Sepsis in paediatrics

Learning objectives.

By reading this article, you should be able to:

• •Describe the clinical signs of septic shock in paediatrics.
• •Explain the initial management of septic shock in children.
• •Discuss the considerations of providing anaesthetic care to a child with sepsis.

Key points.

• •Early signs of septic shock include tachycardia and derangements in temperature, mental status and peripheral perfusion.
• •In younger children, intraosseous (i.o.) access is often easier and achieved more quickly than i. v. access.
• •Broad-spectrum antibiotics should be given within 1 h of presentation.
• •Children in septic shock are often extremely dehydrated and respond favourably to initial resuscitation with fluids.
• •Infusions of inotropic drugs can be started through either the peripheral i.v. or i.o. routes.

Sepsis and septic shock continue to be a major cause of morbidity and mortality in infants and children worldwide. Mortality can be over 10%, and influenced by the child's age and comorbidities, source of infection, causative organism and management.¹ There are persisting disparities between high- and low-to-middle-income areas, with mortality rates exceeding 30% in some countries.² In developed areas, septic shock requiring paediatric intensive care admission is associated with a mortality rate as high as 17%.³ Despite this global burden of disease, uncertainties persist in diagnosis and management, and sepsis remains a hot topic of research in paediatric intensive care medicine.

In this article, we review the diagnosis and management of sepsis in paediatrics. We focus on recognition and initial management, special considerations for the child presenting with sepsis in the community and those requiring emergency anaesthesia and surgery.

Definitions

The pathophysiology of sepsis is complex, involving an altered inflammatory response to infection, paired with derangements in coagulation, cardiovascular, immune, metabolic, hormonal and neuronal responses.⁴

The Third International Consensus Definitions for Sepsis and Septic Shock in adults were published in 2016.⁵ Several concepts were altered significantly to reflect contemporary understanding of pathophysiology and management, and sepsis in adults is now defined as a ‘life-threatening organ dysfunction caused by a dysregulated host response to infection’.⁵ A subset of sepsis, septic shock, is associated with higher mortality and can be defined as sepsis accompanied by significant circulatory, cellular and metabolic abnormalities.⁵

The most recent consensus statement concerning paediatric sepsis was published in 2005.⁶ Age-adapted sequential organ failure assessment (SOFA) scales have recently been validated, and the Society of Critical Care Medicine has commissioned a task force to update the definition of paediatric sepsis.⁷ In the meantime, paediatric sepsis continues to be discussed in terms of the systemic inflammatory response syndrome (SIRS) criteria, defined as the presence of at least two of the following four criteria, one of which must be abnormal temperature or leucocyte count⁶:

• (i)Core temperature of >38.5°C or <36°C
• (ii)Tachycardia, defined as a mean HR >2 standard deviations (sd) above normal for age in the absence of external stimulus, chronic drugs or painful stimuli; or otherwise unexplained persistent increase in HR over a 0.5–4 h time period; or for children <1 yr old: bradycardia, defined as a mean HR <10th percentile for age in the absence of external vagal stimulus, beta-blocker drugs or congenital heart disease; or otherwise unexplained persistent decrease in HR over a 0.5 h time period
• (iii)Mean ventilatory frequency >2 sd above normal for age or mechanical ventilation for an acute process not related to underlying neuromuscular disease or the receipt of general anaesthesia
• (iv)Leucocyte count increased or decreased for age (not secondary to chemotherapy-induced leucopenia) or >10% immature neutrophils

Systemic inflammatory response syndrome in the presence of a known or suspected infection is considered diagnostic of sepsis.⁶ When cardiovascular organ dysfunction exists in the presence of sepsis, the child is considered to be in septic shock.⁶

The consensus criteria define cardiovascular organ dysfunction as despite giving isotonic i. v. fluid bolus ≥40 ml kg⁻¹ in 1 h⁶:

• (i)Decrease in BP (hypotension) <5th percentile for age or systolic BP <2 sd below normal for age, or
• (ii)Need for vasoactive drug to maintain BP in normal range (dopamine >5 kg⁻¹ min⁻¹, or dobutamine, adrenaline [epinephrine] or noradrenaline [norepinephrine] at any dose), or
• (iii)
  Two of the following:

