What to do if noradrenaline (norepinephrine) is not effective in treating septic shock in children?

Management of Norepinephrine-Refractory Septic Shock in Children

When norepinephrine fails to adequately support blood pressure in pediatric septic shock, you should either add vasopressin or further titrate catecholamines, based on the 2020 Surviving Sepsis Campaign guidelines. 1

Primary Recommendation: Add Vasopressin or Escalate Catecholamines

The Surviving Sepsis Campaign suggests either adding vasopressin or further titrating catecholamines in children with septic shock who require high-dose catecholamines (weak recommendation, low quality of evidence). 1 Importantly, no consensus was achieved on the optimal threshold for initiating vasopressin, so this decision should be made according to individual clinician preference. 1

Key Considerations Before Adding Agents:

• Ensure adequate fluid resuscitation first: Children should receive 40-60 mL/kg of fluid resuscitation before escalating vasoactive support 1
• Use advanced hemodynamic monitoring when available to guide therapy, including cardiac output/cardiac index, systemic vascular resistance, or central venous oxygen saturation (ScvO2) 1
• Monitor lactate trends in addition to clinical assessment, as persistent elevation indicates incomplete hemodynamic resuscitation 1

Algorithmic Approach Based on Hemodynamic Profile

Low Cardiac Output with High Systemic Vascular Resistance (Normal Blood Pressure):

• Add vasodilators: Use nitroprusside or nitroglycerin as first-line agents 1
• Alternative inotropes: If toxicity develops or low cardiac output persists, substitute milrinone or inamrinone 1
• Caution: These agents have long elimination half-lives that can lead to slowly reversible toxicities, particularly with abnormal renal or liver function 1

Low Cardiac Output with Low Blood Pressure and Low Systemic Vascular Resistance:

• Add norepinephrine to epinephrine to increase diastolic blood pressure and systemic vascular resistance 1
• Once adequate blood pressure is achieved, add dobutamine, type III phosphodiesterase inhibitors (particularly enoximone), or levosimendan to improve cardiac index and ScvO2 1
• Consider hormone replacement: Thyroid replacement with triiodothyronine for thyroid insufficiency, and hydrocortisone for adrenal insufficiency 1

High Cardiac Output with Low Systemic Vascular Resistance (Vasodilatory Shock):

• Titrate norepinephrine and fluid first 1
• When norepinephrine titration fails: Add low-dose vasopressin, angiotensin, or terlipressin to restore blood pressure 1
• Critical monitoring required: These potent vasoconstrictors can reduce cardiac output, so use with cardiac output/ScvO2 monitoring 1
• May need additional inotropic support: Consider low-dose epinephrine or dobutamine, or reduce vasopressor infusion if cardiac output drops 1
• Terlipressin evidence: A 2006 study showed terlipressin (0.02 mg/kg every 4 hours) rapidly improved mean arterial pressure in 14 of 16 children with catecholamine-refractory shock, though excessive vasoconstriction remains a concern 2

Alternative Catecholamine Options

If norepinephrine is truly ineffective and vasopressin is not available or appropriate:

• Epinephrine is preferred over dopamine in children with septic shock (weak recommendation, low quality of evidence) 1
• Dopamine may be substituted if epinephrine or norepinephrine is not readily available, though it is less preferred 1

Critical Pitfalls to Avoid

Occult Causes of Refractory Shock:

Children with refractory shock must be evaluated for potentially reversible causes 1:

• Pericardial effusion (requires pericardiocentesis)
• Pneumothorax (requires thoracentesis)
• Hypoadrenalism (requires adrenal hormone replacement)
• Hypothyroidism (requires thyroid hormone replacement)
• Ongoing blood loss (requires blood replacement/hemostasis)
• Increased intra-abdominal pressure (requires peritoneal catheter or abdominal release)
• Necrotic tissue or inadequate source control (requires nidus removal and appropriate antibiotics)

Monitoring Parameters:

When escalating vasoactive support, continuously monitor 1:

• Mixed venous/ScvO2 >70%
• Cardiac index 3.3-6.0 L/min/m²
• Normal perfusion pressure for age (MAP minus central venous pressure)
• Urine output, acidosis resolution, and clinical perfusion

Role of Inodilators

The guidelines were unable to issue a recommendation about adding an inodilator in children with septic shock and cardiac dysfunction despite other vasoactive agents. 1 However, in clinical practice with documented cardiac dysfunction and adequate filling pressures, dobutamine (up to 20 μg/kg/min) combined with norepinephrine represents a reasonable approach. 3

Important Nuance on Vasopressin Timing

While the guidelines suggest adding vasopressin as an option for high-dose catecholamine requirements, the exact threshold for "high-dose" was not defined, leaving this to clinical judgment based on the individual patient's response, side effects, and hemodynamic profile. 1