What is the role of noradrenaline (norepinephrine) in treating severe hypotension and septic shock?

Noradrenaline in Severe Hypotension and Septic Shock

Norepinephrine is the mandatory first-line vasopressor for septic shock and severe hypotension, initiated immediately when hypotension persists after initial fluid resuscitation, with a target mean arterial pressure (MAP) of ≥65 mmHg. 1, 2

Initial Management Protocol

Fluid Resuscitation First

• Administer a minimum of 30 mL/kg of crystalloids within the first 3 hours of septic shock recognition 1, 2
• However, do not delay norepinephrine if life-threatening hypotension exists (diastolic BP ≤40 mmHg or diastolic shock index ≥3), as prolonged hypotension independently increases mortality 3, 4
• The CENSER randomized trial demonstrated that early norepinephrine (median 93 minutes from arrival) achieved shock control by 6 hours in 76.1% of patients versus 48.4% with delayed administration 5

Norepinephrine Administration Requirements

• Central venous access is required for safe administration 1, 2, 6
• Place an arterial catheter for continuous blood pressure monitoring as soon as practical 1, 2
• Target MAP ≥65 mmHg in most patients; consider higher targets only in patients with chronic hypertension 1, 2

Physiologic Rationale

Norepinephrine works through multiple mechanisms that make it superior to other vasopressors:

• Increases MAP primarily through α1-adrenergic vasoconstriction while maintaining cardiac output via modest β1-adrenergic stimulation 1, 2
• Transforms unstressed blood volume into stressed blood volume by binding venous adrenergic receptors, increasing mean systemic filling pressure 3
• Rapidly stabilizes arterial pressure more effectively than fluid resuscitation alone, which produces inconstant, delayed, and transitory responses 3, 4
• Improves microcirculation and tissue oxygenation while preventing fluid overload 3, 7, 4

Management of Refractory Hypotension

Second-Line Agent: Vasopressin

• Add vasopressin at 0.03 units/minute (not to exceed 0.03-0.04 units/min) when norepinephrine alone fails to achieve target MAP 1, 2
• Vasopressin acts on different vascular receptors than α1-adrenergic receptors and corrects relative vasopressin deficiency in sepsis 1, 7
• Never use vasopressin as monotherapy—it must always be added to norepinephrine 1, 2, 6

Third-Line Options

• Add epinephrine (0.05-2 mcg/kg/min) when additional vasopressor support is needed beyond norepinephrine and vasopressin 1, 2
• Add dobutamine (up to 20 mcg/kg/min) if persistent hypoperfusion exists despite adequate vasopressors and fluid loading, particularly with evidence of myocardial dysfunction (elevated cardiac filling pressures, low cardiac output) 1, 2

Critical Agents to Avoid

Dopamine

• Use dopamine ONLY in highly selected patients with low risk of tachyarrhythmias or absolute/relative bradycardia 1, 2
• A meta-analysis of 2,043 patients showed dopamine increased mortality (RR 0.91,95% CI 0.83-0.99) and arrhythmias compared to norepinephrine 1
• Strongly discouraged for renal protection—this indication has no evidence base 1, 2, 6

Phenylephrine

• Not recommended except in three specific circumstances: (1) norepinephrine causes serious arrhythmias, (2) cardiac output is documented high with persistently low blood pressure, or (3) salvage therapy when all other agents have failed 1, 2, 6
• Pure α1-agonism may compromise microcirculatory flow and tissue perfusion despite raising blood pressure numbers on the monitor 2

Common Pitfalls and How to Avoid Them

• Do not wait to complete entire fluid resuscitation before starting norepinephrine if profound hypotension threatens organ perfusion—early administration (within first hour) in the CENSER trial reduced cardiogenic pulmonary edema (14.4% vs 27.7%) and arrhythmias (11% vs 20%) 5
• Monitor perfusion markers, not just blood pressure—track lactate clearance, urine output (≥0.5 mL/kg/h), and mental status rather than targeting supranormal MAP values 1, 2
• Avoid excessive vasoconstriction—watch for digital ischemia, decreased urine output, or rising lactate despite adequate MAP 2
• Do not use dopamine as first-line therapy—the evidence clearly favors norepinephrine for both efficacy and safety 1, 2, 6

FDA-Approved Indication

Norepinephrine Bitartrate Injection is indicated to raise blood pressure in adult patients with severe, acute hypotension 8