  • (a)
    Unexplained metabolic acidosis: base deficit >5.0 mEq L⁻¹
  • (b)
    Increased arterial lactate >2 times upper limit of normal
  • (c)
    Oliguria: urine output <0.5 ml kg⁻¹ min⁻¹
  • (d)
    Prolonged capillary refill: >5 s
  • (e)
    Core to peripheral temperature gap >3°C

The SIRS criteria may underidentify children with infection at the highest risk of mortality; research validating an age-adapted SOFA scale demonstrates that this scale may more accurately identify those children most at risk.^7,8 Although definitions are important for prognostication, benchmarking and research endeavours, in clinical practice, the strategies that improve early recognition and initial management of patients with possible sepsis have been shown to decrease morbidity and mortality the most.

Recognition

The American College of Critical Care Medicine recommends the use of bundles for the recognition, resuscitation and stabilisation of children with septic shock.⁹ These bundles promote an institutional approach to septic shock, encouraging the use of a recognition bundle, in which a trigger tool is used to rapidly identify children at risk of septic shock, and a resuscitation bundle, which delineates initial management and promotes evidence-based best practice.⁹

Practitioners need a high index of suspicion to quickly and appropriately recognise the signs of septic shock. If an infection is suspected, then one must play close attention to the child's core temperature, level of consciousness and haemodynamic status, including peripheral perfusion.⁹ In the absence of an institutional specific bundle, the algorithms in Fig 1, Fig 2 may be used to guide recognition and management of children with potential sepsis.

Fig 1.

Paediatric sepsis recognition algorithm.^6,8, 9, 10 LOC, level of consciousness; SBP, systolic BP; VF, ventilatory frequency.

Fig 2.

Paediatric sepsis resuscitation algorithm.^6,9,10 CBC, complete blood count; DIC, disseminated intravascular coagulation; ECMO, extracorporeal membrane oxygenation; GCS, Glasgow Coma Scale; LOC, level of consciousness; POC, point of care; SBP, systolic BP; SVR, systemic vascular resistance; WOB, work of breathing.

Initial management

Monitors and oxygen therapy

Children with suspected septic shock should be monitored continuously and given O₂ 100% via a non-rebreather mask or high-flow oxygen device. Essential monitoring includes oxygen saturation (Spo₂) probe, three-lead ECG with rhythm strip, appropriately sized non-invasive BP cuff, respiratory monitor with ventilatory frequency and thermometer to measure core temperature. When continuous monitors are not available, these vital signs should be rechecked regularly at a minimum interval of 5 min. Urine output and point-of-care glucose concentration should also be monitored, and level of consciousness and capillary refill should be assessed at the beginning of resuscitation and after every intervention.

Early clinical signs that indicate septic shock include tachycardia, derangement in temperature (hypothermia or hyperthermia), alteration in mental status and peripheral vasoconstriction (cold shock) or vasodilation (warm shock). In children, these signs usually occur before significant changes in arterial BP.^9,10 Age-specific guidelines will help guide diagnosis and management. However, in general, critically ill infants with an HR <90 or >160 beats min⁻¹ or a child with an HR <70 or >150 beats min⁻¹ have higher mortality risk.^9,11 Teenagers with sepsis are often tachycardic, and an HR of >110 beats min⁻¹ in an adolescent is also a cause for concern.⁶

Initial management should focus on attaining the therapeutic endpoints of capillary refill <3 s and threshold HR and BP for age with palpable distal pulses.⁹ Mortality increases when capillary refill is prolonged (>3 s), especially when associated with hypotension. However, appropriate resuscitation can dramatically improve survival.^9,12

