What is the dosing protocol for noradrenaline (norepinephrine) in managing severe hypotension and septic shock?

Noradrenaline (Norepinephrine) Dosing Protocol for Septic Shock

Norepinephrine is the mandatory first-line vasopressor for septic shock, initiated via central venous access with continuous arterial monitoring, targeting a mean arterial pressure (MAP) of 65 mmHg. 1, 2

Step 1: Pre-Initiation Requirements

Before or simultaneously with norepinephrine initiation:

• Establish central venous access for safe administration to minimize extravasation risk 1, 3
• Place arterial catheter for continuous blood pressure monitoring as soon as practical 1, 3
• Administer at least 30 mL/kg IV crystalloid within the first 3 hours, though do not delay norepinephrine if life-threatening hypotension (systolic BP <80 mmHg or diastolic BP ≤40 mmHg) is present 2, 3, 4

Critical caveat: Early norepinephrine administration—even before completing full fluid resuscitation—is beneficial when profound hypotension exists, as prolonged hypotension independently increases mortality. 4, 5, 6

Step 2: Initial Norepinephrine Dosing

Starting dose and titration:

• Begin at 0.1-0.5 mcg/kg/min (approximately 8-35 mcg/min for a 70 kg patient) 1
• Titrate to achieve MAP ≥65 mmHg in most patients 7, 1, 2
• Consider higher MAP targets (80-85 mmHg) only in patients with documented chronic hypertension 2
• Monitor blood pressure every 5-15 minutes during initial titration 3

Physiologic rationale: Norepinephrine rapidly increases MAP through α1-adrenergic vasoconstriction while providing modest β1-adrenergic cardiac stimulation, which increases cardiac preload (via venous constriction transforming unstressed blood volume to stressed volume) and improves cardiac output. 5, 8

Step 3: Monitoring During Norepinephrine Infusion

Essential monitoring parameters:

• Continuous arterial blood pressure via arterial line 1, 3
• Perfusion markers beyond MAP: capillary refill, urine output (target ≥0.5 mL/kg/h), lactate clearance, mental status, and skin perfusion 7, 2, 3
• Signs of excessive vasoconstriction: cold extremities, digital ischemia, decreased urine output, rising lactate 1, 3
• SpO2 ≥95% 7

Step 4: Escalation for Refractory Hypotension

When norepinephrine alone fails to achieve MAP ≥65 mmHg:

First Escalation Option: Add Vasopressin

• Add vasopressin at 0.03 units/minute (range 0.01-0.03 units/min) to either raise MAP to target or decrease norepinephrine requirements 7, 1, 3
• Never use vasopressin as monotherapy—it must be added to norepinephrine 1, 3
• Do not exceed 0.03-0.04 units/min except for salvage therapy, as higher doses cause cardiac, digital, and splanchnic ischemia 7, 1

Important threshold: Patients requiring ≥15 mcg/min of norepinephrine already have severe septic shock and should receive vasopressin to spare further norepinephrine escalation, as doses above 15 mcg/min are associated with increased mortality. 1

Second Escalation Option: Add Epinephrine

• Add epinephrine (0.05-2 mcg/kg/min) as an alternative to vasopressin or as a third agent if norepinephrine plus vasopressin fails 1, 2, 3
• Epinephrine should be added when norepinephrine exceeds moderate doses rather than escalating vasopressin beyond 0.03-0.04 units/min 1

For Persistent Hypoperfusion Despite Adequate MAP:

• Add dobutamine (2.5-20 mcg/kg/min) if persistent hypoperfusion exists despite adequate fluid loading and vasopressor therapy, particularly when myocardial dysfunction or low ScvO2 (<70%) is evident 7, 1, 2, 3
• The combination of dobutamine and norepinephrine is recommended as first-line treatment for low cardiac output states 7

Step 5: Agents to AVOID

Critical pitfalls:

• Never use dopamine as first-line therapy—it is associated with higher mortality and more arrhythmias compared to norepinephrine; use only in highly selected patients with low risk of tachyarrhythmias or absolute/relative bradycardia 1, 2, 3
• Never use low-dose dopamine for renal protection—this is strongly discouraged and has no benefit 1, 3
• Avoid phenylephrine except when norepinephrine causes serious arrhythmias, cardiac output is documented to be high with persistently low blood pressure, or as salvage therapy when all other agents have failed 1, 2, 3
• Phenylephrine may raise blood pressure numbers while actually worsening tissue perfusion through excessive vasoconstriction without cardiac output support 1

Step 6: Norepinephrine Tapering Protocol

Once hemodynamic stability is achieved:

• Gradual dose reduction is preferred over abrupt discontinuation 3
• After adding vasopressin at 0.03 units/min, you can either raise MAP to target or decrease norepinephrine dosage while maintaining hemodynamic stability 1, 3
• Continue monitoring perfusion markers during tapering, not just MAP values 3

Special Considerations

Early norepinephrine initiation triggers (consider starting before completing full fluid resuscitation):

• Diastolic blood pressure ≤40 mmHg as a marker of severely depressed vascular tone 4, 6
• High diastolic shock index (heart rate/diastolic BP) ≥3 4
• Patients at risk for fluid overload: acute respiratory distress syndrome, intra-abdominal hypertension, or congestive heart failure 1, 4

In patients with preexisting heart failure:

• Norepinephrine may increase myocardial oxygen requirements but does not contraindicate its use 1
• In sepsis specifically, norepinephrine improves renal blood flow and urine output despite typically causing renal vasoconstriction in other contexts 1
• Consider adding dobutamine early if myocardial dysfunction is evident 1

Pediatric dosing differences:

• Norepinephrine remains the first-line vasoactive drug 7
• Phosphodiesterase III inhibitors may be considered in cases of low cardiac output with normal arterial pressure 7

Adjunctive Therapy for Refractory Shock

If hypotension remains refractory to vasopressors:

• Consider hydrocortisone 200-300 mg/day for at least 5 days, followed by tapering (pediatric dose: 1 mg/kg every 6 hours) 7, 1