Sepsis, septic shock and MODS

Definition and Overview

• Sepsis in children is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.
• Septic shock is a subset of sepsis with cardiovascular dysfunction persisting despite adequate fluid resuscitation, characterised by the need for vasoactive support and/or evidence of tissue hypoperfusion (elevated lactate, altered mental state, prolonged capillary refill).

Paediatric sepsis is distinct from adult sepsis in several respects:

• Children mount a more vigorous inflammatory response and may compensate haemodynamically until late decompensation
• Hypotension is a late and pre-terminal sign in children; the absence of hypotension does not exclude shock
• Age-specific vital sign thresholds must be used (see table below)
• The commonest phenotype of paediatric septic shock is cold shock (high SVR, low CO), in contrast to adults who more commonly present with warm vasodilatory shock

Epidemiology:

• Incidence approximately 2-4% of PICU admissions in Australia and New Zealand; mortality 4-10% in high-income settings, higher in resource-limited environments
• Leading organisms vary by age: Group B Streptococcus and gram-negatives in neonates; Streptococcus pneumoniae, Neisseria meningitidis in infants and toddlers; Staphylococcal and gram-negative enteric pathogens across all ages

Age-Specific Physiological Thresholds

A practical bedside approximation for the lower limit of normal systolic BP in children aged 1-10 years: $\text{SBP}_{\min} = 70 + (2 \times \text{age in years})\,\text{mmHg}$.

Pathophysiology

Initial Inflammatory Cascade

Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) activate pattern recognition receptors (toll-like receptors), triggering release of pro-inflammatory cytokines (TNF-$\alpha$, IL-1, IL-6). This drives:

• Endothelial activation, increased vascular permeability, and third-space fluid shifts
• Coagulopathy (consumptive coagulopathy, DIC)
• Mitochondrial dysfunction and impaired oxygen utilisation

Haemodynamic Phenotypes in Children

$$\text{DO}_2 = \text{CO} \times \text{CaO}_2 = (\text{HR} \times \text{SV}) \times (1.34 \times \text{Hb} \times \text{SpO}_2 + 0.003 \times \text{PaO}_2)$$

• Cold shock (most common in children): elevated SVR, reduced cardiac output, poor peripheral perfusion, mottled cool extremities, prolonged CRT >2 seconds. Adrenaline-responsive.
• Warm shock: reduced SVR, bounding pulses, flash CRT; more common in older children and adolescents, and in gram-negative/endotoxin-mediated sepsis. Noradrenaline-responsive.
• Progression to refractory shock involves absolute adrenal insufficiency, myocardial dysfunction, and multi-organ failure

Clinical Recognition

Red Flag Features

• Altered mental state, inconsolable irritability, or decreased responsiveness
• Prolonged capillary refill time >2 seconds or flash CRT <1 second
• Mottled skin, pallor, or peripheral cyanosis
• Tachycardia out of proportion to fever
• Oliguria (urine output <1 mL/kg/hr in children, <0.5 mL/kg/hr in adolescents)
• Non-blanching petechial or purpuric rash (meningococcaemia until proven otherwise)
• New hepatomegaly (indicator of venous congestion and right heart dysfunction)

PICU Triage: Recognising Fluid-Refractory Shock

• Fluid-refractory septic shock is defined as persistent signs of shock after ≥40 mL/kg of isotonic crystalloid within the first hour.
• These children require urgent vasoactive support, ICU admission, and reassessment of diagnosis.

Investigations

• Lactate is a key marker: elevated lactate in the setting of shock mandates early aggressive resuscitation even if BP is maintained.
• Serial lactate guides response to therapy.

Management

Step 1: Simultaneous Resuscitation and Recognition (0-15 minutes)

1. High-flow oxygen via non-rebreather mask; prepare for early intubation if work of breathing is high or GCS declining
2. Establish two large-bore IV cannulae or intraosseous (IO) access; IO is first-line if IV access fails after 90 seconds
3. Blood cultures (do not delay antibiotics >1 hour)
4. Point-of-care glucose, lactate, gas
5. Activate sepsis pathway and notify PICU/retrieval team early

Step 2: Fluid Resuscitation (First Hour)

• Initial bolus: 10 mL/kg isotonic crystalloid (0.9% NaCl or Hartmann's/PlasmaLyte) over 5-10 minutes, with reassessment after each bolus
• Repeat boluses of 10 mL/kg to a maximum of 40 mL/kg in the first hour, titrating to clinical response (CRT, HR, mental state, urine output)
• After 20 mL/kg: reassess for signs of fluid overload (new hepatomegaly, increased work of breathing, worsening oxygenation); if present, transition earlier to vasoactive support
• Neonates and children with known or suspected cardiac disease: use 5 mL/kg boluses with very careful reassessment; avoid large volume resuscitation without senior review
• Key divergence from adult practice: The FEAST trial demonstrated harm from liberal bolus therapy in resource-limited settings without ICU backup.
• In Australian and New Zealand PICUs, bolus resuscitation with close monitoring and early escalation to vasoactives remains standard; routine restriction of all fluid boluses is not supported in the well-resourced PICU environment, but avoidance of fluid overload >10% body weight is a clear goal.