In children with sepsis, a reduction in oxygen delivery ($\dot{D}$o₂) is the major determinant of derangement in oxygen consumption ($\dot{V}$o₂). Providing adequate oxygenation may improve outcomes and is essential to the resuscitation process.^9,11 Escalation of respiratory support should be dictated by the clinical situation. Apart from the child that presents with a profoundly decreased level of consciousness or inadequate respiratory drive, oxygen therapy alone is usually tolerated during the initial resuscitation process; if shock worsens or is fluid refractory, escalation of respiratory support should be considered.⁸ Non-invasive methods, such as high-flow nasal cannulae, CPAP and BiPAP can be tried in the child with an adequate level of consciousness and respiratory drive. For children with worsening shock, tracheal intubation and invasive ventilation can decrease oxygen demand and potentially improve oxygen delivery.^9,13 Children with sepsis are at risk of pulmonary oedema secondary to fluid resuscitation, SIRS-induced capillary leak and sepsis-related myocardial depression. Other factors that worsen respiratory status include a pneumonic source of infection and sepsis-related acute respiratory distress syndrome. If escalation in respiratory support is needed, appropriate fluid resuscitation and vasopressor support before intubation can improve cardiovascular instability during intubation and mechanical ventilation; high-flow oxygen or CPAP may be used as a bridge to allow for intravascular access and fluid resuscitation before intubation.⁹

Vascular access and blood tests

I.V. or i. o. access should be attained within 5 min of sepsis recognition.⁹ It is often difficult to attain i.v. access in critically ill infants and young children. It is recommended to avoid perseverating on attaining i.v. access if difficult and quickly move to i.o. access in these situations.¹⁴ Intraosseous access is often easier and more quickly attained than i.v. access, especially in younger children, allowing for earlier blood tests and infusion of fluids and medications.^14,15 The exception to this practice are children under 3 kg, in whom the use of i.o. access is contraindicated.⁹

All i.v. medications can be safely given through the i.o. route, including emergency medications, such as adrenaline, antibiotics and all blood products.¹⁴ An i.o. cannula functions similarly to an i.v., so the onset of action of medications is similar, and it can be used as an access for blood tests.¹⁴ All medications should be flushed with saline to ensure access to the vascular system, and fluids should be given continuously through the i.o. cannula via an infusion pump to avoid clotting and loss of access.¹⁴

Once i.v. or i.o. access has been attained, blood work should be sent immediately, ideally before other medications, including antibiotics. Difficulty in attaining blood work from an i.o. access can occur when marrow fat occludes the needle tip; if this occurs, consider attaining blood work through a femoral artery stab. Antibiotics should not be delayed if blood sampling proves difficult or time consuming. A sepsis panel (see Fig. 2), including blood culture, and urinalysis and culture should be obtained as quickly as possible. Depending on the child’s haemodynamic and respiratory stability and coagulation status, consideration should also be given to a lumbar puncture if meningitis is suspected.

Fluids

Resuscitation with fluids should begin as soon as an initial examination of the patient has been performed and i.v. access is attained. An initial fluid bolus of 20 ml kg⁻¹ should be given by rapid infusion or manual push.⁹ In children with signs of cardiogenic shock, such as hepatomegaly, rales, crackles, cardiac gallop or increased work of breathing, consider giving a smaller initial fluid bolus of 5–10 ml kg⁻¹.⁹ Reassess after each fluid bolus for fluid overload or attainment of therapeutic endpoints. Unless the child demonstrates signs of fluid overload, anticipate giving 40–60 ml kg⁻¹ fluids in the first hour of resuscitation before normal BP and perfusion are attained or if fluid-refractory shock is suspected.⁹

The American College of Critical Care Medicine recommends isotonic crystalloid or albumin 5% as the preferred fluid for fluid resuscitation.⁹ In paediatric sepsis, resuscitation with high chloride-containing solutions, such as NaCl 0.9%, is potentially associated with worse outcomes compared with more balanced solutions, such as lactated Ringer’s.¹⁶ This concept remains controversial, as a recent systematic review did not support the use of lactated Ringer's over saline 0.9% in critically ill adults and children.¹⁷ A potentially modifiable factor, hyperchloraemia, is common in children with sepsis and is independently associated with worse outcomes.¹⁸ Within the first 72 h of paediatric sepsis resuscitation, balanced solutions, such as lactated Ringer's, may confer a survival benefit, decrease acute kidney injury and are associated with a shorter duration of vasoactive infusions.¹⁶

