output should be monitored throughout. The use of focused echocardiography is becoming more widespread within pediatric intensive care units and may provide valuable information to differentiate vasodilatory shock from patients with a low cardiac output.[132]

If a patient becomes refractory to the vasopressor or inotrope they were initially responding to, re-evaluation is needed. An additional or substitute vasopressor or inotrope may be required.

Temperature management

There is no evidence for or against the use of antipyretics in febrile children with sepsis, though it is reasonable and recommended to provide antipyretic therapy to optimize patient comfort, reduce extreme body temperature and reduce metabolic demand.[6][133]​​​​​​ Nonprescription antipyretics are safe and effective in reducing fever compared with placebo.​​​​

Source control

When there is the possibility of a localized source of infection that is not likely to be treated by antibiotics alone, consideration should be given to instituting physical measures to remove the source of infection.[6][50] The principles of source control are the same for different age groups, although the practicalities may be different depending on the source of the infection. Expert assistance should be sought.

Examples of source control include:

  • Incision and drainage of abscess or infected fluid collections

  • Debridement of infected soft tissue

  • Removal of infected foreign bodies

  • Removal of urinary catheter in cases of sepsis arising from the urinary tract

  • Removal of percutaneous long lines or central lines in cases of central line-associated bloodstream infection

  • Laparotomy and resection of ischemic bowel (or damage control surgery) in cases of necrotizing enterocolitis.

Cardiac output monitoring and targets

Subsequent intensive care support with therapy guided by advanced hemodynamic monitoring (such as cardiac output/cardiac index, systemic vascular resistance, or central venous oxygen saturation [Scvo2]) is recommended when this is available, alongside clinical assessment.[6][94]  

There are no data from RCTs to support specific hemodynamic targets in children; however the Surviving Sepsis Campaign pediatric guideline panel members reported using mean arterial blood pressure (MAP) targets of either between the 5th and 50th percentile or greater than 50th percentile for age. RCTs to define optimal hemodynamic targets, including MAP, are urgently required to inform practice in pediatric sepsis.[6]

Other means of cardiac output monitoring include:

  • Central venous oxygen saturation, measured by blood gas analysis on a blood sample from the superior vena cava (SVC) through an indwelling central venous catheter

  • Transesophageal doppler ultrasound

  • Ultrasound cardiac output monitoring

  • Pulse index contour cardiac output monitoring.

Antifungal and antiviral therapy

The practice of providing antifungal prophylaxis while receiving antibiotic therapy varies between institutions. Neonates may be given oral nystatin to help prevent candidiasis.[83][134]

Very low birth weight infants (i.e., <1500 g) and immunocompromised children of any age are at particular risk of primary invasive fungal infections or secondary fungal infections, as a result of altered surface-colonizing flora during antibiotic treatment.[135] Patients may require prolonged treatment with intravenous fluconazole or liposomal amphotericin-B if invasive fungal infection is suspected or confirmed. Antifungal treatment should be given in addition to empiric antibiotics in very low birth weight infants and immunocompromised patients with suspected sepsis.[135]

Cover for herpes simplex virus (e.g., acyclovir) should be considered in sepsis or if indicated from the patient history or investigative tests.[59] Herpes simplex virus type 1 (HSV-1) infection may be acquired at birth from mothers with an active infection. Congenital HSV-1 infection can be severe and devastating; therefore, treatment should be started before test results are available in patients with EOS.[136]

For patients with sepsis complicating an influenza-like illness during the local influenza season, empirical antiviral therapy (e.g., oseltamivir) should be given while awaiting respiratory virus testing.[6][137]

Blood transfusion

Hemoglobin is essential for tissue oxygen delivery and therefore very important in the overall management of the septic child who is hemodynamically unstable (poor cardiac output, low mean arterial pressure) with impaired oxygen delivery. It is suggested a hemoglobin concentration of >10g/dL (approximate hematocrit of 0.3) should be maintained in these patients.

Once shock has resolved, a lower transfusion threshold may be appropriate. In a subgroup analysis of the TRIPICU (Transfusion Requirements in the Pediatric Intensive Care Unit) trial, children with hemodynamically stable sepsis showed no significant differences in mortality, length of stay, or progressive organ failure between restrictive and liberal transfusion thresholds (hemoglobin <7 g/dL vs <9.5 g/dL, respectively).[138] There were, however, slightly more temporary protocol suspensions and transfusions in the restrictive group. In the TRISS (Transfusion Requirements in Septic Shock) trial, adult patients with septic shock showed no significant differences in mortality at 90 days, length of life support, and adverse events between transfusion thresholds of <7 g/dL and <9 g/dL.[139] Information on the safety of restrictive transfusion thresholds in children with hemodynamic instability is lacking, particularly in septic shock, and transfusion to a goal of 10 g/dL to achieve signs of adequate oxygen delivery (ScvO₂ ≥70%) is currently recommended by the ACCM.[94]

Corticosteroids

Intravenous hydrocortisone is not recommended by the pediatric Surviving Sepsis Campaign guidelines to treat children with septic shock if fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability, but can be considered in fluid-refractory and inotrope-resistant shock.

No high-quality investigations currently support or refute the routine use of adjunctive corticosteroids for pediatric septic shock or sepsis-associated organ dysfunction. Evidence for their use has often been conflicting.[6][140] There is however, evidence for the use of hydrocortisone in fluid-refractory and inotrope-resistant shock with suspected or proven absolute adrenal insufficiency.[6][141]

Special considerations: newborn septic shock

Septic shock is difficult to differentiate from other forms of shock in the premature neonate or newborn infant. Any newborn presenting with signs of cardiogenic shock (e.g., poor perfusion, cyanosis, heart murmur, hepatomegaly, differential pulse volume and limb pressure between upper and lower limbs) should be started on a prostaglandin infusion (i.e., alprostadil) under expert guidance until a duct-dependent cardiac lesion can be ruled out. Alprostadil can cause apnea above a certain dose. Dinoprostone is used in some countries for the maintenance of ductal patency, but is not currently approved for this use in the US.

In the newborn, umbilical venous and arterial access may be preferred over central venous and peripheral arterial access.

Vasoactive-inotropes that may be used in these patients include dopamine, dobutamine, epinephrine (adrenaline), and norepinephrine (noradrenaline).

Unproven therapies

Intravenous immunoglobulin (IVIG):

  • There is insufficient evidence to support the routine use of IVIG in the management of sepsis.[6] A Cochrane review has shown that IVIG has no effect on outcomes in suspected or proven neonatal sepsis.[9]​​ Another Cochrane review noted no survival benefit with standard and immunoglobulin M-enriched polyclonal immunoglobulins, or standard polyclonal IVIG, when used in infants with sepsis.[142] In this review, IVIG was shown to reduce mortality in some studies, but this was not reproduced in trials with low risk of bias. Both reviews included findings from the large INIS (International Neonatal Immunotherapy Study) trial, which found no beneficial effect with IVIG in neonatal sepsis.[143] 

  • There may be some benefit from use of IVIG in selected pediatric populations.[6] One meta-analysis, including one randomized and four non-randomized trials, indicated a reduction in mortality from 33.7% to 15.7% in patients with clindamycin-treated streptococcal toxic shock syndrome who received IVIG.[144]

Granulocyte macrophage colony-stimulating factor (GM-CSF):

  • Corrects neutropenia, but there is no evidence that GM-CSF has any beneficial effect on survival or short-term outcomes and is, therefore, not currently recommended.[145][146] Trials have primarily been in term and preterm neonates.

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