Step 3: Antimicrobials (within 1 hour of recognition, ideally <30 min for shock)

• Empiric broad-spectrum antibiotics should be given within 60 minutes of recognition (within 30 minutes for septic shock)
• Default regimen in most Australian and New Zealand PICUs: Piperacillin-tazobactam 100 mg/kg (piperacillin component) IV 6-hourly (max 4 g per dose) plus Gentamicin 7 mg/kg IV daily (neonates: age-adjusted dosing, consult pharmacy)
• Add Vancomycin 15 mg/kg IV 6-hourly (max 750 mg per dose) if: central line in situ, gram-positive source suspected, MRSA risk, or neutropenic patient
• Add Aciclovir 10-15 mg/kg IV 8-hourly if HSV encephalitis or neonatal HSV is possible
• Antifungal (Caspofungin $70\,\text{mg/m}^2$ loading, then $50\,\text{mg/m}^2$ daily) in immunocompromised or prolonged broad-spectrum antibiotic exposure
• De-escalate at 48-72 hours when cultures and sensitivities are available

Step 4: Vasoactive Support (Fluid-Refractory Shock)

• Initiate vasoactives if shock persists after ≥20 mL/kg OR signs of fluid overload appear.
• Do not wait for 40 mL/kg if clinical deterioration is evident.

• Peripheral vasoactives are acceptable for short-term stabilisation (30-60 min) while central access is established
• Central venous access should be obtained early for reliable drug delivery and CVP/ScvO$_2$ monitoring
• ScvO$_2$ target ≥70%: if <70% despite fluid and vasopressor optimisation, consider transfusion to Hb ≥80 g/L or addition of inotrope

Step 5: Source Control

• Drain any accessible collection (abscess, empyema, infected effusion) within 6-12 hours of identification
• Remove infected intravascular devices (central lines, PICC lines) where source of bacteraemia; balance against need for access
• Surgical consultation early for necrotising fasciitis, intestinal perforation, or undrained pus

Step 6: Corticosteroids (Catecholamine-Resistant Shock)

• Indicated in catecholamine-resistant septic shock and when adrenal insufficiency is suspected (prolonged steroid use, adrenal haemorrhage, purpuric rash of meningococcaemia)
• Hydrocortisone 1-2 mg/kg/dose IV 6-hourly (max 50 mg per dose); some units use a continuous infusion
• Cosyntropin stimulation testing is not required before commencing in the acute setting

Monitoring Targets During Resuscitation

Special Considerations

Neonatal Sepsis at the PICU Interface

• Group B Streptococcus, Listeria, and gram-negative enteric organisms dominate early-onset; coagulase-negative staphylococci and Candida in late-onset NICU sepsis
• Empiric regimen: Benzylpenicillin 60 mg/kg IV 12-hourly (term) plus Gentamicin 5 mg/kg IV 24-hourly (term neonate); adjust for gestation and age
• Neonates may present with temperature instability, poor feeding, apnoea, or metabolic acidosis rather than classic sepsis signs
• Avoid prolonged fasting; early dextrose-containing fluids to prevent hypoglycaemia

Meningococcaemia

• Ceftriaxone 100 mg/kg IV (max 4 g) stat as soon as blood cultures drawn; do not delay for LP
• Anticipate DIC, adrenal haemorrhage (Waterhouse-Friderichsen), and rapid progression to refractory shock
• Prophylaxis for close contacts: notify public health; ciprofloxacin or rifampicin per weight-based dosing

Immunocompromised Host

• Fever in a neutropenic child (ANC $<0.5 \times 10^9/\text{L}$) is a medical emergency
• Empiric coverage must include gram-negative cover including Pseudomonas: Piperacillin-tazobactam or Meropenem 20 mg/kg IV 8-hourly
• Lower threshold for antifungals, antivirals; consult haematology/oncology early

Retrieval and Transport

• Stabilise before transfer: establish airway if required, secure vascular access, commence vasoactives via peripheral line if needed
• Communicate ISBAR-structured handover; document resuscitation volumes, antibiotics given with times and doses
• Anticipate deterioration in transport: ensure vasoactive infusions are reliable, have adrenaline drawn up for arrest ($10\,\mu\text{g/kg}$ IV/IO)

Complications

• Fluid overload: cumulative fluid balance >10% body weight is independently associated with worse outcomes; use diuretics or early CRRT if oliguric and fluid-overloaded once haemodynamically stable
• PARDS: lung-protective ventilation if intubated ($V_T5-7\,\text{mL/kg}$ IBW, PEEP titration, $\text{FiO}_2$ minimised)
• AKI: monitor creatinine, urine output, electrolytes; avoid nephrotoxic drug accumulation (aminoglycosides: single daily dosing, levels)
• DIC: FFP 10 mL/kg IV, cryoprecipitate 5 mL/kg IV, platelets 10 mL/kg IV as guided by coagulation and bleeding
• Hypoglycaemia: common in infants; check glucose every 1-2 hours during acute resuscitation; treat with 2 mL/kg of 10% dextrose IV
• Hypocalcaemia: ionised calcium <1.1 mmol/L impairs cardiac contractility; replace with Calcium gluconate 0.1 mmol/kg IV slowly

PICU Exam Framing: Viva Anchors

• Always state age-specific thresholds when asked to recognise shock; hypotension is a late sign in children
• Fluid bolus 10 mL/kg with reassessment is the paediatric standard; not 30 mL/kg as in adult Surviving Sepsis; distinguish your practice
• Cold shock = adrenaline first; warm shock = noradrenaline first; this is a high-yield differentiator
• When asked about corticosteroids: reserve for catecholamine-resistant shock; hydrocortisone at stress dosing
• Antibiotics within 60 minutes, ideally within 30 minutes for established shock: state the time target explicitly in viva
• Document and communicate: fluids given, antibiotics with times, vasoactive doses, and response are all essential for safe retrieval handover and PICU admission