Infants in septic shock are prone to hypoglycaemia and hypocalcaemia. An early point-of-care glucose test can help dictate therapy. Both hypoglycaemia and hypocalcaemia should be addressed early in resuscitation efforts. Children who are profoundly hypoglycaemic can be given dextrose solution 10% (10 ml kg⁻¹) rapidly through an i.v. or i.o. cannula.⁹ Hyper-osmolar dextrose solutions may cause irritation and sclerosis of small and fragile veins; in these situations, consider diluting dextrose solutions with normal saline. If access is available, an isotonic solution of dextrose 10% can be given at maintenance rate to prevent hypoglycaemia.⁹ In older children and teenagers, sepsis is more likely to cause a stress-induced hyperglycaemia.⁶ In the ongoing management of sepsis, maintaining a plasma glucose concentration of <10 mmol L⁻¹ has been shown to confer a survival benefit.^6,9 Hypocalcaemia should be treated to normalise ionised calcium concentrations.⁹ Both calcium chloride (10 mg kg⁻¹) or calcium gluconate (30 mg kg⁻¹) may be used, and although calcium chloride is more hypertonic and therefore irritating to peripheral veins, its onset of action is quicker than calcium gluconate, especially in the setting of liver dysfunction.

Antibiotics

Broad-spectrum antibiotics should be given to the child with sepsis within 1 h of presentation.¹⁰ Ideally, blood cultures should be sent before giving antibiotics. However, attaining i.v. access can be difficult in children and should not delay antibiotics that can be given by i.m. injection.¹⁰ Appropriate and timely treatment with antibiotics is critical to the effective management of septic shock, and a delay in antibiotic therapy may increase morbidity and mortality.¹³ In critically ill children, the duration of organ dysfunction and risk of mortality increases with each hour after recognition of sepsis until appropriate initial antibiotics are given.¹⁹

Choice of antibiotics may vary by location. However, in general, the initial antibiotics should be broad spectrum and cover endemic and suspected Gram-negative and Gram-positive organisms, based on source and suspected site of infection.¹³ Combination therapy of at least two antibiotics should be used in septic shock.¹³ Children are more susceptible to toxic shock if clinical symptoms, such as erythroderma, indicate the possibility of toxic shock. Antibiotic coverage should be broadened to include clindamycin because of its anti-toxin properties.¹³ Once an organism has been identified, antibiotics should be narrowed in consultation with your infectious disease (ID) service.

Source control

Although an obvious source of infection is often not apparent in up to 50% of children with sepsis, in those children with an identifiable source, early and aggressive source control is fundamental to their management.¹⁰ Once intravascular or i.o. access has been attained, indwelling lines, if present, should be removed.^10,13 Debridement and drainage of wounds should occur expediently, and intraperitoneal sources, such as a perforated viscus, should be repaired with peritoneal washout as soon as medically and logistically possible.^10,13

Fluid-refractory shock

Children in septic shock are often extremely dehydrated and respond favourably to initial fluid resuscitation.⁹ It can reasonably be expected that a child with sepsis will require 40–60 ml kg⁻¹ fluids within the first hour of resuscitation.⁹ However, fluids should be given with caution because there is emerging evidence that liberal use of fluids may be associated with worse outcomes in paediatric sepsis.^20,21 If resuscitation has been ongoing for more than 15 min and a child is not responding to rapid fluid boluses, consider fluid refractory shock and the need for support with vasoactive drugs.^9,10 Inotrope infusions can be initiated peripherally through either the i.v. or i.o. route.⁹ Although practices vary globally, the American College of Critical Care Medicine recommends adrenaline as the initial inotrope in paediatric cold shock.^9,22 As children usually present in cold shock, adrenaline is the preferred choice for peripheral use and can be initiated at 0.05–0.3 kg⁻¹ min⁻¹ until central access is attained.²³ It is advisable to dilute peripheral adrenaline by a factor of 10 to that given centrally.⁹ The limb, in which adrenaline is infusing, should be monitored closely for signs of infiltration and ischaemia.⁹ Noradrenaline can also be given peripherally, similarly to adrenaline, and is the inotrope of choice in vasodilatory or warm shock. Dopamine is an option if adrenaline is not available, but it is no longer considered first line in infants and children.^9,23 Once central i.v. access has been attained, inotropic and vasopressor drugs can be further tailored to the shock phenotype.

