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

Noradrenaline (Norepinephrine) in Severe Hypotension and Septic Shock

First-Line Vasopressor Selection

Norepinephrine is the mandatory first-choice vasopressor for septic shock and severe hypotension, with an initial target mean arterial pressure (MAP) of 65 mmHg. 1, 2

• Norepinephrine demonstrates superior efficacy and safety compared to all other vasopressors, particularly dopamine, which is associated with higher mortality and increased arrhythmias 1, 2
• The recommendation is Grade 1B (strong recommendation, moderate quality evidence) from the Surviving Sepsis Campaign 1
• Dopamine should only be considered in highly selected patients with low risk of tachyarrhythmias or absolute/relative bradycardia 1, 2

Mechanism and Hemodynamic Effects

Norepinephrine works through dual mechanisms that make it ideal for septic shock 3, 4:

• Alpha-1 adrenergic stimulation: Provides potent vasoconstriction to correct the profound vasodilation characteristic of septic shock 1, 3
• Beta-1 adrenergic effects: Maintains or improves cardiac output while raising systemic vascular resistance 2, 4
• Venous effects: Transforms unstressed blood volume into stressed blood volume by binding venous adrenergic receptors, increasing mean systemic filling pressure 5

Administration Protocol

Route and Monitoring

• Central venous access is required for norepinephrine administration 2, 6
• Arterial catheter placement is recommended as soon as practical for continuous blood pressure monitoring in all patients requiring vasopressors 2, 6
• Peripheral administration is possible in emergency situations but carries risk of extravasation and should be transitioned to central access 6, 7

Dosing

• Initial dose: 0.05-0.1 mcg/kg/min, titrated every 5 minutes to achieve target MAP 6
• Standard concentration: 4 mg norepinephrine in 250 mL D5W or normal saline (16 mcg/mL) 6
• Typical dose range: 0.05-0.5 mcg/kg/min, though doses up to ≥1 mcg/kg/min may be required in refractory shock 3, 4
• Use an infusion pump for precise administration 6

Blood Pressure Targets

• Initial MAP target: 65 mmHg for most patients 1, 2, 6
• Higher targets (70-80 mmHg) should be considered in patients with chronic hypertension 6, 3
• Monitor diastolic arterial pressure (DAP) as a marker of vascular tone to identify patients needing urgent norepinephrine 3

Timing of Initiation

Early administration of norepinephrine is beneficial and should be considered simultaneously with fluid resuscitation in patients with profound hypotension. 4, 5

Indications for Early Norepinephrine

Start norepinephrine early when 5, 8:

• Diastolic blood pressure ≤40 mmHg or diastolic shock index (heart rate/diastolic BP) ≥3 5
• Life-threatening hypotension where relying solely on fluids may unduly prolong hypotension and organ hypoperfusion 5
• Risk of fluid overload exists, particularly in patients with acute respiratory distress syndrome or intra-abdominal hypertension 5

Evidence for Early Administration

• A randomized controlled trial (CENSER) demonstrated that early norepinephrine significantly increased shock control by 6 hours (76.1% vs 48.4%, P<0.001) 8
• Early norepinephrine reduced incidence of cardiogenic pulmonary edema (14.4% vs 27.7%, P=0.004) and new-onset arrhythmia (11% vs 20%, P=0.03) 8
• Median time to norepinephrine administration was 93 minutes in the early group versus 192 minutes in standard care 8

Fluid Resuscitation Integration

• Minimum 30 mL/kg crystalloid bolus should be administered in the first 3 hours for patients with sepsis-induced tissue hypoperfusion 1, 2
• Crystalloids are the initial fluid of choice (Grade 1B recommendation) 1
• Albumin may be considered in patients requiring substantial crystalloid volumes to maintain adequate MAP 1
• Avoid hetastarch formulations (Grade 1B recommendation) 1
• Norepinephrine should not substitute for adequate fluid resuscitation but can be started concurrently in severe hypotension 2, 6

Management of Refractory Hypotension

Second-Line Vasopressor Options

When target MAP cannot be achieved with norepinephrine alone 1, 2:

1. Vasopressin 0.03 units/minute: Add to norepinephrine to either raise MAP to target or decrease norepinephrine dosage 1, 2

   • Should NOT be used as the initial vasopressor or as monotherapy 2
   • Doses higher than 0.03-0.04 units/minute should be reserved for salvage therapy 2

2. Epinephrine: Add when an additional agent is needed to maintain adequate blood pressure (Grade 2B recommendation) 1, 2

   • Typical dosing: 0.05-2 mcg/kg/min IV infusion 2

3. Increasing norepinephrine dose: Escalating to ≥1 mcg/kg/min is an acceptable option before adding second agents 3, 4

Inotropic Support

Dobutamine (up to 20 mcg/kg/min) should be added when 1, 2:

