Maximum Norepinephrine Dose for Hypotension
While no absolute maximum dose is universally defined, doses exceeding 0.4 μg/kg/min (approximately 30 μg/min in a 70 kg adult) are considered high-dose and associated with significantly increased mortality, and doses above 10 μg/min should prompt consideration of adding a second vasopressor rather than continuing to escalate norepinephrine alone. 1, 2
Practical Dosing Framework
Standard Dosing Ranges
Initial dose: Start at 0.25-0.375 mL/min (8-12 μg of base per minute) and titrate to achieve mean arterial pressure (MAP) of 65-100 mmHg 3
Maintenance dose: Average maintenance ranges from 2-4 μg of base per minute (0.0625-0.125 mL/min) 3
Typical therapeutic range: 0.1-2 μg/kg/min for most patients with septic shock 2
High-Dose Thresholds and Clinical Significance
Recent data-driven analysis has established clinically meaningful cutoffs based on mortality outcomes 4:
- Low dose: <0.2 μg/kg/min (hospital mortality ~14%)
- Intermediate dose: 0.2-0.4 μg/kg/min (hospital mortality ~26%)
- High dose: >0.4 μg/kg/min (hospital mortality ~40%)
These thresholds represent validated cutoffs where mortality risk substantially increases, making them practical markers for escalating care or adding alternative vasopressors. 4
When to Stop Escalating Norepinephrine
Consider adding vasopressin or alternative agents when doses exceed 0.4 μg/kg/min rather than continuing to increase norepinephrine, as the risk-benefit ratio becomes unfavorable 5, 4
Doses >10 μg/min are associated with increased mortality and should trigger reassessment of the treatment strategy 1
If blood pressure remains inadequate despite increasing doses, add a second vasopressor agent rather than continuing to escalate norepinephrine alone 1
Indicators of Futility
Rescue treatment with high-dose norepinephrine may be futile in specific clinical scenarios 6:
- APACHE II score >40 (100% mortality)
- Bicarbonate <9.0 mEq/L (100% mortality)
- Concurrent epinephrine requirement ≥0.25 μg/kg/min (100% mortality)
These thresholds should prompt serious discussions about goals of care rather than continued dose escalation 6.
Alternative Strategies for Refractory Hypotension
Adding Vasopressin
Vasopressin is the recommended second-line agent for norepinephrine-refractory shock, as it acts on different vascular receptors (V1) rather than α1-adrenergic receptors 5
Vasopressin is relatively deficient during sepsis, making it physiologically rational 5
Monitoring During High-Dose Therapy
Place an arterial catheter as soon as practical in all patients requiring vasopressors 1
Monitor blood pressure and heart rate every 5-15 minutes during initial titration 2
Assess for signs of excessive vasoconstriction: cold extremities, decreased urine output, elevated lactate 2
Critical Safety Considerations
Administration Route
Central venous access is strongly preferred to prevent tissue necrosis from extravasation 1, 3
Peripheral IV administration can be used temporarily if central access is unavailable, but requires strict monitoring 1, 2
Extravasation Management
If extravasation occurs, immediately infiltrate 5-10 mg of phentolamine diluted in 10-15 mL of saline into the affected site 1, 3
Pediatric dose: 0.1-0.2 mg/kg phentolamine (maximum 10 mg) 2
Volume Status
Always correct hypovolemia before or concurrent with norepinephrine administration 1, 3
Minimum 30 mL/kg crystalloid bolus is required in septic shock before vasopressor initiation 2
Vasoconstriction in hypovolemic patients causes severe organ hypoperfusion despite "normal" blood pressure 2
Special Population Considerations
Pediatric Dosing
Typical range: 0.1-1.0 μg/kg/min, starting at the lowest dose 2
Doses as high as 5 μg/kg/min are sometimes necessary in children, which is substantially higher than adult recommendations 2, 7
Mean maximum doses in pediatric septic shock: 2.5 ± 2.2 μg/kg/min 7