Clinical examination does not always accurately determine the underlying shock phenotype, but during initial resuscitation efforts and in the absence of invasive monitoring, delineating between cold and warm shock can help guide management choices.

The shock phenotype can also change over time. Practitioners must remain vigilant, frequently re-evaluating the child, and adjusting doses of inotropes and vasopressors as the underlying pathophysiology dictates.

Catecholamine-resistant shock

Septic shock that responds poorly to both fluids and increasing doses of initial inotropic or vasopressor support is termed catecholamine-resistant shock. If the child with sepsis is not responding favourably to your efforts at resuscitation, escalation in therapies should be matched with investigations into other potential causes of shock. Ensure source control and broad and appropriate antibiotics. A haemodynamically unstable child may need emergency surgery to address a localised source of infection. Clindamycin and i.v. immunoglobulin should be added for suspected toxic shock. Drugs that treat anaerobic organisms, such as metronidazole, should be added for a suspected gastrointestinal source, and doses of antibiotics for use in meningitis should be used if meningitis is suspected. Other causes of shock, such as pericardial effusion, pneumothorax, increased intra-abdominal pressure, blood loss, adrenal suppression or hypothyroidism, should be actively investigated and managed.^9,10 The use of steroids in septic shock is debated in the literature. Practice varies widely, and although clinical guidelines continue to recommend considering steroids in catecholamine-resistant shock, recent research points towards worsening outcomes in paediatric sepsis.^9,24 Risk of adrenal suppression should be considered in children with catecholamine-resistant shock. However, reserve exogenous steroids for children with laboratory-confirmed adrenal suppression, or those who have received recent high-dose or long-term steroid therapy.

Special considerations for the anaesthetist

Up to a quarter of children hospitalised with severe sepsis will undergo surgery during their management.¹ Sepsis and multi-organ failure in children account for 47% of perioperative cardiac arrests.⁸ It is important that the anaesthetist remains vigilant when caring for a patient with, or at risk for, sepsis or septic shock. Sepsis should remain high on the differential diagnosis of any child with worrisome features, especially if the child has a known infection (see Fig 1, Fig 3).

Fig 3.

Anaesthesia sepsis algorithm.^6,9,10 ECMO, extracorporeal membrane oxygenation; FFP, fresh frozen plasma; Hb, haemoglobin; Scvo₂, central venous oxygen saturation.

It is important to note that sepsis can dramatically alter drug pharmacokinetics, potentially affecting pharmacodynamics, and care must be taken to adjust medication choice and dosage to avoid unexpected effects and iatrogenic harm.²⁵ It is critical that the anaesthetist has a thorough understanding of how sepsis affects the pharmacokinetics and subsequent pharmacodynamics of commonly used anaesthetic medications. Even in the absence of signs of organ failure, sepsis can alter the absorption, distribution, metabolism and excretion of medications.²⁵ Drug absorption from both enteral and non-enteral routes may be unpredictable in sepsis. Medications are best given i.v., as altered blood flow to the gut, skin and muscles resulting from changes in circulatory status can impair oral and subcutaneous absorption.²⁶ Distribution may be affected by changes in tissue perfusion, tissue membrane permeability, protein binding, body water, tissue mass and pH.²⁶ Metabolism of most commonly used anaesthetic medications primarily occurs in the liver, but may also occur in the kidney and lung.²⁶ Sepsis is associated with hepatic dysfunction, with metabolism affected by altered hepatic blood flow, free unbound drug fraction and hepatocyte intrinsic activity.^25,26 Clearance of medications with high hepatic extraction ratios, the fraction of drug cleared from the circulation after one pass through the liver, is altered primarily by hepatic blood flow.²⁵ Clearance of medications with low extraction ratios is altered by drug protein binding and hepatocyte function.²⁵ Renal excretion of medications and their metabolites may also be altered by sepsis-induced renal injury, which may be pre-, renal and post-renal in aetiology.²⁶

Anaesthetic medications and sepsis

Ketamine^25,26

• (i)Induction dose should be reduced (0.25–0.5 mg kg⁻¹), given slowly and titrated to effect.
• (ii)Ketamine is a direct myocardial depressant. (In a child with sepsis and who is ‘adrenergically deplete’, ketamine may cause profound cardiovascular depression.)
• (iii)Hepatic impairment may prolong the effects of ketamine.
• (iv)Consider giving both inotropic and vasopressor drugs or fluids to counteract cardiovascular depressant effects.

