Vasopressin in Severe Sepsis and Septic Shock
Direct Answer
Add vasopressin at 0.03 units/minute as a second-line vasopressor when norepinephrine alone fails to maintain MAP ≥65 mmHg despite adequate fluid resuscitation, but never use vasopressin as monotherapy or as the first-line agent. 1, 2
Algorithmic Approach to Vasopressin Use
Step 1: Establish Norepinephrine as First-Line Therapy
- Norepinephrine is mandatory as the first-choice vasopressor in septic shock, with a Grade 1B recommendation based on an 11% absolute mortality reduction compared to dopamine. 1, 2
- Initiate norepinephrine at 0.1-0.5 mcg/kg/min (approximately 7-35 mcg/min in a 70 kg patient) after administering at least 30 mL/kg crystalloid resuscitation within the first 3 hours. 2, 3
- Target MAP ≥65 mmHg initially, though consider 70-75 mmHg in patients with chronic hypertension. 1, 2
- Establish central venous access for safe norepinephrine administration and place an arterial catheter for continuous blood pressure monitoring. 1, 2
Step 2: Recognize When to Add Vasopressin
Add vasopressin when norepinephrine requirements reach 0.25-0.50 mcg/kg/min or when target MAP cannot be achieved with norepinephrine alone despite adequate fluid resuscitation. 1, 2
The specific triggers include:
- Persistent hypotension with norepinephrine at moderate-to-high doses 1
- Need to either raise MAP to target OR decrease norepinephrine dosage while maintaining hemodynamic stability 1
- Norepinephrine doses ≥15 mcg/min, which indicate severe septic shock and are associated with increased mortality 1
Step 3: Vasopressin Dosing Protocol
- Start vasopressin at 0.03 units/minute as a fixed-dose infusion added to norepinephrine. 1, 2
- Alternative starting approach: Begin at 0.01 units/minute and titrate up by 0.005 units/minute at 10-15 minute intervals until target MAP is achieved. 1
- Maximum dose ceiling: Do not exceed 0.03-0.04 units/minute for routine use. 1, 2
- Doses above 0.04 units/minute should be reserved exclusively for salvage therapy when all other vasopressors have failed, as higher doses cause cardiac, digital, and splanchnic ischemia without additional benefit. 1, 2
Step 4: Mechanism and Expected Effects
Vasopressin works through V1 receptor activation on vascular smooth muscle, causing vasoconstriction via the Gq/11-phospholipase C pathway and intracellular calcium release. 4
Expected hemodynamic changes within 15 minutes of infusion: 4
- Increased systemic vascular resistance and MAP 4
- Decreased heart rate and cardiac output 4
- Norepinephrine-sparing effect, allowing reduction of norepinephrine dose 1, 5
- Potential increase in urine output 1
- Possible decrease in pulmonary vascular resistance 6
The pressor effect peaks within 15 minutes and fades within 20 minutes after stopping the infusion, with no evidence of tachyphylaxis or tolerance. 4
Critical Monitoring Requirements
Monitor beyond just MAP numbers: 1, 2
- Tissue perfusion markers: Lactate clearance, urine output ≥0.5 mL/kg/hr, mental status, capillary refill, skin temperature 1, 2
- Signs of excessive vasoconstriction: Digital ischemia, cold extremities, decreased urine output, rising lactate, worsening organ dysfunction despite adequate MAP 1, 2
- Continuous arterial blood pressure monitoring via arterial catheter 1, 2
Escalation Strategy for Refractory Shock
If target MAP is not achieved with norepinephrine plus vasopressin at 0.03 units/minute: 1
- Add epinephrine at 0.05-2 mcg/kg/min as a third vasopressor agent rather than increasing vasopressin beyond 0.03-0.04 units/minute 1, 5
- Consider dobutamine (2.5-20 mcg/kg/min) if persistent hypoperfusion exists despite adequate MAP and vasopressor therapy, particularly when myocardial dysfunction is evident 1
- Add hydrocortisone 200 mg/day IV for shock reversal in refractory cases 1
Critical Pitfalls to Avoid
Never Use Vasopressin as Monotherapy
Vasopressin must always be added to norepinephrine, never used alone as the initial vasopressor. 1, 2 This is a fundamental principle emphasized repeatedly in guidelines.
Do Not Exceed Dose Ceiling Without Justification
Vasopressin doses above 0.03-0.04 units/minute are associated with cardiac, digital, and splanchnic ischemia without additional hemodynamic benefit. 1, 2 Reserve higher doses only for salvage therapy when all other options have failed.
Avoid Dopamine
Dopamine is strongly discouraged except in highly selected patients with low risk of tachyarrhythmias or absolute bradycardia, as it is associated with higher mortality (11% absolute increase) and significantly more arrhythmias compared to norepinephrine. 1, 2
Do Not Use Low-Dose Dopamine for Renal Protection
This practice has no benefit and is strongly discouraged by all major guidelines. 1, 2
Avoid Phenylephrine as First-Line Therapy
Phenylephrine should only be used 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 It may raise blood pressure numbers while actually worsening tissue perfusion through excessive vasoconstriction.
Evidence Quality and Nuances
The recommendation for vasopressin as second-line therapy is based on: 1, 5
- Its norepinephrine-sparing effect
- Potential benefits on renal function (one meta-analysis showed reduced need for renal replacement therapy when used as first-line, though this is not the guideline recommendation) 7
- No mortality benefit when used early versus as second-line 5, 8
The strongest evidence supports adding vasopressin to norepinephrine rather than escalating norepinephrine doses indefinitely. 1, 8 Norepinephrine doses ≥15 mcg/min are associated with significantly elevated mortality, making vasopressin addition at moderate norepinephrine doses a rational strategy. 1
Vasopressin analogs (terlipressin, selepressin) are not recommended due to higher rates of digital ischemia without proven benefit. 5