What are the guidelines for using norepinephrine (NE) in patients with severe hypotension or septic shock?

Norepinephrine Hemodynamic Effects and Clinical Use

Norepinephrine is the first-choice vasopressor for septic shock and severe hypotension, rapidly increasing mean arterial pressure (MAP) through both arterial vasoconstriction (alpha-1 effects) and venous venoconstriction that transforms unstressed blood volume into stressed volume, thereby increasing cardiac preload, cardiac output, and organ perfusion. 1, 2

Primary Hemodynamic Effects

Arterial and Venous Actions:

• Norepinephrine increases MAP primarily through alpha-1 adrenergic vasoconstriction while providing modest beta-1 cardiac stimulation 2, 3
• It binds venous adrenergic receptors to convert unstressed blood volume into stressed blood volume, increasing mean systemic filling pressure 4
• This venous effect enhances the fluid-induced increase in mean systemic filling pressure, improving cardiac preload 4

Cardiac Effects:

• Early norepinephrine administration increases cardiac index from 3.2 ± 1.0 to 3.6 ± 1.1 L/min/m² and stroke volume index from 34 ± 12 to 39 ± 13 ml/m² 5
• Global end-diastolic volume index increases from 694 ± 148 to 742 ± 168 ml/m², indicating improved preload 5
• Cardiac function index improves from 4.7 ± 1.5 to 5.0 ± 1.6 per minute 5
• These beneficial effects occur even in patients with left ventricular ejection fraction ≤45%, except when MAP ≥75 mmHg is achieved 5

Clinical Guidelines for Use

Initial Target and Monitoring:

• Target MAP of 65 mmHg initially, which preserves tissue perfusion in most patients 1, 2
• Requires central venous access for administration 2, 6
• Arterial catheter placement is recommended as soon as practical for continuous blood pressure monitoring 2, 6

Timing of Initiation:

• Start norepinephrine early in profound, life-threatening hypotension rather than waiting for complete fluid resuscitation 4, 7
• Specifically indicated when diastolic blood pressure ≤40 mmHg or diastolic shock index (heart rate/diastolic BP) ≥3 4
• Early administration reduces fluid volume requirements and improves outcomes by preventing prolonged hypotension 4, 7
• Duration and depth of hypotension strongly worsen outcomes, making rapid blood pressure restoration critical 4

Fluid Resuscitation Context:

• Adequate fluid resuscitation should ideally precede vasopressors, but early vasopressor use as an emergency measure is frequently necessary when diastolic blood pressure is critically low 1
• The response of arterial pressure to volume expansion alone is inconstant, delayed, and transitory 4
• Norepinephrine rapidly increases and better stabilizes arterial pressure compared to fluids alone 4

Refractory Hypotension Management

Second-Line Agents:

• Add vasopressin (0.03 units/minute) to norepinephrine to raise MAP to target or decrease norepinephrine dosage 1, 2
• Vasopressin doses higher than 0.03-0.04 units/minute should be reserved for salvage therapy 1
• Epinephrine can be added to or substituted for norepinephrine when additional agent is needed 1, 2

Alternative Vasopressors:

• Dopamine should only be used as an alternative in highly selected patients with low risk of tachyarrhythmias and absolute or relative bradycardia 1, 2
• Norepinephrine reduces short-term mortality (RR 0.91,95% CI 0.83-0.99) and arrhythmias compared to dopamine 1

Critical Pitfalls to Avoid

Phenylephrine Use:

• Phenylephrine is NOT recommended except when: (a) norepinephrine causes serious arrhythmias, (b) cardiac output is known to be high with persistently low blood pressure, or (c) as salvage therapy when other agents fail 1, 2
• Phenylephrine impairs microcirculatory perfusion and decreases stroke volume due to pure alpha-adrenergic effects 2, 6
• It may raise blood pressure on the monitor while actually worsening tissue perfusion 2

Dopamine Cautions:

• Strongly discouraged for renal protection—this has no benefit 2
• Associated with higher mortality and more supraventricular arrhythmias (RR 0.47,95% CI 0.38-0.58) and ventricular arrhythmias (RR 0.35,95% CI 0.19-0.66) compared to norepinephrine 1

Monitoring Beyond Blood Pressure:

• Supplement MAP targets with assessment of regional and global perfusion: blood lactate concentrations, skin perfusion, mental status, and urine output 1
• Monitor for signs of excessive vasoconstriction: digital ischemia, decreased urine output, rising lactate, or worsening organ dysfunction despite adequate MAP 2

Special Populations

Patients with Chronic Hypertension:

• MAP target may need to be higher than 65 mmHg in patients with atherosclerosis or previous hypertension 1
• A MAP of 65 mmHg might be too low in patients with severe uncontrolled hypertension 1

Patients Requiring Fluid Restriction:

• Early norepinephrine administration should be considered in patients where fluid accumulation would be particularly deleterious (acute respiratory distress syndrome or intra-abdominal hypertension) 4