Early observations and pilot data that first suggested a new direction
For decades, dopamine was the default first-line vasopressor in septic shock, favoured for its perceived renal-protective effects and inotropic properties. However, observational data increasingly suggested that norepinephrine might be superior, with less tachycardia and more predictable haemodynamic effects. The VASST trial (2008) explored vasopressin as an adjunct to norepinephrine in septic shock and found no overall mortality difference, but a pre-specified subgroup analysis suggested benefit in less severe shock — introducing vasopressin into the septic shock pharmacopoeia and challenging the single-agent dogma.
Landmark RCTs and pivotal trials that established the evidence base
The SOAP II trial (2010) provided definitive evidence that norepinephrine should replace dopamine as the first-line vasopressor. In 1,679 patients with shock (predominantly septic), dopamine was associated with significantly more arrhythmic events than norepinephrine, and a pre-specified subgroup analysis of cardiogenic shock patients showed higher mortality with dopamine. While the primary endpoint of 28-day mortality was not significantly different for the overall population, the subgroup analyses and the markedly higher rate of arrhythmias with dopamine (24.1% vs 12.4%) made a compelling case. This trial, combined with a subsequent meta-analysis of six trials by De Backer, established norepinephrine as the undisputed first-line agent and relegated dopamine to historical interest.
Follow-up studies, subgroup analyses, and real-world validation
With norepinephrine established as first-line, research turned to adjunctive agents for refractory shock. The ATHOS-3 trial (2017) demonstrated that angiotensin II, a novel vasopressor acting on the renin-angiotensin system, significantly increased blood pressure in patients with vasodilatory shock refractory to high-dose conventional vasopressors. The VANISH trial (2016) compared vasopressin versus norepinephrine as initial vasopressor therapy and found no difference in kidney failure-free days, but vasopressin was associated with less renal replacement therapy use. The VANCS trial (2017) explored vasopressin versus norepinephrine specifically in post-cardiac surgery vasoplegia and found fewer complications with vasopressin. These trials expanded the armamentarium beyond catecholamines and supported a multi-agent approach for refractory shock.
Integration into clinical practice guidelines and recommendations
The Surviving Sepsis Campaign 2021 guidelines provide a strong recommendation for norepinephrine as the first-line vasopressor in septic shock, with vasopressin recommended as a second-line agent to reduce norepinephrine dose (rather than as an alternative first-line agent). Dopamine is recommended only in highly selected circumstances (bradycardia with low risk of tachyarrhythmia). The guidelines recommend against low-dose dopamine for renal protection, definitively ending this long-standing practice. Angiotensin II is acknowledged but not specifically recommended due to limited data and cost considerations.
Surviving Sepsis Campaign 2021
Strong recommendation for norepinephrine as first-line vasopressor; vasopressin as second-line to reduce norepinephrine requirements; against low-dose dopamine for renal protection
Surviving Sepsis Campaign 2021
Suggest adding vasopressin (up to 0.03 U/min) rather than escalating norepinephrine when MAP target cannot be achieved (weak recommendation)
Now
Current standard of care and ongoing research directions
Norepinephrine is the undisputed first-line vasopressor for septic shock worldwide. The contemporary approach layers vasopressin early (typically when norepinephrine exceeds 0.1-0.2 mcg/kg/min) to exploit its non-catecholamine mechanism and potential renal benefits. Angiotensin II occupies a niche role in refractory vasodilatory shock, limited by cost and availability. Active areas of investigation include early vasopressor initiation via peripheral access to reduce fluid volumes, phenotype-guided vasopressor selection (using clinical or biomarker profiles to match patients to optimal agents), and the potential role of corticosteroids as vasopressor-sparing agents. The VITAMINS and VICTAS trials have tempered enthusiasm for the vitamin C-hydrocortisone-thiamine combination, while the debate over timing and threshold for vasopressor initiation continues to evolve.
The SOAP II trial showed that dopamine caused significantly more arrhythmias (24.1% vs 12.4%) than norepinephrine, with a signal toward higher mortality in cardiogenic shock. Norepinephrine provides more reliable vasoconstriction with less tachycardia and fewer arrhythmic complications. Combined with meta-analyses showing a mortality benefit, this has made norepinephrine the undisputed first-line choice.
When should vasopressin be added?+
Current guidelines suggest adding vasopressin (up to 0.03 U/min) when norepinephrine doses reach 0.25-0.5 mcg/kg/min, though many clinicians initiate earlier (0.1-0.2 mcg/kg/min). Vasopressin exploits a non-catecholamine pathway and may have renal-protective effects. It should be added as an adjunct, not used as a sole first-line agent.
What role does angiotensin II play?+
Angiotensin II (Giapreza) was FDA-approved based on the ATHOS-3 trial for refractory vasodilatory shock. It acts on the renin-angiotensin system, providing an additional vasopressor mechanism when catecholamines and vasopressin are insufficient. It is primarily used as a rescue agent in catecholamine-refractory shock, though its high cost and limited outcome data have prevented widespread adoption.
Can vasopressors be started through a peripheral IV?+
Yes, emerging evidence supports the safety of peripheral norepinephrine infusion (at concentrations up to 8 mcg/mL through a proximal peripheral IV) for early resuscitation. This approach allows earlier vasopressor initiation without waiting for central venous access, potentially reducing excessive fluid administration. Guidelines increasingly support this practice for short-duration peripheral infusion in proximal veins.
