What are the mechanism of action, clinical effects, dosing, and contraindications of norepinephrine (noradrenaline) as a vasopressor for shock?

Noradrenaline (Norepinephrine): Mechanism of Action and Clinical Effects

Norepinephrine is the first-line vasopressor for septic shock, acting primarily through alpha-1 adrenergic receptor stimulation to increase blood pressure via vasoconstriction, with additional beta-1 effects that can transiently improve cardiac output and coronary perfusion. 1

Mechanism of Action

Receptor Activity and Hemodynamic Effects

• Norepinephrine acts predominantly on alpha-1 adrenergic receptors, causing potent vasoconstriction and increased systemic vascular resistance (SVR), which is the primary mechanism for blood pressure elevation 1

• Beta-1 adrenergic receptor stimulation increases stroke volume and can improve cardiac contractility, though these effects are often transient and time-dependent 1

• Beta-2 receptor activity on coronary vessels increases coronary blood flow, which may protect myocardial perfusion during shock states 1

• The positive chronotropic effects are typically counterbalanced by vagal reflex activity triggered by increased blood pressure, resulting in minimal net change in heart rate compared to other catecholamines 1

Cardiovascular Impact

• Effects on cardiac output are inconsistent and time-dependent, related to baseline cardiovascular state, ventriculo-arterial coupling, and potential unmasking of underlying myocardial depression when afterload increases 1

• Norepinephrine increases mean arterial pressure (MAP) primarily through vasoconstrictive effects with less increase in stroke volume and heart rate compared to dopamine 1

• Early administration increases cardiac output and improves microcirculation while avoiding fluid overload, making it beneficial when started early in resuscitation 2

Clinical Effects and Indications

Primary Use in Shock States

• Norepinephrine is recommended as the first-line vasopressor in adults with fluid-refractory septic shock, particularly when characterized by low SVR (wide pulse pressure with diastolic blood pressure less than one-half systolic pressure) 1

• Target MAP should be at least 65 mmHg, with higher targets considered in patients with chronic hypertension 2

• Norepinephrine demonstrates superior mortality outcomes compared to dopamine (RR 0.91,95% CI 0.83-0.99), with significantly fewer arrhythmias (RR 0.47 for supraventricular arrhythmias, RR 0.35 for ventricular arrhythmias) 1

Combination Therapy

• Norepinephrine can be combined with dobutamine when both vasopressor support and inotropic support are needed, as dobutamine's vasodilating properties may counteract excessive vasoconstriction 1

• Vasopressin (≤0.04 units/kg/min) should be added when shock is refractory to norepinephrine, as vasopressin acts on different vascular receptors and is relatively deficient during sepsis 1, 2

• Angiotensin II acts synergistically with norepinephrine to increase blood pressure in vasodilatory shock, though its clinical role is less well-defined 1

Dosing Considerations

Initiation and Titration

• Early administration is beneficial to restore organ perfusion and prevent profound, durable hypotension, which is an independent mortality risk factor 2, 3

• Norepinephrine should be regarded as neurohormonal augmentation therapy to defend decompensating hemodynamic function rather than rescue therapy, representing a shift toward early use in resuscitation 3

• Vasopressors should be titrated to endpoints of perfusion pressure (MAP minus central venous pressure) or SVR that optimize urine output and creatinine clearance, while avoiding excessive vasoconstriction that compromises microcirculatory flow 1

Refractory Hypotension

• When hypotension is refractory to norepinephrine, adding vasopressin is recommended, though increasing norepinephrine dose further cannot be discouraged 2

• Epinephrine should be the first alternative if norepinephrine fails, as randomized trials show no mortality difference between norepinephrine and epinephrine (RR 0.96,95% CI 0.77-1.21) 1

Contraindications and Cautions

Specific Clinical Scenarios

• Phenylephrine (pure alpha agonist) is NOT recommended except when norepinephrine causes serious arrhythmias, cardiac output is known to be high, or as salvage therapy when other agents fail, as it may decrease stroke volume and impair microcirculatory flow 1

• In cardiogenic shock, norepinephrine use is associated with increased 30-day mortality (41% vs 30%, OR 1.61,95% CI 1.09-2.39), requiring more mechanical ventilation and longer ICU stays 4

• Dopamine-resistant shock commonly responds to norepinephrine, particularly in young infants (<6 months) who may have age-specific insensitivity to dopamine due to incomplete sympathetic innervation 1

Monitoring Requirements

• Excessive vasoconstriction compromising microcirculatory flow must be avoided, as studies show increased mortality with nonselective approaches that simply increase blood pressure through excessive vasoconstriction 1

• Cardiac output measurement targeting maintenance of normal or elevated flow is desirable when using vasopressors, particularly when considering vasopressin addition 1