Vasopressin in Septic Shock: New Insights on Timely Addition to Norepinephrine

Early vasopressin initiation in septic shock may improve outcomes beyond the current practice of waiting for higher norepinephrine doses. Recent studies suggest starting AVP earlier can reduce shock duration and hospital mortality. Despite AVP often being started late, a proactive, protocol-driven approach that considers Nor dose, duration, and clinical context is feasible and potentially lifesaving, supporting the need for clear guidelines on AVP timing in septic shock.

Vasopressin (AVP) is a proven catecholamine-reducing second vasopressor in septic shock, in addition to norepinephrine (Nor). However, both international literature and practice data show that the timing of early vasopressin initiation varies widely. The current Surviving Sepsis Campaign (SSC) guidelines recommend starting AVP at Nor doses of 0.25-0.50 μg/kg/min. However, new studies suggest that not only the Nor dose but also the earlier timing of AVP is associated with more favourable outcomes. This aspect requires reconsideration and possible modification of daily/clinical practice.

A recent Dutch multicentre registry study shows that higher Nor doses and longer Nor durations before AVP are associated with longer shock durations from the onset of AVP (Melchers et al. 2025). Although patients with norepinephrine-base ≥0.30 μg/kg/min are more likely to show a haemodynamic AVP response, this response does not appear to be directly related to shorter shock duration or better survival.

However, this group of patients developed less atrial fibrillation and experienced a less significant increase in volume load, likely due to the Nor-sparing effect. These findings highlight that the Nor-sparing effect may contribute to clinically relevant benefits in the short term despite having a limited impact on long-term outcomes.

Therefore, the key question is: Is it more important to administer AVP at a specific Nor dose or earlier in the time after shock onset, regardless of the Nor dose? Two recent extensive studies offer direction. An AI-driven reinforcement learning model concludes that optimal outcomes are achieved if AVP is initiated at a lower norepinephrine-base dose, and earlier, around 0.20 μg/kg/ min, with a median of 4 hours after the onset of shock (Kalimouttou et al. 2025). 

The retrospective analysis by White et al. (2024) confirms that AVP within six hours of the start of first-line vasopressor is associated with lower hospital mortality. 

In addition, multiple analyses have shown that metabolic markers, such as pH and lactate, can provide further information about the likelihood of an AVP response. High lactate levels (>4.0 mmol/L) and low pH predict a lower likelihood of haemodynamic response and a shorter shock duration, respectively. Acidosis reduces V1 receptor sensitivity in smooth muscle tissue. However, it is not a reason to delay AVP administration, especially in severe vasoplegia. In addition, patients with septic shock and obesity show a lower response and longer shock duration (Melchers et al. 2025). This finding needs to be confirmed by further prospective studies.

Finally, current practice has a median difference of +0.16 μg/kg/min between the protocolised NE threshold and the actual NE infusion rate at the time of AVP initiation. As a result, AVP is often only given well above the protocol threshold, which paradoxically leads to a higher response rate but can potentially negatively impact other outcomes, such as shock duration and survival. This delay requires proactive decision-making and appropriate logistics both within and outside intensive care.

Protocol Proposal

Based on recent findings, a protocol proposal (Figure 1) has been developed for the timely initiation of AVP in septic shock, pending the establishment of unambiguous guidelines. 

The core principles include:

• Consider AVP when norepinephrine-base ≥0.20 μg/kg/min and preferably within six hours of starting Nor.
• In case of rapid Nor escalation (>0.05 μg/kg/min per 30 min): Prepare AVP.
• Start AVP before norepinephrine-base ≥0.30 μg/kg/min is reached.

Implementation requires adjustments in PDMS triggers, team training and inventory management. Monitoring adherence to protocol, shock duration, and ICU stay should become part of the quality cycle. 

Conclusion

Not only should the Nor dose trigger AVP initiation, but also the combination of Nor dose, Nor duration, and clinical context. Early AVP initiation, at norepinephrine-base ≥0.20 μg/kg/min and short Nor duration, is feasible, logical, and potentially lifesaving. It is time to establish a clear and workable vasopressin protocol in anticipation of unambiguous national and international guidelines. 

Disclaimer 
Point-of-view articles are the sole opinion of the author(s) and are part of the ICU Management & Practice Corporate Engagement or Educational Community Programme.