• Myocardial dysfunction is present with elevated cardiac filling pressures and low cardiac output 1, 2
• Ongoing signs of hypoperfusion persist despite adequate intravascular volume and adequate MAP 1
• Central venous oxygen saturation (ScvO2) remains below 70% despite optimal vasopressor therapy 1

The combination of dobutamine and norepinephrine is recommended as first-line treatment for patients with low cardiac output and hypotension 1, 2

Agents to Avoid

Phenylephrine

Phenylephrine is NOT recommended except in highly specific circumstances 2, 6:

• When norepinephrine causes serious, life-threatening arrhythmias 2, 9
• When cardiac output is documented to be high with persistently low blood pressure 2
• As salvage therapy when all other vasopressor agents have failed 2, 9

Critical pitfall: Phenylephrine may raise blood pressure numbers on the monitor while actually worsening tissue perfusion through impaired microcirculatory flow and decreased stroke volume 2, 9

Dopamine

Dopamine is strongly discouraged except in highly selected circumstances 1, 2:

• Associated with higher mortality compared to norepinephrine 2
• Increased risk of tachyarrhythmias 1, 2
• Should only be used in patients with low risk of arrhythmias or absolute/relative bradycardia (Grade 2C recommendation) 1
• Never use low-dose dopamine for renal protection—this is strongly discouraged and has no benefit 2

Monitoring and Titration

Hemodynamic Monitoring

Continuous assessment should include 6:

• Arterial blood pressure via arterial catheter (mandatory for all patients on vasopressors) 2, 6
• Urine output: Target ≥0.5 mL/kg/h 1
• Oxygen saturation: SpO2 ≥95% 1
• Central venous oxygen saturation: Target ≥70% 1

Perfusion Markers

Monitor for signs of adequate tissue perfusion 6:

• Mental status improvement
• Capillary refill time
• Skin temperature and color
• Lactate clearance: Decreasing lactate levels indicate improving tissue perfusion 1, 6
• Urine output trends

Titration Strategy

• Adjust norepinephrine dose every 5 minutes based on MAP response 6
• Once hemodynamically stable, gradually taper by 0.05 mcg/kg/min every 15-30 minutes while monitoring MAP 6
• If MAP falls below target during weaning, reinstate the previous effective dose and attempt weaning later 6

Adverse Effects and Complications

Common Pitfalls to Avoid

1. Excessive vasoconstriction: Monitor for digital ischemia, decreased urine output, rising lactate, or worsening organ dysfunction despite adequate MAP 2
2. Extravasation: If peripheral administration is necessary, monitor closely and transition to central access as soon as possible 6, 7
3. Inadequate fluid resuscitation: Ensure adequate volume status before or concurrent with vasopressor initiation 2, 6
4. Targeting supranormal blood pressure: Titrate to adequate perfusion markers, not to supranormal blood pressure targets 2

Safety Profile

• A retrospective study of 91 elderly patients (median age 81 years) with septic shock showed observed ward mortality of 27.5% (better than predicted by APACHE-II scores) 7
• Peripheral administration of norepinephrine did not indicate frequent complications in this cohort, though central access remains preferred 7

Special Populations

Pediatric Considerations

• Norepinephrine is recommended as the first-line vasoactive drug treatment in children with septic shock 1
• Phosphodiesterase III inhibitors may be considered in cases of low cardiac output with normal arterial pressure 1
• Hydrocortisone dosing: 1 mg/kg every 6 hours (compared to 200-300 mg/day in adults) 1

Neurogenic Shock

• Norepinephrine remains the first-choice vasopressor for neurogenic shock 9
• Same initial MAP target of 65 mmHg applies 9
• Dobutamine is the first-line inotrope when myocardial dysfunction is present 9

Corticosteroid Therapy

• Hydrocortisone 200-300 mg/day for at least 5 days, followed by tapering, is recommended in patients who do not respond adequately to fluid resuscitation and vasopressor therapy 1
• Avoid intravenous hydrocortisone if adequate fluid resuscitation and vasopressor therapy restore hemodynamic stability (Grade 2C recommendation) 1

Outcome Considerations

Duration and depth of hypotension strongly worsen outcomes in septic shock patients. 5

• Profound and durable hypotension is an independent factor of increased mortality 4, 5
• Early norepinephrine administration increases cardiac output, improves microcirculation, and avoids fluid overload 4
• The CENSER trial showed no difference in 28-day mortality between early and standard norepinephrine groups (15.5% vs 21.9%, P=0.15), but this was a phase II trial not powered for mortality 8