Benzodiazepines^25,26

• (i)Induction dose should be reduced (i.e. midazolam 0.05–0.1 mg kg⁻¹), titrated to effect, and infusions should be given with caution.
• (ii)Hepatic and renal dysfunction prolongs the effects.
• (iii)Decreased serum albumin concentrations may enhance the response.
• (iv)Consider giving both inotropic and vasopressor drugs or fluids to counteract cardiovascular depressant effects.

Opioids²⁵

• (i)Dose should be reduced and titrated to effect (i.e. fentanyl 0.5–2 mcg kg⁻¹ or morphine 0.025–0.05 mg kg⁻¹).
• (ii)Consider using opioids in combination with other agents (i.e. fentanyl+midazolam).
• (iii)Sepsis-related decreased volume of distribution prolongs the effects.
• (iv)Hepatic hypoperfusion causes decreased clearance of morphine and fentanyl.
• (v)Metabolism of remifentanil is unchanged in sepsis.
• (vi)Consider giving both inotropic and vasopressor drugs or fluids to counteract cardiovascular depressant effects.

Propofol^25,26

• (i)Caution use in patients with sepsis who have cardiovascular instability.
• (ii)Induction dose should be reduced (0.5–1 mg kg⁻¹), given slowly and titrated to effect.
• (iii)Propofol can cause profound cardiovascular depression.
• (iv)Induction may be prolonged secondary to sepsis-induced cardiomyopathy.
• (v)Higher risk of propofol infusion syndrome, dose and duration of infusion should not exceed 4 mg kg⁻¹ h⁻¹.
• (vi)Consider giving both inotropic and vasopressor drugs or fluids to counteract cardiovascular depressant effects.

Rocuronium^25,26

• (i)Hepatic dysfunction, hypoalbuminaemia, electrolyte abnormalities, acidosis and hypothermia prolong the effects.
• (ii)Unpredictable duration of action in sepsis necessitates neuromuscular monitoring.

Suxamethonium^25,26

• (i)Avoid use in children with sepsis, underlying hypotonia, renal injury associated with hyperkalaemia, rhabdomyolysis or prolonged immobility.
• (ii)Sepsis may result in an acquired plasma cholinesterase deficiency.
• (iii)Unpredictable duration of action necessitates neuromuscular monitoring.

Special considerations for the community physician

Regardless of whether a critically ill child presents to a community or tertiary care hospital, initial management strategies remain unchanged. In the absence of hospital-specific sepsis recognition and resuscitation bundles, the algorithms in Fig 1, Fig 2 can help guide initial management. Further considerations for the community physician include timely consultation with tertiary care services, including paediatric intensive care, ID and surgical specialties. If surgical and intensive care services are not available at a local centre, organising urgent transport of a child with sepsis must be considered early. Decisions regarding care do not need to be made in isolation; consulting services can help guide management and provide support until transfer is organised.

Declaration of interests

The authors declare that they have no conflicts of interest.

MCQs

The associated MCQs (to support CME/CPD activity) are accessible at www.bjaed.org/cme/home by subscribers to BJA Education.

Biographies

Heather O'Reilly MD FRCPC is a consultant paediatric anaesthesiologist at Children's Hospital of Eastern Ontario (CHEO) and a lecturer at the University of Ottawa. She completed fellowships in paediatric anaesthesia and critical care. Currently, she is a member of the Ottawa University anaesthesia and paediatric critical care competence committees, and faculty mentor and member of the anaesthesia simulation faculty at CHEO.

Kusum Menon MD MSc FRCPC is a consultant paediatric intensivist and Senior Scientist at Children's Hospital of Eastern Ontario. Her research interests include adrenal insufficiency in critical care and paediatric sepsis. She is a member of the Society of Critical Care Medicine task force for the development of a new definition for paediatric sepsis and of PODIUM for the new definition of MODS.

Matrix codes: 1A02, 2C03, 2D01, 2D01, 3D00